Source: Shepherd J, et al. Lancet. 2002;360:1623-1630.
The pravastatin in elderly individuals at risk of vascular disease (PROSPER) trial is a study of statin therapy in high-risk elderly individuals. PROSPER tested the hypothesis that the benefits of statin therapy on cardiovascular disease, stroke, and cognitive decline would be seen in the elderly, which had not yet been rigorously investigated with respect to LDL lowering with a statin. Three countries—Scotland, Ireland, and The Netherlands—participated; Five thousand eight hundred individuals were assigned pravastatin 40 mg daily or placebo. The study was carried out for a mean of 3.2 years (range 2.8-4.0). It was designed for a relatively short period because of the age of the subjects. Subjects had pre-existing vascular disease (2565) or increased risk due to diabetes, smoking, or hypertension (3242). Individuals from 70 to 82 were enrolled; the mean age was 75. The primary end point was a composite of coronary death, nonfatal myocardial infarction (MI), or stroke. Secondary end points included individual components of the primary end point. Tertiary end points included assessment of transient ischemic attack, cognitive function, and disability.
Pravastatin reduced LDL cholesterol by 27% at 2 years and in compliant individuals by one-third. HDL increased by 5%, and triglycerides fell by 12%. The primary end point had a 15% risk reduction, P = 0.014. A reduction in coronary artery disease (CAD) death and nonfatal MI was noted with a risk reduction of 19% (P = 0.006). There was no reduction in stroke, but there was a trend for reduction in transient ischemic attacks of 25%. There were no differences in the loss of cognitive function or disability over the course of the 3-year trial. Analysis of the data indicated that men, but not women, achieved a risk reduction. There was no benefit in the primary prevention cohort (the majority of enrollees). Also, the patients in the lowest tertile of baseline HDL cholesterol (less than 42 mg/dL) had a 36% risk reduction (P = 0.007) vs a nonsignificant reduction in the intermediate and highest HDL groups. There was a 25% greater risk of new cancers diagnosed in the pravastatin patients, particularly of GI origin. The authors performed a meta analysis of all major statin trials including PROSPER and concluded that there was no excess of cancer with statins. The investigators concluded that the benefits of statin therapy can be seen in elderly individuals after only 3 years with respect to coronary disease but not stroke. "PROSPER suggests that the strategy for vascular risk management in middle-aged people should also be applied to elderly individuals."
Comment by Jonathan Abrams, MD
PROSPER is an interesting and important addition to the large amount of statin data. The results can be viewed as a glass half empty or half full. The latter view is supported by a positive risk reduction for CAD events at only 3 years in this elderly population. However, there was no benefit in stroke or cognitive decline, surely a disappointment to investigators and others interested in the effects of statins on cerebro vascular disease. A "glass half empty" view would point out that in women and in high-risk primary prevention individuals, there was no benefit of pravastatin over placebo. Thus, one can conclude that elderly men, or men and women with low HDL cholesterol, appear to benefit from lipid lowering, but older women with risk factors only did not show a decrease in vascular events over the relatively short course of the study. These data are different from those in the Heart Protection Study (HPS), which demonstrated a reduction of events in 25% of diabetics without overt vascular disease. However, HPS lasted for a longer period of time and involved younger subjects. It has been observed in the past that cholesterol levels in the elderly have a lesser interaction with cardiovascular disease morbidity and mortality. In particular, stroke has not been related to cholesterol, although several of the major statin trials have shown a reduction in stroke as a secondary end point. Shepherd and colleagues suggest that the benefit from statins in stroke may not appear until 4-5 years, although coronary event reduction appears to be seen earlier after statin initiation. The authors do not provide any explanation or comment on the lack of benefit of pravastatin in the high-risk, nonvascular disease subjects. There are very few diabetics, but nevertheless, in the entire cohort of primary prevention individuals (larger than the secondary prevention cohort), there was no significant reduction in any end point.
In an accompanying editorial, Rory Collins, the primary investigator of the HPS, reviews the data and concludes that they fit in with other large-scale lipid trials.
He states, "Long-term statin therapy should be considered routinely for all such high-risk patients, largely irrespective of either their presenting lipid concentrations or their age." However, he does not discuss the lack of benefit in women (nor do Shepherd et al) or in the PROSPER primary prevention cohort, which was different than in the primary prevention patients in HPS, who were dominantly diabetics.
Shepherd et al and Collins brush off the association of statins with an increased cancer incidence. This was based prominently on the "meta-analysis" of all the statin trials, although LIPID and CARE also had a nonsignificant trend toward more cancer. A collaborative overview of all lipid trials with respect to a variety of end points is ongoing and should provide a useful barometer as to whether cancer or other vascular events differ with respect to a variety of baseline parameters, including age, lipid levels, and gender.
Finally, PROSPER appears to echo the philosophy of the HPS, minimizing the role in LDL or total cholesterol levels. The mean baseline LDL cholesterol in the PROSPER individuals was 144 mg/dL and LDL reduction was 34%; total cholesterol at baseline was 226 mg/dL.
In summary, PROSPER does extend the umbrella for the statin treatment to the elderly, but physicians must choose physiologically sound individuals to justify this expensive therapy. Careful attention to HDL cholesterol would appear to be appropriate, based on the PROSPER data. The benefits of lipid lowering in an average 75-year-old individual who has CAD risk factors, but not overt vascular disease, remains to be determined.
Dr. Abrams is Professor of Medicine Division of Cardiology University of New Mexico, Albuquerque, NM.