Cardiovascular Diseases Clinical Trial
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.
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.
;
Allocation: Randomized, Masking: Double-Blind, Primary Purpose: Prevention
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