Title

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

Purpose

To evaluate the effects of cholesterol lowering therapy with pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on coronary heart disease mortality among patients with a history of myocardial infarction or unstable angina and a wide range of baseline cholesterol levels.

Design

Randomized, double blind, placebo controlled, multicenter .

Patients

9014 patients, 31-75 years old, with a history of acute myocardial infarction or unstable angina within 3-36 months prior to enrollment. Patients had to have baseline plasma total cholesterol levels of 155 to 271 mg/dL and fasting triglyceride levels of < 445 mg/dL. Patients with a clinically significant medical or surgical event within the 3 months preceding the study were not included. Patients with heart failure, renal failure, hepatic disease or current use of any cholesterol lowering agents were excluded.

Follow-up

A mean of 6.1 years

Treatment regimen

An 8 week single blind placebo run in phase with dietary advice for low fat diet. Thereafter, patients were randomized to either pravastatin 40 mg/d or placebo.

Additional therapy

Low fat diet (< 30% of the total energy intake).

Results

• After one year, 3 years, and at the end of the study, 6%, 11% and 19% of the pravastatin- assigned patients stopped their
study medications, whereas 3%, 9% and 24% of the placebo- assigned patients began open label cholesterol-lowering
therapy.
• Total plasma cholesterol fell by 39 mg/dL in the pravastatin- assigned group. The reduction in total cholesterol levels
was 18% greater in the pravastatin than placebo- assigned group (p < 0.001).
• The decrease in plasma LDL cholesterol was 25% greater in the pravastatin group.
• Total mortality was 11.0% in the pravastatin group vs 14.1% in the placebo group (reduction in risk 22%, 95% CI 13 to
31%; p < 0.001).
• Mortality from coronary heart disease was 6.4% in the pravastatin group vs 8.3% in the placebo group (reduction in risk
24%; p<0.001).
• Cardiovascular mortality was 7.3% and 9.6% in the pravastatin and placebo groups, respectively (reduction in risk
25%; 95% CI 13 to 35%; p < 0.001).
• Death from trauma, suicide or cancer occurred less often in the pravastatin group (p=NS).
• Myocardial infarction occurred in 7.4% vs 10.3% respectively (reduction in risk 29%; p < 0.001).
• Less patients in the pravastatin group needed CABG (9.2% vs 11.6%; reduction in risk 29%; p<0.001), or PTCA
(4.7% vs 5.6%; reduction in risk 19%; 95% CI 3 to 33%; p=0.024).
• Pravastatin was associated with less hospitalization for unstable angina (22.3% vs 24.6%; p=0.005) and less strokes
(3.7% vs 4.5%; p=0.048).
• Among patients with prior myocardial infarction, coronary heart disease mortality was 23% lower (p=0.004) and total
mortality was 21% lower (p=0.002) in the pravastatin group.
• Among the subgroup of patients with unstable angina, coronary heart disease mortality was 26% lower (p=0.036) and total mortality 26% lower (p=0.004) in the pravastatin group.
• Subgroup analysis revealed that pravastatin was effective in patients with high (³ 251 mg/dL), medium (213-250 mg/dL), and low (< 213 mg/dL) baseline total cholesterol levels. However, the reduction in risk among patients with LDL cholesterol < 136 mg/dL was not significant (16%; 95% CI-4 to 32%).
• Pravastatin therapy was safe. There was no increase in the incidence of newly diagnosed primary cancers, including breast cancer. Increase in serum alanine aminotransferase > 3 times the upper limit of normal occurred in 2.1% of the pravastatin vs 1.9% of the placebo group (p=0.41). There was no increase in the incidence of myopathy or elevation of serum creatine kinase levels. Adverse effects, ultimately attributed to the study medication occurred in 3.2% of the pravastatin vs 2.7% of the placebo group (p=0.16).

Conclusion

Secondary prevention therapy with pravastatin was associated with reduced all-cause mortality and mortality from coronary heart disease in patients with a history of myocardial infarction or unstable angina who had a broad range of initial plasma cholesterol levels.