Post Coronary Artery Bypass Graft (CABG) Study
Condition: Cardiovascular Diseases; Coronary Disease; Heart Diseases; Myocardial Ischemia
MeSH terms: Cardiovascular Diseases; Heart Diseases; Coronary Disease; Myocardial Ischemia; Ischemia
Study type: Interventional
Phase: Phase 3

Summary: 
      To determine the relative effectiveness of moderate versus more aggressive lipid lowering,
      and of low dose anticoagulation versus placebo, in delaying saphenous vein coronary bypass
      graft atherosclerosis and preventing occlusion of saphenous grafts of patients with saphenous
      vein coronary bypass grafts placed 1 to 11 years previously.
    

Detailed description: 
      BACKGROUND:

      A large number of studies have reported that following CABG, the vessels proximal to the
      grafts demonstrate accelerated atherosclerosis and the grafts themselves may show progressive
      obstruction due to thrombosis, fibrosis, and graft atheroma. Pathological and clinical
      studies have documented that graft obstruction during the perioperative period and the first
      year is usually due to technical problems at surgery or thrombosis and occurs in about 15 to
      20 percent of saphenous vein grafts. Antiplatelet drugs such as aspirin have been shown to
      reduce these early graft occlusions by about 50 percent. In addition to thrombosis, during
      the first year, most saphenous vein grafts undergo diffuse fibrosis and some distortion.
      However, the significance of these changes is not known.

      After the first year, lipid deposition and changes histologically similar to atherosclerosis
      have been documented both in experimental studies and in human saphenous vein grafts patent
      at one year completely occlude and an additional 30 percent narrow over a period of ten
      years. These angiographic changes in the saphenous vein grafts correlate with high
      LDL-cholesterol, low HDL-cholesterol and high apolipoprotein B levels. In experimental
      animals, cholesterol deposition in the grafts has been substantially increased or decreased
      by increasing or decreasing the saturated fats and cholesterol in the animal's diets. In
      contrast to changes in the saphenous vein grafts, internal mammary artery grafts have shown
      substantially lower rates of obstruction. The native vessels (both ungrafted vessels and
      grafted vessels at distal or proximal sites), however, show evidence of progressive
      atherosclerosis. The long-term follow-up of grafts also demonstrates thrombotic material and
      even occlusive thrombus as part of acute events.

      Progression of atherosclerotic lesions in grafts and native vessels lead to recurrent angina,
      unaltered long-term survival and reduced efficacy of repeat CABG surgery. Johnson in an 11
      year follow-up of 3,105 post-CABG patients, reported that about 15 percent of patients with
      preoperative angina have recurrent angina at 1 year; with a further 6 percent developing
      angina every subsequent year. In this study, patients with recurrent angina had twice the
      mortality compared to those who were angina-free. Long-term follow-up of the VA Cooperative
      Trial of CABG shows that the survival of the surgical group appears to be initially superior
      compared to the medical group but this benefit is diminished by about ten years. This may
      relate to graft obstruction and progression of native coronary atherosclerosis. Re-operation
      in these patients carries a higher operative mortality risk and the results are less
      impressive. It had been estimated that approximately 5 percent of all CABG surgery in 1984
      were re-operations and that this percentage would double over the next decade. Therefore,
      measures to prevent graft occlusion and progression of atherosclerosis in native vessels, if
      successful, could have substantial clinical and economic importance by reducing mortality,
      morbidity and the numbers of patients undergoing re-operations.

      Apart from trials of aspirin and dipyridamole in post-CABG patients that demonstrated a
      significant reduction in graft closure within the first year after surgery, there were no
      large systematic studies of interventions in these patients. Graft occlusion has been shown
      to correlate with high LDL-cholesterol and low HDL-cholesterol, and the severity of
      atherosclerosis has been additionally shown to be related to cigarette smoking and increased
      levels of coagulation factor. Therefore, lowering the LDL cholesterol (by diet and drugs),
      and anti-thrombotic therapy with warfarin were logical choices for intervention.

      Several studies suggested that CABG surgery relieved angina and improved overall quality of
      life. However, in the available studies, CABG did not consistently appear to be associated
      with an improvement in employment status, physical recreational activity, or life style. The
      reasons for these results were not entirely clear and there was a need to identify the
      biobehavioral and psychosocial factors that predicted successful adjustment after CABG.

      The initiative was proposed by Institute staff and approved by the September 1985 National
      Heart, Lung, and Blood Advisory Council. The Request for Proposals was released in September
      1985 and awards made in April 1987.

      DESIGN NARRATIVE:

      Multicenter, double-blind, randomized, controlled trial. All prospective participants
      received active warfarin treatment for a month prior to randomization. Only participants
      demonstrating a minimal reaction to warfarin and consuming over 90 percent of the prescribed
      medication were randomized. Dietary modification to lower serum cholesterol, an exercise
      program, and a smoking cessation program were implemented. Patients were randomly assigned in
      a 2 X 2 factorial design in four treatment groups: aggressive LDL-C lowering with lovastatin
      40 to 80 mg/d and, as necessary cholestyramine 8 mg/d to achieve and LDL-C of 60 to 85 mg/dl;
      moderate LDL-C lowering with lovastatin 2.5 to 5 mg/d, with cholestyramin as needed, to
      achieve a LDL-C of 130 to 140 mg/dl; warfarin 1 to 4 mg/d to achieve an INR of 1.8 to 2.0;
      and warfarin-placebo. All participants were followed for five years, at the end of which
      selective coronary and graft angiography was performed. The primary angiography endpoint was
      the proportion of major SVG per patient that showed substantial reduction (0.06 mm or
      greater) in lumen diameter. Biobehavioral studies were conducted in 750 participants.

      Planning for the study began in April 1987 and a final protocol was developed by August 1988.
      Patient recruitment has been completed. Follow-up ended on September 1, 1995 and data
      analysis continues through December 1998 under contract N01-HC-75076. .

      The Post CABG Biobehavioral Study examined a cohort of 759 coronary artery bypass patients
      (269 women and 490 men) who were enrolled at five clinical centers. Sociodemographic and
      medical data were obtained by interview and from medical charts. Health-related quality of
      life and psychosocial data were ascertained preoperatively by interview and questionnaire for
      those patients whose condition allowed preoperative assessment and was compared among
      patients from hospitals enrolling both male and female patients.
    

Intervention name(s): lovastatin; cholestyramine; warfarin
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Warfarin; Lovastatin; L 647318; Dihydromevinolin; Cholestyramine Resin
Allocation: Randomized
Masking: Double
Primary purpose: Prevention