Title

a. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.
b. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol And Recurrent Events trial.
c. Reduction of stroke incidence following myocardial infarction with pravastatin: the CARE study .

Purpose

a. To evaluate the effectiveness of lowering blood cholesterol levels with pravastatin in patients after myocardial infarction and its effect on subsequent cardiac events.
b. To determine the relationship between the LDL concentration during therapy, absolute reduction in LDL, and percent reduction in LDL and outcome.
c. To analyze the effect of lipid lowering with pravastatin on the risk of stroke and transient ischemic attacks in the CARE trial.

Design

Randomized, double blind, placebo controlled, multicenter.

Patients

4159 patients, 21-75 years old, who have experienced myocardial infarction 3-20 months before randomization, had plasma total cholesterol < 240 mg/dL, LDL cholesterol 115-174 mg/dL, triglycerides < 350 mg/dL, fasting glucose levels £ 220 mg/dL, left ventricular ejection fraction ³ 25% and no symptomatic congestive heart failure.

Follow-up

Median follow-up 5 years (4-6.2 years)

Treatment regimen

Pravastatin 40 mg/d or placebo. For patients with LDL cholesterol > 175 mg/dL at follow-up, dietary counseling, and then cholestyramine.

Results

• Pravastatin therapy lowered the mean LDL cholesterol of 139 mg/dL by 32% and maintained mean levels of 98 mg/dL.

• During follow-up, LDL cholesterol was 28% lower, total cholesterol was 20% lower, HDL 5% higher, and triglycerides level 14% lower in the pravastatin than placebo group (p <0.001 for all comparisons).

• Primary end points (death from coronary artery disease or nonfatal myocardial infarction) occurred in 13.2% vs 10.2% in the placebo and pravastatin group, respectively (risk reduction 24%, p=0.003).

• Cardiovascular death occurred in 5.7% in the placebo vs 4.6% in the pravastatin group (risk reduction 20%, p=0.10), and non fatal myocardial infarction occurred in 8.3% vs 6.5%, respectively (risk reduction 23%, p=0.02).

• Total mortality was comparable (9.4% vs 8.6% in the placebo and pravastatin group, respectively; 9% risk reduction; p=0.37). There was no difference in mortality from noncardiovascular causes.

• The risk of myocardial infarction was 25% lower in the pravastatin group (7.5% vs 10.0%; p=0.006).

• The rate of coronary artery bypass surgery or PTCA was lower in the pravastatin group (14.1% vs 18.8%; risk reduction 27%)

• There was also a trend toward less unstable angina in the pravastatin group (15.2% vs 17.3%; risk reduction 13%)

• The effect of pravastatin was greater among women than among men (46% vs 20% risk reduction for women and men, respectively).

• Patients with baseline LDL cholesterol > 150 mg/dL had a 35% reduction in major coronary events, as compared with a 26% reduction in those with baseline LDL cholesterol of 125-150 mg/dL, and a 3% increase in those with baseline levels < 125 mg/dL.

• The overall incidence of fatal or nonfatal cancer was comparable (161 in the placebo vs 172 in the pravastatin group). However, breast cancer occurred in 1 patient in the placebo and in 12 in the pravastatin group (p=0.002). Of the 12 cases in the pravastatin group, 3 occurred in patients who had previously had breast cancer. There was no other significant difference between the groups in the occurrence of other types of cancer.

• Coronary death or recurrent MI were reduced by 24% with pravastatin. Coronary event rate declined as LDL was reduced from 174 to about 125 mg/dL; however, no further decline occurred in the LDL range of 71-125 mg/dL.

• Triglycerides but not HDL weakly but significantly were associated with coronary event rate.

• The stroke incidence was 3.7% in placebo patients and 2.5% in patients on pravastatin. Stroke or transient ischemic attack occurred in 6% of patients on placebo and 4.4% of patients on pravastatin. Thus, pravastatin decreased strokes by 32%, it decreased either strokes or transient ischemic attacks by 27% over 5 years.

• Unlike the CARE findings for reduced risk of myocardial infarction (whereby lowering LDL below 125 mg/dL did not further reduce myocardial infarction), the investigators did not observe a threshold effect of LDLs below 125 mg/dL for stroke. Patients with LDLs above 150 had a 44% lower rate of strokes; those between 125-150, a 28% lower a 28% lower stroke rate; and under 125, a 25% reduction in stroke rate with pravastatin.

Conclusion

• Pravastatin therapy lowered cardiac mortality, the need for revascularization, and occurrence of stroke in both men and
women with coronary artery disease, plasma total cholesterol of < 240 mg per deciliter and plasma LDL cholesterol > 125 mg per deciliter. There was no reduction in overall mortality.

• Reduction of LDL down to a concentration of about 125 mg/dL was associated with a reduction in coronary events.
Further reduction to < 125 mg/dL with therapy was not associated with additional benefit.

• In the population of patients in the CARE study, pravastatin reduced the rates of stroke and stroke or transient ischemic
attacks.