1: General Principles

Overview

This chapter reviews several important features of cardiovascular (CV) medicine in the 21st century. The global burden of CV
disease is reviewed first, followed by 3 modules that address the foundations of biostatistics, cost­effectiveness, and quality
performance. The principles of pharmacology and the application of pharmacogenomics to drug therapy are addressed, and the
concluding module of this chapter highlights gender, age and racial/ethnic considerations in patient evaluation and
management.

Authors

Patrick T. O'Gara, MD, FACC

Editor­in­Chief

Thomas M. Bashore, MD, FACC

Associate Editor

James C. Fang, MD, FACC

Associate Editor

Glenn A. Hirsch, MD, MHS, FACC

Associate Editor

Julia H. Indik, MD, PhD, FACC

Associate Editor

Donna M. Polk, MD, MPH, FACC

Associate Editor

Sunil V. Rao, MD, FACC

Associate Editor
1.1: Global Burden of Cardiovascular Disease
Author(s):
Thomas A. Gaziano, MD, MSC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Evaluate the relationship between income and stage in epidemiologic transition in order to prepare for clinical settings in
different areas of the world and use resources in an effective manner.
2. Identify risk factors and be familiar with prevalence data to be aware of patients at risk for cardiovascular disease (CVD).
3. Prescribe a combination of therapeutics in secondary prevention.
4. Assess cost­effectiveness of incremental strategies for treatment of myocardial infarction (MI) or stroke in low­ and
middle­income settings in treatment protocols.
5. Analyze risk factors and effectively employ use of risk scores.
Shifting Burden

Over the last decade, CVD has become the single largest cause of death worldwide.
In 2004, CVD caused an estimated 17 million deaths and led to 151 million
disability­adjusted life­years (DALYs) lost. In 2001, three­fourths of global deaths Figure 1
and 82% of total DALYs lost due to coronary heart disease (CHD) occurred in low­
and middle­income countries.1 Today, CVD accounts for approximately 30% of
deaths worldwide, including nearly 40% in high­income countries and about 28% in
low­ and middle­income countries, and 39% of noncommunicable disease deaths
globally (Figure 1).
Proportion of Noncommunicable Disease Deaths Among Those Under 70 Years
Figure 1
Reproduced with permission from World Health Organization. Global Status Report on Noncommunicable Diseases 2010. Geneva: World Health
Organization. http://http://www.who.int/nmh/publications/ncd_report2010/en/
Epidemiologic Transitions

The overall increase in the global burden of CVD and the distinct mortality patterns in
the various regions (Table 1) result in part from the "epidemiologic transition," which
includes four basic stages, as follows: Table 1

1. Pestilence and famine,

2. Receding pandemics,
3. Degenerative and man­made diseases, and
4. Delayed degenerative diseases.

Movement through these stages has dramatically shifted the causes of death over
the last two centuries, from infectious diseases and malnutrition in the first stage, to
CVD and cancer in the third and fourth stages. Although the transition through the
age of pestilence and famine has occurred much later in the low­ and middle­
income countries, it has also occurred more rapidly, driven largely by the transfer of
low­cost agricultural technologies and public health advances. A fifth stage,
characterized by an epidemic of inactivity and obesity, may be emerging in some
countries.

The first stage, pestilence and famine, is characterized by the predominance of

malnutrition and infectious disease, and by the infrequency of CVD as a cause of
death. Tuberculosis, dysentery, cholera, and influenza are often fatal, resulting in a
mean life expectancy of about 30 years. CVD, which accounts for <10% of deaths,
takes the form of rheumatic heart disease and other cardiomyopathies due to
infection and malnutrition. Approximately 10% of the world's population remains in
the age of pestilence and famine, particularly Sub­Saharan Africa.

Per capita income and life expectancy increase during the age of receding
pandemics as the emergence of public health systems, cleaner water supplies, and
improved nutrition combine to drive down deaths from infectious disease and
malnutrition. The change most characteristic of this phase is a precipitous decline in
infant and child mortality accompanied by a substantial increase in life expectancy.
Deaths due to CVD (rheumatic valvular disease, hypertension, and stroke) increase
to between 10% and 35% of all deaths. Almost 40% of the world's population is
currently in this stage.

The age of degenerative and man­made diseases is distinguished by mortality from

noncommunicable diseases­primarily CVD­surpassing mortality from malnutrition
and infectious diseases. Caloric intake, particularly from animal fat, increases. CHD
and stroke are prevalent, and between 35% and 65% of all deaths can be traced to
CVD. Typically, the rate of CHD deaths exceeds that of stroke by a ratio of 2:1 to 3:1.
During this period, average life expectancy surpasses age 50. Roughly 35% of the
world's population falls into this category.

In the age of delayed degenerative diseases, CVD and cancer remain the major
causes of morbidity and mortality, with CVD accounting for 40% of all deaths.
However, reductions in risk behaviors and factors such as smoking cessation
programs and effective blood pressure control make even greater contributions to
the decline in age­adjusted rates of death. Further, these reductions are aided by
improvements in acute hospital management and technological advances, such as
the availability of bypass surgery. CHD, stroke, and congestive heart failure are the
primary forms of CVD. About 15% of the world's population is now in the age of
delayed degenerative diseases, or is exiting this age and moving into the fifth stage
of the epidemiologic transition.

Troubling trends in certain risk behaviors and risk factors may foreshadow a new
phase of the epidemiologic transition, the age of inactivity and obesity.2 In the
industrialized world, physical activity continues to decline while total caloric intake
increases. Rates of type 2 diabetes mellitus, hypertension, and lipid abnormalities
are on the rise, trends that are particularly evident in children. If these trends
continue, age­adjusted CVD mortality rates, which have declined over the past
several decades in developed countries, could level or even increase in the coming
years.
Stages of the Epidemiological Transition and Its Global Status, by Region
Table 1
CVD = cardiovascular disease.

Reproduced with permission from Gaziano TA, Gaziano JM. Global burden of cardiovascular disease. In: Bonow RO, Mann DL, Zipes DP, Libby
P. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia: Saunders; 2011.
Current Worldwide Variations in Burden of Cardiovascular
Disease

An epidemiologic transition much like the one that occurred in the developed
countries is occurring throughout the world, but unique regional features have Figure 2
modified aspects of the transition in various parts of the world. The rate of transition
varies widely, leading to large discrepancies in disease burden. In terms of
economic development, the world can be divided into two broad categories: 1) high­
income countries, and 2) low­ and middle­income countries, which can be further
subdivided into six distinct economic/geographic regions. Currently, 85% of the
world's population lives in low­ and middle­income countries, and it is these
countries that are driving the rates of change in the global burden of CVD.

High­Income Countries

Nearly 1 billion people live in the high­income countries, where CHD is the dominant
form of CVD, with rates that tend to be two­ to five­fold higher than stroke rates. The
rates of CVD in Canada, New Zealand, Australia, and Western Europe tend to be
similar to those in the United States; however, among the countries of Western
Europe, the absolute rates vary three­fold, with a clear north/south gradient. The
highest CVD death rates are in the northern countries, such as Finland, Ireland, and
Scotland, with the lowest CVD rates in the Mediterranean countries of France, Spain,
and Italy.

Japan is unique among the high­income countries: Stroke rates increased

dramatically, but CHD rates did not rise as sharply over the last century. This
difference may stem in part from genetic factors, but it is more likely that the fish­ and
plant­based, low­fat diet and resulting low cholesterol levels have played a larger
role. Importantly, Japanese dietary habits are undergoing substantial changes,
reflected in an increase in cholesterol levels.

Low­ and Middle­Income Countries

The World Bank groups the low­ and middle­income countries (gross national
income per capita less than US $12,195) into six geographic regions, as follows:

1. East Asia and the Pacific,

2. Eastern Europe and Central Asia,
3. Latin America and the Caribbean,
4. Middle East and North Africa,
5. South Asia, and
6. Sub­Saharan Africa.

Although communicable diseases continue to be a major cause of death, CVD has

emerged as a significant health concern in the low­ and middle­income countries. In
most, an urban/rural gradient has emerged for CHD, stroke, and hypertension, with
higher rates in urban centers.

While CVD rates are rapidly rising, vast differences exist among the regions (Figure
2) and countries, and even within the countries themselves. Many factors contribute
to this heterogeneity. First, the regions are in various stages of the epidemiological
transition. Second, vast differences in lifestyle and behavioral risk factors exist. Third,
racial and ethnic differences may lead to altered susceptibilities to various forms of
CVD. In addition, it should be noted that for most countries in these regions,
accurate country­wide data on cause­specific mortality are not complete, as death
certificate completion is not routine, and most countries do not have a centralized
registry for deaths.

East Asia and Pacific Region

The East Asia and Pacific region, home to nearly 2 billion people, appears to be
straddling the second and third phases of the epidemiological transition, with China,
Indonesia, and Sri Lanka's large combined population driving most of the trends.
Overall, CVD is a major cause of death in China, but like Japan, stroke (particularly
hemorrhagic) causes more deaths than CHD, in a ratio of about 3:1. However, age­
adjusted CHD mortality increased 40% from 1984 to 1999, suggesting further
epidemiologic transition.

China also appears to have a geographic gradient like that of Western Europe, with
higher CVD rates in northern China than in southern China by a factor of six. Other
countries, such as Vietnam and Cambodia, are just emerging from the pestilence
and famine transition.

Eastern Europe and Central Asia

The Eastern Europe and Central Asia region is firmly in the peak of the third phase,
with the highest death rates (58%) due to CVD in the world, nearly double the rate of
some high­income countries. More troubling is that nearly 35% of the deaths from
CHD occur among working­age adults, which is three times the rate of the United
States.

In Russia, increased CVD rates have contributed to falling life expectancy,

particularly for men, whose life expectancy has dropped from age 71.6 years in 1986
to 59 years today. In Poland, by contrast, the age­adjusted mortality rate decreased
by approximately 30% for men during the '90s, and slightly more among women.
Slovenia, Hungary, the Czech Republic, and Slovakia have had similar declines.

Latin America and the Caribbean

In general, Latin America appears to be in the third phase of the epidemiological

transition, although as in other low­ and middle­income regions, there is vast
regional heterogeneity, with some areas in the second phase of the transition and
some in the fourth. Today, approximately 28% of all deaths in this region are
attributable to CVD, with CHD rates higher than stroke rates. Like Eastern Europe,
some countries—Mexico, Costa Rica, and Venezuela—continued an overall
increase in age­adjusted CHD mortality of 3­10% between 1970 and 2002, while in
others­Argentina, Brazil, Chile, and Columbia­rates appear to have declined by as
much as 2% per year over the same time period.

Middle East and North Africa

The Middle East and North Africa region appears to be entering the third phase of
the epidemiological transition, with increasing life expectancy overall and CVD death
rates just below developed nations. CHD is responsible for 17% of all deaths, and
stroke for 7%. The traditional high­fiber diet, low in fat and cholesterol, has changed
rapidly. Over the past few decades, daily fat consumption has increased in most of
these countries, ranging from a 13.6% increase in Sudan to a 143.3% increase in
Saudi Arabia. Over 75% of Egyptians are overweight or obese, and the rate is 67% in
Iraq and Jordan. Nearly 60% of Syrians and Iraqis report that they are physically
inactive (<10 minutes per day).

South Asia

Most people in South Asia live in rural India, a country that is experiencing an
alarming increase in heart disease. CVD accounted for 32% of all deaths in 2000,
and an estimated 2 million deaths will occur due to CHD by 2010, representing a
30% increase over the preceding decade. The transition appears to be in the
Western­style, with CHD as the dominant form of CVD. In 1960, CHD represented
4% of all CVD deaths in India, whereas in 1990, the proportion was >50%. This is
somewhat unexpected because stroke tends to be a more dominant factor early in
the epidemiological transition. This finding may reflect inaccuracies in cause­
specific mortality estimates or possibly an underlying genetic component.

It has been suggested that Indians have exaggerated insulin insensitivity in

response to the Western lifestyle pattern that may differentially increase rates of
CHD over stroke. The South Asia region has the highest overall prevalence of
diabetes in the low­income regions, with rates as high as 14% in urban centers. In
certain rural areas, the prevalence of CVD and its risk factors are approaching urban
rates. Nonetheless, rheumatic heart disease continues to be a major cause of
morbidity and mortality.

Sub­Saharan Africa
For the most part, Sub­Saharan Africa remains in the first phase of the
epidemiological transition, with CVD rates one­quarter of those in developed
nations. This area remains the only region where CVD is not the leading cause of
death. Life expectancy has decreased by an average of 5 years since the early
1990s, largely because of human immunodeficiency virus (HIV)/acquired
immunodeficiency syndrome (AIDS) and other chronic diseases, according to the
World Bank; life expectancies are the lowest in the world. Still, CVD accounts for
46% of noncommunicable deaths, and is the leading cause of death among adults
over the age of 35.

As more HIV/AIDS patients receive antiretroviral treatment, managing CVD risk

factors such as dyslipidemia in this population requires more attention. However,
hypertension continues to be the major public health concern, and has resulted in
stroke being the dominant form of CVD. Rheumatic heart disease is still a
prominent challenge.
Major Causes of Death in Persons of All Ages for Low­ and Middle­Income Regions
Figure 2
Reproduced with permission from Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ, eds. Global Burden of Disease and Risk Factors.
New York: The World Bank and Oxford University Press; 2006.
Global Trends in Cardiovascular Disease

In 1990, CVD accounted for 28% of the world's 50.4 million deaths and 9.7% of the 1.4 billion lost DALYs, and by 2001,
CVD was responsible for 29% of all deaths and 14% of the 1.5 billion lost DALYs. By 2030, when the population is
expected to reach 8.2 billion, 33% of all deaths will be the result of CVD. Of these, 14.9% of deaths in men and 13.1% of
deaths in women will be due to CHD. Stroke will be responsible for 10.4% of all male deaths and 11.8% of all female
deaths.

In the high­income countries, population growth will be fueled by emigration from the low­ and middle­income countries,
but the populations of high­income countries will shrink as a proportion of the world's population. The modest decline in
CVD death rates that began in the high­income countries in the latter third of the 20th century will continue, but the rate of
decline appears to be slowing. However, these countries are expected to see an increase in the prevalence of CVD, as
well as the absolute number of deaths as the population ages.

Significant portions of the population living in low­ and middle­income countries have entered the third phase of the
epidemiological transition, and some are entering the fourth stage. Changing demographics play a significant role in
future predictions for CVD throughout the world. For example, between 1990 and 2001, the population of Eastern Europe
and Central Asia grew by 1 million people per year, whereas South Asia added 25 million people each year.

CVD rates will also have an economic impact. Even assuming no increase in CVD risk factors, most countries, but
especially India and South Africa, will see a large number of people between the ages of 35 and 64 die of CVD over the
next 30 years, as well as an increasing level of morbidity among middle­aged people related to heart disease and stroke.
In China, it is estimated that there will be 9 million deaths from CVD in 2030—up from 2.4 million in 2002—with one­half
occurring in individuals between 35 and 64 years old.
Risk Factors

As indicated earlier, the global variation in CVD rates is related to temporal and
regional variations in known risk behaviors and factors. Ecological analyses of
major CVD risk factors and mortality demonstrate high correlations between Figure 3
expected and observed mortality rates for the three main risk factors—smoking,
serum cholesterol, and hypertension—and suggest that many of the regional
variations are based on differences in conventional risk factors.

Hypertension

Elevated blood pressure is an early indicator of the epidemiological transition.

Worldwide, approximately 54% of strokes and 47% of cases of ischemic heart Figure 4a
disease are attributable to suboptimal (>115 mm Hg systolic) blood pressure, which
is believed to account for more than 7 million deaths annually. Remarkably, nearly
one­half of this burden occurs among those with systolic blood pressure <145 mm
Hg, even as this level is used at the arbitrary threshold for defining hypertension in
many national guidelines.3

Rising mean population blood pressure is apparent as populations industrialize Figure 4b

and move from rural to urban settings. Among urban­dwelling men and women in
India, for example, the prevalence of hypertension is 25.5% and 29.0%, respectively,
whereas it is 14.0% and 10.8%, respectively, in rural communities. One major
concern in low­ and middle­income countries is the high rate of undetected, and
therefore untreated, hypertension. This may explain, at least in part, the higher stroke
rates in these countries in relation to CHD rates during the early stages of the
transition. The high rates of hypertension, especially undiagnosed hypertension,
throughout Asia likely contribute to the high prevalence of hemorrhagic stroke in the
region.

Tobacco

Every year, more than 5.5 trillion cigarettes are produced—enough to provide every
person on the planet with 1,000 cigarettes. Worldwide, 1.3 billion people smoked in
2003, a number that is projected to increase to 1.6 billion by 2030. Tobacco currently
causes about 5 million deaths—9% of all deaths—annually. Approximately 1.6
million are CVD related. If current smoking patterns continue, by 2030, the global
burden of disease attributable to tobacco will reach 10 million deaths annually.

A unique feature of the low­ and middle­income countries is easy access to

smoking during the early stages of the epidemiological transition due to the
availability of relatively inexpensive tobacco products. In South Asia, the prominence
of other locally produced forms of tobacco besides manufactured cigarettes makes
control of consumption more challenging.

Lipids

Worldwide, high cholesterol levels are estimated to cause 56% of ischemic heart
disease and 18% of strokes, amounting to 4.4 million deaths annually. As countries
move through the epidemiological transition, mean population plasma cholesterol
levels tend to rise. Social and individual changes that accompany urbanization
clearly play a role because plasma cholesterol levels tend to be higher among
urban residents than among rural residents. This shift is largely driven by greater
consumption of dietary fats­primarily from animal products and processed vegetable
oils­and decreased physical activity. In the high­income countries, in general, mean
population cholesterol levels are falling, while wide variation is seen in the low­ and
middle­income countries.

Physical Inactivity

The increased mechanization that accompanies the economic transition leads to a

shift from physically demanding, agriculture­based work to largely sedentary
industry­ and office­based work. In the United States, approximately one­quarter of
the population does not participate in any leisure­time physical activity, and only 22%
report engaging in sustained physical activity for at least 30 minutes on 5 or more
days per week (the current recommendation). In contrast, in countries like China,
physical activity is still integral to everyday life. Approximately 90% of the urban
population walks or rides a bicycle to work, shopping, or school daily.

Diabetes

As a consequence of, or in addition to, increasing body mass index and decreasing
levels of physical activity, worldwide rates of diabetes­predominantly type 2 diabetes­
are on the rise. In 2003, 194 million adults, or 5% of the world's population, had
diabetes. By 2025, this number is predicted to increase 72% to 333 million. By 2025,
the number of people with type 2 diabetes is projected to double in three of the six
low­ and middle­income regions: Middle East and North Africa, South Asia, and Sub­
Saharan Africa. There appear to be clear genetic susceptibilities to diabetes mellitus
of various racial and ethnic groups. For example, migration studies suggest that
South Asians and Indians tend to be at higher risk than those of European
extraction.

Obesity

Although clearly associated with increased risk of CVD (Figures 3, 4a, b),4 much of
the risk posed by obesity may be mediated by other CVD risk factors, including
hypertension, diabetes mellitus, and lipid profile imbalances. In the mid­1980s, the
World Health Organization's (WHO's) MONICA Project sampled 48 populations for
CV risk factors. In all but one male population (China), and in most of the female
populations, between 50% and 75% of adults ages 35­64 years were overweight or
obese. In addition, the prevalence of extreme obesity (body mass index [BMI] >40
kg/m2 ) more than tripled, increasing from 1.3­4.9%.

In many of the low­ and middle­income countries, obesity appears to coexist with
undernutrition and malnutrition. Obesity is increasing throughout the world,
particularly in developing countries­where the trajectories are steeper than those
experienced by the developed countries. According to the latest WHO data, this is
equivalent to about 1.3 billion overweight adults in the world. A survey undertaken in
1998 found that as many as 58% of African women living in South Africa may be
overweight or obese.

Diet

Total caloric intake per capita increases as countries develop. With regard to CVD, a
key element of dietary change is an increase in intake of saturated animal fats and
hydrogenated vegetable fats, which contain atherogenic trans fatty acids, along with
a decrease in intake of plant­based foods and an increase in simple carbohydrates.

Fat contributes <20% of calories in rural China and India, <30% in Japan, and well
above 30% in the United States. Caloric contributions from fat appear to be falling in
the high­income countries. In the United States, between 1971 and 2000, the
percentage of calories derived from saturated fat decreased from 13­11%.
Ischemic Heart Disease and Stroke Mortality Versus BMI in the Range 15­50 kg/m2 (excluding the first 5 years of follow­up)
Figure 3
Relative risks at ages 35–89 years, adjusted for age at risk, sex, smoking, and study, were multiplied by a common factor (i.e., floated) to make
the weighted average match the Prospective Studies Collaboration mortality rate at ages 35–79 years. Floated mortality rates shown above each
square and numbers of deaths below. Area of square is inversely proportional to the variance of the log risk. Boundaries of body mass index
(BMI) groups are indicated by tick marks. 95% confidence intervals (CIs) for floated rates reflect uncertainty in the log risk for each single rate.

Reproduced with permission from Whitlock G, Lewington S, Sherliker P, et al., on behalf of the Prospective Studies Collaboration. Body­mass
index and cause­specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009;373:1083­96.
Vascular Risk Factors Versus BMI at Baseline in the Range 15–50 kg/m2 (1 of 2)
Figure 4a

Adjusted for baseline age, baseline smoking status (apart from the smoking findings), and study. Numerical values are shown for 20–22.5 kg/m2,
for 30–32.5 kg/m2, and for the extreme body mass index (BMI) groups. Boundaries of BMI groups are indicated by tick marks. 95% confidence
intervals (CIs) are not shown, but most are narrower than the heights of the plotted symbols.

(A) Blood pressure (in 533,242 males and 348,790 females).

(B) Blood cholesterol fractions (in 62,364 males and 52,575 females with total and high­density lipoprotein (HDL) cholesterol both measured);
dashed line indicates the ratio of mean non­HDL cholesterol to mean HDL cholesterol (mean of the individual ratios would be about 8–12%
greater).

Reproduced with permission from Whitlock G, Lewington S, Sherliker P, et al., on behalf of the Prospective Studies Collaboration. Body­mass
index and cause­specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009;373:1083­96.
Vascular Risk Factors Versus BMI at Baseline in the Range 15–50 kg/m2 (2 of 2)
Figure 4b

Adjusted for baseline age, baseline smoking status (apart from the smoking findings), and study. Numerical values are shown for 20–22.5 kg/m2,
for 30–32.5 kg/m2, and for the extreme body mass index (BMI) groups. Boundaries of BMI groups are indicated by tick marks. 95% confidence
intervals (CIs) are not shown, but most are narrower than the heights of the plotted symbols.

(C) Prevalence in males for alcohol drinking (168,283), cigarette smoking (334,496), and diabetes (378,854).

(D) Prevalences in females for alcohol drinking (129,301), cigarette smoking (226,307), and diabetes (319,401).

Reproduced with permission from Whitlock G, Lewington S, Sherliker P, et al., on behalf of the Prospective Studies Collaboration. Body­mass
index and cause­specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009;373:1083­96.
Scope of Interventions
(1 of 2)

The large reductions in age­adjusted CVD mortality rates that have occurred in high­
income countries result from three complementary types of interventions. One Table 2
strategy targets those with acute or established CVD. A second entails risk
assessment and targeting those at high risk due to multiple risk factors for
intervention before their first CVD event. The third strategy uses mass education or
policy interventions directed at the entire population to reduce the overall level of risk
factors.

This section highlights the variety of cost­effective interventions. Much work remains
Figure 5a
undone in developing countries to determine the best strategies given limited
resources, but, if implemented, these interventions could go a long way toward
reducing the burden. Table 2 lists the cost­effectiveness ratios for many of the high­
yield interventions that could be or have been adopted in developing regions.

Those at highest risk are those suffering an MI or stroke; as many as one­half die
before they ever receive medical attention. For those who do make it to a hospital,
Figure 5b
standard medical therapies were examined in a cost­effectiveness analysis.5 Four
incremental strategies were evaluated for the treatment of MI and compared to a
strategy of no treatment as a base case for the six World Bank low­ and middle­
income regions. The four strategies compared were: 1) aspirin; 2) aspirin and
atenolol; 3) aspirin, atenolol, and streptokinase; and 4) aspirin, atenolol, and tissue
plasminogen activator (t­PA).

The incremental cost per QALY gained for both the aspirin and beta­blocker Figure 6
interventions was under $25 for all six regions. Costs per QALY gained for
streptokinase were between $630 and $730 across the regions. Incremental cost­
effectiveness ratios for t­PA were around $16,000/QALY gained, compared with
streptokinase. Minor variations occurred between regions due to small differences
in follow­up care based on regional costs.

Secondary prevention strategies are equally cost­effective in developing countries. Figure 7a

Studies show that a combination of aspirin, an angiotensin­converting enzyme
inhibitor, a beta­blocker, and a statin for secondary prevention can lead to
acceptable cost­effectiveness ratios in all developing regions.5 Use of currently
available generic agents, even in the absence of the so­called "polypill," could be
highly cost­effective, on the order of $300­$400 per person per QALY gained.6

Primary prevention is paramount for the large number of individuals who are at high Figure 7b
risk for CVD. Given limited resources, finding low­cost prevention strategies is a top
priority. Using prediction rules or risk scores to identify those at higher risk in order
to target specific behavioral or drug interventions is a well­established primary
prevention strategy, and has proven to be cost­effective in developing countries.6, 7
Most have included age, sex, hypertension, smoking status, diabetes mellitus, and
lipid values, while others have also included family history.8, 9

Recently, many investigators have examined whether additional laboratory­based

risk factors can add to predictive discrimination of the risk factors used in the
Framingham Heart Study risk score (Figures 5a, b). The recent analyses in the ARIC
(Atherosclerosis Risk in Communities) study,10 and the Framingham Offspring
Study,11, 12 suggested that little additional information was gained when other
blood­based novel risk factors were added to the traditional risk factors.

Although the Reynolds Risk Score for women,13 which added family history, high­
sensitivity C­reactive protein (hs­CRP), and glycated hemoglobin levels, only had a
marginally higher C­statistic (0.808) than the Framingham covariates (0.791), it
correctly reclassified many individuals at intermediate risk (Figure 6). Some women
deemed low risk by the Framingham risk score were reclassified as intermediate or
high risk according to the Reynolds Risk Score and, thus, would have been eligible
for more aggressive management. Also, some women who were initially high risk
according to Framingham were reclassified as lower risk and, thus, would not have
needed treatment.

More attention is now focused on developing risk scores that would be easier to use
in clinical practice without loss of predictive discrimination in resource­poor
countries. In high­income countries, a prediction rule that requires a lab test is an
inconvenience; in low­income countries, with limited testing facilities, it may be too
expensive for widespread screening or preclude its use altogether. In response to
this real concern, the WHO recently released risk­prediction charts for the different
regions of the world with and without cholesterol.14, 15

A study based on the US National Health and Nutrition Examination Survey

(NHANES) follow­up cohort demonstrated that a nonlab­based risk tool that uses
information obtained in a single encounter (age, systolic blood pressure, BMI,
diabetes status, and smoking status) can predict CVD outcomes as well, as one
that requires lab testing with C­statistics of 0.79 for men and 0.83 for women that
were no different from the Framingham­based risk tool.16 The association between
BMI and cholesterol has been confirmed by large cohorts.4

Further, the results of the goodness­of­fit tests suggest that the nonlaboratory­based
model is well­calibrated across a wide range of absolute risk levels and without
changes in classification of risk. A risk score based on the US NHANES follow­up
cohort can be used to predict CVD events in regions where cholesterol testing is not
available (Figures 7a, b).

