Original Scientific Paper

Risk factors for prolonged QTc among US adults: Third

National Health and Nutrition Examination Survey
Stephen R. Benoit, Aaron B. Mendelsohn, Parivash Nourjah,
Judy A. Staffa and David J. Graham

Food and Drug Administration, Rockville, Maryland, USA.

Received 11 September 2004 Accepted 6 May 2005

Background QT interval prolongation can lead to torsades de pointes, a potentially fatal arrhythmia. Although research
exists on the relationship between QT prolongation and clinical outcome, few studies have described risk factors for
prolonged QT interval in the general population.
Methods The Third National Health and Nutrition Examination Survey (NHANES III) collected electrocardiogram interval
data on 8561 subjects over 40 years of age and projected results to the US population. QT was corrected for heart rate
using Fridericia’s formula. Logistic regression analyses were performed to identify factors independently associated with
prolonged QTc interval, defined as being in the upper 5% of the population QTc interval distribution. Analyses were
conducted separately for women and men as a result of differences in the QT distribution between the sexes and also
because of potential effect modification. Analytical variables included age, race/ethnicity, electrolyte measurements, body
mass index, the recent use of QT-prolonging drugs and past medical histories of stroke, thyroid disease, hypertension,
diabetes and myocardial infarction.
Results Age, female sex, hypocalcemia (men), hypokalemia (women), and a history of thyroid disease and myocardial
infarction (men) were associated with a prolonged QTc interval. In addition, taking QT-prolonging medications in the past
month was associated with more than a twofold increase in the odds of prolonged QTc interval in both men and women.
Conclusions Healthcare practitioners should be aware that a prolonged QTc interval is a potential indicator of
cardiovascular risk, and should exercise caution in prescribing potentially QT-prolonging medications to certain
patients. Eur J Cardiovasc Prev Rehabil 12:363–368 c 2005 The European Society of Cardiology

European Journal of Cardiovascular Prevention and Rehabilitation 2005, 12:363–368

Keywords: medications, NHANES, QTc prolongation, risk factors, torsades

Sponsorship: S.R.B.’s participation in this project was partly supported by an appointment to the Research Fellowship Program at the Center for Drug Evaluation and
Research administered by the Oak Ridge Associated Universities through a contract with the Food and Drug Administration.

Introduction Many factors including age, female sex, hypokalemia,

Prolongation of the QT interval, as measured by an
electrocardiogram (ECG), has been used as a tool to
predict fatal arrhythmic events [1]. Although the true
relationship between the QT interval and clinical out-
come is unknown, some epidemiological studies have
shown an increased risk of cardiac death among those
with prolonged QT intervals [2–6].
Correspondence and requests for reprints to Stephen R. Benoit, MD, MPH,
Centers for Disease Control and Prevention, 1600 Clifton Road NE, MS E-68,
Atlanta, GA 30333, USA.
Tel: + 1 404 498 1267; fax: + 1 404 498 1244;
e-mail: bvy8@cdc.gov
1741-8267 c 2005 The European Society of Cardiology
Downloaded from cpr.sagepub.com at Australian National University on March 16, 2015
cardiac disease and gene mutations have been implicated
in QT interval prolongation [5,7–9]. Drug effects on QT
have also been identified, particularly in the light of fatal
cardiac events associated with the use of terfenadine and
cisapride [10–12]. Certain medications in classes such as
anti-arrhythmics, antibiotics, antipsychotics and anti-
depressants prolong ventricular repolarization, lengthen-
ing the QT interval [13].
Although much is known about the factors that prolong
the QT interval, few have described the epidemiology of
QT duration in a representative sample of the US

Copyright © European Society of Cardiology. Unauthorized reproduction of this article is prohibited.

