Charles H. Hennekens

Bio: Charles H. Hennekens is an academic researcher from Harvard University. The author has contributed to research in topics: Risk factor & Relative risk. The author has an hindex of 150, co-authored 424 publications receiving 117806 citations. Previous affiliations of Charles H. Hennekens include University of Auckland & Erasmus University Rotterdam.

C-Reactive Protein and Other Markers of Inflammation in the Prediction of Cardiovascular Disease in Women

Abstract: Background Since inflammation is believed to have a role in the pathogenesis of cardiovascular events, measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events. Methods We conducted a prospective, nested case–control study among 28,263 apparently healthy postmenopausal women over a mean follow-up period of three years to assess the risk of cardiovascular events associated with base-line levels of markers of inflammation. The markers included high-sensitivity C-reactive protein (hs-CRP), serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type 1 (slCAM-1). We also studied homocysteine and several lipid and lipoprotein measurements. Cardiovascular events were defined as death from coronary heart disease, nonfatal myocardial infarction or stroke, or the need for coronay-revascularization procedures. Results Of the 12 markers measured, hs-CRP was the strongest univariate predictor of the risk of cardiovascular events; the relative risk of events for women in the highest as compared with the lowest quartile for this marker was 4.4 (95 percent confidence interval, 2.2 to 8.9). Other markers significantly associated with the risk of cardiovascular events were serum amyloid A (relative risk for the highest as compared with the lowest quartile, 3.0), slCAM-1 (2.6), interleukin-6 (2.2), homocysteine (2.0), total cholesterol (2.4), low-density lipoprotein (LDL) cholesterol (2.4), apolipoprotein B-100 (3.4), high-density lipoprotein (HDL) cholesterol (0.3), and the ratio of total cholesterol to HDL cholesterol (3.4). Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone (P<0.001). The levels of hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter (3.4 mmol per liter), the target for primary prevention established by the National Cholesterol Education Program. In multivariate analyses, the only plasma markers that independently predicted risk were hs-CRP (relative risk for the highest as compared with the lowest quartile, 1.5; 95 percent confidence interval, 1.1 to 2.1) and the ratio of total cholesterol to HDL cholesterol (relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.9). Conclusions The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying women at risk for cardiovascular events.

Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy Men

Abstract: Background Inflammation may be important in the pathogenesis of atherothrombosis. We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk. Methods We measured plasma C-reactive protein, a marker for systemic inflammation, in 543 apparently healthy men participating in the Physicians' Health Study in whom myocardial infarction, stroke, or venous thrombosis subsequently developed, and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years. Subjects were randomly assigned to receive aspirin or placebo at the beginning of the trial. Results Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infarction (1.51 vs. 1.13 mg per liter, P<0.001) or ischemic stroke (1.38 vs. 1.13 mg per liter, P = 0.02), but not venous thrombosis (1.26 vs. 1.13 mg per liter, P = 0.34), than among men without vascular events. The men in the quartile wit...

Collaborative overview of randomized trials of antiplatelet therapy .1. prevention of death, myocardial-infarction, and stroke by prolonged antiplatelet therapy in various categories of patients