Education and public policy interventions that have reduced smoking rates, lowered
mean blood pressure levels, and improved lipid profiles have contributed to the
reduction in CHD rates.17 Education and policy efforts directed at tobacco
consumption have contributed substantially to the reductions in CVD. In addition,
salt and cholesterol reduction has been evaluated as a cost­effective strategy to
reduce stroke and MI in low­ and middle­income countries by investigators at the
WHO.18 Community interventions have reduced levels of multiple risk factors and, in
some cases, CHD mortality.

Tobacco

Tobacco control can be conceptualized in terms of strategies that reduce the supply
of, or demand for, tobacco. Most public health and clinical strategies to date focus on
reducing demand through economic disincentives (taxes), health promotion (media
and packaging efforts), restricted access (to advertising and tobacco), or clinical
assistance for cessation. The WHO effort to catalyze the creation of a global treaty
against tobacco use was a key milestone. In May 2003, the WHO World Health
Assembly unanimously adopted the WHO Framework Convention in Tobacco
Control (FCTC), the first global tobacco treaty. The FCTC had been ratified by 164
countries as of April 2009, making it one of the most widely embraced treaties in the
United Nations. The FCTC has spurred efforts for tobacco control across the globe
by providing both rich and poor nations with a common framework of evidence­
based legislation and implementation strategies known to reduce tobacco use.

Jha and colleagues presented a landmark analysis in 2006 of tobacco control cost­
effectiveness 19. They calculated the reductions in future tobacco deaths due to a
range of tax, treatment, and nonprice interventions among smokers alive in 2000.
They found that a 33% price increase would result in a reduction of between 19.7
and 56.8 million (5.4­15.9% of total) deaths in smokers from the developing world
who were alive in 2000.19

Calculations show that nicotine replacement therapy (NRT) could reduce the
number of deaths by between 2.9 and 14.3 million (0.8­4.0%) in the 2000 cohort.19 A
range of nonprice interventions such as advertising bans, health warnings, and
smoke­free laws would reduce deaths by between 5.7 and 28.6 million (1.6­7.9% of
total) in that cohort.19 These reductions would translate into developing world cost­
effectiveness values of between $3 and $42 per QALY saved for tax increases (not
including tax revenue), $55 to $761 per QALY for NRT, and $54 to $674 per QALY for
nonprice measures.19
Cost­Effectiveness for a Selection of CHD Interventions in Developing Regions
Table 2
ASA = aspirin; BB = beta­blocker; SK = streptokinase; ACEI = angiotensin­converting enzyme inhibitor; tPA = tissue plasminogen activator.
*Across six World Bank regions.
† CHD = coronary heart disease.
‡ Range includes different estimates of cost of interventions, as well as blood pressure reduction (<$0.50–$1.00).
§ Range includes estimates of cost of interventions (<$0.50–$6.00).

Reference(s):

1. Gaziano TA. Cardiovascular disease in the developing world and its cost­effective management. Circulation 2005;112:3547­53.
2. Gaziano TA, Galea G, Reddy KS. Scaling up interventions for chronic disease prevention: the evidence. Lancet 2007;370:1939­46.
3. Gaziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with a multidrug regimen in the developing world: a cost­
effectiveness analysis. Lancet 2006;368:679­86.
Assessing 10­Year Coronary Heart Disease Risk in Men (1 of 2)
Figure 5a
Adapted with permission from Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease
using risk factor categories. Circulation 1998;97:1837­47.
Assessing 10­Year Coronary Heart Disease Risk in Women (2 of 2)
Figure 5b
Adapted with permission from Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease
using risk factor categories. Circulation 1998;97:1837­47.
Reclassification of Risk Using the Reynolds Risk Score for a Representative Population of 100,000 Intermediate­Risk US Women Without Diabetes
Figure 6
Reproduced with permission from Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment
of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007;297:611­9.
Risk Prediction Chart for Cardiovascular Disease Using Nonlaboratory–Based Measures (1 of 2)
Figure 7a
Reproduced with permission from Gaziano TA, Young CR, Fitzmaurice G, Atwood S, Gaziano JM. Laboratory­based versus non­laboratory­
based method for assessment of cardiovascular disease risk: the NHANES I Follow­up Study cohort. Lancet 2008;371:923­31.
Risk Prediction Chart for Cardiovascular Disease Using Nonlaboratory–Based Measures (2 of 2)
Figure 7b
Reproduced with permission from Gaziano TA, Young CR, Fitzmaurice G, Atwood S, Gaziano JM. Laboratory­based versus non­laboratory­
based method for assessment of cardiovascular disease risk: the NHANES I Follow­up Study cohort. Lancet 2008;371:923­31.
Scope of Interventions
(2 of 2)

Salt and Lipid Reductions

The population­based intervention that is most touted as an effective means to lower blood pressure is reduction of salt
intake. Average consumption of salt in the United States is 10.4 g/day, of which 75% comes from processed foods. In the
United States, reducing salt intake by 3 g/day (1100 mg/day of sodium) would reduce systolic blood pressure by 3.6­5.61
mm Hg for hypertensives, and in all other patients, the effect was 1.8­3.51 mm Hg.20

Meta­analyses of randomized controlled trials examining the long­term effects of salt reduction in people with and without
hypertension have shown that reductions in salt intake can reduce absolute systolic blood pressure by a small, but
important amount.21 Effect of salt reduction on blood pressure reduction was found to be linear over the range of 0­3
g/day, for an approximate 1:1 ratio in reduction in salt intake (grams/day) and decrease in mean systolic blood pressure
(mm Hg). Reducing population­wide salt consumption by only 15%—through mass media campaigns and reformulation
of food products by industry—would avert up to over 8.5 million deaths in 23 high­burden countries over a 10­year
period.21The cost­effectiveness analyses on salt reduction as a result of public education are quite favorable.22, 23 The
intervention ranges from being cost­saving to $200 per DALY averted.

The results of a campaign for reducing saturated fat and replacing it with polyunsaturated fat is also likely to be cost­
effective. In the base case, a 3% decline in cholesterol and $6 per capita education costs were assumed. This resulted in
a cost as low as $1,800/DALY averted in the South Asia region, and up to $4,000/DALY averted in the Middle East and
North Africa region. However, if the cost for the education plan were halved, the ratio would be approximately $900/DALY
and would be cost­saving if the reduction could be achieved for under $0.50 per capita, which may be possible in areas
with much less expensive access to media.

Community Interventions

In the 1970s and 1980s, a series of population­based community intervention studies were conducted to reduce risk
factors for chronic disease, and has been reviewed elsewhere.24 These focused on either changes in health behaviors
or risk factors such as tobacco use, bodyweight, cholesterol, and blood pressure, as well as a reduction in CVD morbidity
and mortality. In general, they included a combination of communitywide actions, as well as those focused on individuals
identified as high risk.

One of the earliest and most often cited community interventions is the North Karelia project, which began in 1972. The
community­based interventions included health education, screening, a hypertension control program, and treatment.
Over the first 5 years of the study, reductions in risk factors as well as a decline in CHD mortality of 2.9%/year versus a
1%/year decline in the remainder of Finland. During the next 10 years, declines were greater in the rest of Finland. Over
25 years of follow­up, a large decline in CHD occurred in both the North Karelia region (73%) and the remainder of
Finland (63%).25

While the overall difference in the decline in CHD deaths was not significantly greater in the study area of North Karelia,
the reduction in male tobacco­related cancers was significant. A similar study in the Stanford, CA, area showed
reductions in risk factors: cholesterol (2%), blood pressure (4%), and smoking rates (13%) when compared to sites
without the intervention, but no impact on disease endpoints.

Later, community interventions in high­income countries showed mixed results, with some showing improvements in
risk factors beyond the secular decline that was occurring throughout most of the developed economies, and others with
no additional decline. However, a meta­analysis of the randomized multiple risk factor interventions showed net
significant decreases in systolic blood pressure (­4.2 mm Hg), smoking prevalence (­4.2%), and cholesterol (­0.14
mmol/L).26 The declines in total and CHD mortality of 3% and 4% were not significant. The limitation to all of the projects
includes the challenge of detecting small changes that on a population level may be significant. It is possible that a 10%
reduction in mortality could have been missed.26

Several community intervention studies have been conducted in developing countries, including China, Mauritius, and
South Africa. The Tianjin Project showed reductions in hypertension and obesity.27 The Mauritius Project, among other
interventions, resulted in a government­led program that changed the prime cooking oil from a predominantly saturated
fat palm oil, to a soybean oil high in unsaturated fatty acids. Overall total cholesterol levels fell 14% during the 5­year
study period from 1987 to 1992. Changes in other risk factors were mixed, with declines in blood pressure and smoking
rates and increases in obesity and diabetes.28

The Coronary Risk Factor Study in South Africa compared a control community to two communities receiving two different
levels of intensity of interventions. The interventions included mass media messages, group­sponsored educational
sessions, and blood pressure screening and follow­up with the health sector when appropriated. Both high­ and low­
intensity interventions showed improvements in blood pressure, smoking rates, and high­density lipoprotein (HDL) to
total cholesterol ratio over the control community, but with little difference between the two intervention communities.29

One other significant reduction of CHD came not through a concerted community intervention, but through changes in
fiscal policy. In Poland, reductions in subsidies for animal products such as butter and lard led to a switch from saturated
to polyunsaturated fats, mainly rapeseed­ and soya bean­based oils. A decrease in CHD mortality of >25% between
1991 and 2002 could not be explained by increased fruit consumption or declines in smoking.
Key Points

CVD accounts for approximately 30% of deaths worldwide. However, there is great variation in regional CVD
mortality rates.
Countries have gone through phases of the epidemiologic transition that are characterized by different life
expectancies, different rates of CVD mortality, and different levels of CVD risk factors.
The age of degenerative and man­made diseases is distinguished by mortality from noncommunicable
diseases­primarily CVD­surpassing mortality from malnutrition and infectious diseases.
There is a continuous relationship between blood pressure, cholesterol levels, BMI, physical activity, and risk for
CVD despite arbitrary numeric thresholds used in guidelines. Patients may have CVD events despite some
individual risk factors being in the "normal" range, due to the overall combined high risk from all risk factors.
Three complementary types of interventions have occurred in high­income countries, to result in large reductions
in age­adjusted CVD mortality rates:
1. Targeting patients with acute or established CVD.
2. Risk assessment and identifying those at high risk due to multiple risk factors for intervention before their
first CVD event.
3. Mass education or policy interventions directed at the entire population to reduce the overall level of risk
factors.
Primary prevention is paramount for the large number of individuals who are at high risk for CVD. A cost­effective
primary prevention strategy includes use of prediction rules or risk scores to identify those at higher risk in order to
target specific behavioral or drug interventions. Risk scores typically include age, sex, hypertension, smoking
status, diabetes mellitus, and lipid values. Some also include family history. Some risk scores do not require
laboratory testing.
Education and public policy interventions that have reduced smoking rates, lowered mean blood pressure levels,
and improved lipid profiles, have contributed to the reduction in CHD rates.
References

1. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ, eds. Global Burden of Disease and Risk Factors. New
York: The World Bank and Oxford University Press; 2006: 552.
2. Gaziano JM. Fifth phase of the epidemiologic transition: the age of obesity and inactivity. JAMA 2010;303:275­6.
3. Lawes CM, Hoorn SV, Rodgers A. Global burden of blood­pressure­related disease, 2001. Lancet
2008;371:1513­8.
4. Whitlock G, Lewington S, Sherliker P, et al., on behalf of the Prospective Studies Collaboration. Body­mass index
and cause­specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet
2009;373:1083­96.
5. Gaziano TA. Cardiovascular disease in the developing world and its cost­effective management. Circulation
2005;112:3547­53.
6. Gaziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with a multidrug regimen in the
developing world: a cost­effectiveness analysis. Lancet 2006;368:679­86.
7. Gaziano TA, Steyn K, Cohen DJ, Weinstein MC, Opie LH. Cost­effectiveness analysis of hypertension guidelines
in South Africa: absolute risk versus blood pressure level. Circulation 2005;112:3569­76.
8. Ferrario M, Chiodini P, Chambless LE, et al. Prediction of coronary events in a low incidence population.
Assessing accuracy of the CUORE Cohort Study prediction equation. Int J Epidemiol 2005;34:413­21.
9. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease
using risk factor categories. Circulation 1998;97:1837­47.
10. Folsom AR, Chambless LE, Ballantyne CM, et al. An assessment of incremental coronary risk prediction using C­
reactive protein and other novel risk markers: The Atherosclerosis Risk in Communities Study. Arch Intern Med
2006;166:1368­73.
11. Wang TJ, Gona P, Larson MG, et al. Multiple Biomarkers for the Prediction of First Major Cardiovascular Events
and Death. N Engl J Med 2006;355:2631­9.
12. Ware JH. The limitations of risk factors as prognostic tools. N Engl J Med 2006;355:2615­7.
13. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment
of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007;297:611­9.
14. Lindholm LH, Mendis S. Prevention of cardiovascular disease in developing countries. Lancet 2007;370:720­2.
15. Mendis S, Lindholm LH, Mancia G, et al. World Health Organization (WHO) and International Society of
Hypertension (ISH) risk prediction charts: assessment of cardiovascular risk for prevention and control of
cardiovascular disease in low and middle­income countries. J Hypertens 2007;25:1578­82.
16. Gaziano TA, Young CR, Fitzmaurice G, Atwood S, Gaziano JM. Laboratory­based versus non­laboratory­based
method for assessment of cardiovascular disease risk: the NHANES I Follow­up Study cohort. Lancet
2008;371:923­31.
17. Ford ES, Ajani UA, Croft JB, et al. Explaining the Decrease in U.S. Deaths from Coronary Disease, 1980­2000. N
Engl J Med 2007;356:2388­98.
18. Asaria P, Chisholm D, Mathers C, et al. Population­wide interventions to prevent chronic diseases. Lancet
2007;370:2044­53.
19. Jha P, Chaloupka FJ, Moore J, et al. Tobacco Addiction. In: Jamison DT, Breman JG, Measham AR, et al. Disease
Control Priorities in Developing Countries. 2nd ed. New York: Oxford University Press; 2006.
20. Bibbins­Domingo K, Chertow GM, Coxson PG, et al. Projected effect of dietary salt reductions on future
cardiovascular disease. N Engl J Med 2010;362:590­9.
21. Asaria P, Chisholm D, Mathers C, Ezzati M, Beaglehole R. Chronic disease prevention: health effects and financial
costs of strategies to reduce salt intake and control tobacco use. Lancet 2007;370:2044­53.
22. Jamison D, Breman JG, Measham AR, et al. Disease Control Priorities in Developing Countries. 2nd ed. New
York: Oxford University Press; 2006.
23. Gaziano TA, Galea G, Reddy KS. Scaling up interventions for chronic disease prevention: the evidence. Lancet
2007;370:1939­46.
24. Puska P, Vartiainen E, Tuomilehto J, Salomaa V, Nissinen A. Changes in premature deaths in Finland:
successful long­term prevention of cardiovascular diseases. Bull World Health Organ, 1998;76:419­25.
25. Ebrahim S, Smith GD. Systematic review of randomised controlled trials of multiple risk factor interventions for
preventing coronary heart disease. BMJ 1997;314:1666­74.
26. Yu Z, Nissinen A, Vartiainen E, Song G, Guo Z, Tian H. Changes in cardiovascular risk factors in different
socioeconomic groups: seven year trends in a Chinese urban population. J Epidemiol Community Health 2000;
54: 692­6.
27. Uusitalo U, Feskens EJ, Tuomilehto J, et al. Fall in total cholesterol concentration over five years in association
with changes in fatty acid composition of cooking oil in Mauritius: cross sectional survey. BMJ 1996:313:1044­6.
28. Rossouw JE, Jooste PL, Chalton DO, et al. Community­based intervention: the Coronary Risk Factor Study
(CORIS). Int J Epidemiol 1993;22:428­38.
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1.2: Biostatistics
Author(s):
Lori B. Daniels, MD, MAS, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Correctly identify the study design used in a given medical study, and list its uses.
2. Describe the p value, and interpret its meaning and relationship to hypothesis testing.
3. Calculate sensitivity, specificity, and positive and negative predictive values for a diagnostic test.
4. Compare various methods to account for confounding variables in clinical studies, including multivariable regression
and propensity analysis.
5. Recognize how survival analysis differs from other regression analyses, and identify when survival analysis should be
used.
Introduction

One of the strengths of the field of cardiology is its strong evidence base. Cardiology is known for its large clinical trials,
which provide a large amount of new information about treatments and practices. A well­qualified cardiologist must
understand biostatistics, to help decide whether results presented in the literature can be believed and should be
applied to their treatment of patients.

The purpose of this module is to provide a basic foundation in biostatistics, so that the reader can better evaluate clinical
literature. The focus is on the interpretation of research methods, rather than on calculations and computational details.
This module emphasizes the biostatistics methods that the cardiovascular specialist is most likely to encounter in
modern medical literature.

An additional resource is the American Heart Association Scientific Statement that reviews the appropriate statistical
evaluation of novel markers of cardiovascular risk. It provides an excellent summary and explanation of some of the most
frequently used biostatistics within the field of cardiovascular medicine.1
Study Designs

Medical research study designs fall into two major categories: 1) observational, and 2) interventional. In observational
studies, subjects are observed, but no medical intervention is performed. The observations may be performed
prospectively (i.e., forward­looking cohort studies), retrospectively (i.e., backward­looking case­control studies), or
simultaneously (i.e., cross­sectional studies). Interventional studies, or clinical trials, evaluate the effects of an
intervention on outcomes, and are considered to provide a stronger level of evidence than observational studies.
Understanding how a study is designed is essential to understanding the conclusions that can be drawn from it.

Cohort Study

A cohort study is an observational study that enrolls a group of subjects with something in common and follows their
natural history prospectively over a period of time. The purpose is to determine which characteristics, exposures, or risk
factors are associated with a given outcome. Unlike cross­sectional or case­control studies, however, the outcome of
interest in a cohort study occurs in the future, after the subject is enrolled.

In the cardiovascular literature, one of the most prominent cohort studies is the Framingham study of cardiovascular risk
factors, which started in 1948, when over 6,000 individuals from the same Massachusetts town were enrolled. The cohort
was then followed with various examinations every 2 years to determine the association of various risk factors with
cardiovascular diseases.

Case Series

A case series is a descriptive account of a collection of patients, in which each case shares some characteristic of
interest. A case series can be the first step in identifying a new disease process, describing a novel physical or imaging
finding, or reporting on a novel treatment method. Case series reports can serve as a catalyst to other studies.

Case­Control Studies

Case­control studies are retrospective studies that start with individuals who already have a disease or trait of interest
(i.e., the cases), then match them with control subjects who lack that disease or trait. The studies then attempt to look
back at events, exposures, and characteristics to see whether any difference exists between the two groups. The idea is
to find a risk factor that is present in the history of the cases, but not the controls.

Cross­Sectional Studies

Cross­sectional studies are descriptive studies about the characteristics of a group of individuals at a single point in
time. These studies describe what is happening “right now” in a group of people. Cross­sectional studies can be used to
establish norms (e.g., for a new biomarker), evaluate the usefulness of a new diagnostic procedure, or poll individuals
about their attitudes (e.g., towards health care).

Clinical Trial

A clinical trial is a study undertaken to determine whether a particular procedure or treatment can improve an outcome for
a selected group of individuals. In controlled clinical trials, the intervention being tested is compared with another
procedure or drug, generally a placebo or the current standard of care. Randomization assigns subjects to either the
active treatment or the placebo group by chance, thereby eliminating bias in patient assignment and allowing patient
characteristics to be evenly distributed between groups.

In double­blind studies, neither the study investigator nor the subject knows whether they are in the treatment group or
the control group, thus eliminating potential bias. The most robust clinical trial design is considered to be the
randomized, double­blind, placebo­controlled trial, because it can provide evidence of causation (i.e., the best indication
that any effects seen are due to the intervention).
Descriptive Statistics

Measures of Central Tendency

The correct measures to use for describing a population depend on the type of data being analyzed. The mean
measures the middle of a distribution of numerical variables, if that variable has a normal (i.e., “bell­shaped”) distribution
in the population being studied. The mean, also called the arithmetic mean, is the average of the observations. The
mean value is sensitive to extreme values, especially in small sample sizes, so it is not used for skewed data.

Instead, the median is used to measure the middle of a distribution of numerical variables that are skewed. Medians are
also used for ordinal data, which are data that have an inherent order among categories (e.g., New York Heart
Association classification for heart failure severity). The median is the point at which half the observations are larger and
half are smaller. Unlike the mean, it is unaffected by extreme values.

Measures of Variation

Range: The range is the simplest measure of spread, and is defined as the highest observed value minus the lowest
observed value. One disadvantage of the range is that it tends to increase as the number of observations increases,
since extreme values are more likely to occur with a greater number of data points. Consequently, reporting percentile
values such as the 25th and 75th percentiles, or the 5th and 95th percentiles, is often preferred. The interquartile range
(i.e., the difference between the 75th and 25th percentiles) is often used in conjunction with the median, to describe a set
of skewed observations.

Standard deviation: The most commonly used measure of dispersion is the standard deviation (SD), a measure of the
spread of data about the mean. The SD is calculated as the square root of the variance, and the variance is the average
of the squares of the deviations from the mean. If the distribution of observations is bell­shaped, then approximately 67%
of observations are within 1 SD of the mean, 95% are within 2 SDs of the mean, and 99.7% lie within 3 SDs of the mean.
Even if the distribution is not bell­shaped, at least 75% of the values will always fall within 2 SDs of the mean.

The mean and SD are also useful for determining whether a set of variables is skewed, when only summary statistics
are provided. If the mean is smaller than 2 SDs, the data are probably skewed.
Hypothesis Testing

The purpose of a hypothesis test is to permit generalizations about a population based upon observations made in a
sample from that population. When making comparisons between two groups (e.g., a group that received some therapy
vs. a group that received a placebo), the hypothesis being tested is that some difference exists between the two groups.
The null hypothesis, which must be disproven in order to claim a difference, is that the two groups are equal.

Errors in Hypothesis Testing

Erroneous conclusions can arise from hypothesis tests in two ways. A type I error is analogous to a false­positive
diagnostic test. A type I error incorrectly concludes significance (and rejects the null hypothesis) when the result is not
really significant. A type II error is analogous to a false­negative diagnostic test. A type II error incorrectly concludes no
significance when the result is, in fact, significant. The probability of making a type II error is known as beta, or β.

The significance level of a test is also known as alpha, or α. This is the probability of making a type I error (i.e., incorrectly
concluding significance). For many statistical tests, the p value can be compared to the significance level to either detect
a statistically significant difference (i.e., reject the null hypothesis), or to conclude that the null hypothesis cannot be
rejected at that significance level. For most studies, a significance level of 0.05 is chosen.

Power

The power of a statistical test is its ability to detect significance when a result is indeed significant. In the case of a
diagnostic test, the power of a statistical test corresponds to the sensitivity of a diagnostic test, or the ability to detect a
disease that is present. Investigators want the statistical test to be sensitive to detecting significance when it should be
detected, and minimizing the risk of a type II error. Power can be calculated as 1 – β, or 1 minus the probability of making
a type II error.

P Values

The p value is the probability of obtaining a result at least as extreme as the one observed, if the null hypothesis is true
(i.e., the groups being compared are equal). The p value can also be thought of as the probability that the observed result
is due to chance alone. After a statistical test has been performed, if its p value is less than α (often set at 0.05), the null
hypothesis is rejected.

Importantly, a “significant” p value does not provide absolute proof that a difference between groups exists; rather, a p
value of 0.05 or less means that if the groups do not differ, results as extreme as those observed would happen only 1 in
20 times or less. Similarly, failure to detect a significant difference does not mean that a difference does not exist.

The p value has often been subject to misinterpretation. The p value is not the probability that the null hypothesis is true. It
also does not indicate the size or importance of the observed effect. Even an effect that is highly statistically significant
(e.g., p < 0.0001) could be clinically insignificant if the magnitude of the difference between groups (i.e., the effect size) is
small, or if the observation is not relevant to clinical practice.

Confidence Intervals

Confidence intervals describe the variability, or margin of error, of a given result. Since point estimates, such as means or
hazard ratios, do not have an associated probability describing how likely that value is, interval estimates are often
provided. Since a level of significance (i.e., α) of 0.05 is often used, investigators commonly report intervals to describe a
95% confidence interval. The 95% confidence interval denotes that if an experiment were repeated numerous times, the
point estimate would fall within the confidence intervals 95% of the time.

Sample Size and Effect Size

A number of statistical considerations go into determining the required sample size for a study, including the magnitude
of the difference to be detected (i.e., the effect size), the frequency of the outcomes to be measured, and the statistical
power desired (i.e., the desired ability to avoid a type II error). With sample sizes that are too small, investigators run the
risk of failing to detect an important difference between the study groups, which would be a type II error. However, if
sample sizes are larger than needed, more patients may be exposed to research risks, and extra resources will be used.

As noted earlier, an effect size is a measure of how much difference exists between two groups, such as a treatment
group and a control group. An effect size can be based on the difference between two means (i.e., numerical outcomes
such as cholesterol level), on proportions, odds ratios, relative risks, or hazard ratios (i.e., nominal outcomes such as
dead vs. alive), or on correlations (i.e., measures of association).

In cardiovascular research, investigators are often interested in the magnitude of the relationship between two
characteristics, such as the presence of a risk factor and the occurrence of a specific outcome. Two ways to express this
relationship are with the relative risk (RR), and the odds ratio (OR). RRs are used in cohort or prospective studies,
whereas ORs are used in case­control studies. The OR is the odds that a person with an adverse outcome was at risk,
divided by the odds that a person without an adverse outcome was at risk.

The RR, used in prospective studies, is the ratio of the incidence of the outcome in people with the risk factor to the
incidence in people without the risk factor. The absolute risk reduction (ARR) is the absolute value of the difference
between the two event rates (i.e., the incidence in those with the risk factor vs. the incidence in those without). ARR is a
useful measure, because it can be used to calculate the number needed to treat (NNT) to prevent one event. The NNT is
the reciprocal of the ARR (i.e., NNT = 1 ÷ ARR). The relative risk reduction (RRR) is also frequently presented, and is the
amount of risk reduction relative to the baseline risk. It is calculated as ARR divided by the baseline event rate (i.e.,
divided by the incidence in those without the exposure).

Example: A new antiplatelet agent is being tested for its ability to decrease the incidence of myocardial infarction (MI) at
60 days. One thousand patients are randomized to either the new drug or to a placebo, resulting in 500 people in each
group. After 60 days, 15 patients in the active treatment group and 25 patients in the placebo group have experienced the
primary outcome (i.e., MI). What is the NNT with this new medication, to prevent one MI? What is the RRR?