 364 European Journal of Cardiovascular Prevention and Rehabilitation 2005, Vol 12 No 4

population. We used data from the Third National Health typically longer in women versus men, separate analyses
and Nutrition Examination Survey (NHANES III) to were performed by sex [7,8,18].
describe QT interval measurements in the US population
as well as to quantify the association between known risk Analysis was conducted using logistic regression. QTc
factors and QT prolongation. The risk factor profile prolongation was defined as those subjects (cases) from
generated by this study may help healthcare providers NHANES III with QTc intervals falling into the upper
avoid QT-prolonging medications in vulnerable popula- 5th percentile of the QTc interval distribution. As there is
tions. no declared threshold of risk for QTc duration, studies
differ in how QTc prolongation is defined. Our goal was to
capture the risk factors of those at highest risk, and the
Methods upper 5th percentile was considered a reasonable
NHANES III was conducted by the National Center for cutpoint. Female cases represented participants with a
Health Statistics between 1988 and 1994, and focused on Fridericia-corrected QTc greater than 463 ms and men
the health and nutrition of US residents 2 months of age greater than 454 ms (Table 1). The reference (controls)
and older. Details of the study design and sampling population for all comparisons was the remaining patients
methods have been published previously [14]. Partici- with ECG and QTc data.
pants aged 40 years and above were eligible for a single
resting 12-lead ECG. QT intervals were machine read and SAS 8.02 (SAS Institute Inc., Cary, North Carolina, USA)
calculated using the Novacode ECG program [15]. and SUDAAN (8.0.2) (Research Triangle Institute,
Research Triangle Park, North Carolina, USA) were used
Of 8561 subjects who underwent ECG testing, 194 were in data analyses. Sample weights were applied to provide
removed as a result of missing QT interval data or other nationally representative estimates and SUDAAN was
key variables. This analysis is based on the remaining used to calculate variance estimates given the complex,
8367 participants. The corrected QT interval (QTc), multistage survey design of NHANES III. Logistic
which adjusts for the effects of heart rate on QT duration, regression was used to examine univariable and multi-
was the outcome variable of interest. In order to variable associations with QTc prolongation. Although the
determine the most appropriate correction formula, Fridericia formula corrects for heart rate, no correction
QTc by heart rate was plotted for both Bazett and formula is ideal and therefore heart rate was included in
Fridericia equations and assessed with univariable linear all models [3]. All analyses utilized the weighted
regression models. As QTc corrects for heart rate, no estimates from the NHANES III dataset. Diagnostics
relationship should exist between heart rate and QTc were assessed using tolerance values. All tolerance values
after correction has been performed (b = 0 for linear were substantially greater than 0.10, indicating that
regression line). A visible association was evident with the collinearity among the independent variables was not
Bazett correction (b = 0.92, P < 0.0001) but much less so present.
with the Fridericia plot (b = – 0.11, P < 0.0001). There-
fore, Fridericia’s formula was used for QT interval Results
correction [16], and heart rate was included in subse- QTc intervals were normally distributed within the
quent regression models. population. The mean QTc was significantly longer in
women than men (426 versus 417 ms, respectively,
Analytical variables selected from the NHANES III P < 0.0001), and was positively correlated with age
dataset included age, sex and race/ethnicity (white, (P < 0.0001) (Table 1, Figs 1 and 2). Little variation
black, Mexican-American and other), as well as other
variables previously found to be associated with QT
Table 1 QTc (Fridericia) characteristics in milliseconds by age, sex
prolongation such as serum calcium (< 2.1 mmol/l = and race/ethnicity. The Third National Health and Nutrition
hypocalcemia) and potassium (< 3.5 mmol/l = hypo- Evaluation Survey, 1988–1994
kalemia), and body mass index (BMI) [7]. We plotted Mean Standard error 95th percentile
BMI versus QTc interval and found a non-linear relation-
Sex
ship, and categorized this variable based on plot results Female 426 0.51 463
and known cutpoints for BMI: underweight (BMI < 18.5 Male 417 0.56 454
kg/m2), reference (18.5 r BMI < 30), obese (30 r BMI Age (years)
40–49 417 0.58 450
<40) and very obese (BMI Z 40). Self-reported history of 50–64 423 0.54 459
stroke, thyroid disease, diabetes, hypertension and myocar- 65 + 428 0.82 469
Race
dial infarction were also evaluated. Finally, we examined the White 422 0.49 459
effects of taking a potentially QT-prolonging drug such as Black 422 0.82 463
certain antimicrobial, anti-emetic and antipsychotic agents Mexican-American 423 0.75 461
Other 423 1.87 452
in the past 30 days [10,17]. Because QTc interval length is

