April 2010 Vol. 16 No.

4
From the publishers of
The New England Journal of Medicine

CA RDI OLOGY
The ACCORD Lipid Study: In both groups, mean LDL levels fenofibrate. The
Fenofibrate Doesn’t Help dropped from ≈100 mg/dL to ≈80 mg/dL. burden of proof is firmly on advocates
Although triglyceride levels improved mark- Mean HDL levels increased from 38.0 mg/ of this drug to justify the cost and risk to
edly with fenofibrate, incidence of adverse dL to 41.2 mg/dL in the fenofibrate group patients.
cardiovascular events was not affected. and to 40.5 mg/dL in the placebo group. — Harlan M. Krumholz, MD, SM
Interventions that improve lipid profiles Median triglyceride levels decreased from
The ACCORD Study Group. Effects of combination
do not always improve patient outcomes. about 160 mg/dL to 122 mg/dL in the feno- lipid therapy in type 2 diabetes mellitus. N Engl J
A common strategy in diabetic patients — fibrate group and to 144 mg/dL in the pla- Med 2010 Mar 14; [e-pub ahead of print]. (http://
cebo group. The primary endpoint, adverse dx.doi.org/10.1056/NEJMoa1001282)
who often have low HDL and elevated
triglyceride levels — is to add fibrate cardiovascular events, occurred with simi-
therapy, despite mixed results in previous lar frequency in the two groups (2.2% vs. The ACCORD Blood Pressure
2.4% per year; hazard ratio, 0.92; P=0.32).
studies. In the government-funded Study: What Target for
ACCORD Lipid Study, researchers evalu- No subgroup analysis was strongly positive,
High-Risk Diabetic Patients?
ated whether adding fenofibrate to statin although women assigned to fenofibrate
had higher adverse event rates than did Achieving systolic blood pressure levels lower
therapy prevents adverse cardiovascular than 140 mm Hg does not prevent adverse
events in patients with type 2 diabetes. women assigned to placebo. Fenofibrate re-
cardiovascular events.
cipients were significantly more likely than
More than 5000 diabetic adults placebo recipients to leave the study (2.4% In epidemiological studies, lower blood
(mean age, 62; 31% women; glycosylated vs. 1.1%) because of a decrease in glomeru- pressure (BP) is associated with lower car-
hemoglobin, ≥7.5%; LDL cholesterol, lar filtration rate. diovascular risk. But, in high-risk patients,
60–180 mg/dL; HDL cholesterol, would achieving blood pressure targets
<55 mg/dL for women and blacks and COMMENT lower than those recommended in guide-
<50 mg/dL for all others) were enrolled. This important negative trial indicates that lines reduce risk further? Researchers
All participants received simvastatin and fenofibrate should not be used for high- evaluated whether a blood pressure target
also were assigned to daily fenofibrate risk diabetic patients. Although it im- of <120 mm Hg in patients with type 2
(160 mg) or placebo. Mean follow-up proved triglyceride profiles, no clinical diabetes would lower risk for adverse
was 4.7 years. benefit was seen. Moreover, worsening of cardiovascular events.
renal function occurred more often with
A total of 4733 high-risk diabetic pa-
tients (mean age, 62; 48% women; glyco-
CONTENTS sylated hemoglobin, ≥7.5%; systolic blood
pressure [SBP], 130–180 mm Hg) who
SUMMARY & COMMENT Sirolimus-Eluting Stents Outperform were taking ≤3 antihypertensive medica-
The ACCORD Lipid Study: Fenofibrate Zotarolimus-Eluting Stents ..................................... 33
tions and had no proteinuria were en-
Doesn’t Help .............................................................. 29 Dual Antiplatelet Therapy After
rolled. Patients were assigned to intensive
The ACCORD Blood Pressure Study: Drug-Eluting Stenting: When to Stop? ................. 34
What Target for High-Risk Clopidogrel and Proton-Pump Inhibitors:
BP control (target SBP, <120 mm Hg) or
Diabetic Patients? .................................................... 29 How Much of a Problem? ....................................... 34 standard BP control (target SBP, <140 mm
Diabetes and Cardiovascular Events: Silent Cerebral Embolism After Hg). Mean follow-up was 4.7 years. Mean
Not a Straight Course .............................................. 30 Transcatheter Aortic-Valve Implantation............ 34 systolic and diastolic BP levels at baseline
Is Elective Coronary Angiography Overused? ....... 31 Statins and Stroke Prevention: were 139 mm Hg and 76 mm Hg, respec-
Dopamine vs. Norepinephrine Is It All About the Cholesterol? .............................. 35
in Treatment of Shock .............................................. 31 tively. At 1 year, average SBP levels were
The Changing Profile of MI ........................................ 35
Postsurgical Pericardial Effusion: 119 mm Hg in the intensive-care group
Rate Control for Atrial Fibrillation:
Do NSAIDs Make a Difference?............................ 32 Can We Relax? .......................................................... 36 and 134 mm Hg in the standard-care
CABG in High-Risk Patients: group. The lower BP in the intensive-care
CLINICAL PRACTICE GUIDELINES WATCH
To Pump or Not to Pump? ....................................... 32
How to Prevent and Manage group was achieved by prescribing more
Adherence to Guidelines for Coronary Cardiac Device Infections ...................................... 33 drugs in every antihypertensive class; the
Revascularization .............................................32
mean number of medications at 1 year
JOURNAL WATCH (AND ITS DESIGN) IS A REGISTERED TRADEMARK OF THE MASSACHUSETTS MEDICAL SOCIETY.
