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Khot UN, Khot MB, Bajzer CT, et al. Prevalence of Conventional Risk Factors in Patients With Coronary Heart Disease. JAMA. 2003;290(7):898–904. doi:10.1001/jama.290.7.898
Author Affiliations: Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio (Drs U. Khot, M. Khot, Bajzer, Brener, Ellis, Lincoff, and Topol and Ms Sapp); and Division of Cardiology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill (Dr Ohman). Drs U. Khot and M. Khot are now with Indiana Heart Physicians, Indianapolis.
Context It is commonly suggested that more than 50% of patients with coronary
heart disease (CHD) lack any of the conventional risk factors (cigarette smoking,
diabetes, hyperlipidemia, and hypertension). This claim implies that other
factors play a significant role in CHD and has led to considerable interest
in nontraditional risk factors and genetic causes of CHD.
Objective To determine the prevalence of the 4 conventional risk factors among
patients with CHD.
Design, Setting, and Patients In 2002-2003, we analyzed data for 122 458 patients enrolled in
14 international randomized clinical trials of CHD conducted during the prior
decade. Patients included 76 716 with ST-elevation myocardial infarction,
35 527 with unstable angina/non–ST-elevation myocardial infarction,
and 10 215 undergoing percutaneous coronary intervention.
Main Outcome Measures Prevalence of each conventional risk factor and number of conventional
risk factors present among patients with CHD, compared between men and women
and by age at trial entry.
Results Among patients with CHD, at least 1 of the 4 conventional risk factors
was present in 84.6% of women and 80.6% of men. In younger patients (men ≤55
years and women ≤65 years) and most patients presenting either with unstable
angina or for percutaneous coronary intervention, only 10% to 15% of patients
lacked any of the 4 conventional risk factors. This pattern was largely independent
of sex, geographic region, trial entry criteria, or prior CHD. Premature CHD
was related to cigarette smoking in men and cigarette smoking and diabetes
in women. Smoking decreased the age at the time of CHD event (at trial entry)
by nearly 1 decade in all risk factor combinations.
Conclusions In direct contrast with conventional thinking, 80% to 90% of patients
with CHD have conventional risk factors. Although research on nontraditional
risk factors and genetic causes of heart disease is important, clinical medicine,
public health policies, and research efforts should place significant emphasis
on the 4 conventional risk factors and the lifestyle behaviors causing them
to reduce the epidemic of CHD.
Appreciation of the crucial role of risk factors in the development
of coronary heart disease (CHD) is one of the most significant advances in
the understanding of this important disease. Extensive epidemiological research
has established cigarette smoking,1 diabetes,2 hyperlipidemia,3 and
hypertension4 as independent risk factors for
CHD. In addition, treatment of these risk factors has been convincingly shown
to reduce the risk of future cardiac events.1,5 Because
of the strength of evidence supporting their role in the pathogenesis of CHD,
these 4 risk factors have often been labeled as "conventional" risk factors.
Although the importance of conventional risk factors is well established,
it is commonly suggested that more than 50% of patients with CHD lack any
of the conventional risk factors.6-13 This
implies that other factors play a significant role in the development of this
disease and, furthermore, that there is a substantial void in current understanding
of the pathogenesis of CHD. This perceived void has led to considerable research
on nontraditional risk factors and genetic causes of heart disease. Yet, data
to support this "50%" belief are limited, and some have suggested that conventional
risk factors play a much more significant role.14,15 Determining
the validity of this idea is important for scientific accuracy and to guide
the practice of clinical medicine, public health policies, and prioritization
of research efforts. In addition, patients and physicians can better understand
the impact of preventing or modifying these specific risk factors on the risk
of future CHD.
We therefore sought to determine the prevalence of the 4 conventional
risk factors—cigarette smoking, diabetes, hyperlipidemia, and hypertension—in
a broad population of patients with CHD.
