Philip J. Barter

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

BACKGROUND In patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain. METHODS In a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease. RESULTS Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P<0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P<0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P<0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P<0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin. CONCLUSIONS Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.

Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome

BACKGROUND In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. METHODS We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. RESULTS At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons). CONCLUSIONS In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.).

Antiinflammatory Properties of HDL

There are several well-documented functions of high-density lipoprotein (HDL) that may explain the ability of these lipoproteins to protect against atherosclerosis. The best recognized of these is the ability of HDL to promote the efflux of cholesterol from cells. This process may minimize the accumulation of foam cells in the artery wall. However, HDL has additional properties that may also be antiatherogenic. For example, HDL is an effective antioxidants. The major proteins of HDL, apoA-I and apoA-II, as well as other proteins such as paraoxonase that cotransport with HDL in plasma, are well-known to have antioxidant properties. As a consequence, HDL has the capacity to inhibit the oxidative modification of low-density lipoprotein (LDL) in a process that reduces the atherogenicity of these lipoproteins. HDL also possesses other antiinflammatory properties. By virtue of their ability to inhibit the expression of adhesion molecules in endothelial cells, they reduce the recruitment of blood monocytes into the artery wall. These antioxidant and antiinflammatory properties of HDL may be as important as its cholesterol efflux function in terms of protecting against the development of atherosclerosis.

Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.

CONTEXT A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus. OBJECTIVE To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy. DATA SOURCES We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators. STUDY SELECTION We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year. DATA EXTRACTION Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I(2) statistic. RESULTS In 5 statin trials with 32,752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I(2) = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I(2) = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events. CONCLUSION In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.

Cholesteryl Ester Transfer Protein A Novel Target for Raising HDL and Inhibiting Atherosclerosis

Abstract—Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from antiatherogenic HDLs to proatherogenic apolipoprotein B (apoB)–containing lipoproteins, including VLDLs, VLDL remnants, IDLs, and LDLs. A deficiency of CETP is associated with increased HDL levels and decreased LDL levels, a profile that is typically antiatherogenic. Studies in rabbits, a species with naturally high levels of CETP, support the therapeutic potential of CETP inhibition as an approach to retarding atherogenesis. Studies in mice, a species that lacks CETP activity, have provided mixed results. Human subjects with heterozygous CETP deficiency and an HDL cholesterol level >60 mg/dL have a reduced risk of coronary heart disease. Evidence that atherosclerosis may be increased in CETP-deficient subjects whose HDL levels are not increased is difficult to interpret and may reflect confounding or bias. Small-molecule inhibitors of CETP have now been tested in human subjects and shown to increase the concentration of HDL cholesterol while decreasing that of LDL cholesterol and apoB. Thus, it seems important and timely to test the hypothesis in randomized trials of humans that pharmacological inhibition of CETP retards the development of atherosclerosis.

Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease

BACKGROUND Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol. METHODS We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease or at high risk for coronary heart disease. Eligible patients who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18 months. The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and deaths were prospectively adjudicated. RESULTS A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group (P<0.001)--a 39.8% reduction with anacetrapib beyond that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001)--a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability (confidence) of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib. CONCLUSIONS Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an acceptable side-effect profile, and, within the limits of the power of this study, did not result in the adverse cardiovascular effects observed with torcetrapib. (Funded by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.).

High-Density Lipoproteins Inhibit Cytokine-Induced Expression of Endothelial Cell Adhesion Molecules

While an elevated plasma concentration of HDLs is protective against the development of atherosclerosis and ensuing coronary heart disease (CHD), the mechanism of this protection is unknown. One early cellular event in atherogenesis is the adhesion of mononuclear leukocytes to the endothelium. This event is mediated principally by vascular cell adhesion molecule-1 (VCAM-1) but also involves other molecules, such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin. We have investigated the effect of isolated plasma HDLs and reconstituted HDLs on the expression of these molecules by endothelial cells. We show that physiological concentrations of HDLs inhibit tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1) induction of these leukocyte adhesion molecules in a concentration-dependent manner. Steady state mRNA levels of TNF-alpha-induced VCAM-1 and E-selectin are significantly reduced by physiological concentrations of HDLs. An an HDL concentration of 1 mg/mL apolipoprotein A-I, the protein expressions of VCAM-1, ICAM-1, and E-selectin were inhibited by 89.6 +/- 0.4% (mean +/-SD, n=4), 64.8 +/- 1.0%, and 79.2 +/- 0.4%, respectively. In contrast, HDLs have no effect on the expression of platelet endothelial cell adhesion molecule (PECAM) or on the expression of the p55 and p75 subunits of the TNF-alpha receptor. HDLs were effective when added from 16 hours before to 5 minutes after cytokine stimulation. HDLs had no effect on TNF-alpha-induced expression of ICAM-1 by human foreskin fibroblasts, suggesting that the effect is cell-type restricted.(ABSTRACT TRUNCATED AT 250 WORDS)

International Day for the Evaluation of Abdominal Obesity (IDEA): a study of waist circumference, cardiovascular disease, and diabetes mellitus in 168,000 primary care patients in 63 countries

Background— Abdominal adiposity is a growing clinical and public health problem. It is not known whether it is similarly associated with cardiovascular disease (CVD) and diabetes mellitus in different regions around the world, and thus whether measurement of waist circumference (WC) in addition to body mass index (BMI) is useful in primary care practice. Methods and Results— Randomly chosen primary care physicians in 63 countries recruited consecutive patients aged 18 to 80 years on 2 prespecified half days. WC and BMI were measured and the presence of CVD and diabetes mellitus recorded. Of the patients who consulted the primary care physicians, 97% agreed to participate in the present study. Overall, 24% of 69 409 men and 27% of 98 750 women were obese (BMI≥30 kg/m2). A further 40% and 30% of men and women, respectively, were overweight (BMI 25 to 30 kg/m2). Increased WC (>102 for men and >88 cm for women) was recorded in 29% and 48%, CVD in 16% and 13%, and diabetes mellitus in 13% and 11% of men and women, respectively. A statistically significant graded increase existed in the frequency of CVD and diabetes mellitus with both BMI and WC, with a stronger relationship for WC than for BMI across regions for both genders. This relationship between WC, CVD, and particularly diabetes mellitus was seen even in lean patients (BMI<25 kg/m2). Conclusions— Among men and women who consulted primary care physicians, BMI and particularly WC were both strongly linked to CVD and especially to diabetes mellitus. Strategies to address this global problem are required to prevent an epidemic of these major causes of morbidity and mortality.

Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: The Treating To New Targets (TNT) study

OBJECTIVE—The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS—A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to double-blind therapy with either atorvastatin 10 (n = 753) or 80 (n = 748) mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first major cardiovascular event, defined as death from CHD, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. RESULTS—End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58–0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48–0.98], P = 0.037) and any cardiovascular event (0.85 [0.73–1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. CONCLUSIONS—Among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg.

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein‐related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid‐lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL−1 in high‐risk patients should be reassessed in the light of the new clinical trial results and a new ultra‐low target of <80 mg dL−1 be considered. The evidence also indicates that the apo B/apo A‐I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein‐related risk of vascular disease.