AN EDITORIALLY INDEPENDENT LITERATURE-SURVEILLANCE NEWSLETTER SUMMARIZING ARTICLES FROM MAJOR MEDICAL JOURNALS. ©2010 MASSACHUSETTS MEDICAL SOCIETY.
ALL RIGHTS RESERVED. DISCLOSURE INFORMATION ABOUT OUR AUTHORS CAN BE FOUND AT http://cardiology.jwatch.org/misc/board_disclosures.dtl
30
EDITOR-IN-CHIEF
Harlan M. Krumholz, MD, SM, Harold H. Hines, Jr.,
Professor of Medicine, Section of Cardiovascular
Medicine, Yale University School of Medicine,
New Haven
EXECUTIVE EDITOR
Kristin L. Odmark
Massachusetts Medical Society
DEPUTY EDITOR
Howard C. Herrmann, MD, Professor of Medicine,
Director, Interventional Cardiology and Cardiac
Catheterization Laboratories, University of
Pennsylvania Medical Center, Philadelphia
ASSOCIATE EDITORS
JoAnne M. Foody, MD, Director, Cardiovascular
Wellness Center, Brigham and Women’s Hospital,
Boston
Joel M. Gore, MD, Edward Budnitz Professor
of Cardiovascular Medicine, University of
Massachusetts, Worcester
Mark S. Link, MD, Associate Professor of Medicine,
New England Medical Center and Tufts University
School of Medicine, Boston
Frederick A. Masoudi, MD, MSPH, Division of
Cardiology, Denver Health Medical Center and
Associate Professor of Medicine, University of
Colorado at Denver
Beat J. Meyer, MD, Associate Professor of
Cardiology, University of Bern; Chief, Division of
Cardiology, Lindenhofspital, Bern, Switzerland
CONTRIBUTING EDITORS
William T. Abraham, MD, Professor of Medicine,
Chief, Division of Cardiovascular Medicine,
The Ohio State University Heart Center, Columbus
Hugh Calkins, MD, Professor of Medicine and
Director of Electrophysiology, The Johns Hopkins
Hospital, Baltimore
FOUNDING EDITOR
Kim A. Eagle, MD, Albion Walter Hewlett Professor
of Internal Medicine and Chief of Clinical
Cardiology, Division of Cardiology, University of
Michigan Medical Center, Ann Arbor
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CARDIOLOGY
was 3.4 in the intensive group and 2.1 in
the standard-care group.
At 5 years, the rate of adverse cardio-
vascular events was 1.9% per year in the
intensive-care group and in 2.1% per year
in the standard-care group (hazard ratio,
0.88; P=0.2). Death rates were similar in
the two groups. No secondary analysis was
strongly positive, except that stroke incidence
was significantly lower in the intensive-care
group than in the standard-care group
(0.32% vs. 0.53%). The intensive-care
group had a higher rate of serious adverse
events, with more decrements in renal
function and more episodes of syncope,
bradycardia, hyperkalemia, and hypoten-
sion. Overall, 3.3% of the intensive-care
group had adverse events attributed to the
medications, compared with 1.3% of the
standard-care group.
COMMENT
This study indicates that intensive blood
pressure control (to levels lower than those
currently recommended by guidelines)
should not be used in high-risk diabetic
patients. The findings leave open the ques-
tion about what the optimal BP target is for
these patients. The overall event rate was
low in both groups, showing what can be
achieved with good contemporary treat-
ment strategies.
— Harlan M. Krumholz, MD, SM
The ACCORD Study Group. Effects of intensive
blood-pressure control in type 2 diabetes mellitus.
N Engl J Med 2010 Mar 14; [e-pub ahead of print].
(http://dx.doi.org/10.1056/NEJMoa1001286)
Diabetes and Cardiovascular
Events: Not a Straight Course
A study of two drugs for the primary pre-
vention of diabetes yielded disappointing
results.
One proposed strategy for reducing the
risk for diabetes in individuals with glu-
cose intolerance is postprandial use of na-
teglinide, a short-acting insulin secret-
agogue. In addition, some studies have
suggested that renin–angiotensin inhibi-
tors (such as angiotensin-converting–
enzyme inhibitors and the angiotensin-
receptor blocker valsartan) might
decrease the risk for diabetes as well as
risks for cardiovascular events (e.g., JW
Cardiol Jan 2002, p. 20, and JAMA 2001;
286:1882); however, this conclusion is
based on secondary endpoints, and the
Vol. 16 No. 4
results have been inconsistent. To find
out more, investigators conducted the
Nateglinide and Valsartan in Impaired
Glucose Tolerance Outcomes Research
(NAVIGATOR) trial, an industry-
sponsored, placebo-controlled, random-
ized trial with a 2×2 factorial design. They
enrolled 9306 adults (50% women; mean
age, 64) with fasting plasma glucose levels
of 95–126 mg/dL and one or more cardio-
vascular risk factors. Median follow-up
was 5.0 years for diabetes incidence and
6.3 years for a composite of cardiovascular
outcomes.
In the valsartan arm, slightly fewer
patients in the valsartan group than in
the placebo group were taking a renin–
angiotensin inhibitor other than the study
drug at the last study visit (20.4% and
24.0%, respectively), and systolic blood
pressure had decreased more in the valsar-
tan group than in the placebo group (6.3
mm Hg vs. 3.8 mm Hg; P<0.001). The
composite cardiovascular outcome rate was
similar in the two groups (14.5% and
14.8% in the valsartan and placebo groups,
respectively; hazard ratio, 0.96; P=0.43).
Diabetes developed in 33.1% of patients in
the valsartan group and 36.8% of patients
in the placebo group (HR, 0.86; P<0.001).
This finding was consistent across sub-
groups. By study’s end, fewer patients in
the valsartan group than in the placebo
group were taking antidiabetic medica-
tions, and the mean increase in fasting glu-
cose level was 0.6 mg/dL lower in the val-
sartan group than in the placebo group.
In the nateglinide arm, the composite
cardiovascular outcome rate was also simi-
lar in the nateglinide and placebo groups
(14.2% and 15.2%, respectively; HR, 0.93;
P=0.20). The between-group difference in
diabetes incidence was not significant
(36% in the nateglinide group and 34% in
the placebo group; HR, 1.07; P=0.05). The
mean increase in fasting glucose level was
0.5 mg/dL lower in the nateglinide group
than in the placebo group. Adverse event
rates were similar in the two groups.
COMMENT
In this trial, nateglinide did not benefit pa-
tients with glucose intolerance, and the
valsartan results were mixed. Although the
rate of progression to diabetes was 14%
lower in the valsartan group than in the pla-
cebo group, no difference in cardiovascular
April 2010
events was seen during the 6-year follow-
up, and the improvement in glycemic con-
trol was modest. Is the benefit gained sub-
stantial enough to justify adding valsartan
to these patients’ regimens?
— Harlan M. Krumholz, MD, SM
The NAVIGATOR Study Group. Effect of valsartan
on the incidence of diabetes and cardiovascular
events. N Engl J Med 2010 Mar 14; [e-pub
ahead of print]. (http://dx.doi.org/10.1056/
NEJMoa1001121)
The NAVIGATOR Study Group. Effect of nateglinide
on the incidence of diabetes and cardiovascular
events. N Engl J Med 2010 Mar 14; [e-pub
ahead of print]. (http://dx.doi.org/10.1056/
NEJMoa1001122)
Nathan DM. Navigating the choices for diabetes
prevention. N Engl J Med 2010 Mar 14; [e-pub
ahead of print]. (http://dx.doi.org/10.1056/
NEJMe1002322)
Is Elective Coronary
Angiography Overused?
In a large registry, less than half of patients
who undergo elective invasive testing had
obstructive coronary artery disease.
Coronary angiography exposes patients to
procedural risks and substantial radiation;
most would agree that we should avoid the
procedure in patients who are unlikely to
require further intervention. To find out
how often patients referred for elective coro-
nary angiography are found not to have
obstructive coronary artery disease (CAD),
investigators for the CathPCI Registry of
the National Cardiovascular Data Registry
assessed the diagnostic yield (prevalence
of obstructive CAD) at 663 participating
sites. Obstructive CAD was defined as
≥50% stenosis of the left main coronary
artery or ≥70% stenosis of a major epicardial
or branch vessel.
Of patients who underwent elective di-
agnostic catheterization (about 20% of all
procedures), 38% had obstructive CAD. If
the definition of obstructive CAD was ex-
panded to ≥50% stenosis in any vessel, the
prevalence increased to only 41%. An in-
crease in diagnostic yield from 2004 (36.8%)
to 2008 (38.8%) was significant but very
small. Almost 70% of the patients under-
going elective coronary angiography had
positive findings on resting electrocardiog-
raphy, echocardiography, computed tomog-
raphy, or stress testing; however, these data
were only available as a composite.
JWatch.org
COMMENT
In this national study, the diagnostic yield
of elective coronary angiography was re-
markably low: only 38%. However, an an-
giogram’s results do not tell us whether it
was appropriately ordered. Because the non-
invasive testing variable included a wide
range of procedures — from resting electro-
cardiography to stress testing — we cannot
speculate from the data how many catheteri-
zations could have been avoided. Nonethe-
less, these results suggest room for improve-
ment and underscore the importance of
implementing evidence-based appropriate-
ness criteria for coronary angiography.
— Harlan M. Krumholz, MD, SM
Patel MR et al. Low diagnostic yield of elective coro-
nary angiography. N Engl J Med 2010 Mar 11;
362:886.
Brenner DJ. Medical imaging in the 21st century —
Getting the best bang for the rad. N Engl J Med
2010 Mar 11; 362:943.
Dopamine vs. Norepinephrine
in Treatment of Shock
A large randomized trial shows significantly
higher mortality with dopamine among
patients with cardiogenic shock.
When fluid therapy is not successful in
reversing a shock state, adrenergic agents
are used, most commonly dopamine
or norepinephrine. These agents differ
in their modes of action, as they affect
α -adrenergic and β -adrenergic receptors
differently. Observational studies have
shown higher death rates with dopamine
than with norepinephrine in patients
with shock; the few randomized trials to
date have been too small to provide mean-
ingful data.
In the current multicenter European
study, 1679 adult patients with shock (signs
of tissue hypoperfusion and systolic blood
pressure <100 mm Hg or mean arterial
pressure <70 mm Hg) that persisted after
treatment with “adequate” fluids (at least
1000 mL of crystalloids or 500 mL of col-
loids) were randomized to receive dopa-
mine or norepinephrine. Patients who had
already received vasopressors for more
than 4 hours were excluded. Treating phy-
sicians were blinded to drug assignment.
Patients with hypovolemic shock, cardio-
genic shock, and septic shock were included.
31
The primary endpoint was the rate of death
at 28 days. Secondary endpoints included
time to hemodynamic stability and inci-
dence of adverse events, such as serious ar-
rhythmias and myocardial necrosis.
Rates of death at 28 days and times to
hemodynamic stability did not differ sig-
nificantly between the dopamine and nor-
epinephrine groups. However, significantly
more patients in the dopamine group than
in the norepinephrine group experienced
arrhythmias (24% vs. 12%). A predefined
subgroup analysis according to type of
shock showed that among 280 patients
with cardiogenic shock, the death rate at
28 days was significantly higher in dopa-
mine recipients than in norepinephrine
recipients. An editorialist notes the rela-
tively low amount of fluids considered by
the investigators to be adequate to gauge
response before starting vasopressors.
COMMENT
The authors “strongly challenge” the cur-
rent American College of Cardiology/
American Heart Association guidelines
that recommend dopamine as a first-line
agent for cardiogenic shock. In such cases,
norepinephrine seems to be the prudent
choice. No evidence supports one agent
over the other for different forms of shock.
— J. Stephen Bohan, MD, MS, FACP,
FACEP, Journal Watch Emergency
Medicine
De Backer D et al. Comparison of dopamine and
norepinephrine in the treatment of shock. N Engl J
Med 2010 Mar 4; 362:779.
Levy JH. Treating shock — Old drugs, new ideas.
N Engl J Med 2010 Mar 4; 362:841.
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32
Postsurgical Pericardial Effusion:
Do NSAIDs Make a Difference?
In a small randomized trial, diclofenac was no
better than placebo at reducing pericardial
effusion and preventing cardiac tamponade.
Asymptomatic pericardial effusion is com-
mon after cardiac surgery. After the im-
mediate postoperative period, pericardial
effusions are considered to be largely caused
by inflammation and are frequently treated
with nonsteroidal anti-inflammatory drugs
(NSAIDs). However, until now, no trials
have examined this practice. To assess
whether the NSAID diclofenac effectively
reduces postoperative pericardial effusion,
investigators conducted a multicenter, ran-
domized, double-blind study.
Researchers assigned 196 patients
(mean age, 63; 80% men) at high risk for
cardiac tamponade because of moderate-to-
large pericardial effusions ≥7 days after
heart surgery to receive diclofenac (50 mg)
or placebo twice a day for 14 days. The two
groups were well matched at baseline in
terms of clinical characteristics, type of sur-
gery, and medication use. The mean grade
of pericardial effusion was 2.58 in the pla-
cebo group and 2.75 in the diclofenac group.
The mean change in grade of pericar-
dial effusion from baseline to 14 days was
–1.08 in the placebo group and –1.36 in the
diclofenac group, a nonsignificant differ-
ence. Secondary endpoints, including the
frequency of cardiac tamponade, also did
not differ significantly between the two
groups.
COMMENT
Compared with placebo, diclofenac failed to
reduce either the size of postcardiac surgery
effusions or the rate of progression to car-
diac tamponade. As an editorialist notes,
these findings underscore our limited
understanding of the pathogenesis of post-
operative pericardial effusions, which might
not be primarily inflammatory. At this
point, asymptomatic, moderate-to-large
effusions probably do not require treatment
unless inflammation is documented.
— Joel M. Gore, MD
Meurin P et al. Nonsteroidal anti-inflammatory
drug treatment for postoperative pericardial effu-
sion: A multicenter randomized, double-blind trial.
Ann Intern Med 2010 Feb 2; 152:137.
Imazio M. Asymptomatic postoperative pericardial ef-
fusions: Against the routine use of anti-inflammatory
drug therapy. Ann Intern Med 2010 Feb 2; 152:186.
CARDIOLOGY
CABG in High-Risk Patients: To
Pump or Not to Pump?
The two types of CABG yielded similar
short-term outcomes.
Randomized comparisons of off-pump
and on-pump coronary artery bypass
grafting (CABG) have primarily focused
on low-risk patients (e.g., JW Cardiol Jun
2004, p. 55, and JAMA 2004; 291:1841).
Now, investigators in Denmark have com-
pared the two types of CABG in a random-
ized trial involving 341 high-risk patients
(mean age, 76; 65% men) who had three-
vessel disease and EuroSCOREs ≥5. In each
group, 18% of patients had diabetes.
The off-pump and on-pump groups
did not differ significantly in the mean
number of grafts per patient or in the com-
pleteness of revascularization. However,
significantly fewer grafts were performed
in the lateral territory of the left ventricle in
the off-pump group than in the on-pump
group (0.97 vs. 1.14; P=0.01).
At 30 days, the two groups had statisti-
cally similar incidences of postoperative
complications and all-cause mortality. In-
cidence of the primary composite endpoint
— death, myocardial infarction (MI), car-
diac arrest with successful resuscitation,
low cardiac output syndrome, stroke, or
coronary reintervention — was also similar
in the off-pump and on-pump groups.
More than 40% of patients in each group
experienced new-onset atrial fibrillation.
The biggest between-group outcome dif-
ference was in MI incidence at 30 days
(off-pump, 5.1%; on-pump, 9.2%), but
this, too, did not reach statistical signifi-
cance. Results did not vary significantly
according to patient EuroSCORE.
COMMENT
In this trial involving high-risk patients
undergoing CABG, 30-day mortality and
morbidity rates were similar after the off-
pump version of the procedure, compared
with the on-pump version. The findings
suggest that off-pump CABG provides no
short-term advantages over on-pump
CABG. — Joel M. Gore, MD
Møller CH et al. No major differences in 30-day
outcomes in high-risk patients randomized to off-
pump versus on-pump coronary bypass surgery:
The Best Bypass Surgery trial. Circulation 2010
Feb 2; 121:498.
Vol. 16 No. 4
Adherence to Guidelines for
Coronary Revascularization
Invasive cardiologists recommend more PCI
often than is indicated by current guidelines.
The American College of Cardiology (ACC)
and the American Heart Association (AHA)
have issued guidelines for coronary revascu-
larization by percutaneous coronary inter-
vention (PCI; published in 2001 and
updated in 2005) and by coronary artery
bypass grafting (CABG; published in 2004).