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 Risk factors for prolonged QTc Benoit et al. 365

Fig. 1 and having a self-reported history of diabetes (OR 2.01)

than female controls.
50 00 000
40 00 000
Multivariable modeling showed a similar effect in men
Men

30 00 000
and women for age and history of thyroid disease. We also
20 00 000
found that the recent use of QT-prolonging medications
10 00 000
achieved statistical significance for both men [OR, 2.11;
0
95% confidence interval (CI), 1.002, 4.44] and women
50 00 000
40 00 000
[OR, 2.15; 95% CI, 1.004, 4.61]. A sex effect was noted
Women

30 00 000
for several other variables. Hypocalcemia and a history of
20 00 000
myocardial infarction were associated with QTc prolonga-
10 00 000
tion in men but not women and the opposite was true for
0 hypokalemia (Tables 2 and 3).
335 350 365 380 395 410 425 440 455 470 485 500
QTC
Discussion
QTc (Fridericia) distribution by sex (weighted counts). The Third Consistent with previous findings, age, female sex,
National Health and Nutrition Evaluation Survey, 1988–1994.
electrolyte disturbances, and a history of thyroid disease,
hypertension, myocardial infarction and recent use of a
QT-prolonging medication were associated with pro-
longed QTc intervals, in univariable or multivariable
Fig. 2 modeling, in this nationally representative sample. For
both men and women, a history of thyroid disease or the
40 00 000 recent use of QT-prolonging medications was associated
40 to 49

30 00 000
20 00 000 with more than a twofold increased risk of having a
10 00 000 prolonged QTc interval.
0
40 00 000
50 to 64

30 00 000 In a study of 2686 healthy middle-aged individuals, black

20 00 000 men had a shorter QTc length than white men [19]. In
10 00 000
0 the present study, no increased risk of QTc prolongation
40 00 000 was found when comparing black and Mexican-American
individuals to whites. A protective effect was found in the
65+

30 00 000
20 00 000
10 00 000
0 group made up 3.2% of the weighted sample and the
335 350 365 380 395 410 425 440 455 470 485 500
QTC
QTc (Fridericia) distribution by age (weighted counts). The Third
National Health and Nutrition Evaluation Survey, 1988–1994.
was noted in the QTc interval among racial groups, with
white individuals having a mean interval of 422 ms; black
individuals 422 ms; Mexican-American individuals 423 ms
and others 423 ms.
Of 4053 men and 4314 women, 270 and 259, respectively,
qualified as cases of QTc prolongation (Tables 2 and 3).
In univariable analysis, age, low potassium levels, and a
history of thyroid disease, hypertension, myocardial
infarction, and recent use of a QT-prolonging medication
were significantly associated with a prolonged QTc
interval for both women and men (Tables 2 and 3). In
addition, male cases had higher odds of hypocalcemia
[odds ratio (OR) 5.92] than male controls, whereas
female cases had higher odds of being obese (OR 1.72)
‘other’ category compared with white individuals. This
racial/ethnic groups included are unknown, making
interpretation difficult.
Hypocalcemia, hypokalemia and hypomagnesemia pro-
long ventricular repolarization, resulting in lengthened
QTc intervals [20]. Sex differences were evident in this
study for hypocalcemia and hypokalemia, with an
association between QTc and hypocalcemia found in
men, and an association for hypokalemia in women.
Limitations, however, necessitate caution in interpreting
these associations. Magnesium, not collected by
NHANES, affects calcium levels and thus is a potential
unmeasured confounder that could distort associations
among these variables [21].
Obesity has been cited as a risk for QTc prolongation [22–
26]. Limitations such as small sample size, lack of control
group comparators and combining men and women in the
analyses may explain discrepancies with the current
study. Although univariable analysis did show a higher
percentage of obese women in the case group, no
association was found in multivariable modeling, suggest-

