Arterial Disease Multifactorial Intervention Trial (ADMIT)
Condition: Arterial Occlusive Diseases; Cardiovascular Diseases; Heart Diseases; Vascular Diseases; Diabetes Mellitus
MeSH terms: Cardiovascular Diseases; Heart Diseases; Vascular Diseases; Arterial Occlusive Diseases
Study type: Interventional
Phase: Phase 3

Summary: 
      To evaluate, in asymptomatic and symptomatic participants with peripheral arterial disease,
      the feasibility of recruitment and adherence, efficacy and safety of HDL-C raising along with
      effective control of LDL-C levels, antioxidant therapy, antithrombotic therapy, and their
      combinations.
    

Detailed description: 
      BACKGROUND:

      Multiple mechanisms are involved in the deposition of LDL-C into the arterial wall, and the
      prevention of such deposition as well as the removal of the LDL-particles. Further, there
      remain questions regarding what causes an existing plaque that has been stable for a long
      period of time to become occlusive or ulcerating and what may prevent it from doing so.
      Prevention and treatment are almost certain to become multifaceted and more complex when
      using several complementary interventions or preventive measures concomitantly.

      Multifactorial prevention and treatment may be particularly useful in people with peripheral
      arterial disease. PAD as manifested by intermittent claudication affects about 0.5 to 1.0
      percent of individuals above age 35, with a twofold predominance in men. There is a
      strikingly increased incidence with age in both sexes, particularly in those above age 50.
      Mortality in patients with intermittent claudication has been shown to be six times higher
      than in other people of similar age and gender. The excess in mortality is primarily due to a
      ninefold increase in cardiovascular disease (CVD) deaths. Those who have asymptomatic but
      measurable PAD (two to two-and-a-half times as many as have intermittent claudication), have
      relative risks of about 3 and 4 for total and CVD mortality, respectively. Therefore,
      interventions that prevent the development or progression of atherosclerotic disease or
      reduce arterial thrombosis should reduce mortality and morbidity due to myocardial infarction
      and stroke while favorably affecting the morbidity directly associated with PAD.

      The National Cholesterol Education Program (NCEP) has included peripheral vascular disease
      (PVD) in its guidelines as a risk factor in the Classification and Decision for Treatment
      Algorithm. This means that patients who have PVD and elevated LDL-C and one other risk factor
      such as male gender, family history, cigarette smoking, or hypertension, should have
      appropriate dietary intervention followed by drug therapy as needed. Even with the guidelines
      in place since the end of 1987, a survey of PVD patients referred to a major medical center
      clinic found that very few patients were on lipid lowering therapy, either diet or drug. The
      reason for the primary care community not modifying lipids in these high risk patients may be
      related to lack of studies demonstrating benefit of lipid modification in those who have PVD.
      It is anticipated that many patients with PAD will require treatment for elevated LDL-C. It
      is not as clear whether interventions aimed at raising HDL-C will result in a slowing of
      progression of atherosclerosis in this population.

      Platelets have been shown to have a key role in the development of occlusive atherosclerosis
      and thrombosis related to coronary heart disease. Inhibition of platelet function has been
      postulated to slow progression of atherosclerosis; specifically, aspirin has been
      demonstrated to reduce lipoprotein deposition in the arterial wall of nonhuman primates. This
      deposition is even further reduced by the addition of a lipid lowering regimen to the
      antiplatelet regimen. It remains unclear whether mini-dose, less intense anticoagulation is
      the most appropriate antithrombotic therapy in people with PAD who are also receiving lipid
      modifying agents.

      DESIGN NARRATIVE:

      Patients were randomized to a control arm or to one of three treatment arms, including a
      lipid modification arm, an antioxidant arm, and an antithrombotic arm. Patients in the lipid
      modification arm were randomized to placebo or treated with nicotinic acid to increase HDL
      while lowering LDL levels equally with the hydroxymethylglutaryl-coenzyme A reductase
      inhibitor pravastatin as needed in the intervention and control groups. Patients in the
      antioxidant arm were assigned to daily doses of 24 mg. of beta-carotene, 800 IU of vitamin E,
      and 1.0 g of vitamin C or to placebo. Patients in the antithrombotic arm received 2 mg/day of
      active or placebo warfarin taken daily until the fifth follow-up visit. Patients were
      followed every six weeks after entry for one year of follow-up. The primary endpoint of the
      study was the efficacy and safety of HDL-C raising along with effective control of LDL-C
      levels, antioxidant therapy, antithrombotic therapy, and their combinations. The secondary
      endpoints were to determine the efficacy of the HDL-C raising arm to achieve an increase in
      HDL-C in the treatment group while also obtaining equivalent reductions in LDL-C in the
      treatment and control groups, to assess the dose-response of niacin on HDL-C raising, to
      determine if the combination of low-dose warfarin plus aspirin versus aspirin alone had the
      expected impact on the hemostatic system, to determine if combination antioxidant therapy
      (vitamins E and C and beta carotene) led to changes in biomarkers for antioxidants, and to
      determine the interaction of the lipid altering strategy with antioxidants for effects on
      biomarkers for antioxidants. Screening began August 1, 1993, randomization began December 1,
      1993 and ended December 31, 1994 with a total of 468 patients enrolled. Support for the trial
      ended in September 1995. Data analysis continues through March 31, 1999 under contract
      N01HC35124.

      The study completion date listed in this record was obtained from the "Completed Date"
      entered in the Query View Report System (QVR).
    

Intervention name(s): niacin; pravastatin; beta-carotene; vitamin E; dietary supplements; vitamin C; warfarin
Intervention type(s): Drug; Drug; Drug; Drug; Behavioral; Drug; Drug
Intervention MeSH terms: Vitamins; Vitamin E; Beta Carotene; Warfarin; Pravastatin; Carotenoids
Allocation: Randomized
Primary purpose: Treatment