To assess the extent to which invasive cardi-
ologists adhere to these guidelines, investi-
gators examined New York State data on
16,142 patients who underwent cardiac
catheterization in 2005–2007.
The analysis included only the 64%
of patients whose final revascularization
strategy recommendation was made by
the catheterization-laboratory cardiologist.
Of patients with guideline indications for
CABG, CABG was recommended for 53%,
PCI for 34%, and medical management for
12%. Of patients with guideline indications
for PCI, PCI was recommended for 94%,
CABG for 2%, and medical treatment for
4%. Of the 17% of patients with guideline
indications for both CABG and PCI, PCI
was recommended for 93%. Of the patients
who had guideline indications for CABG
and had unstable angina or non–ST-
segment-elevation myocardial infarction
and proximal left anterior descending ar-
tery disease in one or two vessels, only 4%
received recommendations for CABG. PCI
was recommended for patients with guide-
line indications for CABG more often in
hospitals with PCI capability than in hospi-
tals without PCI capability.
COMMENT
This provocative study demonstrates that in
the real world, PCI is recommended more
often than it is indicated by current guide-
lines. This might reflect bias of catheteriza-
tion-laboratory cardiologists, disagreement
with the guideline recommendations, prac-
tice changes based on studies more recent
than those that informed the guidelines,
study limitations (sampling errors, absence
of data for patient characteristics and prior
medical therapy), and — very important —
patient preferences. We need outcomes data
to fully understand the implications of these
findings and to assess more-multidisci-
plinary approaches to developing treatment
recommendations for our patients.
— Howard C. Herrmann, MD
April 2010
Hannan EL et al. Adherence of catheterization
laboratory cardiologists to American College of Car-
diology/American Heart Association guidelines for
percutaneous coronary interventions and coronary
artery bypass graft surgery: What happens in actual
practice? Circulation 2010 Jan 19; 121:267.
Gibbons RJ. Get with the guidelines: A new chapter?
Circulation 2010 Jan 19; 121:194.
Sirolimus-Eluting Stents
Outperform Zotarolimus-
Eluting Stents
A randomized trial design combined with
follow-up data from a Danish national
registry generates compelling evidence of
superiority.
Recent concerns about late stent thrombo-
sis and evidence of delayed in-stent reste-
nosis have fueled the development of a
new generation of drug-eluting stents. To
compare the novel zotarolimus-eluting
stent with the well-established sirolimus-
eluting stent, investigators in Denmark
conducted a single-blind, all-comer,
manufacturer-funded trial in patients
undergoing percutaneous coronary inter-
vention for chronic stable coronary artery
disease or acute coronary syndromes
(ACS). A total of 2332 patients (mean
age, 64; 73% men) with 3230 coronary
lesions were randomly assigned to receive
zotarolimus-eluting or sirolimus-eluting
stents. Follow-up data at 9 and 18 months
were obtained from national administra-
tive and healthcare registries.
The incidence of the composite end-
point — cardiac death, myocardial infarc-
tion (MI), and target-vessel revasculariza-
tion — was significantly higher in the
zotarolimus-eluting stent group than in
the sirolimus-eluting stent group at
9 months (6% vs. 3%; P=0.0002) and
18 months (10% vs. 5%; P<0.0001). All-
cause mortality was 2% in both groups at
9 months but was significantly higher in
the zotarolimus-eluting stent group at
18 months (4% vs. 3%; P=0.035).
COMMENT
These findings suggest that sirolimus-
rates in both groups. However, this ap-
eluting stents are superior to zotarolimus-
proach seems cost-saving and allowed
eluting stents and highlight the importance
inclusion of a relatively high number of
of longer follow-up times in drug-eluting
patients with ACS, multivessel disease, or
stent trials. The innovative use of a national
complex lesions who would normally be ex-
healthcare database rather than follow-up
cluded from contemporary clinical trials.
study visits to record clinical outcomes
— Beat J. Meyer, MD
contributed to lower-than-expected event
JWatch.org
CLINICAL PRACTICE GUIDELINE WATCH
How to Prevent and Manage Cardiac Device Infections
Increasing rates of device implantation and associated infections have
prompted the American Heart Association to update its advice to clinicians.
Sponsoring Organization: American
Heart Association (AHA), with en-
dorsement from the Heart Rhythm
Society
Background and Purpose: The use of
cardiovascular implantable electronic
devices (CIEDs), such as pacemakers
and defibrillators, has markedly in-
creased as indications expand and the
population ages. However, the incidence
of CIED infections has risen even faster
(Pacing Clin Electrophysiol 2009), de-
spite technological advances in implan-
tation procedures and in the devices
themselves. Accordingly, the AHA has
updated its scientific statement on
prevention and management of these
infections.
Key Points:
1. Citing recent research, the authors
identify several risk factors for CIED
infection:
• Immunosuppression, including
renal dysfunction, diabetes, and
corticosteroid use
• Oral anticoagulation use
• Coexisting illness
• Periprocedural factors (including
failure to administer perioperative
antibiotic prophylaxis, preopera-
tive fever, and preprocedural
temporary pacing)
• Device revision or replacement
• Coexisting indwelling hardware,
including bloodstream infections
related to such hardware
• Operator inexperience
2. Staphylococcal species account for
60% to 80% of CIED infections,
33
roughly split between Staphylococcus
aureus and coagulase-negative
staphylococci.
3. Class I diagnostic recommendations,
nearly all based on expert consensus,
include drawing at least two sets of
blood cultures before initiating antibi-
otic therapy, Gram stain and culture
of the generator pocket and lead tip,
and transesophageal echocardiogra-
phy in cases of positive blood culture
or high suspicion of endocarditis.
