Rene Belder

Efficacy and safety of high‐dose pravastatin in hypercholesterolemic patients with well‐compensated chronic liver disease: Results of a prospective, randomized, double‐blind, placebo‐controlled, multicenter trial

The hepatotoxic potential of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors in patients with underlying chronic liver disease remains controversial. We performed a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group trial that compared pravastatin (80 mg) to a placebo administered once daily to hypercholesterolemic subjects greater than 18 years of age with at least a 6‐month history of compensated chronic liver disease and with a low‐density lipoprotein cholesterol (LDL‐C) level greater than or equal to 100 mg/dL and a triglyceride (TG) level lower than 400 mg/dL. The efficacy was determined by the percentage change in LDL‐C [along with the total cholesterol (TC), high‐density lipoprotein cholesterol, and TG] from the baseline to week 12. The safety was analyzed by the proportion of subjects who developed at least 1 alanine aminotransferase (ALT) value greater than or equal to 2 times the upper limit of normal for those with normal ALT at the baseline or a doubling of the baseline ALT for those with elevated ALT at the baseline during 36 weeks of treatment. A total of 630 subjects were screened, and 326 subjects were randomized; nonalcoholic fatty liver disease was present in 64%, and chronic hepatitis C was present in 23%. In the intent‐to‐treat population, pravastatin (80 mg/day) significantly lowered the mean LDL‐C, TC, and TG values at week 12 and at other times (weeks 4, 8, 24, and 36) in comparison with the placebo. The incidence of subjects who met the primary prespecified ALT event definition was lower in the pravastatin group at all times over the 36 weeks of therapy in comparison with the placebo group, although the difference was not statistically significant. No differences were seen on the basis of the baseline ALT values or among the different liver disease groups. Conclusion: High‐dose pravastatin (80 mg/day) administered to hypercholesterolemic subjects with chronic liver disease significantly lowered LDL‐C, TC, and TGs in comparison with the placebo and was safe and well tolerated. The concern over an increased potential for statin‐induced hepatotoxicity in patients with chronic liver disease appears to be lessened on the basis of these results. (HEPATOLOGY 2007.)

Comparison of Intensive and Moderate Lipid Lowering With Statins After Acute Coronary Symptoms

background Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. methods We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24). results The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan–Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen. conclusions Among patients who have recently had an acute coronary syndrome, an intensive lipidlowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.

Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy

OBJECTIVE—We sought to evaluate the effects of muraglitazar, a dual (α/γ) peroxisome proliferator–activated receptor (PPAR) activator within the new glitazar class, on hyperglycemia and lipid abnormalities. RESEARCH DESIGN AND METHODS—A double-blind, randomized, controlled trial was performed in 1,159 patients with type 2 diabetes inadequately controlled with metformin. Patients received once-daily doses of either 5 mg muraglitazar or 30 mg pioglitazone for a total of 24 weeks in addition to open-label metformin. Patients were continued in a double-blind fashion for an additional 26 weeks. RESULTS—Analyses were conducted at week 24 for HbA1c (A1C) and at week 12 for lipid parameters. Mean A1C at baseline was 8.12 and 8.13% in muraglitazar and pioglitazone groups, respectively. At week 24, muraglitazar reduced mean A1C to 6.98% (−1.14% from baseline), and pioglitazone reduced mean A1C to 7.28% (−0.85% from baseline; P < 0.0001, muraglitazar vs. pioglitazone). At week 12, muraglitazar and pioglitazone reduced mean plasma triglyceride (−28 vs. −14%), apolipoprotein B (−12 vs. −6%), and non-HDL cholesterol (−6 vs. −1%) and increased HDL cholesterol (19 vs. 14%), respectively (P < 0.0001 vs. pioglitazone for all comparisons). At week 24, weight gain (1.4 and 0.6 kg, respectively) and edema (9.2 and 7.2%, respectively) were observed in the muraglitazar and pioglitazone groups; at week 50, weight gain and edema were 2.5 and 1.5 kg, respectively, and 11.8 and 8.9%, respectively. At week 50, heart failure was reported in seven patients (five with muraglitazar and two with pioglitazone), and seven deaths occurred: three from sudden death, two from cerebrovascular accident, and one from pancreatic cancer in the muraglitazar group and one from perforated duodenal ulcer in the pioglitazone group. CONCLUSIONS—We found that 5 mg muraglitazar resulted in greater improvements in A1C and lipid parameters than a submaximal dose of 30 mg pioglitazone when added to metformin. Weight gain and edema were more common when muraglitazar was compared with a submaximal dose of pioglitazone.

Bayesian survival analysis with nonproportional hazards: Metanalysis of combination pravastatin–aspirin

Both pravastatin and aspirin are approved by the U.S. Food and Drug Administration (FDA) for secondary prevention of cardiovascular events. This article describes statistical analyses used for a successful submission to the FDA that contends that copackaging pravastatin and aspirin provides a health benefit. From the efficacy perspective this is taken to mean that the combination is more effective than either agent considered alone. We present three Bayesian hierarchical survival models and apply them to the results of five randomized clinical trials. These trials evaluated the benefit of pravastatin in the secondary-prevention setting. Aspirin use was recorded for patients in these trials, but assignment to aspirin was not randomized. We compare the effects of pravastatin and aspirin considered in combination and when given alone. We focus on time to myocardial infarction, although it was just one of several endpoints considered in the presentation to the FDA. Two of the models assume proportional hazards and the third does not. In all three models we adjust for known covariates. Our principal focus is the probability that the combination of pravastatin and aspirin is at least as effective as the agents considered separately. We also find the probability that the combination is synergistic in the sense that the effect of the combination is better than the sum of the effects of the two agents taken alone.