Curt D. Furberg

The cardiovascular health study: Design and rationale

The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of coronary heart disease and stroke in adults aged 65 years and older. The main objective of the study is to identify factors related to the onset and course of coronary heart disease and stroke. CHS is designed to determine the importance of conventional cardiovascular disease (CVD) risk factors in older adults, and to identify new risk factors in this age group, especially those that may be protective and modifiable. The study design called for enrollment of 1250 men and women in each of four communities: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. Eligible participants were sampled from Medicare eligibility lists in each area. Extensive physical and laboratory evaluations were performed at baseline to identify the presence and severity of CVD risk factors such as hypertension, hypercholesterolemia and glucose intolerance; subclinical disease such as carotid artery atherosclerosis, left ventricular enlargement, and transient ischemia; and clinically overt CVD. These examinations in CHS permit evaluation of CVD risk factors in older adults, particularly in groups previously under-represented in epidemiologic studies, such as women and the very old. The first of two examination cycles began in June 1989. A second comprehensive examination will be repeated three years later. Periodic interim contacts are scheduled to ascertain and verify the incidence of CVD events, the frequency of recurrent events, and the sequellae of CVD.

Effects of estrogen replacement on the progression of coronary-artery atherosclerosis

Background Heart disease is a major cause of illness and death in women. To understand better the role of estrogen in the treatment and prevention of heart disease, more information is needed about its effects on coronary atherosclerosis and the extent to which concomitant progestin therapy may modify these effects. Methods We randomly assigned a total of 309 women with angiographically verified coronary disease to receive 0.625 mg of conjugated estrogen per day, 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate per day, or placebo. The women were followed for a mean (±SD) of 3.2±0.6 years. Base-line and follow-up coronary angiograms were analyzed by quantitative methods. Results Estrogen and estrogen plus medroxyprogesterone acetate produced significant reductions in low-density lipoprotein cholesterol levels (9.4 percent and 16.5 percent, respectively) and significant increases in high-density lipoprotein cholesterol levels (18.8 percent and 14.2 percent, respectively); however,...

Incidence of and Risk Factors for Atrial Fibrillation in Older Adults

BACKGROUND This study aimed to describe the incidence of atrial fibrillation (AF) among older adults during 3 years of follow-up. METHODS AND RESULTS In this cohort study, 5201 adults > or = 65 years old were examined annually on four occasions between June 1989 and May 1993. At baseline, participants answered questionnaires and underwent a detailed examination that included carotid ultrasound, pulmonary function tests, ECG, and echocardiography. Subjects with a pacemaker or AF at baseline (n=357) were excluded. New cases of AF were identified from three sources: (1) annual self-reports, (2) annual ECGs, and (3) hospital discharge diagnoses. Cox proportional-hazards models were used to assess baseline risk factors as predictors of incident AF. Among 4844 participants, 304 developed a first episode of AF during an average follow-up of 3.28 years, for an incidence of 19.2 per 1000 person-years. The onset was strongly associated with age, male sex, and the presence of clinical cardiovascular disease. For men 65 to 74 and 75 to 84 years old, the incidences were 17.6 and 42.7, respectively, and for women, 10.1 and 21.6 events per 1000 person-years. In stepwise models, the use of diuretics, a history of valvular heart disease, coronary disease, advancing age, higher levels of systolic blood pressure, height, glucose, and left atrial size were all associated with an increased risk of AF. The use of beta-blockers and high levels of alcohol use, cholesterol, and forced expiratory volume in 1 second were associated with a reduced risk of AF. CONCLUSIONS The incidence of AF in older adults may be higher than estimated by previous population studies. Left atrial size appears to be an important risk factor, and the control of blood pressure and glucose may be important in preventing the development of AF.

Nifedipine Dose-Related Increase in Mortality in Patients With Coronary Heart Disease

BACKGROUND The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur. METHODS AND RESULTS We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (P = .01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects. CONCLUSIONS In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.

Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.

BACKGROUND HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease. METHODS AND RESULTS Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02). CONCLUSIONS In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.

ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: A report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents

ACCF TASK FORCE MEMBERS Robert A. Harrington, MD, FACC, Chair; Eric R. Bates, MD, FACC; Charles R. Bridges, MD, MPH, FACC; Mark J. Eisenberg, MD, MPH, FACC; Victor A. Ferrari, MD, FACC; Mark A. Hlatky, MD, FACC; Sanjay Kaul, MBBS, FACC; Jonathan R. Lindner, MD, FACC‡; David J. Moliterno, MD, FACC; Debabrata Mukherjee, MD, FACC; Richard S. Schofield, MD, FACC‡; Robert S. Rosenson, MD, FACC; James H. Stein, MD, FACC; Howard H. Weitz, MD, FACC; Deborah J. Wesley, RN, BSN

Lipoprotein Management in Patients With Cardiometabolic Risk Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation

Risk factors for type 2 diabetes and cardiovascular disease (CVD) often cluster, including obesity (particularly central), insulin resistance, hyperglycemia, dyslipoproteinemia, and hypertension. These conditions can also occur in isolation, and they are exaggerated by physical inactivity and smoking. Since each of these factors increases risk of CVD, the concept of global cardiometabolic risk (CMR) (Fig. 1) is of value (1). Lipoprotein abnormalities, including elevated triglycerides, low HDL cholesterol, and increased numbers of small dense LDL particles, are common findings in patients with CMR. Clinical entities with increased CMR include type 2 diabetes, familial combined hyperlipidemia, familial hypoalphalipoproteinemia, and polycystic ovary syndrome (2). These disorders often share the CMR characteristics of central obesity, insulin resistance, dyslipoproteinemia, and hypertension. There are stringent lipid treatment goals for patients with type 2 diabetes or CVD; however, guidelines for treatment of dyslipoproteinemia in high-risk subjects without diabetes or CVD are less intense and are based primarily on LDL cholesterol concentrations, with non-HDL concentrations a secondary consideration in some subjects. Numerous trials have demonstrated that therapies (primarily statins) directed at LDL cholesterol lowering clearly reduce risk of CVD events in patients with diabetes and in those without diabetes but with other CVD risk factors; yet, a number of questions remain. Even with adequate LDL cholesterol lowering, many patients on statin therapy have significant residual CVD risk. It is unclear whether lipoprotein parameters other than LDL or non-HDL cholesterol provide clinically significant additional prognostic information regarding CVD risk, yield more information about the effectiveness of therapy, or indicate more appropriate treatment targets. Many patients with CMR or diabetes have relatively normal levels of LDL cholesterol but increased numbers of small dense LDL particles and other atherogenic lipoproteins. Some have advocated that assessment of other lipoprotein parameters might be more helpful than assessment limited to LDL or non-HDL …

Use of Nonsteroidal Antiinflammatory Drugs An Update for Clinicians: A Scientific Statement From the American Heart Association

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

Elevations of Inflammatory and Procoagulant Biomarkers in Elderly Persons With Renal Insufficiency

Background—Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease. Methods and Results—The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged ≥65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level ≥1.3 mg/dL in women and ≥1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P <0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar. Conclusion—Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.

pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PlAC-II)

We randomized 151 coronary patients to placebo or pravastatin and treated them for 3 years. B-mode ultrasound quantification of carotid artery intimal-medial thickness (IMT) was obtained at baseline and sequentially during this period. The primary outcome was the change in the mean of the maximal IMT measurements across time. Effects on individual carotid artery segments (common, bifurcation, and internal carotid) and on clinical events were also investigated. Plasma concentrations of total cholesterol were lower with active treatment than with placebo (4.80 vs 6.07 mmol/L [186 vs 235 mg/dl], respectively) as were concentrations of low-density lipoprotein cholesterol (3.11 vs 4.30 mmol/L [120 vs 167 mg/dl], respectively). Plasma concentrations of high-density lipoprotein2 cholesterol were higher with active treatment (0.16 vs 0.14 mmol/L [6.1 vs 5.5 mg/dl], respectively). Active treatment resulted in a nonsignificant 12% reduction in progression of the mean-maximum IMT (from 0.068 to 0.059 mm/year) and a statistically significant 35% reduction in IMT progression in the common carotid. Active treatment was also associated with a reduction in fatal and nonfatal coronary events [corrected] (p = 0.09) and of any fatal event plus nonfatal myocardial infarction (p = 0.04).