4. Device removal may be avoided if in-
fection is superficial and does not in-
volve any hardware. In such cases,
7 to 10 days of oral antistaphylococcal
therapy is reasonable. However, if
any part of the device is infected,
complete removal of all hardware is
recommended.
5. Of course, prophylaxis with an antibi-
otic that has in vitro activity against
staphylococci should immediately
precede all CIED placements.
COMMENT
Given the significant morbidity and
mortality associated with CIED infec-
tions, physicians must be extremely vigi-
lant about preventing them. The focus
should be on appropriate selection of
patients and timing of implantation; use
of preoperative antibiotics and sterile
implantation techniques; and diligent,
guideline-recommended postoperative
care. — Mark S. Link, MD
Baddour LM et al. Update on cardiovascular
implantable electronic device infections and their
management: A scientific statement from the
American Heart Association. Circulation 2010
Jan 26; 121:458.
Rasmussen K et al. Efficacy and safety of zotarolimus-
eluting and sirolimus-eluting coronary stents in rou-
tine clinical care (SORT OUT III): A randomised
controlled superiority trial. Lancet 2010 Mar 15;
[e-pub ahead of print]. (http://dx.doi.org/10.1016/
S0140-6736(10)60208-5)
Webster MWI and Ormiston JA. Sorting out
drug-eluting stents. Lancet 2010 Mar 15; [e-pub
ahead of print]. (http://dx.doi.org/10.1016/
S0140-6736(10)60402-3)
34
Dual Antiplatelet Therapy
After Drug-Eluting Stenting:
When to Stop?
Combined data from two randomized trials
suggest no additional benefit after 1 year.
To determine the optimal duration of dual
antiplatelet therapy (DAPT) with aspirin
and clopidogrel after drug-eluting stent
(DES) implantation, investigators in Korea
combined data from two randomized trials
that had similar designs and slower-than-
anticipated enrollment. A total of 2701 pa-
tients who experienced no major adverse
cardiovascular or bleeding events while
taking DAPT for at least 12 months after
receiving one or more DES (57% sirolimus-
eluting) were assigned to either continue
DAPT or receive low-dose aspirin alone.
Eighty-eight percent were enrolled between
12 and 18 months after stent implantation.
At 2-year follow-up (median, 19
months), the estimated rate of the primary
composite endpoint — myocardial infarc-
tion (MI) and cardiac death — was 1.8% in
the DAPT group and 1.2% in the aspirin-
only group, a statistically nonsignificant
difference. Compared with the aspirin-
only group, the DAPT group showed a
trend toward an increase in the secondary
composite endpoint of MI, cardiac death,
and stroke (hazard ratio, 1.84; P=0.06).
COMMENT
In this analysis, DAPT given >1 year after
DES implantation conferred no benefit
compared with aspirin alone. These find-
ings differ from those of previous studies
that suggested an increase in late stent
thrombosis after clopidogrel discontinu-
ation (JW Cardiol Feb 2007, p. 13, and
Am J Med 2006; 119:1056). This study had
a low event rate and may have been under-
powered for a clinically important differ-
ence in the primary outcome. The results
also might not apply to patients who under-
go surgery or who have multiple or more-
complex stenting procedures, different
DES types, or aspirin resistance. Until a
larger randomized trial is completed, I will
continue to recommend prolonged DAPT
for most of my DES patients who have no
contraindications or adverse effects.
— Howard C. Herrmann, MD
Park S-J et al. Duration of dual antiplatelet therapy
after implantation of drug-eluting stents. N Engl J
Med 2010 Mar 15; [e-pub ahead of print]. (http://
dx.doi.org/10.1056/NEJMoa1001266)
CARDIOLOGY
Berger PB. Optimal duration of clopidogrel use after
implantation of drug-eluting stents — Still in doubt.
N Engl J Med 2010 Mar 15; [e-pub ahead of print].
(http://dx.doi.org/10.1056/NEJMe1002553)
Clopidogrel and
Proton-Pump Inhibitors:
How Much of a Problem?
If an interaction exists, it is unlikely to raise
cardiovascular risks by >20%.
Recent studies have suggested an interac-
tion between clopidogrel and proton-pump
inhibitors (PPIs) that might attenuate
clopidogrel activity. To assess the clinical
relevance of this interaction, researchers
studied 18,000 people (age, ≥65) in the U.S.
and Canada who had been newly treated
with clopidogrel after acute coronary
syndromes or percutaneous coronary
intervention.
In pooled analyses, rates of subsequent
hospitalizations for myocardial infarction
(2.6% vs. 2.1%), death (1.5% vs. 0.9%),
and revascularization (3.4% vs. 3.1%) were
slightly higher in PPI users than in non-
users. In propensity score–adjusted analyses,
point estimates for rates of MI or death
(1.22; 95% confidence interval, 0.99–1.51),
death (1.20; 95% CI, 0.84–1.70), and revas-
cularization (0.97; 95% CI, 0.79–1.21) also
were slightly — but not significantly —
higher.
COMMENT
In this analysis, PPI use was associated
with slightly higher, but not statistically
different, event rates. If an interaction be-
tween PPIs and clopidogrel exists, it is un-
likely to raise risk for adverse cardiovascu-
lar events by more than 20%. An editorialist
suggests three ways to manage this situa-
tion: (1) carefully evaluate whether a PPI is
necessary; (2) if a PPI is needed, consider
using pantoprazole, as data suggest this
agent is less likely than omeprazole to in-
hibit the cytochrome P450 system (CYP is
responsible for converting clopidogrel to its
active metabolite); and (3) stagger timing
of the two medications to take advantage
of transient PPI inhibition and rapid clo-
pidogrel metabolism.