Answer: The incidence of MI in the treatment group was 15 ÷ 500 = 0.03. The incidence in the placebo group was 25 ÷
500 = 0.05. Therefore, the ARR = 0.05 – 0.03 = 0.02, or 2%. The NNT = 1 ÷ ARR = 1 ÷ 0.02 = 50. Therefore, 50 patients
would need to be treated with the new medication for 60 days to prevent one MI. The RRR = 0.02 ÷ 0.05 = 0.40, or 40%.
Assessing Yield of Diagnostic Tests

An important part of cardiology is evaluating the accuracy of diagnostic tests. Even

with advanced diagnostic technology such as cardiac CT scans, nuclear stress
tests, and electrophysiology (EP) studies for diagnosing inducible arrhythmias, the Table 1
possibility of false positive and false­negative test results exists. The accuracy of a
diagnostic test depends on both its sensitivity and its specificity.

Sensitivity

Sensitivity is the probability of a positive test result in patients who have the
condition. It is calculated as: true positives ÷ (true positives + false negatives) (Table
1). Tests with higher sensitivity mean lower chances of missing the disease. A very Table 2
sensitive test, when negative, rules out disease. A helpful mnemonic for this is
“SNOUT”: SeNsitive test = good for rule OUT.

Specificity

The specificity of a test is the test’s ability to identify individuals who do not have
disease. More precisely, specificity is the probability of a negative test result in a Figure 1
patient who does not have the condition being measured. Specificity is calculated
as: true negatives ÷ (true negatives + false positives) (Table 1). Tests with higher
specificity mean that fewer normal people are misdiagnosed as having the disease.
A very specific test, when positive, rules in disease. A helpful mnemonic for this is
“SPIN”: SPecific test = rule IN.

Positive and Negative Predictive Values

Performance of a diagnostic test can also be assessed by the positive predictive

value (PPV) and the negative predictive value (NPV). The PPV is the probability that a
patient whose test is positive actually has the disease. It is calculated as: true
positives ÷ (true positives + false positives). The NPV is the probability that a patient
whose test is negative does not have the disease. It is calculated as: true negatives
÷ (true negatives + false negatives) (Table 1). Unlike sensitivity and specificity, which
tend to be inherent characteristics of the diagnostic test, PPV and NPV depend on
the prevalence of disease in the population being tested.

Likelihood Ratio

The likelihood ratio is an alternative method for incorporating information about the
sensitivity and specificity of a test, and uses odds rather than probabilities. It can be
calculated for both a positive test result and for a negative test result.

The likelihood ratio­positive (+LR) can be used to calculate the odds of disease if a
test is positive. It is calculated as the odds that a positive test result occurs in
patients with the disease (i.e., sensitivity) divided by the odds that the result occurs
in patients without the disease (i.e., false­positive rate, or 1 – specificity). The post­
test odds of a positive test can then be calculated by multiplying the likelihood ratio
by the prior, or pretest odds (i.e., [LR+] x pretest odds = post­test odds). The post­
test odds can be converted to a post­test probability by dividing it by (1 + post­test
odds). This result is the same as the PPV (i.e., the probability that a patient whose
test is positive actually has the disease).

The likelihood ratio­negative (­LR) is defined as: (1 – sensitivity) ÷ specificity. It can

be used to find the odds of disease even if a test is negative.

Bayes’ Theorem

Another method for calculating the predictive value of a positive test uses Bayes’
theorem, a mathematical formula. Bayes’ theorem is used in clinical medicine to
determine the probability of a particular disease in a group of people with a specific
characteristic, such as a positive test result. It considers the overall rate of that
disease and the likelihood of that specific characteristic in healthy versus diseased
individuals, respectively. Bayes’ theorem can be used in clinical decision making to
estimate the probability of a particular diagnosis, given the presence of a particular
symptom, sign, or abnormal test result.
One example is the likelihood of having coronary artery disease in a patient with an
abnormal stress test. This likelihood depends on the patient’s pretest probability of
disease, as well as on the accuracy of the stress test. In a patient with a low pretest
probability of disease, an abnormal stress test may be just as likely to be a false
positive as a true positive. Conversely, a patient with an extremely high risk of having
coronary disease may still be more likely to have coronary disease than not, even if
his stress test is “normal.”

Example: Suppose a cardiovascular stress test has a sensitivity and a specificity of

90% for detection of coronary artery disease. A 30­year­old woman with no
cardiovascular risk factors but with atypical chest pain is referred for this test. Her
pretest probability of coronary artery disease is low (assume 5% for the purposes of
this exercise). If the test comes back as abnormal, what is the likelihood that the
patient actually has coronary artery disease?

Answer: First, generate a 2 x 2 contingency table (Table 2). If 1,000 low­risk

individuals are tested, 50 would be expected to have disease, while 950 would be
disease­free. Since the test is 90% sensitive, the number of individuals with a true
positive test result will be: 0.90 x 50 = 45, leaving 5 patients (i.e., 50 – 45) with a
false­negative result. Since the test is also 90% specific, the number with a true
negative result will be: 0.90 x 950 = 855, leaving 95 patients (i.e., 950 – 855) with a
false positive result. Thus, 140 patients overall will have positive stress test results,
and only 45 patients will be true positives. In other words, an abnormal stress test in
a low­risk patient is more than twice as likely to be a false positive as a true positive
(i.e., PPV = 45 ÷ 140 = 32%). The test will be even less helpful if the true pretest
probability is lower than 5%.

Receiver Operating Characteristic Curves

Sensitivity, specificity, and the parameters outlined earlier work well for evaluating
diagnostic tests with binary results (i.e., tests in which results are either normal or
abnormal). However, a large number of cardiovascular tests have numeric results
with a wide range of possible values (e.g., cholesterol levels, natriuretic peptides,
and cardiac troponins). For continuous tests like these, the sensitivity and specificity
of the test depends on which cut point is used to distinguish normal from abnormal.

Receiver operating characteristic (ROC) curves are used to display the relationship
between sensitivity and specificity for tests with continuous outcomes. ROC curves
are plotted with the sensitivity (i.e., true­positive rate) on the y­axis, and the false­
positive rate (i.e., 1 – specificity) on the x­axis. In essence, ROC curves are a function
of the sensitivity and specificity for each individual value of a test (Figure 1).

ROC curves can be used to assess discrimination, which is one way to assess the
usefulness of a continuous test. It is defined as the probability that the predicted risk
(i.e., test value) is higher for someone with disease than for someone without
disease. A useful measurement derived from ROC curves is the area under the
ROC curve (AUC), which is a measure of discrimination. A test with an AUC of 1.0
would have perfect discrimination, while a test with an AUC of 0.5 would be no better
than tossing a coin to decide. The term c­statistic is often used interchangeably with
AUC. The c­statistic can be used to compare two different tests or two different
models (i.e., one with standard risk factors alone vs. a second, which also includes
a novel risk marker). 2 However, a number of researchers have recently warned
against using a comparison of c­statistics as the sole measure of worth when
evaluating a novel marker or test.3

Discrimination and Reclassification

Recently, clinical researchers who evaluate diagnostic tests have begun placing
more emphasis on measures of reclassification. 4 Reclassification is the ability of a
diagnostic test to more accurately stratify individuals into higher and lower risk
categories. It is essentially a more clinically relevant form of discrimination. A better
prediction ability is implied by an increased probability that patients with disease will
be categorized as high risk, and a decreased probability that patients without
disease will be categorized as high risk. The opposite situation implies a worse
prediction ability.
The net reclassification index (NRI) is one method for assessing discrimination in
this way. Using pre­defined risk categories, it measures how the new test result
induces changes from one risk category to another. It is a measure of the difference
in proportions moving up and down among people with disease versus those
without disease. The integrated discrimination index (IDI) considers the change in
the estimated predicted probability of disease as a continuous variable, rather than
via categories.5,6
Summary of Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value
Table 1
2 x 2 Contingency Table Illustrating Bayes’ Theorem
Table 2
Given: Sensitivity = 90%, Specificity = 90%, Pretest probability = 5%

Calculations:

PPV = true positives ÷ all positive tests

= 45 ÷ 140
= 0.32.
NPV = true negatives ÷ all negative tests
= 855 ÷ 860
= 0.99.
+LR = sensitivity ÷ (1­specificity)
= 0.90 ÷ (1­0.90)
= 9.
Pretest odds = pretest probability ÷ (1 – pretest probability)
= 0.05 ÷ (1 – 0.05)
= 0.053
Post­test odds = Pretest odds x (+LR)
= 0.053 x 9
= 0.48.
Post­test probability = Post­test odds ÷ (1 + post­test odds)
= 0.48 ÷ (1 + 0.48)
= 0.32
= same as PPV.
Receiver Operating Characteristic (ROC) Curve and Area Under the Curve (AUC)
Figure 1
This figure presents an ROC curve for various cutoff levels of B­type natriuretic peptide (BNP) and is used in diagnosing acute heart failure
among emergency department patients with acute dyspnea.

Reproduced with permission from Maisel AS, Krishnaswamy P, Nowak RM, et al., on behalf of the Breathing Not Properly Multinational Study I.
Rapid measurement of B­type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161­7.
Comparing Groups

Comparing Two Groups

The appropriate test to use to evaluate differences between two or more Figure 2
independent groups depends on a number of factors, including whether the data are
continuous or categorical, and whether the data are normally distributed. When the
research question asks whether the mean of two groups are equal, the most
commonly used test is the t test, also called the Student t test. When the question is
whether proportions in two independent groups are equal, the most commonly used
test is the chi­square.

Correlation

The correlation coefficient (denoted by “r”), or correlation, is a measure of the

relationship between two numerical measurements made on the same set of
subjects. A positive r value greater than zero describes two variables that are directly
and positively associated, whereas a negative r value implies an inverse
association. When the correlation coefficient is squared (denoted by “r2 ”), it provides
a more intuitive way to think about correlations. For example, an r2 of 0.58 means
that 58% of the variability in one of the measures is accounted for (i.e., predicted) by
knowing the measurement of the other variable.

Example: If the correlation (r) between age and B­type natriuretic peptide (BNP) level
is 0.2, then r2 = (0.2)2 = 0.04. Thus, 4% of the variability in BNP level is due to age.

Linear and Logistic Regression

Regression models are used to predict the value of one characteristic (i.e., the
dependent variable) based on knowledge of one or more other variables (i.e., the
independent variables). An example is using cardiac risk factors (e.g., age,
cholesterol level, blood pressure, etc.) to predict the risk of coronary artery disease.

Linear regression may be used when the dependent variable (the variable being
predicted) is a continuous numeric variable. For example, linear regression may be
used to predict systolic blood pressure from age, weight, and sex. However, linear
regression modeling assumes that the relationships between the dependent and
independent variables are linear, that the sample used for development of the
model may be generalized to the population it is supposed to represent, and that the
scatter of the data points about the regression line is normally distributed.

When the dependent variable is a binary variable (e.g., presence vs. absence of
coronary disease), logistic regression is used. Logistic regression is commonly
used in cardiovascular research for evaluating outcomes and diagnostic tests. For
example, a new biomarker may appear to predict the risk of heart failure. However,
logistic regression can be used to show that after adjusting the biomarker level for
confounding factors that may be associated with both the biomarker level and the
outcome of interest (e.g., age, sex, renal function), the biomarker is no longer a
significant predictor.

Multivariable, or multiple, regression simply means that more than one independent
variable is included in the prediction equations. Multivariate techniques allow
researchers to adjust for (i.e., weight) the relative contributions of each independent
variable on the dependent variable. Multivariable models provide only estimates of
the true relationship. Models created from larger sample sizes may provide less
uncertainty than models created from smaller sample sizes. Models can be “overfit”
by attempting to adjust for too many independent variables. For logistic regression
models, a good “rule of thumb” is that 10 outcome events are needed for each
independent variable included in the model.

Propensity Analysis

Propensity analysis is an alternative to multivariable regression that is used to

control for a group of confounding factors. Use of propensity scores provides an
alternative method for estimating treatment effects when treatment assignment is
not random. In randomized trials, randomization generates treatment groups that
are generally balanced for confounding factors, especially when large numbers of
patients are involved. In observational studies, however, assignment of patients to
treatment groups is frequently imbalanced for a number of measured and
unmeasured variables (i.e., covariates) and can, therefore, provide a biased
estimation of treatment or exposure effects. This makes it difficult to confidently
attribute any differences between the groups to the treatment.

Propensity analysis attempts to reduce the effect of confounding variables by

developing a “propensity score” based on possible confounders, and then adjusting
predictive models with that score. Propensity scores can also be used in
retrospective studies to match individuals, by selecting and comparing individuals
with similar propensity scores. A disadvantage of propensity analysis is that, despite
including a large number of covariates, propensity scores still may leave significant
biases which are unaccounted for; no score can account for all potential
measureable and non­measureable confounders.

Analyzing Survival Data

Many cardiovascular studies are designed to evaluate whether a new treatment will
improve outcomes. In this situation, investigators may be interested in long­term
outcomes including the incidence of hospitalization, MI, or death. When research
involves time­related variables like these, the timing of the event, not just the fact that
it happened, is important. For example, in a study that is comparing survival times
between groups of individuals who have undergone a standard procedure versus a
novel procedure, a death on the first day after the procedure carries a different value
than a death that occurs after 5 years. Survival analysis provides a way to account for
this type of time­dependent data. Rather than counting the number of events, the
time it takes for an event to happen is considered.

Sometimes there may be limited follow­up data for a subject in long­term study. For
example, if a patient is lost to follow­up, researchers may not know whether the
patient had the outcome of interest or not. In other situations, a patient may have
died from causes unrelated to the cardiovascular disease being studied (e.g., dying
in a motor vehicle accident). Rather than excluding these patients, survival analysis
uses a method called censoring. Censoring is also used when analysis of survival
is done while some patients in the study are still living; the observations on these
patients are censored at the end of the follow­up period, since one does not know
how long these patients will remain alive. Censoring allows the data to be included
up until the last follow­up time that was available.

Kaplan­Meier Plots

Kaplan­Meier plots are used to depict survival data that include censored data
(Figure 2). They show the frequency of patients who developed a given outcome,
such as death, at a given time. Since the number of patients available for such an
analysis decreases with time, estimates of survival become less precise over time.
The log­rank test, also called the Mantel­Cox test, is often used to compare the
survival distributions of two groups. The hazard ratio can be calculated for survival
data, and indicates the risk of an outcome at any time in the group with an exposure
(i.e., the treatment group) compared to the risk in the control group.

Cox Proportional Hazards Models

Proportional hazards models are a type of survival model that permits researchers
to control for confounding variables. Survival models relate the time to an event to
one or more associated covariates. In a proportional hazards model, the
assumption is that the effect of the covariate is multiplicative with respect to the
hazard rate. For example, if taking drug X reduces the risk of death at 30 days by
25%, it also reduces the risk by 25% at 6 months, at 1 year, or at any other time. Cox
proportional hazards models are frequently used in cardiovascular literature to
assess the effect of a new treatment on outcomes, after adjusting for possible
confounders such as patient age, sex, and other comorbid conditions.
Kaplan­Meier Survival Plot
Figure 2
This figure presents a Kaplan­Meier plot depicting survival in Rancho Bernardo Study participants with detectable versus undetectable cardiac
troponin T.

TnT = Troponin T.

Reproduced with permission from Daniels LB, Laughlin GA, Clopton P, Maisel AS, Barrett­Connor E. Minimally elevated cardiac troponin T and
elevated N­terminal pro­B­type natriuretic peptide predict mortality in older adults: results from the Rancho Bernardo Study. J Am Coll Cardiol
2008;52:450­459.
Key Points

Medical research studies can be observational (i.e., case series, case­control, cross­sectional, and cohort
studies) or interventional (i.e., clinical trial), and provide varying levels of evidence depending on the design.
A statistically significant difference between two groups can be identified by either comparing the p value against
the stated alpha, or by determining that the confidence intervals exclude a finding of no difference.
Those taking the American Board of Internal Medicine examination should be able to calculate sensitivity,
specificity, PPV, and NPV, and should understand the concepts of Bayes’ theorem of post­test probability.
ROC curves and the AUC are two ways to assess the usefulness of a diagnostic test.
T tests are used to compare means between two independent groups; chi­square is used to compare
proportions between two groups.
The square of the correlation coefficient, r2 , tells the percentage of the variability in one measure that is predicted
by knowing the measurement of the other variable.
Linear regression and logistic regression are used to predict the value of a dependent variable (i.e., outcome
measure) from one or more independent variables (i.e., covariates).
Kaplan­Meier plots can be used to plot survival or other time­dependent data. Cox proportional hazards models
are used with survival data to adjust for confounding variables.
References

1. Hlatky MA, Greenland P, Arnett DK, et al. Criteria for evaluation of novel markers of cardiovascular risk: a
scientific statement from the American Heart Association. Circulation 2009;119:2408­16.
2. Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P. Limitations of the odds ratio in gauging the
performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol 2004;159:882­90.
3. Cook NR. Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation
2007;115:928­35.
4. Ridker PM. C­reactive protein and the prediction of cardiovascular events among those at intermediate
risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardio 2007;49:2129­38.
5. Pencina MJ, D'Agostino RB Sr, D'Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a
new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157­72;
discussion 207­12.
6. Pencina MJ, D'Agostino RB Sr, Steyerberg EW. Extensions of net reclassification improvement calculations
to measure usefulness of new biomarkers. Stat Med 2011;30:11­21.
Printable PDF

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1.3: Cost­ and Comparative­Effectiveness
Author(s):
Duane S. Pinto, MD, MPH, FACC, FSCAI
Matthew R. Reynolds, MD, MSc, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Explain key concepts in the interpretation of cost­effectiveness analyses (CEAs), including analytic perspective, time
horizon, incremental comparisons, and measures of uncertainty.
2. Identify and differentiate the following CEA methodologies: trial­based, model­based, and hybrid.
3. Compare and contrast the economic implications of cost­minimization studies, cost­effectiveness studies, and cost­utility
studies.
4. Recognize the importance of incremental cost­effectiveness ratios (iCERs) when evaluating new cardiovascular
technology so comparisons to existing technology can be made.
Introduction: Scope of Health Care Expenditures

An economic crisis was narrowly averted during US congressional budgetary negotiations in August of 2011. The
negotiations focused on whether to raise the debt ceiling and/or cut government expenditures. These negotiations, as
well as the subsequent downgrading of the quality of the US government debt, highlighted the limited resources our
society has available to spend on health care and the consequences of growth in health care expenditures.

National health spending is estimated to have reached $2.6 trillion in 2010. The share of the US gross domestic product
spent on health care is projected to increase from 17.6% in 2009 to 19.8% by 2020.1 With limited resources, it becomes
important to consider the most efficient allocation of medical spending. The study of this question is termed “medical
economics.”
Fundamentals of Economic Assessment

There are three methods for the economic assessment of medical interventions: 1)
comparative­effectiveness analysis, 2) CEA, and 3) cost minimization studies. For
cost minimization studies, the aim is to find the least costly among therapies that Figure 1
are deemed equivalent. A major limitation of these studies is the difficulty in proving
equivalence of strategies.

Comparative­Effectiveness Analysis

Comparative­effectiveness analyses evaluate options for diagnosis and treatment in

an attempt to answer important clinical questions and guide medical practice. In an
environment of fixed health care resources, this type of research may
counterbalance a desire to minimize costs and maximize efficient use of health care
monies by focusing on the clinical impact of treatment strategies and the tradeoffs
involved in selecting one strategy over another.

Cost­Effectiveness Analysis

CEA is a form of economic­efficiency analysis in which costs are valued in monetary

terms and health benefits are valued in natural units. Cost­effectiveness research
and comparative­effectiveness research are complementary in that the need to
establish clinical effectiveness is necessary for both. Cost­effectiveness research
has a more comprehensive goal of imparting an economic context for differences in
clinical effectiveness.

A typical CEA is incremental, comparing some new health care technology or

strategy of interest with a relevant alternative. Differences in costs between
strategies are measured in units of currency. Clinical benefits are expressed in
nonmonetary terms, such as life­years gained or adverse events avoided.2

This analysis leads to various possible scenarios (Figure 1). Compared with the
standard of care, a new intervention can be both cost­saving and more effective, in
which case the strategy is termed “dominant.” The new intervention can be cost­
increasing and less effective, in which case the strategy is termed “dominated.” The
most common situations are that the new intervention is cost­increasing and is
more effective, or an intervention is less effective and cost­decreasing. In such
cases, a cost­effectiveness (CE) ratio is calculated. A CE ratio is derived as follows,
where E represents the measure of effectiveness.2

If a therapy is more expensive, it must offer a greater clinical benefit to be cost­

effective. In addition, cost­saving and cost­effective are not synonymous terms, and it
is possible for a less expensive and slightly less effective strategy to be preferred on
health economic grounds, depending upon the acceptable CE ratio. No single
threshold exists for deciding whether or not a CE ratio is acceptable and certainly the
resources available within a certain system apply.

Fearing the perception of “rationing” health care, US policy makers presently are
wary of making coverage decisions based on cost considerations. Nevertheless, CE
ratios of <$50,000 per life­year gained are generally considered attractive and ratios
of >$100,000 per life­year gained are generally considered unattractive. The $50,000
figure is historically linked to estimates of the incremental cost per life­year of
hemodialysis. Because Congress had guaranteed to fund dialysis for all affected
renal failure patients, the decision represents an implicit policy statement by the US
federal government regarding its willingness to pay to save a life­year. Some have
criticized this benchmark as too low since it has not been updated in recent times.

There are certainly examples of the US Medicare program agreeing to cover

therapies with higher CE ratio thresholds.3 In other nations, such as the United
Kingdom and Australia, health economic studies are an integral component of the
evaluation of any new medical treatment, and more or less explicit CE ratio
thresholds are known.4

Measures of clinical effectiveness vary for different disease processes or

interventions, making direct comparisons of health conditions problematic. For
example, the measurable effects of a medication may be in avoiding impaired
quality of life after a stroke. A measurable benefit of percutaneous coronary
intervention (PCI) for acute coronary syndromes may be in reducing recurrent
myocardial infarction. In CEA, measures of effect are most easily interpretable when
they lead to measurable changes in the quantity or quality of life.2

Cost­Utility Analysis

Because many therapies are used primarily to improve quality of life rather than to
increase longevity, it is necessary to have an effectiveness measure that compares
outcomes across interventions which result in different health states. The quality­
adjusted life­year (QALY) is a metric used to measure health benefits. The QALY
incorporates both longevity and patient preferences for the health states
experienced. Cost­utility analyses are a subset of CEA and utilize the QALY by
adjusting for survival within various imperfect health states. The cost per QALY is a
common ratio reported in cost­utility analyses.

To develop the QALY for various disease states, a life­year gained in perfect health
is assigned a value of 1.0. Declining weightings are assigned to various disease
states, and 0.0 is assigned for death. Patient preferences offer a weighting for
various disease states in between perfect health and death, and are termed
“utilities.” The utilities of various health states can be developed in several ways.
Each has limitations, and a major problem with using QALYs for CEA stems from
inaccurate or impractical assessment of patient preferences (i.e., utilities) for
various health states.

Methods of developing utilities include the following:

Time­trade­off. Patients are asked to choose between remaining in a current state of

health for the remainder of life, or being restored to perfect health, but having a
shorter life. The duration of time is varied until the person is indifferent between the
two alternatives.5

Standard gamble. Patients are asked to choose between remaining in a state of ill
health for a period of time, or choosing a medical intervention that has a chance of
either restoring them to perfect health or killing them. The probabilities of the two
outcomes are varied until the patient is indifferent between the two outcomes.

Indirect assessment. Utilities can be assessed indirectly with the use of health­
related quality of life indexes that have preassigned utility weights.5,6 For example,
the EuroQol is a short questionnaire that assesses five health status domains:
mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Utility
weights have been derived for the EuroQoL in both Europe and the United States by
using the standard gamble method.5,7,8
The Cost­Effectiveness Plane
Figure 1
With some reference strategy occupying the origin of the graph, a cost­effectiveness study can plot the incremental costs (y­axis) and benefits
(x­axis) of alternative strategies, relative to this reference, in two­dimensional space. The area above the horizontal is cost­increasing, and to
the right of the vertical, clinically beneficial. When a new strategy adds both benefits and costs (upper right­hand quadrant) or reduces
both (lower left­hand quadrant), a cost­effectiveness (CE) ratio must be calculated to judge benefits relative to costs.

CE = cost­effectiveness.

Reproduced with permission from Cohen DJ, Reynolds MR. Interpreting the results of cost­effectiveness studies. J Am Coll Cardiol 2008;52:2119­
26.
Types of Economic Analyses

Three types of health economic studies have been performed: 1) economic analysis performed alongside a randomized
clinical trial, 2) model­based analysis based on best available evidence, and 3) hybrid studies where observed patient­
level trial data are used for some portion of the analysis and then used to extrapolate beyond the time horizon of the trial
itself.

Clinical Trial­Based Analyses

Clinical trials afford the opportunity to perform CEA with accurate data collection, and randomization reduces the chances
of bias and confounding. These types of analyses are limited by the selected populations enrolled in what is usually a
single clinical trial. Additional limitations include the expense involved in collecting these data, and the limited time span
of these trials in which downstream clinical and economic costs may not be identified.

Disease Simulation Models

When clinical trials are not practical or reflective of the population of interest, other analyses are performed that are
completely based on disease simulation models. Using a wide variety of data sources, models are constructed to predict
the likelihood of various outcomes. Multiple strategies can be assessed and, because various sources of data are used,
there is not overreliance on one population or study. Unfortunately, the quality of the models and conclusions are
fundamentally dependent on the quality of the data used to construct the models. Quality is also dependent on the
simplifying assumptions that are necessary when constructing these models. Results may therefore be uncertain.
However, the results may be useful for generating hypotheses.

Hybrid Studies

Some studies incorporate elements of both modeling and data collection from clinical trials. By deriving models from
clinical trial data and then projecting results into a longer time horizon, the issue of truncated follow­up is partially
addressed. However, the issues of incomplete or inaccurate modeling remain.2
Interpretation of Cost­Effectiveness Analyses

Analytic Perspective

One consideration when interpreting a CEA is the analytic perspective. Each Table 1
member of the health care delivery team (e.g., consumer, insurer, physician,
hospital) has different incentives, constraints and obligations. As such, each may
have different preferences for one therapy over another. Because most patients with
health insurance do not have large out­of­pocket expenses, there is a desire to have
the maximal health benefit, regardless of cost. Hospitals have an incentive to
maximize return for any given episode of care. Insurers seek to maximize the health
of their beneficiaries at the lowest costs. Most CEAs do not deal with these individual
Figure 2
incentives, but instead evaluate therapies from the broader societal or health care
system perspective. As such, these analyses focus upon the aggregate societal
costs and benefits from a strategy, rather than focusing on profits or losses for the
hospital, physician, patient, or insurer.