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 366 European Journal of Cardiovascular Prevention and Rehabilitation 2005, Vol 12 No 4

Table 2 Associations of factors with prolonged QT interval in mena. The Third National Health and Nutrition Evaluation Survey, 1988–1994
Men (n = 4053) Univariable Multivariable

Cases (n = 270) Controls (n = 3783)

Mean/% OR 95% CI OR 95% CI

Heart rate (beats per minute) 64.2 66.9 0.98 (0.95, 1.00) 0.96 (0.95, 0.98)
Age (10 year interval) 65.1 55.5 1.81 (1.49, 2.20) 1.74 (1.41, 2.15)
Race (vs white)
Black 9.9% 8.6% 1.17 (0.80, 1.71) 1.19 (0.74, 1.92)
Mexican-American 3.4% 3.8% 0.92 (0.62, 1.35) 1.15 (0.71, 1.87)
Other 0.7% 3.3% 0.20 (0.05, 0.74) 0.23 (0.06, 0.85)
Calcium (mmol/l)
< 2.1 5.2% 0.9% 5.92 (1.44, 24.41) 6.12 (1.03, 36.53)
Potassium (mmol/l)
< 3.5 4.4% 2.0% 2.42 (1.04, 5.63) 1.80 (0.76, 4.28)
BMI (kg/m2) (vs reference)b
Underweight 2.7% 0.8% 3.43 (0.85, 13.94) 3.76 (0.87, 16.28)
Obese 24.2% 22.5% 1.19 (0.66, 2.13) 1.32 (0.71, 2.46)
Very obese 0.3% 1.5% 0.21 (0.03, 1.27) 0.35 (0.04, 3.00)
Stroke (yes/no) 5.6% 3.0% 1.97 (0.96, 4.08) 0.94 (0.42, 2.12)
Thyroid disease (yes/no) 5.7% 1.6% 3.63 (1.32, 9.99) 3.53 (1.11, 11.16)
Diabetes (yes/no) 9.5% 7.8% 1.32 (0.72, 2.43) 0.83 (0.42, 1.65)
Hypertension (yes/no) 42.5% 31.0% 1.71 (1.17, 2.51) 1.14 (0.77, 1.70)
MI (yes/no) 22.9% 7.0% 4.03 (2.53, 6.44) 2.56 (1.54, 4.25)
QT prolonging medication (yes/no) 7.9% 2.6% 3.51 (1.85, 6.68) 2.11 (1.002, 4.44)

Heart rate was controlled for in all models. bBody mass index (BMI): underweight BMI < 18.5, reference 18.5 r BMI < 30, obese 30 r BMI < 40, very obese Z 40. MI,
a

myocardial infarction; OR, odds ratio; CI, confidence interval.

a
Table 3 Associations of factors with prolonged QT interval in women . The Third National Health and Nutrition Evaluation Survey,
1988–1994
Women (n = 4314) Univariable Multivariable

Cases (n = 259) Controls (n = 4055)