We compiled data from 14 clinical trials involving 122 458 patients
with a wide spectrum of CHD. Briefly, GUSTO I,16 GUSTO
III,17 and GUSTO V18 studied
thrombolytic therapies in ST-elevation myocardial infarction (MI). GUSTO IIb
compared hirudin with heparin in both ST-elevation MI and unstable angina/non–ST-elevation
MI.19 PURSUIT,20 PARAGON
A,21 PARAGON B,22 CAPTURE,23 and GUSTO IV ACS24 studied
intravenous glycoprotein IIb/IIIa inhibitors in patients with unstable angina/non–ST-elevation
MI. EPIC studied abciximab in angioplasty patients with recent MI, unstable
angina, or high-risk angiographic or clinical characteristics.25 EPILOG
studied abciximab in urgent or elective percutaneous coronary intervention
(PCI).26 CAVEAT I and II compared balloon angioplasty
with directional coronary atherectomy in native coronary stenoses27 and saphenous vein graft disease,28 respectively.
Finally, IMPACT II studied the use of eptifibatide in PCI.29
Information regarding cigarette smoking, diabetes, hyperlipidemia, and
hypertension had been prospectively recorded at trial entry in all studies.
Information regarding family history of CHD was not collected in CAPTURE,
GUSTO III, and GUSTO IV ACS. Information regarding body mass index was not
collected in GUSTO IV. Current smoking was noted if the patient smoked at
the time of the index event; however, EPIC, EPILOG, CAPTURE, and GUSTO IV
ACS noted whether the patient had smoked in the previous year. Diabetes, hyperlipidemia,
and hypertension were documented if a diagnosis had been made prior to randomization
and were identified through physician interview and by patient self-report.
The prevalence of each risk factor was calculated. Patients were categorized
according to their number of risk factors. Subgroups included age, sex, geographic
location, and absence of prior CHD. Prior CHD was noted with history of MI,
prior PCI, or prior coronary artery bypass graft surgery. Three further subgroups
included ST-elevation MI (GUSTO I, GUSTO IIb [ST-elevation group], GUSTO III,
and GUSTO V); unstable angina/non–ST-elevation MI (GUSTO IIb [non–ST-elevation
group], PURSUIT, PARAGON A, PARAGON B, CAPTURE, and GUSTO IV ACS); and PCI
(EPIC, EPILOG, CAVEAT I, CAVEAT II, and IMPACT II), which enrolled primarily
those with stable/unstable angina but also a small number with ST-elevation
MI (EPIC and IMPACT II). Furthermore, we determined the relationship between
number of conventional risk factors and mean age at trial entry.
We had access to the original raw data for all of the clinical trials,
and these data were combined to perform the analyses. Categorical data are
presented as percentages and continuous data are presented as means (SDs).
Frequencies were analyzed by χ2 tests and continuous variables
were analyzed by Wilcoxon 2-sample tests. We used SAS version 8 software (SAS
Institute Inc, Cary, NC) to analyze all data. All comparisons were considered
significant at P<.05.
Overall among patients with CHD, the prevalence of those with at least
1 of the 4 conventional risk factors was 84.6% in women and 80.6% in men (Table 1). For all risk factors except cigarette
smoking, the prevalence was significantly higher in women than in men. However,
women aged 65 years or younger had nearly identical rates of smoking as similarly
aged men (Table 2).
The prevalence of the 4 conventional risk factors was related to age.
The majority (85%-90%) of patients with premature CHD had at least 1 conventional
risk factor, with cigarette smoking being the most common. Among women and
men aged 45 years or younger, the prevalence of patients without any of the
4 conventional risk factors was only 9.4% and 11.4%, respectively. There was
a gradual increase with age in the prevalence of patients lacking any of the
conventional risk factors. Only among women older than 75 years and men older
than 65 years did the prevalence of patients lacking any of the 4 conventional
risk factors exceed 20%. Older patients had much lower rates of cigarette
smoking but typically higher rates of diabetes and hypertension.
Few young patients (≤65 years) lacked any of the 4 conventional risk
factors, irrespective of trial entry criteria (Table 3). Fewer older patients (>65 years of age) presenting with
unstable angina/non–ST-elevation MI or for PCI lacked any of the conventional
risk factors than those presenting with ST-elevation MI. Patients presenting
with ST-elevation MI had higher rates of cigarette smoking but lower rates
of diabetes, hyperlipidemia, and hypertension than those with either unstable
angina/non–ST-elevation MI or PCI. Patients presenting for PCI had intermediate
rates of cigarette smoking but the highest prevalence of diabetes, hyperlipidemia,
and hypertension. The overall pattern of conventional risk factors existed
irrespective of geographic origin (Table
4). Patients without prior CHD (74.4% of women and 69.7% of men)
had slightly higher rates of cigarette smoking and slightly lower rates of
hyperlipidemia, hypertension, and diabetes compared with those with prior
CHD (data not shown). The overall prevalence of patients without prior CHD
who lacked any of the 4 conventional risk factors remained largely unchanged
(17.2% in women and 20.7% in men).