Incremental Comparisons

As discussed earlier, CEAs describe the incremental benefits of two or more health
strategies in light of the incremental costs. An iCER is calculated with the
presumption that each strategy is compared with the next best alternative. ICERs
reflect the marginal cost required to achieve a more favorable clinical outcome over
existing therapy, based on the economic concept of “opportunity costs” (Table 1).9

Time Horizon

The time horizon of the analysis has an important effect on a CEA. For example, if
there is a short duration of follow­up in a clinical trial for an intervention that yields
potentially long­lasting benefits, the benefits may be underestimated. This would
result in a spuriously high CE ratio. Furthermore, if there are differences in the rate of
benefit accruing between the strategies being compared, an inappropriate time
horizon for comparison may lead to misleading results. For example, consider a
study comparing the CE ratio of multivessel stenting versus coronary artery bypass
surgery. Assessing the CE ratio of PCI at 1 year is somewhat limited by the fact that
most stents fail earlier, while saphenous vein graft attrition is a phenomenon that
occurs later. This illustrates the fact that a longer­term assessment of costs may
find differing conclusions than early assessment.10

Uncertainty

Because many assumptions are inherent to CEA, the potential influence of uncertain
or assumed parameters should be evaluated systematically through sensitivity
analysis. This method assesses the effect of assumed or uncertain parameters by
recalculating results across an assumed range of plausible values for the uncertain
factor. In this way, assumptions that do not alter the overall results can be identified.
It is also possible to identify the threshold values for important parameters that will
cause one strategy to become preferred over another. Rather than vary one
parameter at a time, complex methods (e.g., Monte Carlo simulations) can be used
to simultaneously vary multiple factors at once so that the overall uncertainty of a
model can be evaluated.

For trial­based analyses, specialized methods are utilized to estimate the

uncertainty around estimates for CE ratios. This is because standard statistical
measures of variance cannot be applied to an iCER. One method, bootstrapping,
involves creating a “dummy” data set by resampling with replacement (i.e., randomly
selecting one patient at a time) from the original data set and repeating this random
patient selection until the dummy data set reaches the same size as the original.
The CE ratio is then recalculated from the dummy data set, and the entire process is
repeated many times (e.g., 1,000 times).

The average CE ratio, calculated over many bootstrap iterations, should approximate
the original estimate from the trial data. However, the variability within the original
study results in a “cloud” of possible outcomes with each bootstrap iteration.
Acceptability curves can be constructed where a probability that an intervention
would be attractive at various CE ratios can be visualized (Figure 2).

CEA affords the ability to evaluate the economic consequences of clinical decisions
that go beyond assessment of clinical outcomes alone. Unfortunately, CEA cannot
be readily applied to an individual patient. It should only be used as one of many
tools available to caregivers and policy makers when making decisions.
Example of Incremental Cost­Effectiveness Ratio
Table 1
iCER = incremental cost­effectiveness ratio.
Bootstrap Analysis of Index Hospital Stay Costs
Figure 2
Performance of 1,000 bootstrap replicates indicates a 94.6% probability of cost savings with bivalirudin monotherapy compared with heparin
(unfractionated or low molecular weight heparin) with upstream glycoprotein IIb/IIIa receptor inhibition (GPI) (yellow line) and a 68.3% probability
of lower cost with bivalirudin monotherapy compared with heparin (unfractionated or low molecular weight heparin) and catheterization
laboratory (cath lab)­initiated GPI (red line).

Reproduced with permission from Pinto DS, Stone GW, Shi C, et al. Economic evaluation of bivalirudin with or without glycoprotein IIb/IIIa inhibition
versus heparin with routine glycoprotein IIb/IIIa inhibition for early invasive management of acute coronary syndromes. J Am Coll Cardiol
2008;52:1758­68.
Examples of Cost­Effectiveness Analyses in Cardiology

The SIRIUS Trial

The SIRIUS (Sirolimus­Eluting Balloon Expandable Stent in the Treatment of Patients With De Novo Native Coronary
Artery Lesions) trial was the first randomized trial to compare a drug­eluting (i.e., sirolimus) coronary stent with a bare­
metal stent. The cost­effectiveness study by Cohen, et al. is a good example of a trial­based CEA.11 All data on clinical
effectiveness (e.g., survival, repeat revascularization procedure rates), medical resource utilization, and costs were
collected and analyzed during the 1­year follow­up period of the trial. This approach was reasonable because the choice
of stent did not impact survival. Also, the time­course of restenosis, the main outcome improved by the drug­eluting stent,
is known to be generally well less than 1 year. The economic analysis of the SIRIUS trial found that sirolimus­eluting
stents slightly increased overall costs, but greatly reduced repeat revascularization procedures. This resulted in iCERs of
$1,650 per repeat revascularization procedure avoided and $27,540 per quality­adjusted year of life gained.

The SCD­HeFT Trial

The SCD­HeFT (Sudden Cardiac Death in Heart Failure Trial) compared amiodarone, placebo, and implantable
cardioverter­defibrillators (ICDs) for the prevention of sudden death in patients with reduced left ventricular ejection
fractions.12 ICDs decreased all­cause mortality compared with placebo, but amiodarone did not. In the CEA published by
Mark, et al., the key comparison was therefore between the ICD and placebo groups.13 An ICD is an example of an
intervention with a high up­front cost and potential long­term benefit. A trial­based CEA for such an intervention would
tend to overestimate the iCER by failing to capture the full benefits of the ICD over time. Mark, et al. therefore performed a
hybrid analysis, in which empirical data from the in­trial period were combined with model­based extrapolations of
lifetime costs and survival. The authors reported iCERs for the ICD compared with the placebo group of $38,389 per life­
year saved and $41,530 per QALY saved.

Cost­Effectiveness of Atrial Fibrillation Ablation

Several small randomized trials have shown that catheter ablation is more effective than antiarrhythmic drugs at
maintaining sinus rhythm in patients with atrial fibrillation who have failed at least one prior drug. None of these trials
have collected the necessary data to perform a CEA. Even if they had, the data would be limited by high crossover rates in
the trials and by relatively short follow­up durations. To overcome these limitations, Reynolds, et al. performed a CEA
using a Markov model.14

A Markov model is a means of estimating the prognosis when the clinical problem is associated with ongoing risk. In a
Markov mode, a finite number of health states (i.e., Markov states) associated with the disease are defined. Each state is
associated with a factor representing the quality of life, as compared with perfect health. The probabilities of transitioning
between different health states, as well as the costs and quality of life of each state, are either taken from published
literature or derived. The time horizon for study is divided into increments (i.e., Markov cycles), and the Markov cycle is
repeated over and over. The time spent in the various Markov states, each associated with an incremental utility, is
estimated. The utility accumulated over the Markov process is the product of the incremental utility of the Markov state and
the number of cycles spent in that state.15,16 In this case, the authors reported that catheter ablation increased both 5­
year costs and 5­year quality­adjusted survival. This resulted in an iCER of $51,000 per QALY.
Key Points

The United States spends a larger proportion of its wealth on health care than any other developed nation, and the
costs of health care are growing at an unsustainable rate. Cost­effectiveness analyses attempt to help us better
understand both the clinical and economic value of alternative clinical strategies.
Cost­effectiveness analyses can be trial­based, model­based, or a hybrid of the two. Trial­based analyses have
excellent precision, but may have insufficient time horizons. Models may suffer from uncertainty, but can provide
insights in cases where clinical trials are not feasible or have not been completed.
An iCER is the ratio of the incremental costs (in units of currency) of one strategy versus another, divided by the
incremental benefits. The benefits are defined as some clinical outcome of value (e.g., life­years gained, adverse
events avoided).
QALYs are a commonly used effectiveness measure in health economics, and are obtained by multiplying life
expectancy by weights ranging from 0 to 1. The weights represent society’s preference for some health states
over others. These weights are called utilities and can be measured in several different ways.
Future Directions

Economic and political realities are currently placing downward pressure on the costs of health care, and this will
continue in the future. Cardiovascular medicine has made very large contributions to the population’s health, longevity,
and quality of life. Cost­effectiveness studies have found that many interventions, even some expensive ones, provide
excellent benefits at a reasonable price. It will be necessary to carefully evaluate the value of new clinical approaches to
diagnosing and treating cardiovascular disease as they emerge.
References

1. Keehan SP, Sisko AM, Truffer CJ, et al. National health spending projections through 2020: economic recovery
and reform drive faster spending growth. Health Aff (Millwood) 2011;30:1594­605.
2. Cohen DJ, Reynolds MR. Interpreting the results of cost­effectiveness studies. J Am Coll Cardiol 2008;52:2119­
26.
3. Chambers JD, Neumann PJ, Buxton MJ. Does Medicare have an implicit cost­effectiveness threshold? Med Decis
Making 2010;30:E14­27.
4. Lee CP, Chertow GM, Zenios SA. An empiric estimate of the value of life: updating the renal dialysis cost­
effectiveness standard. Value Health 2009;12:80­7.
5. Mark DB, Hlatky MA. Medical Economics and the Assessment of Value in Cardiovascular Medicine: Part I.
Circulation 2002;106:516­520.
6. Mortimer D, Segal L. Comparing the incomparable? A systematic review of competing techniques for converting
descriptive measures of health status into QALY­weights. Med Decis Making 2008;28:66­89.
7. Dolan P. Modeling valuations for EuroQol health states. Med Care 1997;35:1095­108.
8. Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ­5D health states: development and testing of the D1
valuation model. Med Care 2005;43:203­20.
9. Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost­Effectiveness in Health and Medicine. New York: Oxford
University Press;1996.
10. Cohen DJ, Lavelle TA, Van Hout B, et al. Economic outcomes of percutaneous coronary intervention with drug­
eluting stents versus bypass surgery for patients with left main or three­vessel coronary artery disease: One­year
results from the SYNTAX trial. Catheter Cardiovasc Interv 2011;May 3:[Epub ahead of print].
11. Cohen DJ, Bakhai A, Shi C. Cost­effectiveness of sirolimus­eluting stents for treatment of complex coronary
stenoses: results from the Sirolimus­Eluting Balloon Expandable Stent in the Treatment of Patients With De Novo
Native Coronary Artery Lesions (SIRIUS) trial. Circulation 2004;110:508­14.
12. Bardy GH, Lee KL, Mark DB, et.al. Amiodarone or an implantable cardioverter­defibrillator for congestive heart
failure. N Engl J Med 2005;352:225­37.
13. Mark DB, Nelson CL, Anstrom KJ, et.al. Cost­effectiveness of defibrillator therapy or amiodrarone in chonic stable
heart failure: results from the Sudden Cardiac Death in Heart Failure Trial (SCD­HeFT). Circulation 2006;114:135­
42.
14. Reynolds MR, Zimetbaum P, Josephson ME, Ellis E, Danilov T, Cohen DJ. Cost­effectiveness of radiofrequency
catheter ablation compared with antiarrhythmic drug therapy for paroxysmal atrial fibrillation. Circ Arrhythm
Electrophysiol 2009;2:362­9.
15. Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making
1993;13:322­38.
16. Briggs A, Sculpher M. An introduction to Markov modelling for economic evaluation. Pharmacoeconomics
1998;13:397­409.
Printable PDF

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1.4: Quality of Care: Measurement and Improvement
Author(s):
Larry Allen, MD, MHS, FACC
John Rumsfeld, MD, PhD, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Define quality of care and describe the major domains of high quality health care.
2. Explain the features of quality initiatives that are relevant to practicing clinicians, including delivery of evidence­based
medicine, public reporting and reimbursement based on quality metrics, and maintenance of certification and licensure.
3. Compare and contrast the tools of quality, including clinical data standards, clinical practice guidelines, quality metrics,
performance measures, and appropriate use criteria (AUC).
4. Describe the health care system features that are necessary to achieve high quality care, including measurement,
feedback, system changes, engaged clinicians, and administrative support.
Introduction

Clinicians may perceive the topic of "measuring and improving quality of care" as one that is largely under the purview of
administrators and health policy makers. Instead, clinicians should be highly motivated to understand how to measure
and improve quality of care for a variety of reasons, including:

Quality of care is "evidence­based medicine." Quality measurement and improvement initiatives help clinicians
to stay current with the best available evidence for therapeutics and care delivery, thereby supporting the practice
of evidence­based medicine.
Quality of care is central to lifelong learning, certification, and licensure. The maintenance of certifications, as
well as state licensure activities, are increasingly centered on quality measurement and improvement. This may
include the demonstration of practice improvement.
Quality of care is at the center of health care reform. Consumer groups, hospitals, health care systems, payers,
states, the Federal government, and other stakeholders are heavily focused on quality of care. There is a
particular focus on unexplained variation in care delivery. This variation is viewed as a marker of variation in
quality, as a major contributor to health care expenditures, and as a target for health care reform.
Quality of care is increasingly about accountability. Public reporting and performance­based reimbursement
are increasingly based on quality measures for both processes of care and outcomes of care.
Quality of care drives health care system improvement. Quality measurement and improvement initiatives
inform changes to the health care system at the practice, hospital, and national levels. This serves to optimize
health care delivery and thus the best care possible for patients.
Why Are There Concerns About Quality?

The rapid growth of health care spending in the United States has focused increased attention on the quality of care that
results from this large commitment of resources. Unfortunately, when the quality of health care in the United States is
measured, significant deficiencies are found. Moreover, there is a lack of correlation between higher expenditures and
higher quality of care.1

Poor quality results from a variety of deficiencies in any one of the properties of high­quality health care, including: unsafe
practices, use of ineffective therapies, application of the wrong therapy to the wrong patient, delayed delivery of care, use
of resource intensive care for marginal benefit, and differential health care delivery strictly based on age, gender, race, or
ethnicity. Deficits in the quality of health care are also framed as deriving from three types of shortcomings, each of which
may constitute a form of inefficiency.2

Overuse occurs when a service is provided that may not be necessary or may expose the patient to greater
potential harm than benefit (i.e., when it is not warranted on medical grounds).
Underuse occurs when a service with a favorable benefit­risk ratio is not provided.
Misuse includes incorrect diagnoses as well as medical errors and other sources of avoidable complications.

One of the most compelling arguments implicating the efficiency of health care in the United States derives from the
marked geographic variation in per capita health care spending, without obvious correlation to measures of health care
quality or patient outcomes. The current substantial growth in the performance of cardiovascular testing and procedures
has been characterized by increasing regional differences, as documented among Medicare beneficiaries in the
Dartmouth Atlas of Cardiovascular Health Care.3 Yet, those regional differences in use do not appear to translate to
significant differences in the performance of well­accepted standards of care or the health of those communities.4
Furthermore, the Institute of Medicine (IOM) and others have issued several reports documenting the extent of medical
errors and their consequences.5,6 Clinicians must recognize that their actions, both in terms of errors of omission (i.e.,
not doing things they should) and errors of commission (i.e., doing things they should not), are under increasing scrutiny.
What Is High Quality Health Care?

The goal of health care is to help people live longer and better lives. Therefore, the extent to which health care delivery
accomplishes this overall goal represents the quality of that care. The IOM report, Crossing the Quality Chasm: A New
Health System for the 21st Century, defines quality as: "the degree to which health care systems, services, and supplies
for individuals and populations increase the likelihood for desired health outcomes in a manner consistent with current
professional knowledge."7 The IOM further defined six domains of the highest quality health care, Health care should be:7

Safe: Avoiding harm to patients from the care that is intended to help them
Effective: Providing services based on scientific knowledge to all who could benefit and refraining from providing
services to those not likely to benefit (avoiding underuse and misuse, respectively)
Patient­Centered: Providing care that is respectful of and responsive to individual patient preferences, needs, and
values and ensuring that patient values guide all clinical decisions
Timely: Reducing waits and sometimes harmful delays for both those who receive care and those who give care
Efficient: Avoiding waste, including the waste of equipment, supplies, ideas, and energy
Equitable: Providing care that does not vary in quality because of personal characteristics such as gender,
ethnicity, geographic location, and socioeconomic status
How Should We Assess Quality?

The Donabedian model is frequently used to conceptualize quality assessment. It focuses on three domains: structure,
process, and outcomes.8

Structure refers to the resources available to provide care. This typically includes such domains as personnel,
equipment, facilities, laboratory systems, training, certification, and protocols.

Process refers to the way in which care is delivered. The ideal process is to do the "right thing for the right patient at the
right time." Processes refer to the actions performed in the delivery of patient care, including the timing and technical
competency of their delivery. Process of care measures often focus on patient selection and administration of therapies
(e.g., prescription of aspirin for patients with acute myocardial infarction).

Outcomes refer to the results of care. These are measures of the "end­results" of health care delivery. From the patient,
clinician, and societal perspectives, primary outcomes concepts are reflected in just two questions. The first question is
related to mortality versus survival: Did the care/therapy delivered help patients live longer? The second question is
related to morbidity versus quality of life: Did the care/therapy improve patient health status and/or make patients feel
better? For a variety of reasons, outcomes measures have focused largely on survival, which is objective and easy to
obtain, or on surrogate measures (e.g., blood pressure). However, there is a growing recognition of the importance of
patient­centered outcomes, including patient health status or quality­of­life measurements such as angina burden (e.g.,
Seattle Angina Questionnaire).

The Donabedian model proposes that each component has a direct influence on the next. In other words, the structural
attributes of the system in which care occurs (i.e., resources and administration) dictate processes of care (i.e., delivery
of therapeutics) which in turn affect the outcomes (i.e., goal achievement). Importantly, the patient is at the center, with the
ultimate goal of improving outcomes that are important to patients and their families.

It is also important to note that patients have different demographic and clinical profiles (e.g., comorbidities, severity of
disease). Thus, clinicians and hospitals care for different case­mixes of patients. As such, it is generally true that valid
measures of patient outcomes, especially for comparison among hospitals or other groups, must be risk­adjusted (i.e.,
case­mix adjusted).

What About Cost?

There is an increasing interest in assessing quality in relationship to resource use. Multiple studies have shown that
higher costs of care and higher resource utilization do not translate into higher quality of care.2 Therefore, many current
quality assessment and improvement efforts are focused on efficiency of care (i.e., cost per outcomes). A similar concept
is that of value, which is the measurement of patient health outcomes, including the patient experience with care,
achieved per dollar spent.9 It is the ratio that is critical. Costly interventions are not necessarily of low value, if they have
significant benefit. Conversely, cheap interventions are not necessarily of high value, if they have minimal or no benefit.

A Systems Problem, A Systems Solution

For most clinicians, day­to­day interest in quality would seem to focus on individual decisions as they relate to the delivery
of cardiovascular care to individual patients. However, quality improvement cannot rest upon individual clinicians being
asked to "do more" or "do better."10 Instead, quality should be considered largely on a system level. As such, quality
improvement is achieved through a systems approach that provides a supportive environment for the delivery of health
care. Continuous quality improvement is an organized, scientific process for evaluating, planning, improving, and
controlling quality. The following sections describe the pieces of continuous quality improvement, and how they fit
together to promote optimal care delivery both at the national and local levels.
The Tools of Quality Assessment
(1 of 2)

The success of achieving ideal quality in health care delivery requires that a "quality
infrastructure" be in place. This quality infrastructure consists of clinical evidence, Table 1
standardized definitions, clinical guidelines, performance measures and other
quality metrics, and AUC (Table 1). The goal of these tools is to promote the optimal
use of evidence­based medicine in care delivery, thereby maximizing efficiency by
promoting diagnostic and therapeutic strategies with the highest value to patients.

The Evidence

The determination of care quality is grounded in clinical evidence. Evidence­based Figure 1

medicine involves two fundamental principles.11 First, a hierarchy of evidence exists

from which to guide clinical decision making. While individual clinical observations
can generate important hypotheses, unsystematic clinical observations are limited
by sample size and deficiencies in the ability to make accurate causal inferences.
Thus, only systematic approaches to data collection and analysis are generally
considered as evidence to guide clinical decisions. These systematic approaches,
listed in increasing order of strength of evidence for informing clinical decision
making, include: physiological experiments, case series, cross­sectional studies,
case­control studies, retrospective observational cohorts, prospective observational
cohorts, and randomized clinical trials. Stronger study designs minimize bias and
improve power, leading to improved evidence to support clinical decision making.

It is important to note that this evidence hierarchy is not absolute. For example,
randomized clinical trials can suffer from studying only highly selected patients, and
thus may have limited generalizability. Similarly, observational studies must be
cautious of unmeasured factors that can confound the interpretation of attribution, yet
may give a broader assessment of care and outcomes in routine clinical practice.
Thus, a synthesis of all available evidence, such as in a systematic review and/or
evidence­based clinical practice guideline, may enhance the assessment of
benefits and risks of a given therapy. A systematic review will provide guidance for
care decisions above and beyond any single study.

The second fundamental principle is that evidence alone will never be sufficient to
make a clinical decision. Decision makers must always integrate and trade the
benefits, risks, inconveniences, and costs associated with alternate management
strategies. This should be done within the context of patient's goals, values, and
preferences.

Data Standards

Standardized sets of definitions, nomenclature, and data elements facilitate

accurate communication and fair comparison. They help avoid the "Tower of Babel"
syndrome with the inability to accurately compare clinical trials and other outcomes
assessments due to differing definitions of clinical status and adverse outcomes.
The American College of Cardiology (ACC), in association with the American Heart
Association (AHA), has implemented Clinical Data Standards, the lexicon needed to
achieve commonality and consistency in definitions in many areas of cardiovascular
disease.12 Standardized definitions allow accurate comparisons between multiple
relevant clinical trials as well as clinical outcomes collected through clinical registry
programs.13

Clinical Practice Guidelines

The creation of clinical guidelines is intended to summarize the body of evidence­

based medicine for a given disease process or clinical content area. Preferably
these guidelines are based upon multiple large, randomized controlled trials. When
substantial randomized clinical trial data are lacking, smaller clinical trials, carefully
performed observational analyses, or even "expert consensus" opinion is utilized as
the weight of evidence for a particular clinical guideline. Over the past 25 years, the
ACC and the AHA have published multiple cardiovascular clinical guidelines
covering many relevant areas of cardiology, with continued updating as clinical
advances dictate. These include acute myocardial infarction, unstable angina,
chronic stable angina, coronary revascularization, heart failure, supraventricular
arrhythmias, atrial fibrillation, implantation of pacemakers, and antiarrhythmia
devices.14 These practice guidelines are intended to assist health care providers in
clinical decision making through describing generally acceptable approaches for the
diagnosis, management, or prevention of disease states.15­17

Figure 1 provides a framework for evaluating various procedures and treatments.

The framework includes both levels of evidence and types of evidence.16

Levels of Evidence: Recommendations are given one of the following indication

classifications based on the evaluation of evidence by a panel of guidelines experts.

Class I: procedure or treatment should be performed or administered; the

benefit to risk ratio is favorable.
Class IIa: it is reasonable to perform the procedure or treatment; benefit to
risk ratio is probably favorable.
Class IIb: procedure of treatment may be considered; benefit to risk ratio is
unknown.
Class III: the procedure or treatment should not be performed; no benefit or
risk outweighs benefit.

Types of Evidence: The weight of evidence to support a given recommendation is

listed as A, B, or C. The highest level of evidence, A, implies data derived from
multiple randomized trials, while the lowest level of evidence, C, reflects the
consensus opinion of experts, case studies, or "standard of care."

Although we would like guidelines to be based on the highest level of evidence in

the hierarchy, multiple factors (e.g., the difficulty of conducting large randomized
trials) limit the extent to which the wide array of clinical decisions can be strongly
recommended. Of the 16 ACC/AHA clinical practice guidelines that report levels of
evidence in September 2008, only 11% of 2,711 recommendations were classified
as Level of Evidence A, whereas 46% were level C.17
The Toolkit of Quality Improvement
Table 1
Levels of Evidence for Clinical Practice Guidelines
Figure 1
Reproduced with permission from The Evidence­Based Medicine Working Group. User's Guide to the Medical Literature: A Manual for Evidence­
Based Clinical Practice. 2nd ed. Chicago: American Medical Association Press.
The Tools of Quality Assessment
(2 of 2)

Performance Measures

Performance, or care accountability, measures are those process, structure, efficiency, and outcome measures that have
been developed using ACC/AHA methodology. This includes the process of public comment and peer review, and the
specific designation as a performance measure by the ACC/AHA Task Force on Performance Measures.18,19 This may
occur in collaboration with other national practice organizations and federal agencies, such as the National Quality Forum
(NQF), Centers for Medicare and Medicaid Services (CMS), or the Joint Commission on Accreditation of Health Care
Organizations.

Performance measures must have a number of qualities that allow them to be used for both continuous quality
improvement as well as accountability and reimbursement, including: 1) face validity in routine practice; 2) practical
identification of those patients for whom a specific action should be taken (a clear denominator); 3) easy determination of
whether or not the measure has been performed (a clear numerator); 4) adherence to the measure results in meaningful
improvements in clinically meaningful outcomes; and 5) opportunities for timely feedback to clinicians and institutions to
promote continuous quality improvement.19

Process Performance Measures

Process performance measures are distilled from clinical guideline therapeutic recommendations, generally capturing
those Class I or Class III, Level of Evidence A recommendations for which the evidence is particularly strong. Process
performance measures describe discrete processes of care which are explicit diagnostic or therapeutic actions to be
performed or not performed (e.g., the provision of aspirin for acute myocardial infarction). The implication is that clinicians
are in error if they do not follow these care processes, or do not document specific reasons for disregarding these
recommendations.

Outcome Performance Measures

Outcome performance measures are being increasingly used as performance measures. Adding outcomes measures
to process measures has important benefits. For example, process measures, even when reported together, capture a
small fraction of the care delivered; in contrast, outcomes measures, such as mortality or health­related quality of life,
should integrate the totality of care that a patient receives.20 The government website, Hospital Compare, reports 30­day
risk­standardized mortality and rehospitalization rates for fee­for­service Medicare beneficiaries after hospitalization for
heart failure, acute myocardial infarction, or pneumonia.21 These statistics are used for reimbursement purposes.

Critiques of outcomes measures include, for example, that the methods for risk­standardization are not sufficiently fair to
account for important differences in case mix. Also, outcomes measures do not tell clinicians and institutions specifically
what they are doing correctly or incorrectly. Therefore, risk­standardized outcomes measures should be combined with
detailed measures of structure and process performance, thereby providing clinicians and institutions with audit and
feedback on their overall performance alongside data highlighting those areas in particular need of quality improvement
activities.

Composite Measures

Composite measures have been constructed and deployed to address the proliferation of performance measures and
the need to ensure that these measures comprehensively represent health care quality.22 Composite measures utilize
data reduction in order to simplify presentation and interpretation. They also promote scope expansion to better integrate
multiple metrics into a more comprehensive assessment of provider performance. However, these advantages come at
a cost. Standard psychometric properties of composites can be more complex to determine, methods for scoring (e.g.,
all­or­none vs. any vs. weighting) can lead to different conclusions, and problems with missing data can be amplified.

Quality Metrics

Quality metrics are those measures that have been developed to support self­assessment and quality improvement at
the provider, hospital, and/or health care system level.18 These metrics are often a major focus of clinical registry and
quality improvement programs.13 These metrics may not have been formally developed using the ACC/AHA performance
measure methodology. However, they may be identified as "preliminary," "candidate," "test," "evolving," or "quality"
measures, which indicates that they may be worthy of consideration for further development into performance measures.
Quality metrics may not meet all specifications of formal performance measures used in public reporting and
accountability, but can still represent valuable tools to aid clinicians and hospitals in improving quality of care and
enhancing patient outcomes.
Appropriate Use Criteria

AUC are intended to be a supplement to clinical practice guidelines and performance measures, and differ from them in
important ways. AUC identify common, prototypical patient subgroups for which expert clinicians, using available
evidence from the medical literature and clinical practice, assess the benefits and risks of a test or procedure on patient
outcomes. AUC are scored as follows: a score of 7­9 means appropriate, 4­6 means uncertain, and 1­3 means
inappropriate.23 Ideally, AUC define "what to do," "when to do," and "how often to do" a certain modality or procedure, with
consideration for local care environments and patient goals, preferences, and value. AUC should ideally be simple,
reliable, valid, and transparent. AUC offer a framework from which to examine the rationale of diagnostic and therapeutic
actions to support a more efficient use of medical resources. The primary goals of AUC are to identify overuse, and in so
doing improve the safety and cost­effectiveness of care.

