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Title: Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range

Authors: Lewis SJ, Moye LA, Saks FM, et al.

Reference: Ann Intern Med 1998; 129: 681-9

Reviewer: Luis Rosario

Problem addressed: Three fourths of myocardial infarctions (MI) occur in patients 65 years of age or older and a majority has average serum cholesterol levels. The possible effect of lipid lowering secondary prevention in this age group is controversial. First, because after 65 years of age, cholesterol levels are not strong predictors of coronary events and second because major trials of lipid lowering therapy have excluded patients older than 65. Although the relative risk of coronary events related to cholesterol levels decreases with age, the absolute risk increases as the incidence of cardiovascular events increases with age. The Cholesterol and Recurrent Events (CARE) study showed that in patients with average cholesterol levels after MI, secondary prevention with pravastatin reduced the risk of coronary death by 25% (p<0.006), reduced the risk of PTCA or CABG by 27% (p<0.001) and reduced the risk of stroke by 31% (p<0.03).

Study design: Randomized double blind, placebo controlled study with a planned follow up of five years.  Patients were eligible 3 to 20 months after an acute myocardial infarct, with plasma levels less than 6.2 mmol/L (<240mg/dL); LDL cholesterol of 3.0 to 4.5 mmol/L (< 115 to 174mg/dL) and fasting triglyceride levels inferior to 4.0 mmol/L (<350mg/dL).  Primary outcome was fatal MI. For the primary analysis in subgroups an expanded end point was used (death for coronary artery disease, nonfatal MI, angioplasty or coronary artery bypass grafting), called major coronary events.

Results:  Baseline coronary risk factors differed in the two groups: older patients group had more females (18% vs 12%); hypertension was more prevalent (48% vs 40%); more had diabetes (19% vs 12%); less were current smokers (12% vs 24%); and less had a family history of coronary artery disease (33% vs 44%); from the time of infarction until enrollment older patients were less likely to receive thrombolysis, angiography, angioplasty or CABG; therapy at the time of randomization was different in older patients were less likely to be taking beta blockers and more were receiving calcium channel blockers, ACE inhibitors, digitalis and diuretics.

In older patients the rate of major coronary events was 28% with placebo and 19.7% with pravastatin; relative risk reduction of 32% and an absolute risk reduction of 9.0%.  Death from coronary artery disease in the placebo group was 10.3% vs 4.5% in the therapy arm; relative risk reduction of 45% and absolute risk reduction of 4.6%.  Stroke incidence was 7.3% in the placebo group vs 4.5% in the therapy arm; relative risk reduction of 40% and absolute risk reduction of 4.5%, this was a unique finding within cholesterol lowering trial. The number of older and younger patients needed to treat to prevent a major coronary event during five years was 11 and 20 respectively; corresponding numbers were 15 and 67 for coronary death or non fatal MI and 34 and 250 for stroke. There were no significant differences in the relative risk reductions between younger and older patients. 

Discussion: This sub group analysis of the CARE trial demonstrates that in a high risk group - older patients post MI - the secondary prevention with pravastatin is statistically and clinically important, due to the small number of patients needed to treat to prevent an event.  There are remaining issues concerning primary prevention in this age group and if there is an age limit for the cholesterol lowering therapy. The issue of primary and secondary prevention in older women remains unsettled.

Comments: This subgroup analysis of the CARE trial brings important data to three issues in the prevention of atherosclerotic morbidity and mortality with lipid lowering therapy:

- This is the first study to find a reduction in stroke, irrespective of age, with lipid lowering therapy in a population with symptomatic coronary artery disease. Further studies are needed, both in secondary and primary prevention, to properly define the role of lipid lowering therapy in stroke prevention

- For the first time secondary prevention with a cholesterol lowering drug proves to be beneficial in patients older than 65 years with history of myocardial infarction.

- The issue of how low a level of cholesterol is desirable and if there is a J curve effect in lipid lowering therapy rises again, as in this trial patients were in the average range. Unfortunately the authors present no data on the relationship between the magnitude of serum cholesterol reduction and the risk reduction.

It is important to keep in mind that this trial was sponsored by a pharmaceutical company, makers of pravastatin. Although dietary counseling was provided at enrollment, no data on its efficacy or influence on outcomes is presented by the authors. We remain expectant on who would sponsor studies to further characterize the potential benefits of those inexpensive therapies like lifestyle modification compared to pharmacologic treatments.