Cholesterol Reduction in Seniors Program (CRISP)
Condition: Atherosclerosis; Cardiovascular Diseases; Coronary Disease; Heart Diseases; Hypercholesterolemia; Myocardial Ischemia
MeSH terms: Cardiovascular Diseases; Heart Diseases; Atherosclerosis; Coronary Disease; Myocardial Ischemia; Hypercholesterolemia; Ischemia
Study type: Interventional
Phase: Phase 2

Summary: 
      To conduct a pilot study to determine whether lowering elevated serum cholesterol levels with
      3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors reduced mortality due
      to the sequelae of atherosclerotic cardiovascular disease in older men and women.
    

Detailed description: 
      BACKGROUND:

      Circulating levels of cholesterol, specifically cholesterol associated with the low-density
      lipoprotein (LDL) fraction, have been established by observational epidemiologic studies and
      by metabolic, pathologic, genetic studies in humans and selected animal models, and by
      randomized clinical trials as a major etiologic factor in coronary heart disease. The ratio
      between the percent reduction in coronary heart disease incidence and the percent reduction
      in cholesterol levels associated with treatment in randomized trials, approximately 2:1, is
      almost exactly that predicted by numerous observational epidemiologic studies of this
      relationship. However, the clinical trials demonstrating that lowering LDL-cholesterol levels
      reduces subsequent incidence of coronary heart disease events have been confined by and large
      to middle-aged men with hypercholesterolemia as in the Lipid Research Clinics Coronary
      Primary Prevention Trial (LRC-CPPT) or to men with established coronary heart disease as in
      the Coronary Drug Project (CDP). Experimental confirmation that cholesterol-lowering
      treatment is worthwhile after as well as before age 60 is lacking. Thus, although the
      guidelines issued in October 1987 by the National Cholesterol Education Program's (NCEP)
      Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults did
      not discriminate explicitly by age, the absence of direct evidence of efficacy led them to
      allow room for physician judgment in applying their recommendations to older patients. This
      uncertainty in the application of the NCEP guidelines to older men and women is a matter of
      considerable consequence to the public health.

      Epidemiologic studies suggest that the prognostic power of cholesterol levels diminishes with
      advancing age. Subdivision of the participants in several cohort studies into those above or
      below age 50 at entry shows that the increment in coronary heart disease risk per increment
      in total or LDL cholesterol level is nearly always substantially lower in the older group. In
      the Framingham Heart Study, the study with the most follow-up data beyond age 60, a 0.5
      percent increment in the coronary heart disease incidence rate was estimated per 1 mg/dl
      increment in plasma cholesterol level -- about 60 percent of the increment seen in
      middle-aged men and women. However, the absolute numbers of potentially preventable coronary
      heart disease deaths, 80 percent of which occur after age 65, and myocardial infarctions
      attributable to high plasma cholesterol levels in Framingham and other observational studies
      appear to increase with increasing age.

      Previous clinical trials of cholesterol-lowering drugs have been weakened by their limited
      efficacy and acceptability to patients. In older patients, the administration of
      cholesterol-lowering drugs may be further complicated by interactions with drugs taken for
      other more pressing conditions. However, since the Food and Drug Administration approved the
      HMG CoA reductase inhibitor, lovastatin, in September 1987, the agent has been efficacious
      and well-tolerated by patients of all ages, and has been used increasingly widely.

      In 1986, an ad hoc committee of the National Heart, Lung, and Blood Institute's
      Atherosclerosis, Hypertension, and Lipid Metabolism Advisory Committee (AHLMAC) recommended a
      randomized clinical trial of cholesterol-lowering using an HMG CoA reductase inhibitor in the
      elderly. The recommendation was endorsed by the full AHLMAC and approved by the National
      Heart, Lung, and Blood Advisory Council (NHLBAC) in May 1987. However, due to the high cost
      of such a trial and concerns about feasibility, an initiative for a two-year pilot study at
      five clinical centers was developed and approved by the NHLBAC in September 1988. The Request
      for Applications was released in February 1989 and awards made in July 1990.

      DESIGN NARRATIVE:

      There were five clinical centers and a coordinating center in the pilot study. There were
      four pre-randomization visits at four to six week intervals. Subjects were eligible for
      inclusion if their LDL cholesterol levels remained above 120 mg/dl after the introduction of
      the American Heart Association Step 1 Diet at Visit 2. Subjects were randomized to diet plus
      a low dosage of lovastatin (20 mg), diet plus a high dosage of lovastatin (40 mg), or to diet
      plus a placebo. End points were changes in blood lipid levels. Data on other blood chemistry
      values, as well as quality-of-life measures and coronary heart disease morbidity and
      mortality, were also collected. LDL cholesterol levels were measured at clinic visits six and
      twelve weeks after randomization and at twelve week intervals thereafter. Serum alanine
      aminotransferase levels were measured at six week intervals to determine liver function and
      slit lamp exams were performed before and after study medication to detect lenticular
      opacities. Subjects were followed for a minimum of six months and a maximum of fifteen
      months.

      The study completion date listed in this record was obtained from the "End Date" entered in
      the Protocol Registration and Results System (PRS) record
    

Intervention name(s): lovastatin
Intervention type(s): Drug
Intervention MeSH terms: Lovastatin; L 647318; Dihydromevinolin
Allocation: Randomized
Primary purpose: Prevention