Ramachandran S. Vasan, MD; Lisa M. Sullivan, PhD; Peter W.F. Wilson, MD; Christopher T. Sempos, PhD; Johan Sundström, MD, PhD; William B. Kannel, MD; Daniel Levy, MD; Ralph B. D'Agostino, PhD
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Ramachandran S. Vasan, MD, Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, MA 01702-5803; e-mail, email@example.com.
Current Author Addresses: Drs. Vasan, Kannel, and Levy: Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, MA 01702-5803.
Drs. Sullivan and D'Agostino: Boston University Statistics and Consulting Unit, 704 Commonwealth Avenue, 5th Floor, Boston, MA 02215.
Dr. Wilson: Department of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 215, Charleston, SC 29425.
Dr. Sempos: Department of Social & Preventive Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214.
Dr. Sundström: Department of Public Health & Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.
Author Contributions: Conception and design: R.S. Vasan, L.M. Sullivan, P.W.F. Wilson, J. Sundström, W.B. Kannel, D. Levy, R.B. D'Agostino.
Analysis and interpretation of the data: R.S. Vasan, L.M. Sullivan, P.W.F. Wilson, C.T. Sempos, J. Sundström, W.B. Kannel, D. Levy, R.B. D'Agostino.
Drafting of the article: R.S. Vasan, L.M. Sullivan, J. Sundström, W.B. Kannel, D. Levy, R.B. D'Agostino.
Critical revision of the article for important intellectual content: R.S. Vasan, P.W.F. Wilson, C.T. Sempos, J. Sundström, W.B. Kannel, D. Levy.
Final approval of the article: R.S. Vasan, L.M. Sullivan, P.W.F. Wilson, C.T. Sempos, J. Sundström, W.B. Kannel, D. Levy, R.B. D'Agostino.
Provision of study materials or patients: P.W.F. Wilson, D. Levy, R.B. D'Agostino.
Statistical expertise: L.M. Sullivan, R.B. D'Agostino.
Obtaining of funding: R.S. Vasan, R.B. D'Agostino.
Administrative, technical, or logistic support: P.W.F. Wilson, D. Levy, R.B. D'Agostino.
Collection and assembly of data: P.W.F. Wilson, D. Levy, R.B. D'Agostino.
Clinical trials indicate that a sizable proportion of adults have multiple borderline coronary risk factors and may benefit from treatment.
To estimate the relative and absolute contributions of borderline and elevated risk factors to the population burden of coronary heart disease (CHD) events.
A prospective cohort study and a national cross-sectional survey.
The Framingham Study and the Third National Health and Nutrition Examination Survey (NHANES III).
White non-Hispanic persons in the Framingham Study and in NHANES III who were between 35 to 74 years of age and had no CHD.
Occurrence of first CHD events according to 5 major CHD risk factors: blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol levels, glucose intolerance, and smoking. Three categories—optimal, borderline, and elevated—were defined for each risk factor per national guidelines. Sex-specific 10-year CHD event rates from the Framingham Study were applied to numbers of at-risk individuals estimated from NHANES III and the 2000 U.S. Census.
Twenty-six percent of men and 41% of women had at least 1 borderline risk factor in NHANES III. According to estimates, more than 90% of CHD events will occur in individuals with at least 1 elevated risk factor, and approximately 8% will occur in people with only borderline levels of multiple risk factors. Absolute 10-year CHD risk exceeded 10% in men older than age 45 years who had 1 elevated risk factor and 4 or more borderline risk factors and in those who had at least 2 elevated risk factors. In women, absolute CHD risk exceeded 10% only in those older than age 55 years who had at least 3 elevated risk factors.
The generalizability of the findings to persons of other ethnic backgrounds is unknown.
Borderline CHD risk factors alone account for a small proportion of CHD events.
Are borderline levels of risk factors responsible for much coronary heart disease (CHD)?
These researchers applied 10-year CHD event rates from the Framingham Study to risk factor levels measured in a recent national probability sample. Twenty-six percent of men and 41% of women age 35 to 74 years had border-line risk factors, but only one tenth of the projected CHD events were attributed to borderline levels. Most events were attributable to elevated risk factors; among men, nearly one sixth occurred before age 55 years.
In the United States, borderline levels of risk factors prob-ably account for a small proportion of CHD events.
Table 1. Distribution of Individual CHD Risk Factors in Framingham Heart Study Participants and in the Third National Health and Nutrition Examination Survey
Table 2. Age-Specific Prevalence of Risk Factor Groups in the Third National Health and Nutrition Examination Survey
Table 3. Hard Coronary Heart Disease Rates and Absolute Number of Events according to Risk Factor Groups in Men
Table 4. Rates of Hard CHD Events and Absolute Numbers of Events according to Risk Factor Groups in Women
Appendix Table 1. Cox Model for Men
Appendix Table 2. Distribution of Risk Factor Combinations in the Framingham Study and the Third National Health and Nutrition Examination Survey
Appendix Table 3. Rates of Hard Coronary Heart Disease Events according to Risk Factor Groups
Estimated numbers of U.S. individuals at risk for hard coronary heart disease events, according to estimated 10-year absolute risk.
Estimated proportion of hard coronary heart disease (CHD) events according to numbers of borderline and elevated risk factors for all ages pooled and within age groups for men and women.