The ACC, in partnership with relevant specialty and subspecialty societies, has been developing an increasing portfolio
of AUC in a variety of diagnostic modalities (e.g., cardiac computed tomography, cardiac magnetic resonance imaging,
cardiac radionuclide imaging, transthoracic and transesophageal echocardiography, stress echocardiography) as well
as procedural modalities (e.g., coronary revascularization).

Ideally, such AUC would arise from high­quality research evaluating the benefits and risks of performing imaging studies
for various common clinical scenarios. Additionally, a complete evaluation of appropriateness might also include a
comparison of the relative marginal cost and benefits of each imaging modality. Regrettably, there is currently insufficient
evidence to make such evaluations across a broad spectrum of potential clinical indications for diagnostic and
procedural decisions.
Quality Improvement

The tools of quality assessment fit into a comprehensive cycle of activities that work
to define, measure, and ultimately promote quality health care (Figure 2).24
Discoveries from basic science are translated into clinical diagnostics and Figure 2
therapies. These are then tested in clinical trials to determine efficacy and safety.
This evidence is then synthesized into clinical practice guidelines which are made
available for consumption. A select group of these guidelines are condensed into
performance measures, which are used for benchmarking, public reporting, and pay
for performance. Outcomes measures provide assessment of how well this
process is achieving its ultimate goals. Any of this information can be fed back into
the cycle to guide and refocus quality efforts at all steps. Figure 3

National Quality Improvement Registry Programs

The foundation of any quality improvement effort is measurement. Without

systematic assessment and evaluation, it is difficult to know the quality of various
care decisions. Participation in national clinical registries and quality improvement
programs, such as the National Cardiovascular Data Registry® (NCDR®), offers a
Figure 4
method for accurately assessing clinical outcomes and offers feedback on how
individual hospital and clinician practices compare with their peers. This is done
through benchmarking performance against aggregate national or similar hospital
outcomes following adjustment for case mix (Figure 3).13,25 Participation in these
feedback systems is known to be a critical element in quality improvement. The
feedback of process and outcomes data to clinicians pinpoints opportunities to
improve clinical performance and quality. For example, they can also be used to help Figure 5
state regulatory agencies oversee the quality of demonstration projects, such as
percutaneous coronary intervention (PCI) without onsite surgical backup. They also
offer opportunities for post­market device surveillance, particularly for low frequency
adverse events.

National Quality Initiatives

National quality initiatives can also be effective. One illustrative example is the Door­
To­Balloon Alliance. It is known that PCIs for acute myocardial infarction are
grounded in the principle of rapid reperfusion. There is strong evidence that a
shorter time from patient presentation (i.e., emergency room "door") to coronary
artery opening via angioplasty (i.e., "balloon" inflation in the catheterization
laboratory) is associated with better patient outcomes, particularly when these door­
to­balloon (D2B) times are less than 90 minutes.

However, despite D2B recommended quality measures being in place for years, as
of 2006 only 40% of hospitals were able to consistently perform primary PCI in less
than 90 minutes. A team of cardiovascular outcomes researchers evaluated
hospitals with best practices and identified the key processes of care that were
associated with shorter D2B times. Six of these strategies became the core
strategies of the D2B alliance. These are: having emergency medicine physicians
activate the catheterization laboratory, having a single call to a central page operator
activate the catheterization laboratory, having the emergency department activate the
catheterization laboratory while the patient is en route to the hospital, expecting staff
to arrive in the catheterization laboratory within 20 minutes after being paged, having
an attending cardiologist always on site, and having staff in the emergency
department and the catheterization laboratory use real­time data feedback.26

The ACC thereby supported the national D2B Alliance to promote participation by
hospitals, physician champions and strategic partners committed to addressing the
D2B challenge. Participating hospitals committed to implementing as many of the
six strategies as possible. The goal of the D2B Alliance was to achieve D2B times of
<90 minutes for at least 75% of non­transfer primary PCI patients with ST­segment
elevation myocardial infarction in all participating hospitals performing primary PCI.
This national initiative, guiding and supporting local implementation at more than
1,100 hospitals, led to a significant increase in adoption of the strategies, and there
were significant improvement in D2B times nationally, reaching the goal of the
initiative.27
National quality initiatives such as the D2B alliance can serve as an important way of
disseminating best practices, and thus bolstering quality of care. Not surprisingly,
these initiatives are often most successful if they are tied to national clinical registry
programs so that measurement and feedback of performance can be included. They
are also successful when they support the specific local quality improvement
activities of hospitals and practices.

Local Activities

Local quality improvement activities apply the principles as outlined above,

including: collection of relevant data, feedback regarding processes and outcomes
of care, and implementation of appropriate interventions to improve performance
and efficiency.

Lessons learned about successful quality improvement from the study of high and
low quality hospitals emphasize the following key points. Data must be perceived as
valid. Risk­adjustment and benchmarking improve the meaningfulness of data
feedback. Data feedback must persist in an iterative form to sustain improved
performance. Clinician champions and administrative support is critical to
successful performance improvement (Figure 4).10,25 Alignment of local activities
with national quality assessment and improvement programs (such as national
clinical registry programs) is also important, often providing a solid infrastructure for
quality measurement and improvement.

Local activities for quality improvement should be iterative, and involve breaking
down quality efforts into small pieces. Multiple small quality cycles should be
occurring in various domains of local health care delivery, involving multidisciplinary
members of the team. The quality initiatives should be supported by administration,
and aligned with external entities (i.e., regulatory agencies and national quality
improvement initiatives). For example, a hospital with a high risk­adjusted mortality
rate among its patients with acute myocardial infarction cannot set on a single
course of action to fix this problem. Instead, it is necessary to have an integrated
approach involving multiple smaller initiatives within the continuum of care. This
could include community education, emergency medical services, the emergency
department, the interventional catheterization laboratory, in­hospital care, transitional
services, and ambulatory follow up. Measurement within each level should target
areas for improvement.

At the individual and local level, the Institute for Health Care Improvement (IHI)
promotes the Model for Improvement, developed by Associates in Process
Improvement.28 The model organizes quality improvement into actionable parts.

1. Set Aims: These should be small goals that are targeted to a defined group
of patients. They should be time­specific and measureable.
2. Establish Measures: Pick a quantitative measure that can determine if a
specific change leads to an improvement in quality.
3. Select Changes: All improvement requires making changes, but not all
changes result in improvement. Clinicians and organizations must identify
the changes that they believe are most likely to result in improvement.
4. Test Changes: Once the first three fundamental questions have been
answered, the Plan­Do­Study­Act (PDSA) cycle should be used to test and
implement changes in real work settings. The PDSA cycle uses action­
oriented learning to determine if the change is an improvement. This is done
by planning it, trying it, observing the results, and acting on what is learned
(Figure 5).

Including the right people on a process improvement team is critical to a successful

improvement effort. Teams vary in size and composition, but typically involve
multidisciplinary representation.
The Cycle of Quality
Figure 2
A cycle of specific efforts is needed to create systematic approaches to translating knowledge across the continuum from discovery science to
public health intervention. The cycle begins with the discovery of fundamental biological, physical, and social constructs. Once a discovery is
made, it undergoes a development cycle including extensive preclinical applied research before it can be developed as a treatment with plausible
human benefit. Evidence is then gathered in human experiments, and assessments are made about the intervention’s value; these evaluations
continue after the treatment is clinically available. What is learned through the cycle is often fed back to refine the science of discovery. At the
clinicians level, measurement and education are central to completing the cycle.

Reproduced with permission from Califf RM, Harrington RA, Madre LK, Peterson ED, Roth D, Schulman KA. Curbing the cardiovascular disease
epidemic: aligning industry, government, payers, and academics. Health Aff (Millwood) 2007;26:62­74.
Example of a Quality Metrics Report From the NCDR® CathPCI Executive Summary
Figure 3
Reproduced with permission from Rumsfeld JS, Dehmer GJ, Brindis RG. The National Cardiovascular Data Registry ­­ Its Role in Benchmarking
and Improving Quality. US Cardiology 2009;Touch Briefings:11­15.
The Central Role of Data and Benchmarking in Quality Improvement
Figure 4
EMR = electronic medical record.

Adapted with permission from Rumsfeld JS, Dehmer GJ, Brindis RG. The National Cardiovascular Data Registry—Its Role in Benchmarking and
Improving Quality. US Cardiology 2009;6:11­5.
The Plan­Do­Study­Act (PDSA) Model for Improvement
Figure 5
Reproduced with permission from Langley GJ, Nolan KM, Norman CL, Provost LP, Nolan TW. The Improvement Guide: A Practical Approach to
Enhancing Organizational Performance. New York: Jossey­Bass; 1996.
Conclusion

For clinicians who want to deliver the best possible care, be graded and reimbursed appropriately, and maintain
certification and licensure, understanding quality and being engaged in quality measurement and improvement must
become central to clinical practice. Feedback of process and outcomes are critical elements leading to quality
improvement. If you do not measure it, you will not improve it.
Key Points

Health care quality is highly relevant to patients, clinicians, and society.

The highest quality health care is that which is effective, safe, timely, efficient, equitable and patient centered.
The major domains of quality assessment are structure, process, and outcomes (Donabedian’s triad).
Key tools for defining and measuring quality of care include: evidence, data standards, clinical practice guidelines,
quality metrics, performance measures, and appropriateness criteria.
Quality improvement requires accurate data collection, risk­adjustment and benchmarking to make performance
measurement meaningful, persistent and iterative cycles of quality improvement, clinician champions, and a
supportive organizational context.
National clinical registry programs such as the NCDR® utilize data standards, standardized tools for data
collection, risk­adjustment, and benchmarking.
References

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content, quality, and accessibility of care. Ann Intern Med 2003;138:273­87.
2. Orszag PR. The Overuse, Underuse, and Misuse of Health Care: Testimony before the Committee on Finance,
United States Senate, July 17, 2008. Congressional Budget Office, Washington, DC; 2008.
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Academy Press; 2000.
6. Leape LL. Reporting of adverse events. N Engl J Med 2002;347:1633­8.
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System for the 21st Century. Washington DC: National Academy Press; 2001.
8. Donabedian A. Explorations in Quality Assessment and Monitoring, Volume 1. The Definition of Quality and
Approaches to its Assessment. Ann Arbor, MI: Health Administration Press; 1980.
9. Porter ME. What is value in health care? N Engl J Med 2010;363:2477­81.
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11. Guyatt G, Rennie D, Meade MO, Cook DJ. User’s Guide to the Medical Literature: A Manual for Evidence­Based
Clinical Practice. 2nd ed. New York: McGraw­Hill Professional; 2008.
12. Cannon CP, Battler A, Brindis RG, et al. American College of Cardiology key data elements and definitions for
measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the
American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing
Committee). J Am Coll Cardiol 2001;38:2114­30.
13. Bufalino VJ, Masoudi FA, Stranne SK, et al. The American Heart Association's recommendations for expanding the
applications of existing and future clinical registries: a policy statement from the American Heart Association.
Circulation 2011;123:2167­79.
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http://www.cardiosource.org/science­and­quality/practice­guidelines­and­quality­standards.aspx. Accessed
11/30/2011.
15. Gibbons RJ, Smith S, Antman E. American College of Cardiology/American Heart Association clinical practice
guidelines: Part I: where do they come from? Circulation 2003;107:2979­86.
16. Gibbons RJ, Smith SC Jr, Antman E. American College of Cardiology/American Heart Association clinical practice
guidelines: Part II: evolutionary changes in a continuous quality improvement project. Circulation 2003;107:3101­
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17. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice
guidelines. JAMA 2009;301:831­41.
18. Bonow RO, Masoudi FA, Rumsfeld JS, et al. ACC/AHA classification of care metrics: performance measures and
quality metrics: a report of the American College of Cardiology/American Heart Association Task Force on
Performance Measures. Circulation 2008;118:2662­6.
19. Spertus JA, Eagle KA, Krumholz HM, Mitchell KR, Normand SL. American College of Cardiology and American
Heart Association methodology for the selection and creation of performance measures for quantifying the quality
of cardiovascular care. Circulation 2005;111:1703­12.
20. Krumholz HM, Normand SL, Spertus JA, Shahian DM, Bradley EH. Measuring performance for treating heart
attacks and heart failure: the case for outcomes measurement. Health Aff (Millwood) 2007;26:75­85.
21. US Department of Health and Human Services. Hospital Compare. 2011. Available at:
www.hospitalcompare.hhs.gov. Accessed 11/30/2011.
22. Peterson ED, Delong ER, Masoudi FA, et al. ACCF/AHA 2010 Position Statement on Composite Measures for
Healthcare Performance Assessment: a report of the American College of Cardiology Foundation/American Heart
Association Task Force on Performance Measures (Writing Committee to Develop a Position Statement on
Composite Measures). J Am Coll Cardiol 2010;55:1755­66.
23. Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness Criteria for
Coronary Revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria
Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American
Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology
Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of
Cardiovascular Computed Tomography. J Am Coll Cardiol 2009;53:530­53.
24. Califf RM, Harrington RA, Madre LK, Peterson ED, Roth D, Schulman KA. Curbing the cardiovascular disease
epidemic: aligning industry, government, payers, and academics. Health Aff (Millwood) 2007;26:62­74.
25. Brindis RG, Dehmer GJ, Rumsfeld JS. The National Cardiovascular Data Registry ­­ Its Role in Benchmarking
and Improving Quality. US Cardiology. 2009;www.touchcardiology.com:11­15.
26. Bradley EH, Herrin J, Wang Y, et al. Strategies for reducing the door­to­balloon time in acute myocardial infarction.
N Engl J Med 2006;355:2308­20.
27. Bradley EH, Nallamothu BK, Herrin J, et al. National efforts to improve door­to­balloon time results from the Door­
to­Balloon Alliance. J Am Coll Cardiol 2009;54:2423­9.
28. Langley GJ, Nolan KM, Norman CL, Provost LP, Nolan TW. The Improvement Guide: A Practical Approach to
Enhancing Organizational Performance. New York: Jossey­Bass; 1996.
Printable PDF

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1.5: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics
Author(s):
David E. Lanfear, MD, FACC
James Kalus, PharmD

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Demonstrate understanding and knowledge of pharmacokinetic drug interactions for common cardiovascular drugs.
2. Describe how principles of pharmacokinetics and pharmacodynamics can influence rational drug prescribing.
3. Define pharmacokinetics and pharmacodynamics as characteristics of medical therapeutics.
4. State principles of pharmacogenetics in cardiovascular drug therapy, and cite relevant examples.
Introduction

The ultimate effect a medication has on the body is the complex summation of how it
enters, affects, and leaves the body, and these can all vary substantially from one
person to another depending on a wide variety of factors. This body­drug interaction Figure 1
can be broken down for better understanding into pharmacokinetics (drug
processing) and pharmacodynamics (drug effects), as illustrated in Figure 1,
and each of these broad areas can in turn be affected by an individual’s genetic
makeup leading to pharmacogenetics (Figure 2). In this module, the authors attempt
to breakdown and simplify each focus for better understanding, and then reunite
them as is best for practical application, using a case example.
Figure 2
Schematic of a Drug Pathway Depicting Transport, Targeting, and Metabolism
Figure 1
Schematic of Background Genetic Variation and Altered Medication­Related Outcomes
Figure 2
Pharmacokinetics

The term “pharmacokinetics” refers to the action the body takes on a medication.
When a medication is ingested or administered, the medication is absorbed,
distributed, metabolized, and eliminated. Key pharmacokinetic parameters exist for Table 1
all four of these actions. Knowledge of general pharmacokinetic principles can be
helpful in understanding the likelihood of adverse effects of a medication, avoiding
drug interactions, predicting likely onset or duration of action, or understanding the
influence of organ dysfunction on the use of a medication.

Absorption

A medication can be absorbed from the gastrointestinal (GI) tract, through the oral
mucosa (e.g., sublingual nitroglycerin), through the skin (e.g., transdermal
clonidine), or subcutaneously (e.g., enoxaparin). Absorption is not relevant in the
setting of intravenous (IV) administration because the drug is administered directly
into the bloodstream. Medications that are available as immediate­release dosage
forms begin to be absorbed upon ingestion.

Some medications are available in formulations that allow for slower release of the
medication (i.e., extended­release, sustained­release, delayed­release). After
ingestion, these drugs are slowly made available for absorption, which allows for
less frequent dosing. For example, nifedipine is available both as an extended­
release and as an immediate­release formulation, with sharp clinical differences
between them. The extended­release formulation can be given once daily, whereas
the immediate­release formulation must be administered three times daily and can
cause rapid hemodynamic changes, which may contribute to adverse cardiac
events.

Absorption of a drug may also be affected by a variety of factors including the

presence or absence of food, co­administration with other medications (e.g.,
antacids) that may bind with the medication, or GI tract abnormalities. When a
transdermal patch is used, absorption can be altered if the patch has been cut, or by
changes in cutaneous blood flow (e.g., a high dose of vasopressors causing
reduced cutaneous perfusion).1

The amount of drug available after absorption by a non­IV route, divided by the
amount of drug available after IV administration is referred to as "bioavailability." All
medications have an inherent bioavailability related to efficiency of absorption and
other factors. For example, the bioavailability of oral amiodarone is approximately
50% because one­half as much drug is available after oral administration, as
compared to IV administration.

P­glycoprotein (P­gp) also often plays a role in determining bioavailability. P­gp is an

adenosine triphosphate (ATP)­dependent drug transporter that can efflux certain
drugs back into the GI tract or kidney after absorption, thereby decreasing
absorption. Co­administration of a medication with an inhibitor of P­gp may thus
increase bioavailability of the medication. Since P­gp affects or is effected by many
medications, it is important to note which drugs are P­gp inhibitors and substrates
in order to anticipate these interactions. For example, a clinically relevant P­gp
interaction occurs when digoxin and amiodarone are co­administered. P­gp efflux of
digoxin into the GI tract is inhibited by amiodarone, leading to a doubling of the
digoxin concentration. Therefore, digoxin dose should be decreased by one­half
when initiating amiodarone.

Other important inhibitors of P­gp are quinidine, verapamil, cyclosporine, tacrolimus,

and many of the protease inhibitors.2 It should also be noted that P­gp induction can
also occur, although less commonly. One example of a drug interaction that occurs
due to P­gp induction is the clinically significant interaction between rifampin (a P­gp
inducer) and the new oral anticoagulant, dabigatran, whose bioavailability may be
compromised by this.

Another factor that may impact bioavailability is whether or not the drug undergoes
"first­pass" metabolism by the liver. First­pass metabolism refers to rapid
metabolism that occurs after absorption, but before the drug has reached the
systemic circulation where it will have its effects. A drug that undergoes extensive
first­pass metabolism will have relatively lower oral bioavailability than otherwise
expected.

Distribution

All medications have an apparent volume of distribution (Vd), a calculated value that
relates dose of drug (e.g., millograms) to the concentration achieved in the blood
(e.g., millograms per deciliter). Typically, Vd is expressed as a volume (liter) or
volume/body weight (liter per kilogram). For medications where specific drug levels
are targeted, knowledge of the typical volume of distribution of a drug can be useful
in estimating the concentration that will be achieved with a given dose of the drug.

Vd can also assist the clinician in understanding the extent of distribution. For
example, amiodarone has one of the largest volumes of distribution of any
cardiovascular agent (approximately 50 L/kg). This is notable because amiodarone
is well known to cause extracardiac adverse effects, and appears to distribute to a
variety of tissues. A newer agent, dronedarone, has pharmacologic properties
similar to those of amiodarone, yet has fewer extracardiac toxicities and a much
smaller volume of distribution (approximately 15 L/kg).

In an individual patient, Vd can differ from population estimates due to numerous

factors including age, body habitus, disease states, nutritional status, pregnancy,
and critical illness. For example, selection of the appropriate bolus dose of lidocaine
is based on Vd and can be affected by these factors. Typical loading doses are 1­1.5
mg/kg. The 1 mg/kg dose is often used in the elderly or in patients with heart failure
because these patients have a lower volume of distribution than younger patients or
those with normal ventricular function. Therefore, a lower dose will be required to
achieve an appropriate lidocaine level.

Protein binding may also influence Vd, because an increase or decrease in binding
of drug to blood proteins can lead to a corresponding alteration in calculated Vd. For
example, digoxin loading doses should generally be reduced in patients with severe
renal dysfunction (creatinine clearance <20 ml/min) because reduced protein
binding in this setting results in a lower Vd and, thus, a smaller initial dose
requirement.3

Metabolism

Drug metabolism occurs primarily through the liver via Phase I (oxidation, hydrolysis,
reduction) and Phase II (conjugation) reactions. Phase I reactions include those
mediated by the cytochrome P450 (CYP) enzyme system, which is particularly
important in drug metabolism, estimated to act on over 90% of all medications.4
Often CYP system actions lead to formation of inactive/less active metabolites,
although it can also activate some medications. Regardless, CYP­mediated drug
metabolism leads to many drug interactions via changes in rate of activation or
inactivation.

The most common CYP enzyme involved with drug interactions is CYP 3A4.
Numerous cardiac medications are either inhibitors or substrates of CYP 3A4,
including amiodarone, simvastatin, and several calcium channel blockers. When co­
administered, these medications can reduce the inactivation of the other and, thus,
increase medication exposure, resulting in toxicities.

Table 1 summarizes important CYP 450 enzyme system substrates and inhibitors.
As mentioned previously, CYP enzymes also play an important role in activating
certain medications, referred to as prodrugs. For example, CYP 2C19 is a key
enzyme in the conversion of clopidogrel (which is an inactive prodrug in its native
state) into its active metabolite, which actually causes platelet inhibition.

Recently, much attention has been given to a potential drug interaction between
omeprazole and clopidogrel. The mechanism of this drug interaction is inhibition of
CYP 2C19 by omeprazole, which results in reduced conversion of clopidogrel to its
active metabolite, thus reducing clopidogrel effectiveness; however, the clinical
significance of this interaction continues to be debated.5

Medications can also be CYP 450 enzyme inducers. Important CYP enzyme
inducers are rifampin (2C9, 3A4), carbamazepine (3A4), tobacco (1A2), phenytoin
(3A4), and phenobarbital (3A4). When a CYP 450 enzyme substrate is administered
with an inducer of the same enzyme system, there is potential for increased
metabolism of the target drug and, therefore, potential reduction in drug
concentrations.

Elimination

Elimination refers to how the medication actually exits the body. A few important
pharmacokinetic parameters are relevant to drug elimination. The first is "half­life,"
which is the amount of time required for the concentration of drug to be reduced by
one­half. When discontinuing a medication, it generally takes 4­5 half­lives for the
drug to be completely removed from the body. Conversely, when initiating a drug, 4­5
half­lives will also be required to achieve steady state concentrations.

"Steady state" is the point at which drug administration is equal to drug elimination.3
All medications are either eliminated from the body unchanged, or if acted upon by
drug metabolizing enzymes (as described earlier), they are converted to active or
inactive metabolites and subsequently eliminated.

The majority of medication/metabolite elimination occurs through renal

mechanisms. Patients with renal dysfunction have reduced renal clearance of drugs
and are often at greater risk of toxicity of agents that depend on this route. For
example, digoxin is eliminated via renal mechanisms, and the frequency of dosing
decreases from daily to every other day in severe renal dysfunction. Most often renal
elimination occurs via filtration at the glomerulus, although some medications are
secreted into the renal tubules. Both mechanisms can mediate alterations of drug
clearance and drug interactions. For example, dofetilide is secreted in renal tubules
and, thus, may interact with agents that block tubular secretion (e.g., cimetidine,
trimethoprim, and ketoconazole), resulting in higher dofetilide levels.
Selected Substrates and Inhibitors of the CYP 450 System
Table 1

*Produces active form of agent from prodrug.

CYP = cytochrome; HMG­CoA = hydroxy­methyl­glutaryl coenzyme A.

Reproduced with permission from R, DR G, ML R, PH V. Digoxin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics: Principles
of Therapeutic Drug Monitoring. Vancouver, WA: Applied Therapeutics, Inc.; 1992.
Pharmacodynamics

The term "pharmacodynamics" refers to the action the drug takes on the body, or the biologic response that is elicited by
the drug. Medications are generally thought to interact with a particular target in the body, and this interaction alters the
function of the target, thus producing the medication's effects. The drug target can be a wide variety of macromolecules in
the body, such as neurohormonal signaling receptors (e.g., adrenergic receptors), enzymes (e.g., HMG­CoA reductase,
vitamin K 2,3­epoxide reductase), ion channels (e.g., calcium channels), and many others in which the medication
directly or indirectly alters the function of a biologically active substance.

The pharmacodynamic effects of a drug could refer to both the desired therapeutic effects, as well as the toxic effects. The
term "therapeutic index" refers to the difference between the minimal therapeutic threshold and the minimal toxic
threshold. Some medications have a narrow therapeutic index, meaning there is little difference between doses that
produce efficacy and doses that produce toxicity in a given patient. However, most drugs have a broader therapeutic
index, where doses much higher than usual therapeutic doses must be given to cause toxicity. Often, drug levels of
medications with a narrow therapeutic index can be monitored in order to avoid toxicity (e.g., digoxin, procainamide,
lidocaine).

When a medication elicits a response by interacting with the drug target, there is often a dose­response pattern which
can take different forms. Most medications exhibit a linear dose­response relationship through their therapeutic range,
where the pharmacologic effect increases proportionately with number/proportion of occupied targets. Nonlinear dose­
response relationships occur as well, but are less common at typical doses of most medications.

Medications that stimulate a signaling receptor, such as the beta­adrenergic receptor, are called "agonists" (e.g.,
epinephrine), whereas medications that block the action of a receptor are called "antagonists" (e.g., metoprolol).
Antagonists can be either competitive or noncompetitive. Competitive antagonists take the place of a naturally occurring
ligand to block activity, whereas noncompetive antagonists bind elsewhere and, thus, are less affected by the
concentration of the usual ligand. Agents that affect the adrenergic system or those that interact with neurotransmitters
(e.g., opioids) are good examples of this type of mechanism.

Many cardiovascular drugs produce their pharmacodynamic effect by inhibiting the action of cardiac ion channels.
Calcium channel blockers inhibit the influx of calcium into the cardiac pacemaker cells, which can limit the inotropic and
chronotropic activity of the heart. Vaughan Williams class I antiarrhythmic drugs typically inhibit influx of sodium through
sodium channels, whereas class III antiarrhythmics inhibit efflux of potassium through potassium channels. A notable
pharmacodynamic effect of the class III antiarrhythmic drugs is prolongation of the QT interval. Concomitant use of more
than one medication that prolongs the QT interval could result in a pharmacodynamic drug interaction, increasing the
patient's risk for developing torsade de pointes.