— Kirsten E. Fleischmann, MD, MPH,
Journal Watch General Medicine
Rassen JA et al. Cardiovascular outcomes and mor-
tality in patients using clopidogrel with proton pump
inhibitors after percutaneous coronary intervention
or acute coronary syndrome. Circulation 2009 Dec
8; 120:2322.
Vol. 16 No. 4
Juurlink DN. Proton pump inhibitors and clopidogrel:
Putting the interaction in perspective. Circulation
2009 Dec 8; 120:2310.
Silent Cerebral Embolism
After Transcatheter
Aortic-Valve Implantation
Two studies from Germany show that
it is common.
Transcatheter aortic-valve implantation
(TAVI) is a new therapy approved in
Europe for high-risk patients with aortic
stenosis. The risk for stroke after TAVI ap-
pears similar to that after aortic-valve re-
placement (AVR) surgery, an observation
that is being tested in an ongoing U.S. ran-
domized trial. In the meantime, investiga-
tors in Germany have assessed the risks for
silent and clinical cerebral ischemic events
after TAVI in two case series.
In one study, 32 patients (mean age,
80) underwent TAVI: 22 with the balloon-
expandable SAPIEN device and 10 with the
self-expanding CoreValve device. Many
patients had other potential sources of em-
bolism (chronic atrial fibrillation in 6 pa-
tients, reduced left-atrial appendage peak
velocity in 16, moderate aortic-arch ather-
oma in 5, and carotid stenosis >30% in 12).
The National Institutes of Health Stroke
Scale ratings and measures of global cogni-
tive function showed no significant changes
between pre-TAVI assessments and those
done at about 3 days and at 3 months after
TAVI. Diffusion-weighted magnetic reso-
nance imaging (MRI) detected new cerebral
lesions after TAVI in 84% of the patients;
the foci were multiple and dispersed, sug-
gesting embolic origin. No new lesions
appeared between 3 days and 3 months
after TAVI. In a group of 21 historical con-
trols (mean age, 67) who had undergone
AVR surgery, new cerebral lesions after
open surgery were significantly less com-
mon (48%), but of larger volume, than
after TAVI. Stroke was diagnosed in one
AVR patient 2 days after surgery.
In the other study, 22 patients (mean
age, 79) underwent TAVI with the CoreValve
device. Diffusion-weighted MRI detected
new lesions soon after TAVI in 73% of the
patients. Lesions tended to be left-sided
and to occur in patients with substantial
baseline cerebrovascular and peripheral
arterial disease. Longer procedure duration
did not correlate with the presence of
April 2010
lesions. Neurological deficits were evident
in three patients within 2 days after TAVI
but persisted in only one patient at 3 months.
COMMENT
These studies of TAVI document a high
short-term incidence of postprocedure cer-
ebral emboli, most of which were clinically
silent. Causes might include procedural
hypotension, catheter manipulation in a dis-
eased aorta, or balloon and device effects
on the stenotic aortic valves. The findings
point to a possible need to develop strate-
gies and devices for cerebral protection
during TAVI. Longer-term studies and
more-sensitive neuropsychological testing
are necessary to rule out late neurocogni-
tive decline.
— Howard C. Herrmann, MD
Kahlert P et al. Silent and apparent cerebral ische-
mia after percutaneous transfemoral aortic valve
implantation: A diffusion-weighted magnetic reso-
nance imaging study. Circulation 2010 Feb 23;
121:870.
Adams HP Jr. Ischemic cerebrovascular complica-
tions of cardiac procedures. Circulation 2010 Feb
23; 121:846.
Ghanem A et al. Risk and fate of cerebral embolism
after transfemoral aortic valve implantation: A pro-
spective pilot study with diffusion-weighted mag-
netic resonance imaging. J Am Coll Cardiol 2010
Feb 24; [e-pub ahead of print]. (http://dx.doi
.org/10.1016/j.jacc.2009.12.026)
Statins and Stroke Prevention:
Is It All About the Cholesterol?
In a meta-analysis, stroke reduction was
proportional to the lipid-lowering effect
of the intervention.
Trial data indicate that statins reduce the
incidence of stroke, but the mechanism of
this reduction remains unclear. Some have
suggested that statins’ benefit with regard
to stroke is independent of LDL or total
cholesterol reduction and might relate to
pleiotropic effects.
To assess the association between
stroke reduction and change in total cho-
lesterol, investigators performed a large
meta-analysis of randomized trials of lipid-
lowering treatments, involving reported
outcomes in 266,973 patients. Overall,
the odds ratio for stroke incidence was
0.88 (95% confidence interval, 0.83–0.94;
P<0.001) in treated individuals versus pla-
cebo or no treatment. Statin therapy was
associated with a reduction in risk for total
stroke (OR, 0.85; 95% CI, 0.78–0.92;
JWatch.org
P<0.001), whereas the ORs for nonstatin
interventions were smaller and nonsignifi-
cant (nondrug interventions, 0.92; fibrates,
0.98; other drugs, 0.81).
The investigators noted a significant
linear association between reduction in
total and LDL cholesterol levels and per-
cent reduction in total stroke incidence
(P=0.0017). Specifically, each 1% reduc-
tion in total cholesterol predicted a 0.8%
reduction in relative risk for stroke. After
multiple adjustments, stroke reduction was
not significantly associated with changes in
HDL or triglyceride levels.
