Editorials

The aspirin papers

The first paper (p 81)¹ reviews the efficacy of such treatments in preventing death, myocardial infarction, and stroke in patients with documented atherosclerosis (for example, unstable angina, or previous myocardial infarction, transient ischaemic attack, or stroke). This large overview confirms that antiplatelet treatment reduces vascular events by about a quarter in these high risk patients. Non-fatal myocardial infarction and stroke are reduced by one third; vascular deaths (from fatal myocardial infarction and stroke) fall by one sixth.

In this heterogeneous group of patients these benefits are apparent irrespective of age, sex, blood pressure, or the presence of diabetes. Aspirin alone, at doses ranging from 75 mg to 325 mg, seems as effective as any other antiplatelet regimen, with little risk of adverse side effects (such as gastrointestinal or intracerebral haemorrhage). The most effective dose of aspirin for long term treatment still needs to be determined, but in emergencies - for example, acute myocardial infarction - a daily dose of at least 160 mg to ensure a rapid onset of action seems sensible.⁵ The optimum duration of treatment in this group of patients is unknown as the trials analysed lasted only two years on average, but lifelong treatment may be advantageous unless specific contraindications exist.

The first overview also considered the effect of antiplatelet treatment on low risk subjects - those with no history of vascular events. Benefits were difficult to show, possibly because of the low overall incidence of vascular events,⁴ (and because a few cerebral haemorrhages may have been caused), although the risk of non-fatal myocardial infarction fell by 5 per 1000 treated cases. Until further work has been carried out the routine use of antiplatelet treatment for primary prevention cannot be recommended.⁶

In patients undergoing revascularisation procedures, antiplatelet agents have been extensively investigated, although a standard protocol for coronary artery bypass surgery is still lacking.⁷ This may reflect the fact that all published trials have used different inclusion and exclusion criteria and have assessed patency of the graft at different times postoperatively. In addition, factors other than adjuvant treatment influence the development of occlusion of the graft (for example, the diameter of grafted vessels and distal artery run off). An overview of all these trials is therefore helpful in providing some practical recommendations for treatment.

Aspirin enhances patency of grafts

Conclusive evidence exists that antiplatelet treatment enhances the early patency of coronary vein grafts. Aspirin alone seems as effective as any other agent, with a dose of 325 mg as beneficial as higher doses. Lower doses may be as efficacious, but no trial has shown this directly. To be effective, treatment should be started early after the procedure, as indicated by a previous meta-analysis,⁸ and indeed the trials that have failed to show benefit with treatment have been those in which antiplatelet treatment was delayed until the second or third postoperative day.^9,10 Preoperative treatment increases the risk of bleeding,¹¹ but administration within six hours after operation seems safe and effective.¹² Again the question of the duration of treatment arises. At least one year's treatment reduces new lesions in vein grafts,¹³ but these patients also have residual native coronary atheroma and, as this week's paper suggests, may therefore benefit from more prolonged treatment.

Patients undergoing peripheral vascular procedures accrue similar benefits in terms of graft patency.² What is unclear, however, is which cohort of patients benefits most. Debate continues over the need to treat patients with peripheral saphenous vein (as opposed to prosthetic) grafts,¹⁴ but, although treatment may not enhance survival of the graft, it may still reduce the incidence of subsequent vascular events in these patients with generalised atherosclerotic disease (two thirds of these patients will die of cardiovascular or cerebrovascular events¹⁵. No trial has addressed this issue. Antiplatelet treatment is now routinely given during coronary angioplasty, although only a few prospective studies have been carried out. Of the studies reviewed, each used a different antiplatelet agent, but similar falls in rates of acute thrombosis (by about half) were observed in the two larger trials.