The inclusion of a family history of CHD and obesity (body mass index
[calculated as weight in kilograms divided by the square of height in meters]
≥30) as risk factors further reduced the prevalence of patients without
risk factors to 8.5% in women and 10.7% in men.
As the number of conventional risk factors increased, the mean age at
the time of CHD event (at trial entry) decreased by a decade (Figure 1), primarily because of cigarette smoking in both sexes
Our study indicates that in patients with CHD, conventional risk factors
were present at a much higher prevalence than commonly believed, with only
15% to 20% of patients lacking any of the conventional risk factors for the
disease. In younger patients (men ≤55 years and women ≤65 years) and
most patients presenting with either unstable angina or for PCI, the prevalence
of conventional risk factors was even higher, with only approximately 10%
to 15% of patients lacking any of the 4 conventional risk factors. This overall
pattern was largely independent of sex, geographic region, or entry criteria
of the trial. Thus, in direct contrast with conventional thinking, only a
small minority of patients with CHD lacks conventional risk factors.
Cigarette smoking played a critical role in the development of premature
CHD, reducing the age at trial entry by about 1 decade in every risk factor
subgroup. In addition, more than 70% of the 12 154 patients aged 45 years
or younger were current cigarette smokers. Although cigarette smoking is harmful
at any age, the increase in relative risk of coronary events in young persons
is particularly magnified given their baseline low risk. Furthermore, cigarette
smoking acts synergistically with other conventional risk factors, greatly
increasing the baseline risk associated with each risk factor individually.30 Thus, elimination of cigarette smoking is of dramatic
public health importance because it could delay the onset of CHD by a decade.
Overall, the prevalence of risk factors was greater in women than in
men. Because CHD typically presents 10 years later in women than in men, higher
risk factor prevalence in women is necessary to lead to the development of
CHD at the same age as in men.31 The higher
prevalence of diabetes in women than in men is consistent with other studies
that have shown that diabetes is a powerful risk factor in women, virtually
negating the usual protection women have against cardiac disease.32 The only risk factor with a lower prevalence in women
was cigarette smoking. However, younger women (≤65 years) smoked at a virtually
identical rate to men, reflecting widespread adoption of smoking among this
generation of women. Cigarette smoking has a similar effect on increasing
the risk of CHD in both men and women.33 Therefore,
reductions in the prevalence of diabetes and smoking cessation have the potential
to dramatically reduce the burden of CHD in women.
Our observation of a steadily decreasing prevalence of conventional
risk factors with age may be explained by 3 reasons. First, clinical trials
have a selection bias limiting enrollment to a healthier subset of the elderly
population.34 Second, age steadily increases
the absolute baseline risk of CHD independent of the conventional risk factors35; therefore, patients without risk factors will tend
to present at a much later age once their baseline absolute risk increases
sufficiently to cause a significant prevalence of disease. Third, this decreasing
prevalence reflects an inherent survivor bias because patients with conventional
risk factors die at a much younger age.15 Conventional
risk factors increase the risk of coronary events in elderly persons at a
similar magnitude to that of middle-aged individuals.36 Thus,
given their increased absolute baseline risk, the benefit of preventing or
treating conventional risk factors in elderly patients is greater in absolute
terms than the benefit in younger patients.37
Although widely asserted,6-13 the
belief that more than 50% of patients with CHD lack conventional risk factors
is not supported by primary data. A related assertion is that the conventional
risk factors explain less than 50% of the incidence of CHD.38 Yet,
there are inaccuracies in the interpretation of the primary data that have
been referenced to support this claim.14 In
fact, 2 studies have shown that lack of hypertension, hyperlipidemia, and
cigarette smoking was associated with a 77% to 92% reduction in cardiovascular
mortality,15 findings similar to other studies.14,30 In essence, patients without conventional
risk factors are unlikely to develop CHD.
