Prevention of Recurrent Venous Thromboembolism (PREVENT)
Condition: Cardiovascular Diseases; Heart Diseases; Peripheral Vascular Diseases; Thromboembolism; Vascular Diseases; Venous Thromboembolism
MeSH terms: Cardiovascular Diseases; Heart Diseases; Thromboembolism; Vascular Diseases; Venous Thromboembolism; Peripheral Vascular Diseases; Peripheral Arterial Disease
Study type: Interventional
Phase: Phase 3

Summary: 
      A multicenter randomized, double blind placebo controlled trial to determine the efficacy of
      long-term, low dose warfarin in the secondary prevention of venous thromboembolism.
    

Detailed description: 
      BACKGROUND:

      Venous thromboembolism is associated with more than 300,000 hospitalizations and results in
      thousands of deaths annually. Conventional therapy consists of intravenous heparin followed
      by oral anticoagulants usually given for three to six months. The recommended intensity of
      oral anticoagulants (warfarin) has been derived from clinical trials. Such therapy is usually
      quite effective. However, some patients develop recurrent disease after the oral
      anticoagulants are stopped. A recent randomized study evaluated the optimal duration of oral
      anticoagulant therapy. After acute treatment with heparin, subjects were treated with oral
      anticoagulants for either six weeks or six months with a target INR * of 2 to 2.85. There was
      no difference in mortality in the two groups. Recurrence was not seen while the patients were
      under treatment. When anticoagulants were stopped, recurrent thrombosis was documented in 18
      percent of the patients treated for six weeks and in 9.5 percent of those treated for six
      months. The period of greatest risk of recurrence for the six weeks patients was immediately
      after therapy was stopped. There was a linear increase in cumulative risk of 5 to 6 percent
      per year for both treatment groups during the following 18 months.

      For patients who have experienced idiopathic venous thrombosis, the risk of recurrence may
      continue even after several months of conventional therapy. Further prophylactic therapy
      might be beneficial for the patients who are at risk for late recurrence. But, because of the
      presumed risk of bleeding and inconvenience of monitoring standard warfarin therapy, most
      physicians usually limit treatment to three to six months.

      In 1997, Simioni showed a cumulative recurrence rate of VTE of 39.7 percent among those with
      factor V Leiden mutation, with all recurrences occurring within three years, a rate 2.4 times
      higher than among individuals without the mutation. The factor V Leiden mutation is found in
      4 to 6 percent of Caucasians and is the single most important cause of thromboembolism in a
      variety of conditions. Heterozygous carriers with the mutation have VTE at a younger age than
      do noncarriers. Among those with first VTE, the prevalence of the mutation is 15 to 40
      percent and among those with a family history of VTE, as high as 50 percent. However, in a
      large study of men participating in the Physicians Health Study, those individuals with the
      mutation had an increased rate of VTE over time. These age-specific incidence rate
      differences ranged from 1.23 to 5.97 in those aged 70 or older. These data suggest that
      confounders other than genetic predisposition are important in the development of VTE.

      * The INR or international normalized ratio is the ratio of patient prothrombin to control
      prothrombin multiplied by the international sensitivity index. The INR was introduced by the
      World Health Organization to standardize control of anticoagulant therapy internationally.

      DESIGN NARRATIVE:

      Multicenter, randomized, double-blind, placebo-controlled. A total of 253 patients were
      randomized to usual care plus placebo and a total of 255 patients to usual care plus a
      three-to-four year regimen of low-dose warfarin (target INR 1.5 to 2.0), which after initial
      titration required infrequent outpatient monitoring. Double-blind INR assessment and dose
      adjustment were performed every three months to ensure patient safety and to monitor
      compliance. Primary endpoints included recurrent venous thromboembolism, major bleeding
      episodes, and all-cause mortality. Separate analysis was performed of all-cause mortality in
      the total patient population and in those with factor V Leiden.

      The study consisted of 52 clinical centers, a laboratory coordinating center, the clinical
      coordinating center, and the data coordinating center.

      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): warfarin
Intervention type(s): Drug
Intervention MeSH terms: Warfarin
Allocation: Randomized
Masking: Double
Primary purpose: Prevention