Abstract: Abstract Objective: To determine the effects of “prolonged” antiplatelet therapy (that is, given for one month or more) on “vascular events” (non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths) in various categories of patients. Design: Overviews of 145 randomised trials of “prolonged” antiplatelet therapy versus control and 29 randomised comparisons between such antiplatelet regimens. Setting: Randomised trials that could have been available by March 1990. Subjects: Trials of antiplatelet therapy versus control included about 70 000 “high risk” patients (that is, with some vascular disease or other condition implying an increased risk of occlusive vascular disease) and 30 000 “low risk” subjects from the general population. Direct comparisons of different antiplatelet regimens involved about 10 000 high risk patients. Results: In each of four main high risk categories of patients antiplatelet therapy was definitely protective. The percentages of patients suffering a vascular event among those allocated antiplatelet therapy versus appropriately adjusted control percentages (and mean scheduled treatment durations and net absolute benefits) were: (a) among about 20 000 patients with acute myocardial infarction, 10% antiplatelet therapy v 14% control (one month benefit about 40 vascular events avoided per 1000 patients treated (2P< 0.00001)); (b) among about 20 000 patients with a past history of myocardial infarction, 13% antiplatelet therapy v 17% control (two year benefit about 40/1000 (2P<0.00001)); (c) among about 10 000 patients with a past history of stroke or transient ischaemic attack, 18% antiplatelet therapy v 22% control (three year benefit about 40/1000 (2P<0.00001)); (d) among about 20 000 patients with some other relevant medical history (unstable angina, stable angina, vascular surgery, angioplasty, atrial fibrillation, valvular disease, peripheral vascular disease, etc), 9% v 14% in 4000 patients with unstable angina (six month benefit about 50/1000 (2P<0.00001)) and 6% v 8% in 16 000 other high risk patients (one year benefit about 20/1000 (2P<0.00001)). Reductions in vascular events were about one quarter in each of these four main categories and were separately statistically significant in middle age and old age, in men and women, in hypertensive and normotensive patients, and in diabetic and non: diabetic patients. Taking all high risk patients together showed reductions of about one third in non-fatal myocardial infarction, about one third in non-fatal stroke, and about one sixth in vascular death (each 2P<0.00001). There was no evidence that non-vascular deaths were increased, so in each of the four main high risk categories overall mortality was significantly reduced. The most widely tested antiplatelet regimen was “medium dose” (75-325 mg/day) aspirin. Doses throughout this range seemed similarly effective (although in an acute emergency it might be prudent to use an initial dose of 160-325 mg rather than about 75 mg). There was no appreciable evidence that either a higher aspirin dose or any other antiplatelet regimen was more effective than medium dose aspirin in preventing vascular events. The optimal duration of treatment for patients with a past history of myocardial infarction, stroke, or transient ischaemic attack could not be determined directly because most trials lasted only one, two, or three years (average about two years). Nevertheless, there was significant (2P<0.00001) further benefit between the end of year 1 and the end of year 3, suggesting that longer treatment might well be more effective. Among low risk recipients of “primary prevention” a significant reduction of one third in non: fatal myocardial infarction was, however, accompanied by a non-significant increase in stroke. Furthermore, the absolute reduction in vascular events was much smaller than for high risk patients despite a much longer treatment period (4.4% antiplatelet therapy v 4.8% control; five year benefit only about four per 1000 patients treated) and was not significant (2P=0.09). Conclusions: Among a much wider range of patients at high risk of occlusive vascular disease than is currently treated routinely, some years of antiplatelet therapy - with aspirin 75-325 mg/day or some other antiplatelet regimen (provided there are no contraindications) - offers worthwhile protection against myocardial infarction, stroke, and death. Significant benefit is evident not only among patients with unstable angina, suspected acute myocardial infarction, or a past history of myocardial infarction, stroke, or transient ischaemic attack, but also among many other categories of high risk patients (such as those having vascular procedures and those with stable angina or peripheral vascular disease). There is as yet, however, no clear evidence on the balance of risks and benefits of antiplatelet therapy in primary prevention among low risk subjects.

Epidemiology in Medicine

Abstract: Epidemiology is the simplest and most direct method of studying the causes of disease in humans, and many major contributions have been made by studies that have demanded nothing more than the ability to count, to think logically, and to have an imaginative idea. With the accumulation of knowledge, however, its has become harder for individuals working alone to make effective contributions, and epidemiological research is becoming increasingly a matter of teamwork, not only because of the large number of people that may have to be studied and the large amount of data that have to be collected and analyzed, but also because of the need to bring together for the design and conduct of the study clinical experience, biological understanding, statistical expertise, and many other special skills that vary from one study to another. But if, in this sense, epidemiological research is becoming more complex, the core of the subject remains essentially simple, and a good epidemiological study should be capable of description in such a way that all who are interested in the cause of disease can follow the argument and decide for themselves the validity of the conclusions.

Bias in meta-analysis detected by a simple, graphical test

Abstract: Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

Atherosclerosis — An Inflammatory Disease

Abstract: Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Abstract: The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount.

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial

Abstract: Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 85 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998 Interventions Participants received conjugated equine estrogens, 0625 mg/d, plus medroxyprogesterone acetate, 25 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102) Main outcomes measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes Results On May 31, 2002, after a mean of 52 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits This report includes data on the major clinical outcomes through April 30, 2002 Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 129 (102-163) with 286 cases; breast cancer, 126 (100-159) with 290 cases; stroke, 141 (107-185) with 212 cases; PE, 213 (139-325) with 101 cases; colorectal cancer, 063 (043-092) with 112 cases; endometrial cancer, 083 (047-147) with 47 cases; hip fracture, 066 (045-098) with 106 cases; and death due to other causes, 092 (074-114) with 331 cases Corresponding HRs (nominal 95% CIs) for composite outcomes were 122 (109-136) for total cardiovascular disease (arterial and venous disease), 103 (090-117) for total cancer, 076 (069-085) for combined fractures, 098 (082-118) for total mortality, and 115 (103-128) for the global index Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures The absolute excess risk of events included in the global index was 19 per 10 000 person-years Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 52-year follow-up among healthy postmenopausal US women All-cause mortality was not affected during the trial The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD