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Antithrombotic therapy in the primary prevention of acute myocardial infarction
1Medical Research Council Epidemiology and Medical Care Unit, Northwick Park Hospital, Harrow, Middlesex, England.
Insights
Low-dose warfarin therapy shows promise for primary prevention of coronary heart disease in high-risk men. A pilot study confirmed feasibility and safety, paving the way for a larger trial investigating warfarin and aspirin combinations.
Area of Science:
- Cardiovascular Medicine
- Hematology
- Preventive Cardiology
Background:
- Elevated factor VII coagulant (VIIc) activity is observed in men at high risk for coronary heart disease (CHD).
- Restoring normal hemostatic activity via oral anticoagulants may offer effective primary CHD prevention.
Purpose of the Study:
- To assess the feasibility and safety of long-term, low-dose warfarin therapy for primary prevention of CHD in high-risk men.
- To lay the groundwork for a large-scale trial evaluating warfarin and aspirin for thrombosis prevention.
Main Methods:
- A randomized, double-blind, placebo-controlled pilot study involving middle-aged men at high risk for CHD.
- Warfarin dosage was adjusted to achieve target VIIc levels and prothrombin time international normalized ratio (1.6).
- Feasibility, safety, compliance, and withdrawal rates were assessed.
Main Results:
- The pilot study confirmed the feasibility of the randomized trial design.
- No increased risk of serious bleeding was observed with low-dose warfarin.
- High participant compliance and low withdrawal rates were achieved.
Conclusions:
- Long-term, low-dose warfarin therapy is a feasible and safe approach for primary CHD prevention in high-risk men.
- A full-scale trial, including a factorial design with aspirin, has been launched to further investigate thrombosis prevention.
- Preliminary evidence suggests combined warfarin and aspirin therapy does not elevate bleeding risk compared to aspirin alone.
Abstract:
The high factor VII coagulant (VIIc) activity in men at high risk of coronary heart disease suggests that restoring normal hemostatic activity with appropriate oral anticoagulants might constitute effective primary prevention. A pilot study was therefore undertaken of a randomized, double-blind, placebo-controlled trial of long-term, low-dose warfarin therapy. Middle-aged men at high risk (mean VIIc 120% of standard) but without clinical coronary heart disease or contraindications to anticoagulants were randomized to warfarin or placebo. The initial warfarin dose (2.5 mg/day) was increased at intervals to lower VIIc to 70% of standard and increase the prothrombin time international normalized ratio to 1.6. The control participants received the same dose sequence of placebo. The pilot study confirmed the feasibility of the design, the absence of any increased risk of serious bleeding, and the high compliance and low withdrawal rate from randomized treatment. Accordingly, a full-scale thrombosis prevention trial has been launched, which, in addition to low-dose warfarin, includes a low-dose aspirin regimen (75 mg/day) in a factorial design. The aim of this trial is to produce a 30% reduction in coronary heart disease in 6,000 high-risk men aged 45 to 69 years. The men will receive either separate or combined therapy and will be followed up for 5 years. Evidence so far indicates that the risk of bleeding in those receiving combined therapy will be no higher than that in those taking aspirin alone.