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Enrique J. SÃ¡nchez-Delgado
Hospital Metropolitano Vivian Pellas, Managua, Nicaragua
March 24, 2005
Risk Factors: Rules of Thumb for Real Win
The study by Vasan et. al. has a real impact, despite some limitations. I missed, though, the analysis of obesity, and still better, of the Pulse by Mass Index or PMI (Body Mass Index by Resting Heart Rate/1730 or 24x72, or BMIxRHR/1730), which highly correlates with the global cardiovascular risk (1). For instance, a 45 years old man with a BMI of 30 and a RHR of 60 has less global risk than the same man with a RHR of 90 (PMI of 1.04 vs. PMI of 1.56, which would probably correlate with a global risk of less than 10% vs. more than 20%).
I agree with the importance of risk assessment, which can be complemented either with the exercise EKG test or with the coronary calcium score. It also has educational and motivational purposes, and help to focus on the real important modifiable factors. Indeed, the higher the risks, the higher the benefits.
We can focus on the "Terrible couples" like Diabetes plus Hypertension or Smoking plus Hypercholesterolemia. They have both the highest relative and absolute or global risk. Hypertension or Hypercholesterolemia can be easier to achieve an optimal control than Diabetes or Smoking.
If we obtain an optimal blood pressure in a diabetic patient, and add low dose aspirin, the initial global risk of, lets say, 25% or more, could be reduced to 15% in 10 years. That means, the NNT in five years would be of 20 or less. For every 20 treated patients we could avoid a death, a myocardial infarction or a stroke. That fits perfectly with the "Rule 3- 30" of Evidence Based Medicine, a pattern I have observed in the best and most widely accepted therapeutics trials (2). They all have a Relative Risk Reduction of 20 to 30% or more, an Absolute Risk Reduction of 2 % to 3 % or more, and an NNT of 30 or less (between 20 to maximal 50).
I also believe in "Intelligent Combinations" of two proven drugs, of which several examples already exist, instead of a too broad and unfocused "polypill". They are not only more focused and convincing for patients and doctors, but also allow a much better control of their mechanism, indications and actions, evidence of effects, interactions and adverse reactions. At the same time they facilitate the compliance or adherence of the patients and probably -they should- reduce the costs while improve the effectiveness.
References: 1.- SÃ¡nchez-Delgado E, Liechti H. Lancet 1999;353:924-925 (13 March)
2.- SÃ¡nchez-Delgado E. BMJ 2001;323:1100 ( 10 November ).
Nicholas J Wald
Wolfson Institute, Barts and the London School of Medicine and Dentistry
April 28, 2005
Heart Disease Prevention: Target the disease, not individual risk factors
Vasan and colleagues endorse the value of measuring cardiovascular disease risk factors to determine who should receive preventive treatment. But their data confirm that its discriminatory potential is small. The 12% of men with "high" levels of three or more risk factors accounted for only 25% of coronary heart disease (CHD) events, the 40% of men with two or more risk factors for 65% of events, and the 74% of men with one or more risk factors for 91% of events (see figure 2).
Although the paper is detailed, these figures alone provide the key message. For risk factor-based screening to be worthwhile, it should concentrate the majority of those who will develop disease events into a relatively small subset of the population. It cannot do this. The risk factors considered are poor predictors because they do not discriminate well between those who will and will not have CHD events. The risk factor measurement strategy may avoid treatment in only about 25% of the population but it will also miss 9% of people who will have CHD events, and many of them would move into a higher risk category a few years later. Setting up a complicated and expensive screening procedure before offering treatment serves more as a barrier to preventive treatment than a facilitator. It unnecessarily denies people the full benefit available from medical interventions. It is incorrect to infer that people with only one "elevated" risk factor (say serum cholesterol) should receive treatment only for that one risk factor; their risk would be further reduced if their blood pressure were lowered, irrespective of its starting level. CHD is common because population average levels of several risk factors are high, so substantial protection requires intervening on multiple risk factors simultaneously.
Our PolypillTM strategy is not a "shotgun or scattershot approach". The target is overall cardiovascular disease prevention rather than individual risk factor reduction. Both approaches will treat people who will not develop CHD, but the PolypillTM will have the much larger effect.
Mulrow and Kussmaul express opinions that we may have overestimated the benefits and underestimated the side effects, though we provided detailed evidence from observational epidemiology and randomised trials to support our estimates.The PolypillTM approach could have enormous impact in reducing heart attack and stroke throughout the world, including "the middle aged and older American", a group Mulrow and Kussmaul single out in their editorial as somehow being different.
Nicholas J Wald Malcolm Law
Wolfson Institute of Preventive Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ
1. Vasan R, Sullivan LM, Wilson PWF, Sempos CT, Sundstrom J, Kannel WB, Levy D, D'Agostino RB. Relative importance of borderline and elevated levels of coronary heart disease risk factors. Ann Intern Med 2005;142:393 -402
2. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419-23
3. Mulrow C, Kussmaul W. The middle-aged and older American: Wrong prototype for a preventive Polypill? Ann Intern Med 2005;142:487-8
NW and ML have filed a patent application on the formula of a combined pill to simultaneously reduce four cardiovascular risk factors (granted in UK). Trademark registration for the name Polypill is pending.
Vasan RS, Sullivan LM, Wilson PW, Sempos CT, Sundström J, Kannel WB, et al. Relative Importance of Borderline and Elevated Levels of Coronary Heart Disease Risk Factors. Ann Intern Med. ;142:393–402. doi: 10.7326/0003-4819-142-6-200503150-00005
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Published: Ann Intern Med. 2005;142(6):393-402.
Cardiology, Coronary Risk Factors, Prevention/Screening.
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