Enzyme inhibition is another important target of many medications. The hydroxy­methyl­glutaryl coenzyme A (HMG­CoA)
reductase inhibitors are an important example of a cardiovascular medication class that produces a pharmacodynamic
response through enzyme inhibition. HMG­CoA reductase inhibitors block the enzyme responsible for the final step of
cholesterol formation, leading to reductions in intracellular cholesterol levels in the liver, which then cause enhanced
reuptake of low­density lipoprotein (LDL) particles from plasma to liver, thus lowering plasma LDL levels.

Another example is vitamin K 2,3­epoxide reductase (VKORC1), which is the target of warfarin. Warfarin inhibits VKORC1
from reducing vitamin K and, thus, impairs production of vitamin K­dependent clotting factors.

Drugs may also bind to other types of proteins and enhance or impair their physiologic processes. Heparin is a good
example of this. Antithrombin is a protein that can inactivate activated thrombin, serving a counter­regulatory function in
the coagulation cascade. Heparin enhances antithrombin's action, producing an antithrombotic effect due to greater
inactivation of thrombin. On the other hand, bivalirudin is a direct thrombin inhibitor; it binds to thrombin and prevents
thrombin from converting fibrinogen to fibrin, resulting in the antithrombotic effect.

An understanding of pharmacodynamics can be important in drug selection. When selecting a positive inotropic therapy
for the treatment of end­stage systolic heart failure, two available options are milrinone or dobutamine. Milrinone and
dobutamine both produce increases in intracellular calcium concentrations, increased heart rate, and increased
contractility; however, the mechanism by which they achieve this effect is quite different. Dobutamine acts as an agonist
for the beta­1 receptors on the myocardium, increasing cyclic adenosine monophosphate (cAMP) intracellularly, and
subsequently increasing calcium influx. Milrinone achieves this action by inhibiting the breakdown of cAMP, bypassing the
beta­receptors, yet still increasing cAMP and calcium concentrations.

Considering this, in patients requiring inotropic support who have recently taken or are planned for future beta­adrenergic
blocking agents, milrinone may be a more sensible choice. Similarly, one might expect milrinone and dobutamine to
have synergistic effects (and toxicities) when co­administered because they are both enhancing the same pathway, but at
different steps.
An understanding of the interplay between pharmacokinetics with pharmacodynamics is also important in practice.
Aspirin irreversibly inhibits the action of cyclooxygenase (COX) enzyme in the platelets, leading to prevention of platelet
activation. While the pharmacodynamic effect of most drugs will not be present 4­5 half­lives after discontinuation, the
pharmacodynamic effect of aspirin persists long after 4­5 half­lives have passed (approximately 12­24 hours for aspirin).
This is because the irreversible inhibition of the COX enzyme in platelets renders those platelets permanently inactive.
Therefore, the antiplatelet effect of aspirin does not resolve until new functional platelets have been generated, which
generally takes approximately 1 week.
Pharmacogenetics

Pharmacogenetics is the area of research and medicine that is concerned with

understanding how genetic variation impacts drug response. While still largely a
research field, it now has burgeoning clinical applications. Important relationships Figure 1
between genetic variation and drug effect have been observed for a growing number
of commonly used drugs,6 and ongoing studies should continue to increase the
relevance of pharmacogenetics to clinical practice. There are commercially available
pharmacogenetic diagnostic tests and a handful of examples with published
guidelines for genetically­guided therapy, some of which are relevant to the
cardiovascular system (e.g., warfarin). Thus, it is worthwhile to understand this topic
conceptually as well as in practical terms. Figure 2

While the average population response for most approved medications is favorable,
it is clear that significant interindividual variation exists in the response to most
therapeutics. Genetic variants exist throughout the genome, and many such variants
reside in genes related to medication response (e.g., drug receptors, drug
metabolizing enzymes) and have known functional consequences.

Inherited differences in medication response were recognized as early as the Table 2

1950s, then focused mainly on drug metabolism.8,9 Since then, as our

understanding of pharmacokinetics and dynamics has deepened, many points of
genetic influence throughout a drug pathway have come into better focus (Figure 1).
This includes variants that impact absorption, distribution, excretion, binding to drug
targets, and even downstream effect mediators.6

The genetic sequence variants of potential interest come in many forms, with single
nucleotide polymorphisms (SNP) being the most common. There are likely at least
30 million SNPs in the human genome, each of which represents a change of one
base­pair to another at a given location in the DNA sequence. This may or may not
result in a change in function or amount of the resulting transcript and thus protein,
depending on the nucleotide change and location.

SNPs in protein­coding regions can either be synonymous (resulting in no amino

acid change) or nonsynonymous, which results in an amino acid alteration, and may
impact protein function directly. They can also occur in regulatory sequences such
as promoter regions, which despite being noncoding, can impact gene expression.
Even more often, SNPs are located in other areas with less certain functional
impacts, such as introns or intergenic regions, though functional impact cannot be
ruled out based on location alone.

Other types of sequence variants that are less common also occur. These include
repeats (short or long sequences that occur a variable number of times), and
insertion/deletion polymorphisms (one or more base pairs which are either present
or absent). Similar principles regarding location and impact apply to these variants
as well (e.g., variants are more likely to have a functional impact if they are within a
gene vs. intergenic region). More recently, larger­scale genetic variation has been
recognized, which can also impact gene function, for example, copy number variants
(i.e., entire gene or larger segments that are duplicated).

As science has learned more about the interplay of drugs and genes, genetic
sequence variants have helped to explain more of the variation in response between
patients; in specific examples, this has ranged widely, and as high as 95%. The
ultimate goal of pharmacogenetics (both in terms of research and as a clinical tool)
is to leverage this knowledge to help physicians provide more rational, efficient, and
targeted treatments to their patients (Figure 2).7

On the other hand, due to the fact that one may not always have a perfect
understanding of a drug pathway, and with the emergence of high­throughput
genotyping technology, genome­wide approaches are now also being used in
research, giving birth to "pharmacogenomics." As discussed in the previous
sections on pharmacokinetics and dynamics, many nongenetic factors (e.g., age,
organ function, drug interactions) influence medication response; thus, it is
important to view pharmacogenetic factors within this larger framework,
supplementing (not supplanting) other more conventional predictors. In this way,
pharmacogenetic knowledge will often supplement and interact with one's
knowledge about pharmacokinetics and dynamics.

Initial applications of pharmacogenetics were limited to medications with very

narrow therapeutic indices. A classic example of pharmacogenetics being used
clinically is azathioprine and the gene thiopurine methyl transferase (TPMT).
Azathioprine is used as an immunosuppressive agent in heart transplantation, as
well as a treatment in some types of cancer. TPMT is responsible for inactivation of
azathioprine (actually metabolizing the active metabolite 6­mercaptopurine into an
inactive product).

Sequence variants in TPMT can disable this enzyme, thus exposing the patient to
higher than anticipated levels of the active metabolites and causing toxicity, typically
bone marrow suppression. This example also illustrates how a pharmacogenetic
interaction operates via alteration of pharmacodynamic or pharmacokinetic factors.
The pharmacogenetic impact of TPMT variants would be difficult to appreciate
without understanding the pharmacokinetics of azathioprine, and furthermore, it
suggests the solution­reduced doses of azathioprine in subjects with the alternative
alleles.

Advances in pharmacogenetics are now showing promise for a broader range of

medications, including cardiovascular medications. A well­developed example of
pharmacogenetics relevant to cardiovascular disease is warfarin. Warfarin acts by
binding to the vitamin K 2,3­epoxide reductase complex (VKORC1), the enzyme
responsible reducing vitamin K into its active form, and genetic variants in this drug
target cause resistance to warfarin effects, requiring higher dosing. Warfarin is
primarily metabolized by CYP 2C9 (CYP2C9), and genetic variants in this enzyme
result in reduced enzyme function and, thus, greater warfarin exposure. Genetic
polymorphisms in VKORC1 and CYP2C9 account for roughly 40% of variation in
warfarin dose.

Many other cardiovascular drugs have been studied and have significant
pharmacogenetic interactions, but have yet to become clinically applicable.
Examples include beta­adrenergic antagonists and adrenergic­receptor gene
variants, HMG­CoA reductase inhibitors and the risk of myopathy, and clopidogrel
effectiveness with CYP2C19 polymorphisms. These and other examples are
summarized in Table 2.
Schematic of a Drug Pathway Depicting Transport, Targeting, and Metabolism
Figure 1
Schematic of Background Genetic Variation and Altered Medication­Related Outcomes
Figure 2
Summary of Key Cardiovascular Pharmacogenetic Interactions
Table 2
ADRB1 = beta 1 adrenergic receptor gene; LVEF = left ventricular ejection fraction; I/D = insertion/deletion; ADRA2C = adrenergic receptor, alpha
2c; ACE = angiotensin­converting enzyme gene; GRK5 = G­protein coupled receptor kinase 5 gene; AA = African American; HF = heart failure;
INR = international normalized ratio; LVH= left ventricular hypertrophy; BP = blood pressure; CYP2C9 = cytochrome P450, family 2, subfamily C,
polypeptide 9; EF = ejection fraction; EDV = end­diastolic volume; ESV = end­systolic volume.
Principles Applied in a Case Discussion

Pharmacokinetics, pharmacodynamics, and pharmacogenetics can impact medication effects, explain drug interactions,
or suggest modifications of dosing. These principles do not act in isolation, but rather clinical application of each is
critically dependent on appreciating the others as well. Thus, understanding the interplay of principles is important to
optimizing clinical care. The following case discussion is presented to provide an illustrative example of applying these
principles together in a case­based setting:

Case Study

A 50­year­old man with a history of hypertension, systolic heart failure, and hyperlipidemia presents to the emergency
department with palpitations and shortness of breath which started today, and he is found to be in atrial fibrillation. Home
medications include hydroclorothiazide 25 mg daily, metoprolol XL 100 mg daily, aspirin 81 mg daily, digoxin 0.25 mg
daily (last digoxin level = 1.5),and simvastatin 40 mg daily. He is admitted, cardioverted, and warfarin is initiated.

Discussion

Warfarin is a good example of pharmacogenetic interactions operating via both pharmacodynamic and pharmacokinetic
aspects of the drug. Recommended algorithms for determining initial warfarin dosing based on genotype have been
published, commercial testing is available for genotype, pharmacogenetic dosing is routinely used at some institutions,
and it has been associated in multiple studies with more rapidly and more often achieving therapeutic international
normalized ratio (INR).

CYP2C9 variant alleles (so­called *2 or *3) are associated with reduced enzyme activity, resulting in delayed clearance of
warfarin and, thus, lower dose requirements (i.e., a genetic­ pharmacokinetic effect). On the other hand, VKORC1
variants are associated with increased activity or resistance to warfarin's effects, thus requiring greater warfarin dose to
achieve a similar effect as compared to a patient with wild type VKORC1 (i.e., a genetic­pharmacodynamic interaction).

Testing for genotype can help generate a more accurate initial estimate of stable warfarin dosing. Routine testing for this
or other variants to help determine initial warfarin dosing is used at some centers, but remains controversial and is the
subject of an ongoing National Institutes of Healthmulticenter trial. Pharmacogenetic warfarin dosing is most often
currently utilized in patients who are planned in advance for impending warfarin initiation (e.g., joint replacement patients)
because of the current turnaround time in genotype testing (several days). In the near future, more rapid testing will be
available, which will allow pharmacogenetic dosing to be utilized in a wider variety of patients and indications.

Case Study (continued)

The man is subsequently discharged in sinus rhythm on the same medicines. He is asymptomatic at rest. Three weeks
later, he presents again to the emergency department in atrial fibrillation with rapid ventricular response. He is admitted
and undergoes repeat cardioversion, and initiation of amiodarone to attempt maintenance of sinus rhythm.

Discussion (continued)

Several pharmacokinetic drug interactions should be considered when adding amiodarone in this situation. Amiodarone
inhibits metabolism of warfarin by CYP2C9. This patient is currently on a stable dose of warfarin, and addition of
amiodarone would likely increase the INR unless the warfarin dose is reduced. Typically, warfarin dose is reduced by 30­
50% when initiating amiodarone.

Another concern is the use of simvastatin with amiodarone. Simvastatin doses >10 mg are contraindicated in
combination with amiodarone due to increased risk of myopathy from simvastatin.10 In this case, the interaction is due to
amiodarone inhibition of CYP 450 3A4 metabolism of simvastatin, leading to increased simvastatin concentrations.
Interestingly, there are also genetic variants that appear to predispose to statin­induced myopathy. In the case of
simvastatin, fairly strong evidence points to a polymorphism in the gene SLCOB1, which is associated with 20% lifetime
risk of myopathy in patients treated with simvastatin.

Finally, there is an interaction between amiodarone and digoxin. Amiodarone is an inhibitor of P­gp, and digoxin is a
substrate of P­gp. Therefore, addition of amiodarone to digoxin without adjustment would likely lead to a doubling of the
patient's digoxin level, with significant risk of toxic symptoms.

Case Study (continued)

The patient improves and is discharged on amiodarone. He follows up 6 months later, reports no further episodes of
palpations, and is in sinus rhythm. However, he has developed skin discoloration and photosensitivity, and you
discontinue amiodarone. You consult the electrophysiology service who considered dofetilide as an alternative rhythm
control strategy.
Case Discussion

The most important issue regarding the initiation of dofetilide in this patient is the current use of hydroclorothiazide.
Hydrochlorothiazide is contraindicated for use with dofetilide due to the potential for hydrochlorothiazide to increase
dofetilide levels through reduced renal secretion, as well as the potential for hydroclorothiazide to reduce potassium
levels predisposing to proarrhythmia. Hydrochlorothiazide would, therefore, need to be discontinued prior to initiation of
dofetilide.
Key Points

Pharmacokinetics refers to all aspects of drug absorption, transport, and metabolism, which can greatly impact
optimal dosing and drug interactions.
CYP P450 enzymes in the liver metabolize a large proportion of medications and are a very common reason for
cardiovascular drug interactions.
The actions of a medication in the body are known as pharmacodynamic effects, and knowledge of these can aid
in avoiding toxicities and anticipating pharmacodynamic drug interactions.
Pharmacogenetics seeks to use knowledge of genetic variation and how it affects drug response to better target
medications.
Current clinically relevant examples of pharmacogenetic impacts on cardiovascular medication use include
warfarin, while emerging applications include simvastatin, clopidogrel, and beta­blockers.
References

1. Dorffler­Melly J, de Jonge E, Pont AC, et al. Bioavailability of subcutaneous low­molecular­weight heparin to patients on
vasopressors. Lancet 2002;359:849­50.
2. Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.
2009. Available at:
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm.
Accessed 12/12/2011.
3. RH R, DR G, ML R, PH V. Digoxin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics: Principles of
Therapeutic Drug Monitoring. Vancouver, WA: Applied Therapeutics, Inc.; 1992.
4. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211­21.
5. Depta JP, Bhatt DL. Omeprazole and clopidogrel: Should clinicians be worried? Cleve Clin J Med 2010;77:113­6.
6. Evans WE, McLeod HL. Pharmacogenomics­­drug disposition, drug targets, and side effects. N Engl J Med
2003;348:538­49.
7. Lanfear DE, McLeod HL. Pharmacogenetics: using DNA to optimize drug therapy. Am Fam Physician 2007;76:1179­82.
8. Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529­37.
9. Lehmann H, Ryan E. The familial incidence of low pseudocholinesterase level. Lancet 1956;271:124.
10. Food and Drug Administration. FDA Drug Safety Communication: Ongoing safety review of high­dose Zocor (simvastatin)
and increased risk of muscle injury. 2010. Available at:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm.
Accessed 12/12/2011.
11. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect
and clinical efficacy of clopidogrel therapy. JAMA 2009;302:849­57.
12. Lillvis JH, Lanfear DE. Progress toward genetic tailoring of heart failure therapy. Curr Opin Mol Ther 2010;12:294­304.
Printable PDF

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1.6: Gender, Age, and Race/Ethnicity
Author(s):
Michael A. Chen, MD, PhD, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Recognize that women and older adults with coronary artery disease (CAD) sometimes present with atypical symptoms.
A higher index of suspicion is warranted to enable rapid diagnosis and treatment.
2. Identify significant comorbidities and appropriate goals of care in older adult patients with cardiovascular disease (CVD).
3. Recognize the differences that exist in care patterns and patient outcomes across various populations (i.e., women, older
adults, ethnic/racial groups).
Epidemiology of Cardiovascular Disease in Women
(1 of 2)

CVD is the leading cause of death in the United States in both men and women,
resulting in over one­half million deaths per year. However, only about one half of Figure 1
women surveyed in 2005 realized that CVD is the major threat to their health. While
mortality rates for CVD have fallen for both men and women in recent decades, they
have done so more rapidly for men. In addition, hospitalizations for heart failure have
increased at a faster rate for women than for men. Coronary heart disease (CHD)
and heart failure risk factors, presentation, and management are different in some
respects in women; the similarities and differences will be discussed in this
section.1 Table 1

Coronary Heart Disease

CHD generally presents 10 years later in women than in men. This long­known
observation was confirmed in the multi­national INTERHEART study (A Study of Risk
Factors for First Myocardial Infarction in 52 Countries and Over 27,000 Subjects ).2
Although it has been hypothesized that estrogen present in premenopausal women Table 2
was protective, postmenopausal replacement therapy has not been shown to be
effective in preventing CV events.

Risk Factors

Age is one of the most powerful risk factors for CHD among men and women. Prior
to age 50, the prevalence of CHD is higher in men than in women. However, in the
next decade the prevalence equalizes, and after that, the prevalence in women
exceeds that of men. Family history also affects patients’ risks of developing CHD.
Although a few mutations have been identified to affect CVD expression, most
genetic factors are commonly thought to be complex and to interact with a variety of
environmental factors to contribute to atherosclerosis and CV events.

Modifiable risk factors for CHD include hypertension, dyslipidemia, diabetes and the
metabolic syndrome, and lifestyle factors. Hypertension is extremely common. It is
estimated that overall 31.3% of the US population has hypertension. Hypertension is
more prevalent in men than women until age 45; from age 45­64 the percentage is
similar, but after age 64, a much higher percentage of women than men have
hypertension.3 Although rates increase with age in both sexes, from 45­54 years of
age, the rate of increase is greater among women. The relationship between
hypertension and CHD risk is similar for both men and women, with some analyses
suggesting that the link is slightly stronger in women. Women are undertreated for
hypertension, however, with suboptimal control rates.

Dyslipidemia is the risk factor with the most gender differences. In the United States,
over 50% of women have a total cholesterol of >200 mg/dl and approximately 35%
have a low­density lipoprotein (LDL) >130 mg/dl. These rates are similar among
both women and men. However, while 23% of Americans in the general population
have a high­density lipoprotein (HDL) <40 mg/dl, only 12.6% of women have an HDL
that low. Upon menopause, lipid profiles change. In general, total and LDL
cholesterol increase by an average of 10%. Triglycerides follow a similar trend, but
with more variability. HDL levels decline gradually in the 2 years prior to menopause
and then level off.4 It is believed that the postmenopausal increase in CHD risk is, at
least in part, due to these lipid changes.

Diabetes, impaired glucose tolerance, and the metabolic syndrome are important
risk factors for CVD. Rates of these risk factors have increased. It is currently
estimated that 10.8% of women over the age of 20 have diabetes, and 23% have the
metabolic syndrome.5 Women with diabetes are twice as likely to have CVD, and
four times as likely to be hospitalized for CVD as those without it. Data from
the INTERHEART trial showed that while the strength of association with myocardial
infarction (MI) was similar for most of the risk factors evaluated (i.e., apolipoprotein
[apo]B/apo A­I ratio, cigarette smoking, hypertension, diabetes, abdominal obesity,
psychosocial factors), there was a markedly stronger association between diabetes
and MI in women.
In addition, lifestyle factors are important risk factors in women as well as in men. In
the INTERHEART trial, it appeared that exercise, moderate alcohol consumption,
and fruit and vegetable intake were more protective for women than for men.

Presentation

In both genders, myocardial ischemia and infarction are most often accompanied by
typical symptoms (e.g., chest pain/pressure/squeezing that may radiate to the
neck/shoulder/back/arms, dyspnea, epigastric discomfort, diaphoresis,
nausea/vomiting, palpitations). However, women are known to describe the
symptoms atypically, for example, reporting generalized fatigue or generally mild
symptoms. Among patients who presented to the hospital with MI, but without chest
pain, women more often presented with the following symptoms: dyspnea,
nausea/vomiting, indigestion, fatigue, diaphoresis, and arm or shoulder pain.

Comorbidities such as hypertension at presentation are more common in women

as opposed to men. Women tend to present later and are more likely to have heart
failure and tachycardia at presentation than men.

Hospitalizations for chest pain are more common in men (4 million/year) than in
women (2.4 million/year). Women are more likely to have less severe obstructive
coronary lesions, or have vasospasm or a noncardiac etiology discovered. In fact,
the National Institutes of Health­sponsored WISE (Women’s Ischemia Syndrome
Evaluation) study found a markedly lower observed rate of CHD discovered on
angiography when compared with predicted rates.6 In addition, while 42% of men
with MI experience prehospital sudden death, that proportion is 52% among women.
There is evidence that women are more likely to have plaque erosion (37% in
women vs. 18% in men), whereas plaque rupture is more likely in men (82% in men
vs. 63% in women).

In women, diagnosis of CHD via exercise stress testing has been somewhat
controversial, because prior studies of women with low pretest probability of
disease have resulted in a high false­positive rate. However, the most recent
consensus statement from the American Heart Association (AHA) on the role of
noninvasive testing in the clinical evaluation of women with suspected coronary
artery disease, still recommends a standard exercise electrocardiogram (ECG)
stress test as the initial test in women with an intermediate to high likelihood of CHD
who have either typical or atypical chest pain, have a normal ECG, and are able to
exercise (Figure 1). For those with an intermediate­risk result on the exercise stress
test, stress imaging is recommended. Stress imaging is also recommended for
women who, prior to testing, had an abnormal resting ECG, diabetes, or uncertain
exercise capacity.

Stress imaging with echocardiography and single­photon emission computed

tomography (SPECT) are believed to perform similarly in men and women. The
prognostic implications of the results are similar as well.

Treatment

In general, the 2004 American College of Cardiology (ACC)/AHA Guidelines for the
Management of Patients With ST­Segment Elevation Myocardial Infarction (STEMI),7
and the 2007 ACC/AHA Guidelines for the Management of Patients With Unstable
Angina/Non­STEMI (UA/NSTEMI)8 are gender neutral, but they contain some gender­
based differences. The 2004 STEMI guidelines, which were updated in 20079 and
2009,10 acknowledge the differences in womens’ presentation and comorbidities
(especially symptom differences), and advise different criteria for dosing of
medications such as anticoagulants (e.g., enoxaparin), thrombolytics, and
aldosterone agents based also on renal function. Different criteria for waist
circumference (i.e., >35 inches for women, >40 inches for men) and HDL (i.e., <50
mg/dl for women, <40 mg/dl for men) for the diagnosis of the metabolic syndrome
are noted as well. In addition, the 2004 ACC/AHA STEMI guidelines list Class III
recommendations regarding hormone therapy (Table 1).

The 2007 UA/NSTEMI guidelines, which were updated in 2011,11 address women
as a “Special Group.” Four Class I recommendations are listed (Table 2).
Algorithm for Evaluation of Symptomatic Women Using Exercise ECG or Cardiac Imaging
Figure 1

CVA = cerebrovascular accident; ECG = electrocardiogram; EF = ejection fraction; ETT = exercise treadmill test; LBBB = left bundle branch block;
LV = left ventricular; TM = thrombomodulin.

Reproduced with permission from Mieres JH, Shaw LJ, Arai A, et al. Role of noninvasive testing in the clinical evaluation of women with
suspected coronary artery disease: Consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the
Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association.
Circulation 2005;111:682­96.
Class III Recommendations Regarding the Use of Hormone Replacement Therapy in Women
Table 1
Reproduced with permission from Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST­
elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
(Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:E1­E211.
Class I Recommendations Regarding the Treatment of Women
Table 2
Reproduced with permission from Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with
unstable angina/non­ST­elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non­ST­Elevation
Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular
Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary
Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:e1­e157.
Epidemiology of Cardiovascular Disease in Women
(2 of 2)

Prevention Guidelines

The AHA recently produced updated guidelines for the prevention of CVD in women.12 This guideline and other issues of
CVD prevention for women are discussed in detail in the module on Gender­Related Issues in chapter 4.

Current Practice and Disparities

Although women experience 45% of all MIs, a review of all randomized clinical trials of MI (1966­2000) showed that only
27% of the participants were women. Because of evidence that women can present differently and may respond
differently to treatment, the under­representation of women in clinical trials is problematic. The available data suggest
that women derive the same benefit as do men from aspirin, clopidogrel, anticoagulants, beta­blockers, angiotensin­
converting enzyme (ACE) inhibitors, and statins. However, many, but not all, studies have shown decreased rates in their
use in women compared with men. One often observed pattern is that women are prescribed aspirin and other
antithrombotics less frequently.13

Although women benefit from the use of antiplatelet and anticoagulant medications, women with acute coronary
syndrome (ACS) also have an increased risk of bleeding from these therapies. Thus, the 2007 ACC/AHA Guidelines for
the Management of Patients With UA/NSTEMI suggest that a low maintenance dose of aspirin (75­162 mg) should be
used, especially in conjunction with clopidogrel. In addition, the guidelines emphasize utilizing creatinine clearance in
dosing renally cleared medications (e.g., low molecular weight heparins, glycoprotein (GP) IIb/IIIa inhibitors).8

In one large registry study, 42% of patients with UA/NSTEMI were administered excessive dosing of at least one
antiplatelet or anticoagulant. Predictors of excessive dosing were: female, older age, renal insufficiency, low body weight,
and diabetes. Excessive dosing predicted major bleeding.14

Older data suggested that women had poorer outcomes after percutaneous coronary intervention (PCI) and coronary
artery bypass grafting (CABG), but more recent studies suggest equal to better results. Clinical trials have more
consistently shown the benefit of a direct invasive strategy for men with UA/NSTEMI, while demonstrating heterogeneous
results in women. Women generally composed only about one­third of the patients enrolled, and many trials were
underpowered to evaluate women as a subgroup. Also, there were differences in the trials with regard to the use of GP
IIb/IIIa inhibitors and criteria for MI.

Women presenting with UA/NSTEMI with high­risk features (e.g., elevated biomarkers) should be considered for an
invasive strategy and GP IIb/IIIa inhibitor use. In low­risk women, not only is there no benefit of a direct invasive strategy,
there is evidence of an increased risk of adverse events. This may be because of different etiologies for rest­pain in
women. It may also be due to performing interventions on incidentally discovered stable coronary lesions. These low­risk
women should be managed conservatively.

In addition to differences in discharge prescriptions, women appear to be at higher risk for failing to adhere to
medications prescribed for prevention. The reasons for this are not clear, but may be related to the under­recognition or
denial of heart disease as a significant threat to women’s health on the part of patients as well as physicians. Studies
have shown that physicians may also underestimate women’s overall risk. Although cardiac rehabilitation is
recommended in multiple guideline documents, women are less likely than men to be referred to rehabilitation or to
participate.

These disparities are the target of programs such as the ACC’s Guidelines Applied in Practice (GAP) program.

