Advertisement

Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction: The cholesterol and recurrent events trial (CARE)

  • Frank M. Sacks
    Correspondence
    Address for reprints: Frank M. Sacks, MD, CARE, 454 Brookline Avenue, Suite 3, Boston, Massachusetts 02115.
    Affiliations
    From the Channing Laboratory and the Cardiovascular Division, Department of Medicine, Brigham USA

    From the Women's Hospital and Harvard Medical School, Boston, Massachusetts USA

    From the University of Texas School of Public Health, Houston, Texas USA

    From the Washington University School of Medicine, St. Louis, Missouri USA
    Search for articles by this author
  • Marc A. Pfeffer
    Affiliations
    From the Channing Laboratory and the Cardiovascular Division, Department of Medicine, Brigham USA

    From the Women's Hospital and Harvard Medical School, Boston, Massachusetts USA

    From the University of Texas School of Public Health, Houston, Texas USA

    From the Washington University School of Medicine, St. Louis, Missouri USA
    Search for articles by this author
  • Lemuel Moye'
    Affiliations
    From the Channing Laboratory and the Cardiovascular Division, Department of Medicine, Brigham USA

    From the Women's Hospital and Harvard Medical School, Boston, Massachusetts USA

    From the University of Texas School of Public Health, Houston, Texas USA

    From the Washington University School of Medicine, St. Louis, Missouri USA
    Search for articles by this author
  • Lisa E. Brown
    Affiliations
    From the Channing Laboratory and the Cardiovascular Division, Department of Medicine, Brigham USA

    From the Women's Hospital and Harvard Medical School, Boston, Massachusetts USA

    From the University of Texas School of Public Health, Houston, Texas USA

    From the Washington University School of Medicine, St. Louis, Missouri USA
    Search for articles by this author
  • Peggy Hamm
    Affiliations
    From the Channing Laboratory and the Cardiovascular Division, Department of Medicine, Brigham USA

    From the Women's Hospital and Harvard Medical School, Boston, Massachusetts USA

    From the University of Texas School of Public Health, Houston, Texas USA

    From the Washington University School of Medicine, St. Louis, Missouri USA
    Search for articles by this author
  • Thomas G. Cole
    Affiliations
    From the Channing Laboratory and the Cardiovascular Division, Department of Medicine, Brigham USA

    From the Women's Hospital and Harvard Medical School, Boston, Massachusetts USA

    From the University of Texas School of Public Health, Houston, Texas USA

    From the Washington University School of Medicine, St. Louis, Missouri USA
    Search for articles by this author
  • C.Morton Hawkins
    Affiliations
    From the Channing Laboratory and the Cardiovascular Division, Department of Medicine, Brigham USA

    From the Women's Hospital and Harvard Medical School, Boston, Massachusetts USA

    From the University of Texas School of Public Health, Houston, Texas USA

    From the Washington University School of Medicine, St. Louis, Missouri USA
    Search for articles by this author
  • Eugene Braunwald
    Affiliations
    From the Channing Laboratory and the Cardiovascular Division, Department of Medicine, Brigham USA

    From the Women's Hospital and Harvard Medical School, Boston, Massachusetts USA

    From the University of Texas School of Public Health, Houston, Texas USA

    From the Washington University School of Medicine, St. Louis, Missouri USA
    Search for articles by this author
  • The CARE Investigators
    Footnotes
    Affiliations
    From the Channing Laboratory and the Cardiovascular Division, Department of Medicine, Brigham USA

    From the Women's Hospital and Harvard Medical School, Boston, Massachusetts USA

    From the University of Texas School of Public Health, Houston, Texas USA

    From the Washington University School of Medicine, St. Louis, Missouri USA
    Search for articles by this author
  • Author Footnotes
    ∗ See Appendix for all participating centers.
      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol decreases the incidence of coronary heart disease in patients with elevated plasma cholesterol. However, it is not known whether patients with established coronary artery disease and normal plasma cholesterol can be benefited. Several previous prevention trials reviewed in this report found that patients who had plasma cholesterol levels at baseline in the upper portion of the eligibility range (e.g., >240 mg/dl) received greater benefit from hypolipidemic diet or drug therapy than patients who had lower plasma cholesterol levels at baseline. The recent availability of drugs that are more potent and less prone to cause adverse reactions than previous regimens permits this important question to be addressed. The Cholesterol and Recurrent Events trial is testing whether pravastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, will decrease the sum of fatal coronary heart disease and nonfatal myocardial infarction (MI) in patients who have recovered from a MI and who have normal total cholesterol levels. Fatal cardiovascular disease and total mortality are important secondary end points. The trial is enrolling 4,000 men and women from 80 centers throughout North America, age 21 to 75 years, who have survived MI for 3 to 20 months, who have plasma total cholesterol <240 mg/dl (6.2 mmol/ liter) and low-density cholesterol of 115 to 174 mg/dl (3.0 to 4.5 mmol/liter), and who are representative of the general population of patients with MI. Patients are randomized to either active or inactive drug therapy. Active therapy consists of pravastatin, 40 mg/day, designed to achieve an average decrease in low-density lipoprotein cholesterol of approximately 30%, and an increase in high-density lipoprotein of 5%. The average duration of follow-up will be ≥5 years. To protect against a lower than expected rate of recurrent events, the trial will be continued until a predetermined fixed number of coronary heart disease events occurs in the entire cohort so that the original sensitivity of the trial will be maintained.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Keys A
        Seven Countries Study.
        Harvard University Press, Boston, MA1980
        • Pekkanen J
        • Linn S
        • Heiss G
        • Suchindran CM
        • Leon A
        • Rifkind BM
        • Tyroler HA
        Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease.
        N Engl J Med. 1990; 322: 1700-1707
        • Kannel WB
        • Castelli WP
        • Gordon T
        Cholesterol in the prediction of atherosclerotic disease. New perspectives on the Framingham Study.
        Ann Intern Med. 1979; 90: 85-91
        • Martin MJ
        • Hulley SB
        • Browner WS
        • Kuller LH
        • Wentworth D
        Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men.
        Lancet. 1986; 2: 933-936
        • Rose G
        • Reid DD
        • Hamilton PJ
        • McCartney P
        • Keen H
        • Jarrett RJ
        Myocardial ischemia, risk factors and death from coronary heart-disease.
        Lancet. 1977; 1: 105-109
        • Frost PH
        • Verter J
        • Miller D
        Serum lipids and lipoproteins after myocardial infarction: associations with cardiovascular mortality and experience in the Aspirin Myocardial Infarction Study.
        Am Heart J. 1987; 113: 1356-1364
        • Coronary Drug Project Research Group
        Natural history of myocardial infarction in the Coronary Drug Project: long-term prognostic importance of serum lipid levels.
        Am J Cardiol. 1978; 42: 489-498
        • Buchwald H
        • Varco RL
        • Matts JP
        • Long JM
        • Fitch LL
        • Campbell GS
        • Pearce MB
        • Yellin AE
        • Edmiston WA
        • Smink RD
        • Sawin HS
        • Campos CT
        • Hansen BJ
        • Tuna N
        • Karnegis JN
        • Sanmarco ME
        • Amplatz K
        • Castaneda-Zuniga WR
        • Hunter DW
        • Bissett JK
        • Weber FJ
        • Stevenson JW
        • Leon AS
        • Chalmers TC
        • The POSCH group
        Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH).
        N Engl J Med. 1990; 323: 946-955
        • Dayton S
        • Pearce ML
        • Hashimoto S
        • Dixon WJ
        • Tomiyasu U
        A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis.
        Circulation. 1969; 39 and 40: II-1-II-63
        • Research Committee of the Scottish Society of Physicians
        Ischaemic heart disease: a secondary prevention trial using clofibrate.
        Br Med J. 1971; 4: 775-784
        • Carlson LA
        • Rosenhamer G
        Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid.
