To review the evidence regarding the efficacy and safety of combination antithrombic therapy with warfarin (or related coumarins) and acetylsalicylic acid (ASA), versus monotherapy with either agent.

MEDLINE was searched from 1966 to February 1998 using the following search terms: 'warfarin', 'coumarin', 'ASA' and 'acetylsalicylic acid', 'anticoagulation', 'combination', 'combined', 'atrial fibrillation', 'myocardial infarction' and 'mechanical waves'. The references of identified articles were also examined.

The included studies were non-randomised uncontrolled trials, and double-blind randomised controlled trials where one arm received combined ASA and any coumarin anticoagulant (e.g. warfarin), and another arm received either ASA or an anticoagulant as monotherapy. Trials published only in abstract form, and noncomparative trials (e.g. case series, uncontrolled trials), were excluded from the analyses. Trials were categorised as either A or B.

Category A trials were randomised, controlled and double-blind trials that used the INR to measure anticoagulation, and reported complete safety and efficacy data. Trials in this category were considered highly interpretable.

Category B trials were either of a suboptimal trial design (non-randomised or uncontrolled), or did not report complete interpretable efficacy and safety data. These included reported trials using non-INR anticoagulation measurement methods, and those providing inadequate information regarding target or achieved anticoagulation intensity. Trials in this category were considered to be less reliable than category A trials.

The follow-up periods ranged from 10 weeks to 7 years (excluding those studies focusing specifically on safety issues).

The specific interventions were: warfarin (international normalised ratio, INR, 1.5 to 4.5); ASA (75 to 325 mg/day); ASA plus warfarin (various combinations of doses); acenocoumarin (prothrombin time, PT, 1.8 to 2.3 times); warfarin plus dipyridamole (PT 1.5 to 2.5 times); acenocoumarin (1.8 to 2.3 times) plus ASA (500 mg/day); ASA plus heparin and warfarin (various combinations of doses).

Patients undergoing antithrombic therapy for a variety of cardio and cerebrovascular conditions including: the prevention of stroke; the treatment of angina and myocardial infarction; the prevention of thrombosis after angioplasty, valve replacement and stent insertion; and the treatment of atherosclerosis.

Incidence of thromboembolism, embolic episodes, and major and minor bleeding were assessed.

The authors do not state how the papers were selected for the review, or how many of the authors performed the selection.

The authors do not report a method for assessing validity. However, the trials were categorised on the basis of the quality and interpretability of the results, study design, outcome measures used, and the completeness of reporting.The authors do not state how the assessment was performed.

The authors do not state how the data were extracted for the review, or how many of the authors performed the data extraction.

The studies were combined narratively, grouped under the following headings: mechanical valve thromboembolic prophylaxis, ischaemic heart disease, atrial fibrillation, and coronary artery bypass grafting.

The authors do not state how differences between the studies were investigated.

Sixteen trials involving over 21 684 participants were included in the review. There were 5 studies of mechanical valve replacement; 5 of ischaemic heart disease; 1 of ischaemic stroke, 1 of atrial fibrillation, 1 of coronary artery bypass; and 5 additional safety studies. Two meta-analyses involving participants with mechanical heart valve replacement were also included.

Mechanical valve thromboembolic prophylaxis: 3 of the 5 trials indicated that combined antithrombic therapy was superior to monotherapy (warfarin alone), whereas 2 studies indicated that there were no significant differences between the two groups. Three of these studies indicated that the addition of ASA led to increased bleeding, whilst 2 suggested that there was no difference in bleeding. The 2 meta-analyses that evaluated combined antithrombic therapy after heart valve replacement found a significant decrease in mortality and systemic embolism with combined therapy. Both meta-analyses also showed an increase in bleeding.

Ischaemic heart disease: Only one of the 5 studies demonstrated that combined therapy was superior to monotherapy; 3 of the 5 studies showed an increase in bleeding.

Atrial fibrillation: only one study investigated antithrombic therapy for atrial fibrillation. This was stopped early (mean follow up 1.1 years) when an interim analysis showed that adjusted-dose warfarin was significantly more protective against strokes than the combined, fixed low-dose warfarin with ASA. The annual ischaemic stroke rate was 2.6% in warfarin-treated patients, compared with 7.8% in patients receiving combination therapy (the number-needed-to-treat was 20). There were no significant differences between the groups in terms of the rates of major and minor bleeding.

Coronary artery bypass graft: one large post-coronary artery bypass graft trial found no differences between combined therapy and monotherapy. The bleeding rates were not reported.

The authors also present a section on additional safety results.

Combined warfarin and ASA therapy may be beneficial for patients with prosthetic heart valves at high risk of thromboembolism, compared with warfarin alone. Combination therapy may also be used for primary prevention in patients at high risk of ischaemic heart disease, although the expected benefits are small. Evidence does not support the use of combined antithrombic therapy in patients with established ischaemic heart disease, ischaemic stroke, coronary artery bypass grafts or atrial fibrillation. Combination therapy is associated with an increased risk of minor and major bleeding. The highest dose of ASA that can be recommended in combination with warfarin is 100 mg daily.

The review focused on a well-defined question. The inclusion and exclusion criteria were appropriate, and the studies were summarised appropriately.

The search was fairly narrow and could have been extended to include other databases, such as EMBASE, and an attempt to identify unpublished literature. A direct quality assessment of the included studies was not performed. It would have been useful to assess whether blinding of assessment and concealment of randomisation were undertaken in the individual studies. Some details of the individual studies were presented, whereas others, such as the participants' characteristics (e.g. average age and gender) were not. The authors did not state whether or not the data were extracted in an intention to treat format.

The authors' conclusions follow from the results.

Practice: The authors suggested that the addition of low-dose ASA to the recommended intensity of warfarin (INR 2.5 to 3.5) should be considered for patients with mechanical valves in two situations.

1. Patients at high risk of thromboembolism, provided that they are considered to be at low risk for bleeding.

2. Patients who have experienced a thromboembolic event despite adequate anticoagulant therapy.

The daily dose of ASA should not exceed 100 mg. Combined antithrombic therapy cannot be recommended for ischaemic stroke, coronary artery bypass graft and atrial fibrillation.

This record is a structured abstract written by CRD reviewers. The original has met a set of quality criteria. Since September 1996 abstracts have been sent to authors for comment. Additional factual information is incorporated into the record. Noted as [A:....].