Mean/% OR 95% CI OR 95% CI

Heart rate (beats per minute) 65.2 69.3 0.98 (0.95, 1.00) 0.96 (0.94, 0.98)
Age (10 year interval) 63.3 57.2 1.38 (1.20, 1.60) 1.33 (1.13, 1.56)
Race (vs white)
Black 12.2% 9.5% 1.30 (0.86, 1.97) 1.15 (0.69, 1.94)
Mexican-American 3.9% 3.3% 1.29 (0.76, 2.20) 1.56 (0.85, 2.85)
Other 1.8% 3.2% 0.60 (0.17, 2.07) 0.89 (0.22, 3.59)
Calcium (mmol/l)
< 2.1 2.6% 1.3% 2.30 (0.64, 8.21) 2.76 (0.79, 9.66)
Potassium (mmol/l)
< 3.5 10.0% 4.8% 2.47 (1.34, 4.56) 1.93 (1.01, 3.69)
BMI (kg/m2) (vs reference)b
Underweight 3.2% 2.4% 1.69 (0.37, 7.73) 2.16 (0.52, 8.99)
Obese 31.5% 23.5% 1.72 (1.10, 2.68) 1.39 (0.88, 2.19)
Very obese 5.5% 4.0% 2.00 (0.78, 5.15) 1.81 (0.73, 4.46)
Stroke (yes/no) 4.1% 2.8% 1.66 (0.76, 3.62) 0.96 (0.42, 2.23)
Thyroid disease (yes/no) 18.2% 9.4% 2.09 (1.15, 3.77) 2.06 (1.14, 3.74)
Diabetes (yes/no) 13.0% 7.9% 2.01 (1.11, 3.62) 1.27 (0.70, 2.30)
Hypertension (yes/no) 51.7% 33.1% 2.23 (1.61, 3.10) 1.46 (0.97, 2.19)
MI (yes/no) 9.6% 3.6% 2.76 (1.56, 4.87) 1.66 (0.96, 2.88)
QT prolonging medication (yes/no) 7.0% 3.1% 2.59 (1.20, 5.61) 2.15 (1.004, 4.61)
a
Heart rate was controlled for in all models. bBody mass index (BMI): underweight BMI < 18.5, reference 18.5 r BMI < 30, obese 30 r BMI < 40, very obese Z 40. MI,
myocardial infarction; OR, odds ratio; CI, confidence interval.

ing that obesity is not an independent risk factor for QTc
prolongation.
Acute strokes can prolong QTc intervals [27], and stroke
patients with prolonged QTc intervals are at a higher risk
of cardiac death [28]. Individuals with type 2 diabetes
who have prolonged QTc intervals are more likely to have
strokes [29]. However, in our study, stroke by itself did
not appear to be an independent risk factor for prolonged
QTc.
A previous study using NHANES III data examined the
relationship between QTc and diabetes, and found
women (but not men) with diabetes to be more likely
to have prolonged QTc intervals [25]. However, that
study used Bazett’s corrected QT formula, established
cutpoints using terciles, and defined the upper tercile as
a QTc of 440 ms for both men and women. It also
excluded patients with treated hypertension and those
reporting a past myocardial infarction. Multivariable
adjustment included age, race, heart rate and education,