Heart Failure

Overall, heart failure prevalence is similar between men and women. However, women account for more hospital
discharges than men for heart failure. Heart failure more often accompanies acute MI in women. Finally, about 60% of
deaths due to heart failure are in women.

Pathophysiologic Differences

Heart failure with a preserved ejection fraction (sometimes called “diastolic heart failure” or “heart failure with normal
ejection fraction”) is increasingly common, and up to 80% of affected patients are women. Data from the CHS
(Cardiovascular Health Study) suggested that among subjects with prevalent heart failure, women had normal ejection
fractions more frequently than men (67% in women vs. 42% in men).15 Heart failure with a preserved ejection fraction is
discussed in detail in the module on Heart Failure With Preserved Ejection Fraction in Chapter 11.

Most of the trials in heart failure, on which current recommendations are based, were performed on populations that were
predominantly male and in patients with low ejection fractions. However, guidelines for both “systolic” and “diastolic”
heart failure suggest that treatment be similar for both genders and many of the same treatments are recommended
regardless of the type of heart failure. Caution is advised in the use of medications that are renally excreted/active, such
as spironolactone and digoxin.

As with other trials, women are under­represented in trials of device therapy, including pacemakers and defibrillators.
However, current guidelines for the use of these therapies are no different for men and women.

Treatment Differences

Both men and women who are hospitalized with heart failure tend to have suboptimal rates of receiving evidenced­based
therapies for heart failure. However, women are even less likely to receive them than men. Because the evidence base
for heart failure with preserved ejection fraction is currently not well developed, it is difficult to assess ideal treatments.

Peripheral Vascular Disease

Increasingly recognized, peripheral vascular disease (PVD) is a coronary disease equivalent and portends a risk of CV
death nearly six times that of unaffected people. The recommendations for diagnosis and management of PVD are
gender neutral. In patients with renal artery stenosis, women (particularly young women) are more likely to have
fibromuscular dysplasia than men. Abdominal aortic aneurysms related to atherosclerosis are more common in men
than in women. Age and smoking are also important risk factors.
Age
(1 of 2)

Demographics/Aging of the Population

Figure 2
The population of the United States and most of the rest of the world is aging rapidly.
Life expectancy continues to increase (Figures 2, 3). In the year 2000, 35 million
people in the United States were over 65 years of age (i.e., 12.4% of the population).
By 2030, it is estimated that this number will grow to 71 million (i.e., 19.6% of the
population). Those over 80 years are the fastest growing segment of the population.

Increasing age is a major risk factor for CVD. Figure 4 shows the dramatic
increases in the prevalence of CVDs with increasing age. Although in the United Figure 3
States those over age 65 comprise about 13% of the total population, they account
for over 60% of all hospital admissions for CV causes. More dramatically, people
over age 75 account for only about 6% of the total population, but over one third of CV
hospitalizations occur in this age group. Table 3 shows the remarkable
predominance of hospital admissions for various CV causes in the older age group,
while also demonstrating the high rate of mortality that befalls the elderly with these
conditions. Figure 4

Age­Related Changes in the Cardiovascular System

CV aging affects the peripheral CV system as well as the heart itself. These
changes are interdependent and extremely complex. These age­related changes
are not considered disease, but they do predispose to disease. In essence, there is
a marked reduction in CV reserves. When disease does occur, treatment is often Table 3
very effective. However, these baseline changes in the CV system and the effect of
comorbidities need to be factored into the evaluation of older adults, because they
can profoundly influence aspects of the symptomatology, presentation, diagnosis,
and treatment.

Peripheral and Cardiac Changes

With advancing age, there is an increase in systemic vascular impedance Figure 5

(stiffness), especially in larger arteries, as a result of connective tissue deposition in
the adventitia and media. This, in turn, causes the typical increase in systolic blood
pressure, and therefore pulse pressure, that is common with advancing age. In
response to this increase in cardiac afterload, there is left ventricular (LV) myocardial
hypertrophy(LV hypertrophy), and collagen is deposited in the LV walls, which
contributes to increased myocardial stiffness and reduces passive diastolic
compliance. Figure 6

Diastolic function and dysfunction are reviewed in detail in ACC’s EchoSAP. Briefly,
normal diastolic function allows adequate filling of the left ventricle at rest and with
exercise at normal pressures. Adequate filling results in normal stroke volume and
is affected by a number of factors, many of which will be described below.

The first factor is active relaxation in early diastole that is dependent on appropriate
Figure 7
calcium handling, in particular, the removal of calcium ions from troponin C by the
sarcoplasmic reticulum. This is an active and energy­dependent process. Once LV
pressure is lower than left atrial pressure, the mitral valve opens and rapid early
filling begins. Normally this active relaxation (and elastic recoil from the previous
systole) is sufficient to “suck” blood into the left ventricle, and left atrial pressure itself
is less important. Usually about 80% of filling occurs during this phase. As LV
pressure rises and meets left atrial pressure, inflow decelerates. In late diastole, a
second positive pressure gradient is created by the atrial contraction, accounting for Figure 8
the remaining 15­20% of filling. These two filling phases are depicted in Figure 5 as
the E (early) and A (atrial) waves, as sampled by Doppler signals of mitral valve
inflow.

Impaired active/early relaxation is the simplest example of diastolic dysfunction, and

the Figure 5 demonstrates that, as relaxation is delayed in early filling, there is a
longer and slower decline in filling such that there is a greater reliance on atrial Figure 9
contraction (so­called “atrial kick”) for LV filling. This is a pattern commonly seen with
normal aging, and usually does not cause any symptoms at rest. Abnormal diastolic
function can result in higher filling pressures being needed to “force” blood into the
LV from the left atrium to maintain LV filling/stroke volume. As they are transmitted to
the pulmonary circulation, these elevated filling pressures (pulmonary capillary
wedge pressure) may result in the sensation of dyspnea. Sometimes these
symptoms may only occur with exercise and/or increased heart rate (HR). Figure 10

Additional age­related changes are a result of diminished responsiveness to beta­

adrenergic stimulation. In the heart, decreased ß­1 responsiveness results in both:
1) reduced maximum HR, and 2) reduction in the ability to augment contractility,
resulting in a decrease in maximum cardiac output (CO) with stress.

Decreased Peak Heart Rate

Peak HR in normal individuals is approximately 220 – age. A young person can

roughly triple the CO by an increase in HR alone, while the older person can only
double the CO by increasing the HR. This is due to a reduction in HR reserve (peak
HR – resting HR). These changes are described in Figures 6 and 7.

Reduced Ability to Increase Contractility (Ejection Fraction)

Decreased ß­1 responsiveness, the loss of total functioning myocytes with age, and
reduced mitochondrial function all contribute to a decreased ability to increase the
ejection fraction as one ages (Figure 8).

Thus, the decrease in peak oxygen consumption in the elderly is in large part a
result of the two effects just described: 1) reduction in the peak HR (and HR
reserve), and 2) the decreased ability to increase contractility with age (Figure 9).
Note, however that training can increase peak O2 consumption regardless of age
(Figure 10).
United States Population Projections in the Elderly
Figure 2
Reproduced with permission from Bonow RO, Mann DL, Zipes DP, Libby P. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine.
9th ed. Philadelphia: Saunders; 2011: Figure 80­1.
United States Life Expectancy as a Function of Age
Figure 3
Reproduced with permission from the Centers for Disease Control and Prevention. Life Expectancy. Final 2007 data. Available at:
www.cdc.gov/nchs/fastats/lifexpec.htm. Accessed 10/27/2011.
Prevalence of Cardiovascular Disease in Adults ≥20 Years of Age by Age and Sex
Figure 4

Prevalence of cardiovascular disease in adults ≥20 years of age by age and sex (from the National Health and Nutrition Examination Survey:
2005–2008). These data include coronary heart disease, heart failure, stroke, and hypertension.

Source: National Center for Health Statistics and National Heart, Lung, and Blood Institute.
Cardiovascular Disease Morbidity and Mortality, ≥65 Years Old
Table 3

Reference:

1. Buie VC, Owings MF, DeFrances CJ, Golosinskiy A. National Hospital Discharge Survey: 2006 summary. National Center for Health
Statistics. Vital Health Stat 13(168). 2010.
Normal LV Filling Versus Impaired Relaxation
Figure 5

IVRT = isovolumic relaxation time; LA = left atrial; LV = left ventricular.

Adapted with permission from Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis,
prognosis, and measurements of diastolic function. Circulation 2002;105:1387­93.
Age and Peak Heart Rate
Figure 6
Peak heart rate falls with increasing age (peak heart rate is approximately 220 − age).
Ability to Increase Heart Rate in Young Versus Old
Figure 7

Young = average age 28 years; old = average age 68 years.

Reference:

1. Stratton JR, Levy WC, Cerqueira MD, Schwartz RS, Abrass IB. Cardiovascular responses to exercise. Effects of aging and exercise
training in healthy men. Circulation 1994;89:1648­55.
Ability to Increase Ejection Fraction by Age
Figure 8

EF = ejection fraction.

Reference:

1. Stratton JR, Levy WC, Cerqueira MD, Schwartz RS, Abrass IB. Cardiovascular responses to exercise. Effects of aging and exercise
training in healthy men. Circulation 1994;89:1648­55.
Maximal Volume O2 Uptake by Age and Gender
Figure 9
Adapted with permission from McArdle WD, Katch FI, Katch VL. Essentials of Exercise Physiology, Volume 1. Philadelphia: Lippincott Williams &
Wilkins; 2010: Section III Energy Transfer. Figure 7.15, page 251.
Training Effects on Volume O2 Max (ml/kg/min) in the Young and Old
Figure 10
VO2 = volume of oxygen.

Reference:

1. Stratton JR, Levy WC, Cerqueira MD, Schwartz RS, Abrass IB. Cardiovascular responses to exercise. Effects of aging and exercise
training in healthy men. Circulation 1994;89:1648­55.
Age
(2 of 2)

Other Aging Changes

Table 4
Other aging changes include impaired endothelial function, especially endothelium­
mediated vasodilation, which reduces maximum coronary blood flow. This can
predispose an individual to myocardial ischemia, even in the absence of a fixed
stenosis in a coronary artery. In the periphery, in addition to the large artery stiffness
noted previously, there is impaired peripheral vasodilation (ß­2). This is due in part
to a decrease in the arterial baroreceptor’s afferent activity because of the increased
rigidity, and also due to a reduction in the total amount of norepinephrine contained
Table 5
in the sympathetic nervous system endings. Table 4 provides a summary of aging
changes to the CV system that result in decreased reserve.

Substrate­Disease Interactions: The Example of “Diastolic Heart Failure”

Decreased CV reserve in healthy older adults can predispose them to symptoms or

disease states when confronted with hemodynamic challenges that a younger
person may tolerate well. Physical exercise is an example of this interaction. As Table 6
previously described, older adults cannot increase their CO to the extent that
younger people can, due to a reduction in maximum HR and augmentation of
contractility (and therefore, ejection fraction).

In addition, most older adults have a "delayed relaxation" pattern of diastolic filling,
thus making them more dependent on the late diastolic atrial contribution to LV
filling (i.e., "atrial kick"). With exercise and increases in HR, diastole is shortened Table 7
and, thus, there is less time for LV filling, which may result in elevated left atrial
pressures that can be transmitted backward to the lungs and cause dyspnea and
exercise intolerance. Atrial fibrillation can be difficult for the elderly to tolerate
because without coordinated atrial contraction, that component of filling is lost. As a
result, symptoms such as dyspnea can occur, even at rest.

Dyspnea or fatigue at rest (and especially with exertion), with elevated filling
pressures that may cause pulmonary congestion and even peripheral edema, can Figure 11
be seen in the syndrome of heart failure in the absence of a low ejection fraction. In
many studies, over half of patients with the diagnosis of heart failure have normal or
near normal ejection fractions. Among the elderly, this syndrome is even more
common. Contractility and stroke volume are normal in this setting, but the increase
in ventricular stiffness results in an elevated end­diastolic pressure at a lower (i.e.,
normal) LV volume. In other words, smaller increases in volume result in larger
increases in pressure. Clinically, elevated pressures further impair LV filling, and
lead to increases in left atrial, pulmonary venous, and pulmonary capillary
pressures. This can cause pulmonary congestion, dyspnea, and exercise
intolerance, as well as other symptoms of heart failure. This is termed “diastolic
heart failure,” “heart failure with normal/preserved systolic function,” or “heart failure
with normal ejection fraction.”

Studies suggest that in patients with heart failure who are <65 years of age, the
majority have a reduced ejection fraction, but that in those over 65 years of age,
≥50% have a normal ejection fraction. The treatment paradigm for systolic heart
failure that utilizes multiple medications is based on many large trials that have
shown impressive mortality benefits. These medications include ACE inhibitors,
angiotensin­receptor blockers (ARBs), beta­blockers, spironolactone, and others.
While there have been some large­scale trials of diastolic heart failure utilizing ACE
inhibitors and ARBs that have shown some decrease in symptoms and
hospitalizations, none have shown a mortality benefit.

Aside from diuresis for symptoms of congestion (i.e., volume overload), to this point,
the most important treatment seems to be control of hypertension. This is reflected
in guidelines from the ACC/AHA,16 and the Heart Failure Society of America.17 Heart
failure with preserved ejection fraction is addressed in detail in the module on Heart
Failure With Preserved Ejection Fraction in Chapter 11.

Guidelines
2007 ACC/AHA UA/NSTEMI Guidelines

The 2007 ACC/AHA Guidelines for the Management of Patients With UA/NSTEMI
address older patients as a group and offer several Class I recommendations
(Table 5).8 The document recognizes that older patients are more likely to have
atypical presentations (e.g., dyspnea without chest pain), substantial comorbidities,
have more difficult­to­interpret ECGs, and may respond differently to medications.
They further recognize that although older patients are at highest risk, guideline­
recommended therapies are used less frequently, and that although their outcomes
with interventions and surgery may not always be as favorable as those of younger
patients, coronary revascularization should be recommended when indicated. Also
emphasized is patient­centered care, which considers such issues as comorbidity,
cognitive status, anticipated life expectancy, and patient or family preferences.

2007 ACC/AHA STEMI Guideline Focused Update

The 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of
Patients With STEMI,9 addresses age by recommending that “a strategy of coronary
angiography with intent to perform PCI (or emergency CABG) is reasonable in
patients 75 years of age or older who have received fibrinolytic therapy, and are in
cardiogenic shock, provided that they are suitable candidates for revascularization.
(Level of Evidence: B).” The 2009 Guideline update mentions age in advising caution
with prasugrel in age >75 years. In patients ≥75 years old, “prasugrel is generally
not recommended because of the increased risk of fatal and intracranial bleeding
and uncertain benefit, except in high­risk situations (patients with diabetes or a
history of prior MI) in which its effect appears to be greater and its use may be
considered.”

2007 AHA Scientific Statement

In 2007, the AHA published a two­part Scientific Statement regarding ACS in the
elderly.18,19 Recapitulation of the entire statement, which reviews the state of the
data on treatment of the elderly with ACS, is beyond the scope of this module, but
some of the critical points made include that patient heterogeneity, atypical
presentations, and limited trial representation are common themes in management
of STEMI and non–ST­segment–elevation ACS in the elderly.

Typically, although the elderly are at higher risk, they tend to benefit the most from
intervention and treatment. For example, in STEMI, in patients up to age 85 years old,
a benefit is associated with reperfusion. The selection between fibrinolytics or PCI is
determined by shock, time from presentation, and comorbidity, which often tip the
balance toward PCI in the elderly. The safety and efficacy of reperfusion, specifically
fibrinolytic therapy for STEMI in the very elderly (≥85 years of age), remain significant
questions for future investigation. In addition, the high rate of shock, myocardial
rupture, and death in the very old make understanding pathophysiology related to
ischemia in the aging heart important.

The statement calls for more information from registries and increased enrollment
of the elderly in clinical trials to help define the risks and benefits in the older age
groups. Comorbid and outcome measures should focus on functional outcomes,
cognitive status, and issues such as frailty and quality of life.

Hypertension

Hypertension is discussed in detail in Chapter 5 on Hypertension. People who are

normotensive at age 55 have a 90% lifetime risk for developing hypertension, and
the elderly have the lowest rates of blood pressure control. Although systolic blood
pressure increases with age, diastolic blood pressure remains relatively constant
from 50 to 80 years. In the elderly, isolated systolic hypertension is very common,
and affects 8% of people ages 60­70 years and 25% of those over 80 years.
Treatment of hypertension has impressive benefits (Table 6). However, in patients
>80 years old, some epidemiologic data have suggested that survival is increased
with higher blood pressures.

The landmark HYVET (Hypertension in the Very Elderly Trial),20 published in 2008,
studied 3,845 patients ≥80 years of age with a systolic blood pressure ≥160 mm Hg.
The nonplacebo group was treated with a nonthiazide sulphonamide diuretic (i.e.,
indapamide) supplemented by an ACE inhibitor (i.e., perindopril) when needed to
achieve a target systolic blood pressure of 150 mm Hg. After 2 years, blood
pressure was decreased to 144/78 mm Hg in the treatment group versus 161/84
mm Hg in the placebo group. There were statistically significant reductions in new­
onset heart failure (64%), fatal stroke (39%), all­strokes (30%), and total mortality
(21%). The number needed to treat for 2 years was 94 for stroke and 40 for mortality.
The benefits were seen early and treatment was safe.

In part because of the results in the trial, the 2011 ACCF/AHA Consensus Document
on Hypertension in the Elderly was released,21 which acknowledges that the
general recommended goal of <140/90 mm Hg for uncomplicated hypertension is
based on expert opinion in the older population and not on randomized controlled
trials. The document states that it is unclear if target systolic blood pressure “should
be the same in patients 65­79 years of age as in patients >80 years of age.” Table 7
provides the document’s recommendations for patients ≥80 years of age.

Joint National Committee VII Report

The Joint National Committee (JNC) 7 report on hypertension,22 recommends

treatment utilizing the “same principles outlined for the general care of
hypertension,” but also notes that in many patients, lower initial drug doses may be
indicated, although standard doses and multiple agents may be necessary to
achieve control. In addition to these recommendations, it would be prudent to
evaluate for orthostatic hypotension. Orthostatic hypotension is common, can be
exacerbated by other medications such as anti­Parkinsonian and antipsychotics,
and puts patients at risk for falls. In addition, because there is often a postprandial
decrease in blood pressure in the elderly, it is prudent to avoid fast­acting
medications, particularly with meals.

One shoule be aware that pseudohypertension is also possible. This is defined as

measured systolic and diastolic blood pressures ≥10 mm Hg above the directly
measured intra­arterial pressure. It is thought to result from thickened, calcified
arteries, and should be suspected when there is marked cuff hypertension without
evidence of end­organ damage, and when symptoms of hypoperfusion (e.g.,
dizziness, weakness) occur with therapy. Although oscillometric recorder or
finger/wrist blood pressure measurement may be informative, the only proof comes
with direct measurement of the intra­arterial pressure.

Older Patients: Special Considerations

Dementia and cognitive impairment are more common in hypertensives, and there
is evidence that there is reduced progression of cognitive impairment with
hypertension control. Osteoporosis is common in the elderly. The lifetime risk of
osteoporotic fractures is 40% in women and 13% in men. Thiazides are associated
with higher bone mineral density and a reduced relative risk of hip fracture. However,
urinary frequency and incontinence are common in the elderly and may limit
thiazides’ tolerability in this population.

Drugs in the Older Adult

Particularly after 75­80 years of age, body composition changes. There are
decreases in body size, total body water, intravascular volume, and muscle mass. In
older adults, drug levels are higher with the same doses. There are declines in
glomerular filtration, tubular absorption, and secretion with age (which are lower in
women at all ages). Although the rate of change is highly variable, glomerular
filtration rate drops approximately 10% per decade and is about 15­25% lower in
women.

An important point is that renal impairment can be significant, even with a normal
creatinine. Thus, it is important to formally estimate creatinine clearance before: 1)
initiating renally cleared medicines, 2) risk stratification prior to procedures, and 3)
nephrotoxic agent administration. Note that the creatinine clearance estimates may
not be accurate if the patient is unstable.

With regard to liver metabolism, there is a decrease in CYP450

metabolism/clearance with increasing age (and is lower in women), although there
is marked variability. Examples of medications that may be affected include alpha­
blockers (e.g., doxazosin, prazosin, terazosin), some beta­bolockers (e.g.,
metoprolol, propranolol), some calcium channel blockers (e.g., diltiazem, verapamil)
and some statins (e.g., atorvastatin, fluvastatin).

Adverse drug events are responsible for about 5% of hospital admissions, and
among hospitalized patients, cardiovascular medications are involved in adverse
drug events over 2 times more often than other classes. Some of the most common
medications involved include digitalis, warfarin, diuretics, and calcium­channel
blockers. The biggest factor in adverse drug events is the number of drugs
prescribed. In fact, the chronic administration of four medications is associated with
a 50­60% risk of adverse drug events, and with eight or nine medications, the risk is
nearly 100%.23

Adherence to medication regimens can be difficult in older adults. In patients

hospitalized for heart failure, medication noncompliance has been estimated to be
as high as over 40%.24 Reasons for noncompliance may include cost, lack of
understanding, complicated regimens, visual/hearing impairment, memory
problems, and insufficient education. Some strategies to enhance compliance
include geriatric­friendly packaging, medi­sets, and enlisting the assistance of
family or other care providers.

Comorbidities

Comorbidities greatly influence the medical and surgical management of older

adults. Eighty percent of the elderly have at least one chronic medical condition. Sixty
percent of those over 65 years of age have arthritis, 20% have diabetes, and among
community dwelling elderly, over 10% have Alzheimer’s disease (this increases to
about 40% at age 80). Comorbidities can complicate diagnosis because it can be
confusing to determine which symptoms are coming from which disorders, and they
can complicate management as well.

For example, nonsteroidal anti­inflamatory drugs (NSAIDs) are commonly used in

the management of arthritis, but can worsen blood pressure control as well as
cause salt and water retention. In one case control study evaluating 1,016 patients
hospitalized for the first time with heart failure, the use of NSAIDs (other than low­
dose aspirin) in the previous week was associated with a doubling of the odds of a
hospital admission for heart failure. In particular, NSAID use by patients with a
history of heart disease was associated with a 10 times increased risk of first
admission with heart failure. In those without a history of heart disease, the risk was
still increased by 60%.25

Another example of the influence of comorbidities is the effect of cognitive

impairment. In 1,113 patients hospitalized with heart failure, those with cognitive
impairment had a much lower in­hospital survival. In fact, cognitive impairment was
associated with an almost fivefold increase in mortality after adjusting for several
potential confounders (Figure 11).26

Goals of Care in the Elderly and Disparities

As patients age, their priorities often change as well. As patient age increased,
patients prioritized preserving their mental abilities and independence over
prolonging life.

The elderly are under­represented in many clinical trials of CVD. For example, in a
cross­sectional study of Medicare patients discharged for heart failure in 1998­1999,
it was determined that only a small percentage met the criteria for enrollment in
studies.27 Using the study enrollment criteria, only 18% met criteria for participation
in the SOLVD (The Effects of Enalapril on Survival in Patients with Reduced Left
Ventricular Ejection Fractions and Congestive Heart Failure) trial, 13% met criteria
for the MERIT­HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive
Heart Failure), and 25% for the RALES (Randomized Aldactone Evaluation Study).
Under­representation in trials and the resultant reduced evidence base in older
adults make it difficult to establish guidelines for ideal care in these patients.
However, there are also data to suggest that patients without contraindications are
not treated as aggressively as the existing guidelines would support.
Summary of Aging Changes to the Cardiovascular System That Result in Decreased Cardiovascular Reserve
Table 4
Class I Recommendations Regarding the Care of Older Adults
Table 5
Reproduced with permission from Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with
unstable angina/non­ST­elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non­ST­Elevation
Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular
Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary
Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:e1­e157.
Trials of the Treatment of Hypertension in the Elderly
Table 6
All CVD = all cardiovascular disease composite endpoint; ACE = angiotensin­converting enzyme; Am = amiloride; ARB = angiotensin receptor
blocker; ATEN = atenolol; Beta = beta­blocker; CAD = coronary artery disease; CAND = candesartan; CCB = calcium channel blocker; Chlor =
chlorthalidone; D = diastolic; HCTZ = hydrochlorothiazide; HF = heart failure; Meth = methyldopa; N = number of subjects; NIF = nifedipine; NITR =
nitrendipine; NR = not statistically significant; PER = perindopril; Res = reserpine; S = systolic; TR = triamterene; Type = type of hypertension.

Reproduced with permission from Bonow RO, Mann DL, Zipes DP, Libby P. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine.
9th ed. Philadelphia: Saunders; 2011.

Sources:

1. Five­year findings of the hypertension detection and follow up program: I. Reduction in mortality of persons with high blood pressure,
including mild hypertension. JAMA 1979;242:2562­71.
2. Five­year findings of the hypertension detection and follow­up program: II. Mortality by race­sex and age. Hypertension Detection and
Follow­Up Program Cooperative Group. JAMA 1979;242:2572­7.
3. Amery A, Birkenhager W, Brixko P, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the
Elderly trial. Lancet 1985;1:1349­54.
4. Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. BMJ 1986;293:1145­51.
5. Dahlof B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP­
hypertension). Lancet 1991;338:1281­5.
6. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ 1992;304:405­12.
7. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic
hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255­64.
8. Staessen J, Fagard R, Thijs L, et al. Randomised double­blind comparison of placebo and active treatment for older patients with isolated
systolic hypertension. The Systolic Hypertension in Europe (Syst­Eur) Trial Investigators. Lancet 1997;350:757­64.
9. Gong L, Zwang W, Zhu Y. Shanghai Trial of Nifedipine in the Elderly. In: Seventh European Meeting on Hypertension; 1995 June 9­12;
Milan, Italy.
10. Liu L, Wang JG, Gong L, Liu G, Staessen JA; for the Systolic Hypertension in China (Syst­China) Collaborative Group. Comparison of
active treatment and placebo for older patients with isolated systolic hypertension. J Hypertens 1998;16:1823­9.
11. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized
double­blind intervention trial. J Hypertens 2003;21:875­86.
 12. Beckett NS, Peters R, Fletcher AE, et al.; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J
Med 2008;358:1887­98.

Recommendations Regarding the Treatment of Hypertension in Patients ≥80 Years Old

Table 7
Reproduced with permission from Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the
elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus documents developed in
collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American
Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Coll
Cardiol 2011;57:2037­114.
In­Hospital Survival by Presence or Absence of Cognitive Impairment
Figure 11
Reproduced with permission from Zuccala G, Pedone C, Cesari M, et al. The effects of cognitive impairment on mortality among hospitalized
patients with heart failure. Am J Med 2003;115:97­103.
Race/Ethnicity

Race and ethnicity are in many ways more of a sociological construct than a
physiologic one. Geneticists estimate that only 0.1% of the genetic code varies
among “races.” However, race/ethnicity is important in the evaluation of risk and Figure 12
treatment of CVD.28 In most studies, race has been self­defined, and increasingly
multi­ethnic designations are chosen.

Demographics

The demographics of the United States with regard to race are changing
dramatically. By 2050, it is estimated that non­Hispanic whites will comprise
approximately 52% of the population (76% in 1990), with Hispanics comprising 22%
African Americans over 15%.29 Asian and Hispanic populations are the fastest
growing groups throughout the United States.

