PROSPER: The Prospective Study of Pravastatin in the Elderly at Risk

Luis Gruberg, MD, FACC

Disclosures

November 21, 2002

Presenter: James Shepherd, MD, Princeton, New Jersey

Cardiovascular disease is the leading cause of morbidity and mortality in people aged 70 and older and is correlated to low levels of low-density lipoprotein (LDL) cholesterol. Although previous randomized trials have demonstrated the beneficial effect of statin therapy in middle-aged patients with either normal or elevated total cholesterol levels, the therapy regimen has not been closely examined in an older patient population (> 70 years). If positive, the prescription rates for statin therapy could significantly soar, making the drugs more readily accessible to this older patient population. In addition, increased usage of statin therapy could help combat other cardiovascular-related comorbidities such as cognitive decline and dementia. This hypothesis is based on the published results of PROSPER, (published this week in The Lancet)[1] in which Shepherd and colleagues state that some observational studies "have raised the possibility" that statins could help lower the risk of cognitive decline in an elderly population.[2]

Methods

The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was designed to determine whether pravastatin (Pravachol; Bristol-Myers Squibb Company [New York, NY]) 40 mg/day has primary and secondary roles in reducing coronary and cerebral events in older patients with preexisting vascular disease or who are at high risk for vascular disease and stroke.

The double-blinded, randomized, controlled trial initially screened 23,770 patients, and the patient population was subsequently narrowed (due to ineligibility or refusal to participate) to 5804 patients who were then randomized to either placebo (n = 2913) or 40 mg of pravastatin (n = 2891) (Figure 1).

Patients were recruited if they had either preexisting vascular disease (coronary, cerebral, or peripheral) or were at increased risk for vascular disease due to such factors as smoking, hypertension, or diabetes. Inclusion criteria called for men and women between the ages of 70 and 82 years with a total plasma cholesterol of 155-350 mg/dL (4-9/mmol/L) and triglyceride levels < 200 mg/dL (6 mmol/L) . Patients were excluded if they showed signs of cognitive decline, which was assessed by a Mini Mental State Examination and a series of psychometric tests. The study population was distributed evenly between those with existing vascular disease and those with qualifying risk factors. Patients were followed every 3 months for an average of 3.2 years.

The primary composite endpoint, definite or suspected death from coronary heart disease (CHD), nonfatal myocardial infarction (MI), or fatal/nonfatal stroke, was measured at 3-year follow-up. According to the Lancet article, investigators expected to find a 20% reduction in the primary endpoint among those treated with statin therapy, assuming a 16% cardiac event rate in placebo-treated patients. Secondary endpoints included assessing the individual effects of statin therapy on coronary and cerebrovascular disease. Analyses were conducted that evaluated (1) CHD-related death or nonfatal MI, and (2) fatal or nonfatal stroke. Subanalyses were also performed to assess the benefits of the drug based on gender and for those with and without preexisting vascular disease.

Figure 1. PROSPER: trial design.
Results

The 3 participating centers for the study were located in Cork, Ireland; Glasgow, Scotland; and Leiden, The Netherlands. Both groups of patients (patients receiving pravastatin and those receiving placebo) had near identical baseline clinical characteristics, including the fact that the average age in both groups was 75 years (Table 1). Gender was also evenly distributed across the entire patient cohort (female 52%, male 48%). In addition, baseline lipid profiles were well balanced between the 2 groups (Table 2).

Table 1. PROSPER: Baseline Clinical Characteristics
  Placebo Pravastatin
Age (yrs) 75.3 75.4
Female (%) 52 52
History of any vascular disease, n (%) 1259 (43.2) 1306 (45.2)
Current smoker, n (%) 805 (27.6) 753 (26.0)
History of hypertension, n (%) 1793 (61.6) 1799 (62.2)
Mean SBP/DBP (mm Hg) 154.6/83.94 154.7/83.64
History of diabetes, n (%) 320 (11.0) 303 (10.5)
Table 2. PROSPER: Baseline Lipid Profile
  Placebo Pravastatin
Total cholesterol (mg/dL) 221 221
HDL-C (mg/dL) 50 50
LDL-C (mg/dL) 147 147
Triglycerides (mg/dL) 133 133
Use of Statins Improved Baseline Lipid Levels in This Elderly Population

Overall, pravastatin therapy lowered LDL-C levels by 34%, total cholesterol by 23%, triglycerides by 13%, and increased HDL-C by 5% at 3 months follow-up.

The Primary Endpoint of the Trial Was Met

At 3-year follow-up, the primary composite endpoint (CHD-related death, nonfatal MI, and stroke) was reduced by 15% in the pravastatin group (16.2% vs 14.1%, P = .014) (Figure 2).

Figure 2. PROSPER: primary endpoint (coronary death, nonfatal MI, and stroke).
Statin Therapy Significantly Reduced the Incidence of CHD-related Death or Nonfatal MI but Showed No Impact on Cerebrovascular Disease

The secondary endpoints (death from CHD or nonfatal myocardial infarction) were reduced by 19% (P = .006) (Figure 3), and coronary death alone was reduced by 24% (Figure 4).

Figure 3. PROSPER: rates of CHD-related death and nonfatal MI.
Figure 4. PROSPER: rate of CHD-related death.

There was no significant difference in the incidence of fatal or nonfatal stroke between the 2 groups (4.5% vs 4.7%, P = .81) (Figure 5).

Figure 5. PROSPER: rates of fatal and nonfatal stroke.

Other tertiary endpoints were similar between the 2 groups -- statin therapy did not influence the rate of heart failure requiring hospitalization, revascularization procedures, cognitive function, or disability. The incidences of myalgia and rhabdomyolysis were also comparable between the 2 groups.

Pravastatin Patients Had Higher Incidence of Cancer

One particularly interesting finding was that there was a 25% higher incidence of new cases of cancer in patients randomized to pravastatin therapy vs placebo -- 8.5% (n = 245) vs 6.8% (n = 199, P < .05) -- but this rate was still lower than the expected incidence of cancer in this general age group. Investigators stressed that they were not particularly concerned about the increased incidence of cancer, as there were no consistent patterns among the various tissues affected, so it was assumed that the cancer had started to develop in these patients prior to the study.

Study Limitations Include Short Follow-up Period

Compared with other trials evaluating statin therapy, the 3.2-year follow-up of the PROSPER study was considerably shorter. However, investigators were quick to point out that they chose a shorter timeframe due to the fact that these patients were older and likely in their last decade of life. This shorter follow-up period may be part of the reason that statin therapy did not reduce the incidence of stroke or affect cognitive function.

Conclusions

The results of PROSPER clearly show that the benefits of statin therapy observed among middle-aged adults are extended to include older patients (> 70 years). Pravastatin, at a dose of 40 mg, was well tolerated and achieved a 15% relative risk reduction in the primary endpoint at 3.2 years follow-up. Treated patients had coronary events significantly reduced by 19% and coronary mortality by 24%; however, the drug did not seem to have an effect on stroke or cognitive function. These results emphasize the need to expand statin therapy to include this elder patient population in order to reduce the incidence of vascular-related events.

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