The effect of antiplatelet treatment on the incidence of venous thromboembolism is not widely appreciated. The third review shows that in trials in which deep vein thrombosis was assessed systematically, antiplatelet treatment significantly reduced its incidence.³ Importantly, in this group of patients (those undergoing general surgical and orthopaedic procedures, and at risk and immobile medical patients) the incidence of pulmonary embolism fell significantly. The review does not suggest that antiplatelet agents should replace subcutaneous heparin for routine prophylaxis, but, interestingly, the combination of heparin and an antiplatelet agent may be better than heparin alone in preventing pulmonary embolism. This conclusion is based on a small number of trials, and further studies are clearly needed to determine the exact role of antiplatelet treatment in this group of patients.

These three major overviews of the use of antiplatelet treatment in various groups of patients provide valuable information on which to base clinical practice; they also highlight topics requiring further investigation. Patients with established atherosclerosis (affecting their cardiac, cerebral, or peripheral arteries) benefit in terms of fewer subsequent vascular events. Patients undergoing revascularisation procedures (coronary grafting, peripheral grafting, and angioplasty) also benefit in terms of better patency of the vessel and fewer vascular events unrelated to the procedure. The role of antiplatelet treatment in prophylaxis against venous thromboembolism is less certain as other effective treatment (subcutaneous heparin) exists.¹⁶

In all groups of patients aspirin, at a dose of 75-325 mg, seems as effective as any other single agent or combination of agents. The duration of treatment still needs to be determined, but for those with established atherosclerosis lifelong treatment may be indicated. For patients without clinically apparent atherosclerotic disease the potential haemorrhagic complications of routine use of aspirin may outweigh its benefit.

M J Underwood, R S More 

1. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet treatment. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106. [Abstract/Free Full Text]
2. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet treatment. II. Maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ 1994;308(in press).
3. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet treatment. III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994;308(in press).
4. Davey-Smith G, Egger M. Who benefits from medical interventions? BMJ 1994;308:72-4.
5. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;ii:349-60.
6. Willard JE, Lange RA, Hillis LD. The use of aspirin in ischemic heart disease. N Engl J Med 1992;327:175-81. [Medline]
7. Angelini GD, Bryan AJ, West RR, Newby AC, Brekenridge IM. Coronary artery bypass surgery: current practice in the United Kingdom. Thorax 1989;44:721-4. [Abstract]
8. Henderson WG, Goldman S, Copeland JG, Moritz TE, Harker LA. Antiplatelet or anticoagulant therapy after coronary artery bypass surgery. A meta-analysis of clinical trials. Ann Intern Med 1989;111:743-50.
9. Pantley GA, Goodnight SH, Rahimtoola S, Harlan BJ, DeMots H, Calvin L, et al. Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary artery bypass. N Engl J Med 1979;301:962-6. [Abstract]
10. Sharma GVRK, Khuri SF, Josa M, Foiland ED, Parisi AF. The effect of antiplatelet therapy on saphenous vein coronary artery bypass graft patency. Circulation 1983;68(suppl II):218-21.
11. Sethi GK, Copeland JG, Goldman S, Moritz T, Zadina K, Henderson WG. Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 1990;15:15-20. [Abstract]
12. Goldman S, Copeland JG, Moritz T, Henderson WG, Zadina K, Ovitt T, et al. Starting aspirin therapy after operation: effects on early graft patency. Circulation 1991;84:520-6. [Abstract/Free Full Text]
13. Gavaghan TP, Gebski V, Baron DW. Immediate post-operative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. Circulation 1991;83:1526-33. [Abstract/Free Full Text]
14. McCollum C, Alexander C, Kenchington G, Franks PJ, Greenhalgh R. Antiplatelet drugs in femoropopliteal vein bypasses: a multicentre trial. J Vasc Surg 1991;13:150-62. [Medline]
15. Dormandy J, Mahir M, Ascady G. Fate of the patient with chronic leg ischemia. J Cardiovasc Surg 1989;30:50-7. [Medline]
16. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by peri-operative administration of subcutaneous heparin. N Engl J Med 1988;318:1162-73. [Medline]