Disease and Risk Factor Epidemiology

The prevalence of risk factors varies with the population studied. Hypertension is
present in 41% of African Americans, and obesity is present in 47% of African
American women.30 This is associated with death rates that are 4­5 times greater
than among Caucasians.31 Hispanic Americans have high rates of diabetes and
obesity. Asians, especially southeast Asians, have high rates of hypertension. Native
Americans have high rates of diabetes. Overall, African Americans have 2­3 times
the risk of death from heart disease as do Caucasians. Hispanics and African
Americans have higher hospital readmission rates for heart failure.

With regard to the major diseases, heart failure incidence rates are higher and the
disease tends to occur earlier in African Americans. It is also generally more
clinically severe and usually presents with more advanced LV systolic dysfunction.
Ischemic heart disease is less common in Hispanic Americans. Among Asians,
ischemic heart disease is similar in incidence to Caucasians. It is more common
among African Americans, although obstructive coronary disease is less common.
However, when epicardial coronary disease is present in this population, it is more
likely to be multi­vessel.

Guidelines

Guidelines are generally either silent on the topic of race or recommend equivalent
care regarding the diagnosis and treatment of various CVDs (e.g., ACS, heart failure,
PVD, and hypertension). The JNC 7 document does note that because data show
that African Americans have a reduced response to monotherapy (i.e., beta­blockers,
ACE inhibitors, ARBs) as compared to diuretics and calcium channel blockers,
combination therapy that includes a diuretic should be strongly considered.22

Of note, African Americans have rates of ACE inhibitor­associated angioedema 2­4

times other groups. Guidelines related to heart failure also recommend the
standard approach of neurohormonal modulation with beta­blockers and ACE
inhibitors because it is effective. However, in addition, because of positive data
regarding the combination of nitrate and hydralazine as an additional therapy in
African Americans, it can also be considered in this population.32,33

Outcome and Treatment Differences/Disparities

CV outcomes vary in these racial groups, but the reasons are multifactorial. One
reason stems from the lack of knowledge of important differences in presentation
and treatment due to under­representation in trials and other studies of CVD. Other
reasons include access to care, potential bias in decision­making, and compliance
with recommended therapies.

Although the fact that CVDs differentially affect various populations will affect
outcomes, differential care can affect outcomes as well. For example, multiple
studies have demonstrated that people of color are less likely to receive cardiac
catheterization, PCI, CABG, and implanted defibrillators.34­36 When stents are
placed in these populations, they are less likely to receive a drug­eluting stent.
Patients with Medicaid or who have no insurance were also less likely to receive a
drug­eluting stent.37

Physician concern over an ability to pay for long­term dual antiplatelet therapy as well
as patients’ preferences may play a role in these differences. Thrombolytics for
acute MI, PCI, and CABG are all less frequently performed in African Americans,
especially African American women.38,39 In the care of acute MI, by 2008, in­hospital
and discharge medications prescriptions were similar across ethnic groups.
However, Hispanic and African Americans had longer delays to reperfusion with
longer door­to­balloon times when compared to Whites (Figure 12).

Studies of data from the PINNACLE (Practice Innovation and Clinical Excellence)
Registry) and the NEPTUNE II (National Cholesterol Education Program Evaluation
Project Utilizing Novel E­Technology) survey have also shown reduced achievement
of preventative goals in African Americans when compared to Caucasians with
regard to hypertension and LDL levels.40,41 Similar data are available for Mexican
and Native Americans.

Only one third of cardiologists surveyed in 2005 acknowledged that racial and ethnic
health care disparities exist, and <5% thought that such disparities existed in their
own practice.42

Reducing Disparities

Recognition of differences in care and outcomes is one step toward reducing

disparities. Recognition of disparities is the first step in closing the gap.43
Interventions aimed at increasing “cultural competency” and provider or site­specific
feedback have also been useful. Cultural competency training focuses on factors
such as:

Understanding the patient as a unique person;

Exploration of and respect for patient beliefs, values, meaning of illness,
preferences and needs;
Awareness of one’s own biases and assumptions; and
Provision of information and education tailored to patient level of
understanding.

Identifying the written and spoken language preferences of patients and providing
cultural and language interpreter services are important as well. The ACC
established the Coalition to Reduce Disparities in CV Outcomes (credo) to help
meet the needs of an increasingly diverse population. It provides online tools for
evaluating inpatient and discharge performance measures, which can provide data
by race and sex. Educational materials including in­person cultural competency
training for providers and materials for patient education (e.g., Spanish language
materials) are available or are in development. The credo program also includes
strategies and tools for measuring performance before and after the implementation
of such initiatives.
Delays to Reperfusion by Race/Ethnicity
Figure 12
DTB = door­to­balloon.

Reproduced with permission from ACTION Registry­GWTG 2008.

Key Points

CAD generally presents 10 years later in women than in men.

Even in women, myocardial ischemia and MI are most often accompanied by typical symptoms. However, women
may more often present with milder symptoms or may describe dyspnea, nausea/vomiting, indigestion, fatigue,
diaphoresis, and arm or shoulder pain instead of chest pain.
Heart failure with a preserved ejection fraction (sometimes called “diastolic heart failure” or “heart failure with
normal ejection fraction”) is increasingly common, and up to 80% of affected patients are women. Over 50% of
patients with heart failure over 65 years of age have a normal or near normal ejection fraction.
Older patients with ACS are also more likely to have atypical presentations (e.g., dyspnea without chest pain),
substantial comorbidities, more difficult to interpret ECGs, and altered responses to medications.
Clinical trials (e.g., the landmark HYVET trial) have shown benefits of treatment of hypertension even in patients
≥80 years of age. Benefits include a reduction in the incidence of stroke (fatal and nonfatal), heart failure, CV
death, and all­cause mortality.
CV outcomes vary by racial/ethnic groups. The reasons are multifactorial, including a lack of knowledge of
important differences in presentation and treatment due to under­representation in clinical trials and other
studies, access to care, potential bias in decision­making, as well as compliance with recommended therapies.
Recognition of differences in care and outcomes is the first step toward reducing treatment and outcome
disparities. Interventions aimed at increasing “cultural competency” and provider­ or site­specific feedback have
also been useful.
References

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6. Shaw LJ, Bairey Merz CN, Pepine CJ, et al., on behalf of the WISE Investigators. Insights from the NHLBI­
sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study. Part I: Gender differences in traditional and
novel risk factors, symptom evaluation, and gender­optimized diagnostic strategies. J Am Coll Cardiol
2006;47:S4­S20.
7. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST­elevation
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Myocardial Infarction). J Am Coll Cardiol 2004;44:E1­E211.
8. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with
unstable angina/non­ST­elevation myocardial infarction: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the
Management of Patients With Unstable Angina/Non­ST­Elevation Myocardial Infarction) developed in collaboration
with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and
Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and
Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:e1­157.
9. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 Guidelines for the
Management of Patients With ST­Elevation Myocardial Infarction: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines (Writing Group to Review New Evidence and
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Am Coll Cardiol 2008;51:1­38.
10. Kushner FG, Hand M, Smith SC Jr., et al. 2009 focused updates: ACC/AHA guidelines for the management of
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ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused
update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol 2009;54:2205­41.
11. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007
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12. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness­based guidelines for the prevention of cardiovascular disease
in women—2011 update: a guideline from the American Heart Association. Circulation 2011;123:1243­62.
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diagnosis and treatment of non­ST­segment elevation acute coronary syndromes: large­scale observations from
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14. Alexander KP, Chen AY, Roe MT, et al.,on behalf of the CRUSADE Investigators. Excess dosing of antiplatelet and
antithrombin agents in the treatment of non­ST­segment elevation acute coronary syndromes. JAMA
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15. Kitzman DW, Gardin JM, Gottdiener JS, et al. Importance of heart failure with preserved systolic function in
patients_> or_= 65 years of age. CHS Research Group. Cardiovascular Health Study. Am J Cardiol 2001;87:413­
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the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the
International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53:e1­
17. Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. Section
11: Evaluation and Management of Patients with Heart Failure and a Preserved Left Ventricular Ejection Fraction. J
 Card Fail 2010,16:e1­191.
18. Alexander KP, Newby LK, Cannon CP, et al. Acute coronary care in the elderly, part I: Non­ST­segment­elevation
acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart
Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation
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19. Alexander KP, Newby LK, Cannon CP, et al. Acute coronary care in the elderly, part II: ST­segment­elevation
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2007;115:2570­89.
20. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J
Med 2008;358:1887­98.
21. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the
elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus
documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society,
American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology,
Association of Black Cardiologists, and European Society of Hypertension. J Am Coll Cardiol 2011;57:2037­114.
22. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560­72.
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homes. Age Ageing 1989;18:52­6.
24. Michalsen A, Konig G, Thimme W. Preventable causative factors leading to hospital admission with
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25. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an
underrecognized public health problem. Arch Intern Med 2000;160:777­84.
26. Zuccala G, Pedone C, Cesari M, et al. The effects of cognitive impairment on mortality amoung hospitalized
patients with heart failure. Am J Med 2003;115:97­103.
27. Masoudi FA, Havranek EP, Wolfe P, et al. Most hospitalized older persons do not meet the enrollment criteria for
clinical trials in heart failure. Am Heart J 2003;146:250­7.
28. Peterson E, Yancy CW. Eliminating racial and ethnic disparities in cardiac care. N Engl J Med 2009;360:1172­4.
29. Barnett E, Casper ML, Halverson JA, et al. Men and Heart Disease: An Atlas of Racial and Ethnic Disparaities in
Mortality, 1st edition. Office for Social Environment and Health Research, Morgantown, WV, West Virginia
University; 2001.
30. Mensah GA, Mokdad AH, Ford ES, Greenlund KJ, Croft JB. State of disparities in cardiovascular health in the
United States. Circulation 2005;111:1233­41.
31. Rahman M, Douglas JG, Wright JT Jr. Pathophysiology and treatment implications of hypertension in the African­
American population. Endocrinol Metab Clin North Am 1997;26:125­44.
32. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for
the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the
International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53:e1­e90.
33. Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. Section
15: Heart Failure in Special Populations. J Card Fail 2010;16:e1­191.
34. Sonel AF, Good CB, Mulgand J, et al. Racial variations in treatment and outcomes of black and white patients with
high­risk non­ST­elevation acute coronary syndromes: insights from CRUSADE (Can Rapid Risk Stratification of
Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines?).
Circulation 2005;111:1225­32.
35. Farmer SA, Kirkpatrick JN, Heidenreich PA, Curtis JP, Wang Y, Groeneveld PW. Ethnic and racial disparities in
cardiac resynchronization therapy. Heart Rhythm 2009;6:325­31.
36. Mukamel DB, Weimer DL, Buchmueller TC, Ladd H, Mushlin AI. Changes in racial disparities in access to
coronary artery bypass grafting surgery between the late 1990s and early 2000s. Med Care 2007;45:664­71.
37. Gaglia MA Jr, Torguson R, Xue Z, et al. Insurance type influences the use of drug­eluting stents. JACC Cardiovasc
Interv 2010;3:773­9.
38. Schulman KA, Berlin JA, Harless W, et al. The effect of race and sex on physicians’ recommendations for cardiac
catheterization. N Engl J Med 1999;340:618­26.
39. Cram P, Bayman L, Popescu I, Vaughan­Sarrazin MS. Racial disparities in revascularization rates among patients
with similar insurance coverage. J Natl Med Assoc 2009;101:1132­9.
40. Clark LT, Maki KC, Galant R, Maron DJ, Pearson TA, Davidson MH. Ethnic differences in achievement of
cholesterol treatment goals.Results from the National Cholesterol Education Program Evaluation Project Utilizing
Novel E­Technology II. J Gen Intern Med 2006;21:320­6.
41. Yood MU, McCarthy BD, Kempf J, et al. Racial differences in reaching target low­density lipoprotein goal among
individuals treated with prescription statin therapy. Am Heart J 2006;152:777­84.
42. Lurie N, Fremont A, Jain AK, et al. Racial and ethnic disparities in care: the perspective of cardiologists.
Circulation 2005;111:1264­9.
43. Bonow RO, Grant AO, Jacobs AK. The cardiovascular state of the union: confronting healthcare disparities.
Circulation 2005;111:1205­7.
Printable PDF

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Chapter 1 Exam

Visit the online version of the product to see the correct answer and commentary.

1.

Which region of the world currently has the highest proportion of deaths due to CVD?

A. Sub­Saharan Africa.

B. Eastern Europe and Central Asia.

C. High­income countries.

D. South Asia.

E. Latin America and the Caribbean.

2.

Which of the following percentages of ischemic heart disease and stroke deaths
occurs among people with a systolic blood pressure below 145 mm Hg?

A. 1%.

B. 2%.

C. 5%.

D. 10%.

E. 50%.

3. A researcher has hypothesized that a new study drug will increase high­density
lipoprotein (HDL) cholesterol levels in patients who take it daily. He wishes to
compare the mean HDL cholesterol level achieved in patients randomized to the
new medication, with the mean HDL level achieved in patients randomized to
placebo. The null hypothesis is that there is no difference in mean HDL cholesterol
levels between the two groups.

Which of the following is the appropriate statistical test to use, to determine whether
the null hypothesis can be rejected?

A. Chi­square.

B. T test.

C. Logistic regression.

D. Linear regression.

E. Log­rank.

4. A team of researchers would like to determine whether vitamin D levels are

associated with a history of MI among community­dwelling individuals. They set up a
booth at the local shopping center, and enroll 1,000 shoppers on the spot. After
providing informed consent, the shoppers fill out a questionnaire about their history
of heart attacks plus their other cardiovascular risk factors, and then a sample of
their blood is drawn and frozen for future measurement of vitamin D levels.

Which one of the following study designs is being used?

A. Case series.

B. Case­control.

C. Cross­sectional.

D. Cohort.

E. Clinical trial.

5.

Which of the following statements is correct regarding CEAs?

A. CEAs are able to identify which therapies are less costly, but not necessarily
those that are more efficacious

B. CEAs are always performed alongside clinical trials.

C. CEAs are how the US government makes decisions of whether or not to pay
for a technology.

D. CEAs are always incremental, comparing the incremental cost of a new

therapy to an established therapy.

6.

Which of the following statements is correct regarding health care utilities?

A. They are values that reflect society’s preferences for their members to have
different health outcomes.

B. They are valued on a scale of 1­100, with 100 being perfect health.

C. They require adjustment for inflation.

D. They can be measured using standard gamble and time trade­off

methodologies.

7.

Which of the following statements is correct regarding a health economic analysis?

A. It attempts to predict whether a new technology will drive more demand for a
new technology or service.

B. It attempts to provide a standardized measure to compare various disease

areas and populations.
 C. It attempts to model how much money society will save by utilizing a new
technology compared with an established technology.

D. It defines the strategy that should be the standard of care for an individual
patient.

8.

Which of the following is the definition of quality of care?

A. The distillation of clinical evidence into clinical practice guidelines.

B. Care which eliminates variation and is provided at low cost.

C. Care that is delivered in the order of Plan­Do­Study­Act (PDSA).

D. The degree to which health care systems, services, and supplies for
individuals and populations increase the likelihood for desired health outcomes
in a manner consistent with current professional knowledge.

9.

Which of the following is one of the domains in Donabedian’s triad for quality
assessment?

A. Misuse.

B. Outcomes.

C. Efficiency.

D. Data standards.

10.

Which of the following tools identifies common clinical situations for prototypical
patient subgroups for which expert clinicians provide a graded recommendation for
or against the use of a test or procedure?

A. Clinical practice guidelines.

B. Quality metric.

C. Performance measure.

D. AUC.

11.

Which of the following would be more characteristic of an administrative data set

rather than a national clinical registry program?
 A. Relying mostly on claims­based data rather than clinical data for evaluating
care processes.

B. Feedback of clinical data reflecting performance and outcomes to clinicians,

including risk adjustment and benchmarking of the data.

C. Helping state regulatory agencies oversee quality of demonstration projects.

D. Collection of post­market device surveillance information, particularly for low

frequency adverse events.

12. You wish to start a patient on anticoagulation for atrial fibrillation. As warfarin has
a narrow therapeutic window and much interindividual variability in effect, you wish to
utilize your patient’s genetic information to optimize the initial dose selection.

Which of the following is the best next step?

A. Request genotyping for CYP2C19 polymorphisms.

B. Nothing, because genetic variation does not significantly impact warfarin

dosing requirements.

C. Request genotyping for CYP2C9 and VKORC1 because variants in these

genes account for roughly 40% of interindividual variability in warfarin dosing.

D. Request genotyping for VKORC1, and if alternative alleles are present,

choose a lower initial warfarin dose.

13. A 70­year­old female presents to the ED after being found unconscious. Her past
medical history is significant for hypertension, previous non­ST­segment elevation
myocardial infarction, and atrial fibrillation. Her medications include
hydrochlorothiazide 25 mg daily, metoprolol 50 mg BID, aspirin 81 mg, digoxin 0.125
mg daily, diltiazem 360 mg daily, and clopidogrel 75 mg daily. Recent lab values
include: sodium 140, potassium 4.0 serum creatinine 0.8 mg/dl. Vitals are as
follows: blood pressure 130/80 mm Hg, heart rate 45 bpm, respiration rate 12.

Which of the following may have led to this patient’s episode of syncope?

A. Digoxin dose was too high for renal function.

B. Pharmacokinetic drug interaction via the CYP P450 system.

C. Pharmacodynamic drug interaction.

D. P­gp drug interaction.

14.

You are caring for a 66­year­old woman who experienced an NSTEMI at your
hospital. Which of the following is most accurate regarding women with UA/NSTEMI
(as opposed to men)?

A. They are younger.

 B. They have fewer comorbidities such as hypertension and diabetes.

C. They are more likely to have had a prior MI or a cardiac procedure.

D. They are more likely to manifest atypical symptoms.

E. They are more likely to have an obstructive lesion on cath.

15.

Which of the following is the most significant change to the aging cardiovascular
system that reduces an older adult’s ability to increase their CO with stress (e.g.,
exercise)?

A. Impaired endothelial function in the coronary arteries.

B. Reduced ability to increase LV ejection fraction.

C. Reduced ability to increase HR.

D. Impaired peripheral vasodilatation.

E. Increase in pulse pressure.

Please visit the online version to engage in this Exam.

1. The correct answer is B. Eastern Europe and Central Asia have the highest mortality, at 58%.
These countries are in the third phase of the epidemiologic transition, the age of degenerative
and man­made diseases. Overall, high­income countries (option C) have a rate of about 40% of
deaths due to CVD. Low­income countries have a combined rate of about 28%, but there is
marked variation in the regions, ranging from 11­58%.

Answer A is incorrect because Sub­Saharan Africa is the only region in the world where CVD is
not the leading cause of death, with CVD deaths rates of about 11% of the total. South Asia and
Latin America and the Caribbean have rates of 32% and 28%, respectively.

References

1. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ, eds. Global Burden of Disease and Risk
Factors. New York: The World Bank and Oxford University Press; 2006.
2. Gaziano TA. Cardiovascular disease in the developing world and its cost­effective management.
Circulation 2005;112:3547­53.

2. The correct answer is E. Nearly 50% of global deaths attributable to elevated blood pressure
occur among people with a systolic blood pressure <145 mm Hg. This is a result of the
continuous relationship between blood pressure and disease down to systolic levels as low as
115 mm Hg, and the large proportion of the populations with systolic blood pressures between
the 115­145 mm Hg range.

References

1. Lawes CM, Hoorn SV, Rodgers A. Global burden of blood­pressure­related disease, 2001. Lancet
2008;371:1513­8.

3. The correct answer is B. T tests are used to determine whether the mean of two
independent groups are equal. Chi­square tests are used for determining whether proportions in
two groups are equal (e.g., whether the percentage of men versus women is the same in each of
the two study groups).

Logistic regression and linear regression are used to predict a dependent (or outcome) variable
based on knowledge of other independent variables. An example of a use of linear regression
would be to predict a patient’s final HDL level based on knowledge of the subject’s age, sex,
randomization group, and starting HDL level. The log­rank test is used to compare the survival
distributions of two groups.

4. The correct answer is C. All data are collected at one point in time; thus, this is a cross­
sectional study. Even though the vitamin D levels will be measured in the future, the blood that
will be used for this test was drawn at the same time that the questionnaire was administered. If
the participants were followed with subsequent study visits, this would be a cohort study. It is not
a clinical trial because no intervention was performed. It is not a case­control study because
study participants were all­comers and were not selected based on a specific disease being
present. It is also not a case series, which is simply a descriptive account of a collection of
patients that all share some specific characteristic of interest.

5. The correct answer is D.

References

1. Cohen DJ, Reynolds MR. Interpreting the results of cost­effectiveness studies. J Am Coll Cardiol
2008;52:2119­26.
2. Weinstein MC. Recent developments in decision­analytic modelling for economic evaluation.
Pharmacoeconomics 2006;24:1043­53.

6. The correct answer is D.

References

1. Whitehead SJ, Ali S. Health outcomes in economic evaluation: the QALY and utilities. Br Med Bull
2010;96:5­21.
2. Torrance GW. Measurement of health state utilities for economic appraisal. J Health Econ 1986;5:1­
30.

7. The correct answer is B.

References

1. Cohen DJ, Reynolds MR. Interpreting the results of cost­effectiveness studies. J Am Coll Cardiol
2008;52:2119­26.

8. The correct answer is D. The IOM provided the definition in option D in its document,
Crossing the Quality Chasm: A New Health System for the 21st Century (2001): “The degree to
which health care systems, services, and supplies for individuals and populations increase the
likelihood for desired health outcomes in a manner consistent with current professional
knowledge.” The IOM further broke down quality into six primary domains: safe, effective, patient­
centered, timely, efficient, and equitable.

The distillation of clinical evidence into clinical practice guidelines (option A) is a tool of quality,
but is not the definition of quality of care. Unexplained variation in care is a reflection of variation
in quality of care, but the definition of quality of care is not the elimination of variation, nor is it to
provide low­cost care (option B). PDSA cycles describe a model for improving quality, but do not
define quality (option C).

9. The correct answer is B. Donabedian’s triad is a frequently used model to conceptualize

quality assessment. The Donabedian model is composed of: 1) structure (resources available to
deliver care), 2) process (the way in which care is delivered), and 3) outcomes (the results of
care).

Misuse (option A) includes incorrect diagnoses as well as medical errors and other sources of
avoidable complications; misuse reduces quality. Efficiency (option C) implies leveraging of
health care delivery resources to achieve high­quality care yet avoid wasteful testing and
unnecessary procedures that add little or no incremental value in health care delivery, often
measured as a unit of cost for a given outcome; one of the intended results of quality
assessment is improved efficiency. Data standards (option D) are agreed upon definitions,
nomenclature, and data elements that facilitate accurate communication and fair comparison;
data standards help facilitate quality measurement and improvement.
10. The correct answer is D. AUC are described in this module. AUC are derived from panels of
expert clinicians who, using available evidence from the medical literature and clinical practice,
assess the benefits and risks of a test or procedure on patient outcomes for common,
prototypical patients and situations. Each scenario receives a score between 1 and 9, with 7­9
considered appropriate, 4­6 uncertain, and 1­3 inappropriate. Ideally, AUC define “what to do,”
“when to do,” and “how often to do” a certain modality or procedure, with consideration for local
care environments and patient goals.

Clinical practice guidelines (option A) are intended to summarize the body of evidence­based
medicine for a given disease process or clinical content area. Quality metrics (option B) are
those measures that have been developed to support self­assessment and quality improvement
at the provider, hospital, and/or health care system level, but may not meet all specifications of
formal performance measures used in public reporting and accountability. Performance
measures (option C) are those process, structure, efficiency, or outcome measures that have
been developed using ACC/AHA methodology, including the process of public comment and
peer review, and are intended not only for clinical quality improvement but also may be
considered for purposes of public reporting or other forms of accountability.

11. The correct answer is A. In contrast to administrative data sets, a particular value of existing
national registries is the reliance on detailed clinical data utilizing real­time or retrospective data
entry. National registries have data quality checks and an auditing function to help ensure
accurate assessment of clinical outcomes and processes.

12. The correct answer is C. Option A is incorrect because CYP2C19 variation has been
associated with altered clopidogrel metabolism, not warfarin.1 Option B is incorrect because
several studies have shown association with stable warfarin dose and greater time in
therapeutic window with pharmacogenetic dosing schemes. Option C is correct. These two
genes have a substantial impact on warfarin dosing, and studies have estimated that their
incremental impact (in addition to known clinical predictors) accounts for roughly 40% of warfarin
dose variability. Option D is incorrect because VKORC1 alternative alleles are associated with
rough doubling of required warfarin dose.2

References

1. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the
antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009;302:849­57.
2. Lillvis JH, Lanfear DE. Progress toward genetic tailoring of heart failure therapy. Curr Opin Mol Ther
2010;12:294­304.

13. The correct answer is C. Choice A is not correct because this dose is reasonable given this
patient’s renal function, although renal function is an important consideration with digoxin.
Choice B is incorrect because there are no relevant pharmacokinetic interactions between these
medications. Choice D is incorrect because digoxin is the only medication in this list that is a
substrate of P­gp. Choice C is the correct answer because this patient is taking three
medications that decrease heart rate (metoprolol, digoxin, diltiazem), which leads to additive
effects of these drugs on heart rate. Given that heart rate reduction is an expected
pharmacodynamic effect of these drugs, this would be best described as a pharmacodynamic
drug interaction.

14. The correct answer is D. There are many differences between men and women with
NSETMI. Women are typically older and have more comorbidities (e.g., hypertension, diabetes,
heart failure with preserved LV ejection fraction), and are more likely to present with atypical
symptoms than men. When catheterized, they more often have nonobstructive CAD, and are
more likely than men to have vasospasm or endotheial dysfunction. They are less likely to have
had prior MI or cardiac procedures.

References

1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of
patients with unstable angina/non­ST­elevation myocardial infarction: a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing
Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non­
ST­Elevation Myocardial Infarction) developed in collaboration with the American College of
Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the
Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and
 Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol
2007;50:e1­e157.
2. Glaser R, Herrmann HC, Murphy SA, et al. Benefit of an early invasive management strategy in
women with acute coronary syndromes. JAMA 2002;288:3124­9.

15. The correct answer is C. All of the choices are seen in aging, but the most consistently
found cause for the reduced ability to increase CO in older adults is a reduced capacity for
increasing HR. For example, a 20­year­old would be expected to achieve a peak HR of 200 bpm
(calculated as 220 – 20 = 200). At age 80, the anticipated peak HR would be 140 bpm (calculated
as 220 – 80 = 140). The heart rate reserve (HRR) is the change in HR from rest to peak exercise.
If the 20­year­old starts exercise at a resting HR of 70, the HRR would be 130 bpm (calculated as
200 – 70 = 130), whereas the 80­year­old would have an HRR of only 70 bpm (calculated as 140
– 70 = 70). Thus, the young person can roughly triple the CO by an increase in HR alone (i.e.,
chronotropy), whereas the older person can only double the CO by an increase in HR.

References

1. Fleg JL, O’Connor F, Gerstenblith G, et al. Impact of age on the cardiovascular response to dynamic
upright exercise in healthy men and women. J Appl Physiol 1995;78:890­900.