        Acta Med Scand. 1988; 223: 405-418
        • Dorr AE
        • Gundersen K
        • Schneider JC
        • Spencer TW
        • Martin WB
        Colestipol hydrochloride in hypercholesterolemic patients — effect on serum cholesterol and mortality.
        J Chron Dis. 1978; 31: 5-14
        • Manninen V
        • Huttunen JK
        • Heinonen OP
        • Tenkanen L
        • Frick MH
        Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study.
        Am J Cardiol. 1989; 63: 42H-47H
        • Committee of Principal Investigators
        A cooperative trial in the primary prevention of ischaemic heart disease using clofibrate.
        Br Heart J. 1978; 40: 1069-1118
        • Lipid Research Clinics Program
        The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.
        JAMA. 1984; 251: 351-364
        • The Coronary Drug Project Research Group
        Clofibrate and niacin in coronary heart disease.
        JAMA. 1975; 231: 360-381
        • Leren P
        The Oslo Diet-Heart Study. Eleven-year report.
        Circulation. 1970; 42: 935-942
      1. Trial of clofibrate in the treatment of ischaemic heart disease. Five-year study by a group of physicians of the Newcastle Upon Tyne region.
        Br Med J. 1971; 2: 767-775
        • Rossouw JE
        • Lewis B
        • Rifkind BM
        The value of lowering cholesterol after MI.
        N Engl J Med. 1990; 323: 1112-1119
        • Canner PL
        • Berge KG
        • Wenger NK
        • Stamler J
        • Friedman L
        • Prineas RJ
        • Friedewald W for the Coronary Drug Project Research Group
        Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.
        J Am Coll Cardiol. 1986; 8: 1245-1255
      2. Report of the Committee of Principal Investigators. W.H.O. Cooperative Trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up.
        Lancet. 1980; 2: 379-385
        • Committee of Principal Investigators
        WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up.
        Lancet. 1984; 2: 600-604
        • Muldoon MF
        • Manuck SB
        • Mathews KA
        Lowering cholesterol concentrations and mortality; a quantitative review of primary prevention trials.
        Br Med J. 1990; 301: 309-314
        • The Coronary Drug Project Research Group
        The Coronary Drug Project. Findings leading to discontinuation of the 2.5-mg/day estrogen group.
        JAMA. 1973; 226: 652-657
        • The Coronary Drug Project Research Group
        The Coronary Drug Project. Findings leading to further modifications of its protocol with respect to dextrothyroxin.
        JAMA. 1972; 220: 996-1008
        • Hunninghake DB
        • Mellies MJ
        • Goldberg AC
        • Kuo PT
        • Kostis JB
        • Schrott HG
        • Insull W
        • Pan HY
        Efficacy and safety of pravastatin in patients with primary hypercholesterolemia.
        Atherosclerosis. 1990; 85: 219-227
        • Newman TJ
        • Kassler-Taub KB
        • Gelarden RT
        • Korzin EG
        • DeVault AR
        • McGovern ME
        • Pan HY
        Safety of pravastatin in long-term clinical trials conducted in the United States.
        J Drug Dev. 1990; 3: 275-281
      3. The Lipid Research Clinics Population Studies Data Book. vol. I. The Prevalence Study.
        in: 5th ed. NIH publication no. 80-1527. U.S. Dept of Health and Human Services, Public Health Service, National Institutes of Health, 1980
      4. Report of the National Cholesterol Education Program expert panel on detection, evaluation and treatment of high blood cholesterol in adults.
        Arch Intern Med. 1988; 148: 36-69
        • Warnick GR
        • Knopp RH
        • Fitzpatrick V
        • Branson L
        Estimating LDL cholesterol by the Friedwald equation is adequate for classifying patients on the basis of nationally recommended cutpoints.
        Clin Chem. 1990; 36: 15-19
        • Willett WC
        • Reynolds RD
        • Cottrell-Hoehner S
        • Sampson L
        • Browne ML
        Validation of a semi-quantitative food frequency questionnaire: comparison with 1-year diet record.
        J Am Diet Assoc. 1987; 87: 43-47
        • Reihner E
        • Rudling M
        • Stahlberg D
        • Berglund L
        • Ewerth S
        • Bjorkhem I
        • Einarsson K
        • Angelin B
        Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol.
        N Engl J Med. 1990; 323: 224-228
        • Vega GL
        • Krauss RM
        • Grundy SM
        Pravastatin therapy in primary moderate hypercholesterolaemia: changes in metabolism of apolipoprotein B-containing lipoproteins.
        J Intern Med. 1990; 227: 81-94
        • Halperin M
        • Lan KKG
        • Ware JH
        • Johnson NJ
        • DeMets DL
        An aid to data monitoring in long term clinical trials.
        Controlled Clin Trials. 1982; 3: 311-324
        • Lann KKG
        • Simon R
        • Halperin M
        Stochastically curtailed tests in longterm clinical trials.
        Communications in Statistics — Sequential Analysis. 1982; 1: 207-219