COMMENT
In this meta-analysis, the benefits of statins
for stroke prevention outstripped the ben-
efits of other lipid-lowering approaches,
consistent with findings from individual
clinical trials. The overall benefit was pro-
portional to the reductions in total and
LDL cholesterol levels, but these data do
not demonstrate that lipid-lowering per se
mediates the effect. Given that the evidence
for statins’ effectiveness is strong, and the
evidence for the effectiveness of other in-
terventions is both scarce and weak, the
use of nonstatin therapies for stroke pre-
vention is unjustified at this time.
— JoAnne M. Foody, MD
De Caterina R et al. Cholesterol-lowering interven-
tions and stroke: Insights from a meta-analysis of
randomized controlled trials. J Am Coll Cardiol
2010 Jan 19; 55:198.
The Changing Profile of MI
MIs are becoming less severe, and early
survival is improving, but long-term
outcomes remain a challenge.
In August 2000, the biomarker component
of the diagnostic criteria for myocardial
infarction (MI) changed from creatine
kinase-MB (CK-MB) to troponin, compli-
cating efforts to track trends in MI inci-
dence, severity, and outcomes. Fortunately,
data gathered for decades in Olmsted
County, Minnesota, make the task feasible.
From 1987 through 2006, 2816 patients
in that region (43%women; 39% aged ≥75)
were hospitalized for MI. Of the 1127 MIs
that occurred after August 2000, 25% met
the troponin but not the CK-MB criteria.
Patients whose MIs met only the troponin
criteria were older, were more likely to be
female, and had more comorbidities than
those whose MIs met the CK-MB criteria.
35
When both CK-MB–diagnosed and
troponin-diagnosed MIs were counted, in-
cidence did not change significantly over
time. When only CK-MB–diagnosed MIs
were counted, age- and sex-adjusted inci-
dence per 100,000 people declined mark-
edly (from 186 in 1987 to 141 in 2006;
P=0.02). Regardless of the MI definition
used, significant declines occurred during
the study period in incidence of ST-segment-
elevation MI (which decreased by 41%),
the proportion of patients in a Killip class
>1, and the median peak CK-MB ratio.
Time from symptom onset to first electro-
cardiogram (ECG) remained roughly
constant.
The 30-day case fatality rate declined
by 4.3% per year, equivalent to a 56% re-
duction in the hazard ratio from 1987
through 2006. This trend did not vary by
age or sex or when troponin-diagnosed
MIs were excluded. Interestingly, survival
beyond 30 days (mean follow-up, 6.0
years) did not change. However, the
percentage of posthospitalization deaths
attributable to cardiovascular causes
dropped from 62% to 50%.
COMMENT
These data provide remarkable insights
into the changing nature of MI. Early sur-
vival has improved, and incidence has not
increased, despite the use of more-sensitive
tests. We must continue to strive to shorten
the time from symptom onset to first ECG
and to improve outcomes after 30 days.
— Harlan M. Krumholz, MD, SM
Roger VL et al. Trends in incidence, severity, and
outcome of hospitalized myocardial infarction.
Circulation 2010 Feb 23; 121:863.
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from “Adherence to Guidelines for Coronary
Revascularization” (p. 32)
JWatch.org
Which of the following statements
describes a finding from a study of
interventional cardiologists’ adherence
to guidelines?
A. Of patients with indications for CABG,
PCI was recommended for 12%.
B. Of patients with indications for PCI,
PCI was recommended for 94%.
C. Most patients with indications for
CABG who had proximal left anterior
descending artery disease and MI
received recommendations for CABG.
D. Of patients with indications for CABG,
medical management was recom-
mended for about 25%.
Category: Cardiovascular Diseases
Exam Title: Coronary Revascularization
Posted Date: Mar 9 2010
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CME FACULTY
Kelly Anne Spratt, DO, FACC, Section Editor, Cardiology

36 CARDIOLOGY Vol. 16 No. 4

Rate Control for Atrial Fibrillation:
Can We Relax?
In a randomized trial, patients whose heart
rates were strictly controlled fared no better
than those treated more leniently.
In many patients with relatively few symp-
toms, atrial fibrillation (AF) can be man-
aged with heart rate control alone, with-
out rhythm correction. Traditionally, the
target in such cases has been the rate that
would be expected in a similar patient in
sinus rhythm. However, a retrospective
analysis of data from two trials of rate
versus rhythm control (http://dx.doi
.org/10.1093/europace/eul106) showed no
clinical benefit from such strict control. In
the current prospective Dutch trial, inves-
tigators randomized 614 patients with AF
suitable for management with rate control
alone to either strict control (<80 beats/
minute at rest and <110 beats/minute dur-
ing moderate exercise) or lenient control
(<110 beats/minute at rest).
At the end of the dose-titration phase of
the trial, the mean resting heart rate was
markedly different in the strict- and lenient- Van Gelder IC et al. Lenient versus strict rate
control in patients with atrial fibrillation. N Engl J
control groups (76 vs. 93 beats/minute),
Med 2010 Mar 15; [e-pub ahead of print]. (http://
but by 1 year, the difference had narrowed dx.doi.org/10.1056/NEJMoa1001337)
(75 vs. 86 beats/minute). At 3 years, the
Dorian P. Rate control in atrial fibrillation. N Engl J
composite rate of death, hospitalization for Med 2010 Mar 15; [e-pub ahead of print]. (http://
heart failure, stroke, embolization, bleeding, dx.doi.org/10.1056/NEJMe1002301)
and life-threatening arrhythmia did not dif-
fer significantly between the groups.
COMMENT
This study is the third to show no outcome
improvement in patients with atrial fibril-
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short-term trials, and remodeling associ- • Relevant information and practical
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Furthermore, even the patients in the that affects your practice
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alist reminds us, adverse drug effects may key sources
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