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but failed to control for other factors such as electrolyte
abnormalities and QT-prolonging medications. In our
study, although diabetes was a significant risk factor in
univariable analyses for women, it was not statistically
associated with QTc in multivariable modeling. As Veglio
and colleagues [30] demonstrated, QT interval length in
diabetes is prolonged by complications and concomitant
conditions such as ischemic heart disease, nephropathy,
neuropathy and hypertension. Controlling for some of
these factors here probably explains why diabetes was not
found to be an independent risk factor for QTc
prolongation in our study.
QT-prolonging drugs were independent risk factors for
QTc prolongation in both men and women. This variable
was based on self-report, included only medications
consumed in the past 30 days and did not address the
length of therapy. Despite these limitations, our results
emphasize the potential population impact of the wide-
spread use of QT-prolonging drugs in the general US
population.
This study had a number of limitations. First, the QTc
was measured and calculated based on one ECG reading.
The QTc interval varies throughout the day and can be
affected by factors such as sleep or meals [31–33]. The
time of day of NHANES III ECG was not standardized,
which could result in variability of the data. However, we
have no reason to believe that there was a systematic
variation in the time of day ECG were performed
between cases and controls. In addition, debate exists
over the most precise QT interval measurement techni-
que. NHANES III used an automated method that may
fail to define the end of the T wave precisely or
differentiate T from U waves [34]. Nonetheless, studies
have found similar results between automated and
manual readings [35], and consistent measurements were
maintained between cases and controls.
The QTc interval may be affected by multiple factors not
accounted for in this study. Genetic determinants, meals,
sleep, alcoholism, cardiomyopathy, cirrhosis and electro-
lyte imbalances such as magnesium have been shown to
be risk factors for QTc prolongation [7]. NHANES III
either did not collect information related to these factors
or data were too incomplete to permit analyses. Whether
the magnitude or direction of the findings for the
variables considered in this study would change with
the inclusion of these other factors is unknown.
The validity of NHANES data could also introduce
misclassification bias. A history of stroke, thyroid disease,
diabetes, hypertension and myocardial infarction were
acquired from patient responses and were not validated
by medical records. Such misclassification would probably
be non-differential with respect to QTc, and thus would
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Risk factors for prolonged QTc Benoit et al. 367
reduce the strength of association between these factors
and QTc prolongation. Although agreement between self-
report and medical records varies depending on the
condition, self-report is reasonably accurate for well-
defined diseases such as diabetes, and cardio- and
cerebrovascular disease [36–39]. Results, however,
vary depending on age, education and the population
studied [40].
Multiple QT correction formulas exist to account for
heart rate. Bazett’s equation is most commonly applied,
but overcorrects for heart rates above 60 beats per minute
(bpm) and undercorrects for heart rates less than 60 bpm
[41,42]. Although no formula is perfect, Fridericia’s
provides a more accurate QT correction and is preferable
in most studies [42]. This was confirmed in our study
in which plots of QTc by heart rate showed that
the Fridericia correction provided a more robust estimate
of QTc.
The strength of this study is that it provides an
epidemiological description of the QTc interval based
on a representative sample of the US adult population.
Previous studies described QTc in various populations as
a predictor of a clinical outcome. Others looked at the
relationship between QTc and specific risk factors. This
is the first study that attempts to incorporate most of the
suspected QTc interval-prolonging risk factors and
quantify their magnitude of association in the general
population. Given sex differences in the QTc interval
distribution, men and women were analysed separately,
and conservative cutpoints for QTc prolongation were
established by identifying the upper 5% extreme of the
normally distributed QTc interval curve for each sex.
Upper limits of 470 ms for women and 450 ms for men
(using Bazett’s correction) have been proposed as
prolonged QTc intervals [43]. Using Bazett’s equation,
our QTc cutpoints were 476 ms for women and 464 ms for
men, both above the proposed upper limits of normal.
Therefore, this study identified the risk factors associated
with the most pronounced QTc interval prolongation;
factors that may be important for the development of
future cardiovascular arrhythmias.
In summary, this study found that age, female sex, serum
electrolytes, a history of thyroid disease, myocardial
infarction (in men) and the use of a QT-prolonging
medication in the past month were strongly associated
with being in the upper 5% tail of the QTc distribution.
Those who fall into this upper extreme may be at higher
risk of sudden cardiac death as a result of the fatal
arrhythmia known as torsades de pointes [10,44]. Until
future genetic and molecular studies better delineate the
functionality of cardiac channel variants and the risk of
sudden cardiac death [45], this study’s QTc risk factor
information may aid healthcare providers in avoiding
reproduction
 368 European Journal of Cardiovascular Prevention and Rehabilitation 2005, Vol 12 No 4
additional risk in vulnerable populations. Assessing
patient age, sex, serum electrolytes and medical history
may help determine whether a screening ECG is
warranted before prescribing medications that have the
potential to prolong the QT interval.
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reproduction