Much attention has recently focused on the identification of genetic
factors that play a role in the development of CHD. Although genetic differences
may explain an individual's propensity to develop CHD in the setting of conventional
risk factors, it is doubtful that the populationwide prevalence of CHD is
explained by genetic factors. Epidemiological studies have convincingly shown
that the risk of CHD in various populations is largely dependent on the prevalence
of conventional risk factors and other environmental factors, such as diet.3,39 Furthermore, the prevalence can vary
dramatically as environmental conditions change over short periods, as seen
in Japanese migration studies40 and, more recently,
in country-specific data from the World Health Organization.41 In
fact, a family history of CHD, traditionally believed to be due to a shared
genetic predisposition, may simply represent a shared exposure to a higher
prevalence of conventional risk factors.42 All
of these studies underscore the crucial importance of environmental influences
and conventional risk factors in the development of CHD, even in populations
with similar genetic profiles.
The true prevalence of the conventional risk factors is certainly higher
than identified in our study. Approximately 32% of patients with hypertension
are unaware that they are hypertensive.43 Higher
rates of unawareness, approaching 50%, have been documented for hyperlipidemia
and diabetes.44,45 More stringent
cutoffs for abnormal blood pressure, lipid levels, and blood glucose levels
have been increasingly recommended as evidence accumulates supporting lower
targets. In addition, physicians typically underdiagnose conventional risk
factors.46 Moreover, the index cardiac event
may lead to the diagnosis of previously unknown risk factors. For example,
nearly one third of nondiabetic patients presenting with ST-elevation MI are
found to have diabetes by formal glucose tolerance testing.47 Thus,
detailed assessment for conventional risk factors using contemporary targets
will almost certainly lead to higher prevalence rates than those reported
in our study.
Our study has several limitations. We did not have a control group without
CHD for comparison, although the prevalence of conventional risk factors noted
in our patients with CHD is substantially greater than the prevalence in the
general population.48 Our analyses were limited
to a clinical trial population. However, because clinical trials enroll healthier
patients with fewer comorbidities than those found in the general community,
our findings almost certainly overestimate the prevalence of patients lacking
conventional risk factors.49 Our study also
has a survival bias because only patients with CHD who survived to hospitalization
were included. Yet, the conventional risk factors have been shown to be predictive
of sudden cardiac death50 and of all-cause
mortality,30 making it quite likely that our
findings would also pertain to these patients. We acknowledge that the mere
presence of a particular risk factor in an individual patient with CHD does
not guarantee that it plays a causal role and may suggest a role for both
nontraditional risk factors and genetic causes at the individual level. However,
the causal role of conventional risk factors at the population level is incontrovertible.
Our study largely consisted of patients with acute coronary syndromes,
making its relevance to subclinical manifestations of atherosclerosis unclear.
However, because the conventional risk factors predict subclinical atherosclerosis,
such as carotid intima-media thickness, our findings are applicable to this
population.51 Our study also relied on patient
self-report of risk factors, which may not accurately compare with more objective
measurements involving physical examination and laboratory testing. Self-report
of cardiac risk factors has been shown to systematically underestimate the
true prevalence of risk factors as measured objectively, further reducing
the prevalence of patients without any conventional risk factors.52 Our study failed to account for low levels of high-density
lipoprotein cholesterol, a potent conventional risk factor53 that
is not typically considered hyperlipidemia. However, the inclusion of high-density
lipoprotein cholesterol would diminish the number of patients without conventional
risk factors. Finally, our study consisted of a largely white, Western population.
However, the risk factor patterns outside of North America and Western Europe
were similar to that found in the study as a whole (Table 4). In addition, the recent Inter-Heart study showed that
conventional risk factors also are predictive of the risk of MI in non-Western
It is increasingly clear that the 4 conventional risk factors and their
resulting health risks are largely preventable by a healthy lifestyle.55 The continued emphasis on patients lacking conventional
risk factors, a situation that we have shown occurs only in a small minority
of patients with CHD, fails to acknowledge the important insights that have
been made in current understanding of the relationships among lifestyle, conventional
risk factors, and CHD. These insights indicate that intense focus on the 4
conventional risk factors and the lifestyle behaviors causing them has great
potential to decrease the worldwide epidemic of CHD.