Aspirin
Aspirin acetylates prostaglandin (PG) H-synthase and irreversibly inhibits cyclooxygenase activity. In platelets the formation of thromboxane is inhibited (thromboxane induces which inhibits platelet aggregation and vasoconstriction. Within an hour of ingestion, cyclooxygenase is inhibited 1. Although there is a theoretical question of inducing a prothrombotic effect at high doses, in vivo studies have not demonstrated a prothrombotic effect of ASA in doses up to 1300 mg/day. Clinically important platelet inhibition has been shown to occur in doses as low as 30 mg/day with minimal side effects 2. With respect to cardiac events, the Antiplatelet Trialists’ Collaboration 3(ATC) performed a meta-analysis of 145 randomized studies and noted that 160 mg was effective in treating acute myocardial infarction and 75 mg/day was effective for all other primary and secondary prevention indications with no difference in efficacy between low (< 160 mg/day), medium (160 – 325 mg/day, and high (> 325 mg/day) doses. Finally, concerning the risk of gastrointestinal bleeding, there appears to be a significant increase in the associated risk as the dose of ASA increases above 325 mg/day. Interestingly, a difference in gastrointestinal bleeding was not found among the different preparations (i.e. plain vs. enteric-coated vs. buffered) of ASA at doses < 325 mg/day. However, there were not enough patients taking high-dose enteric-coated ASA to comment on its relative risk of serious gastrointestinal bleeding4.
Primary Prevention
There have been several trials to date exploring the role of ASA in the primary prevention of death from cardiovascular causes. Unfortunately these studies have been plagued by the inherently low incidence of mortal cardiovascular events in an otherwise young healthy population without significant risk factors for cardiovascular disease 5,6. For example, in the Physician’s Health Study 5, although there was a clear but small reduction in non-fatal myocardial infarctions within the study group (absolute reduction = 1 %), these gains were tempered by an increase in side effects which included gastrointestinal bleeding, increased transfusion requirements, and a trend toward increased hemorrhagic strokes (absolute risk increase for hemorrhagic strokes = 0.2%, p = 0.06). The Thrombosis Prevention Trial 7 randomized 5085 men at high risk of developing ischemic heart disease (coronary death, fatal and nonfatal MI) to low-dose warfarin (INR goal 1.5), low-dose ASA (75 mg/day), both, or neither. There was an all-cause mortality benefit for those taking warfarin (11.6 % vs.13.9 %). For patients taking ASA, there was a significant reduction in nonfatal myocardial infarctions (9.5 % vs.11.8 %); however, this occurred at a cost of a significant (0.5 %, p = 0.01) increase in hemorrhagic strokes without any change in all-cause mortality. The ATC evaluated primary prevention randomized controlled trials that sought to use ASA to decrease the combined end point of myocardial infarction, stroke, and vascular death. No difference was found between the placebo arm and the ASA arm 3. Given the nearly equal risk vs. benefit ratio, the current ACCP recommendations are to not prescribe ASA for the purpose of primary prevention of ischemic heart disease in those under 50 years old. For those patients greater than 50 years old who have atherosclerotic risk factors, ASA should be considered for primary prevention. Alternatively, low-dose warfarin or a combination of warfarin and ASA should be considered 8.
Secondary Prevention
Known atherosclerosis. Many of the secondary prevention trials failed to reach statistical significance largely due to a lack of an adequate sample size. For example, the SAPAT 9 (Swedish Angina Pectoris Aspirin Trial) randomized over 2,000 men with stable angina to ASA and sotalol or placebo and sotalol. There was a reduction in nonfatal MIs and a significant reduction in sudden death but a failure to demonstrate an all-cause mortality benefit. Similarly, a subgroup analysis of the Physician’s Health Study also failed to demonstrate a mortality benefit for those presenting with stable angina 10. Two other studies failed to show a secondary prevention mortality benefit: PARIS 11 (The Persantine-Aspirin Reinfarction Study) and AMIS 12 (Aspirin Myocardial Infarction Study) enrolled patients after they had experienced a previous myocardial infarction. Both trials accepted patients with a remote history of infarction, perhaps after the demonstrable benefit of ASA had passed, and neither demonstrated a mortality benefit. The ATC performed subgroup analysis as part of their meta-analysis. In evaluating the combined endpoint consisting of myocardial infarction, stroke and any vascular death and demonstrated a beneficial effect of ASA. Those with a prior CVA or TIA had a significant reduction of events from 22.2 % to 18.4%. Those with prior MI also had a significant reduction from 17.1 % to 13.5 %. Lastly, those with stable angina had an absolute reduction of events from 15 % to 10 % but this was not statistically significant3. Based upon these results, the ACCP recommendations are to treat patients with chronic coronary artery disease with 160 to 325 mg ASA/day 8.
Unstable Angina. Trials of ASA in unstable angina have generally been more convincing. The RISC Group randomized 796 men to 75 mg ASA/day, a bolus IV heparin regiment, both, or neither. There was a significant absolute reduction of myocardial infarction and death from 13.4 % to 4.2 % at five weeks follow-up.13 A Veterans Administration Cooperative Study randomized patients to 324 mg ASA/day vs. placebo and found similar results at 12 weeks (combined endpoint reduction from 10 % to 5 %) 14. Again, the ATC found a combined endpoint reduction in patients with unstable angina from 14 % to 9 %3. The current ACCP guidelines recommend 160 to 325 mg/day of ASA to patients presenting with unstable angina 8.
Acute MI. Interestingly, several randomized controlled trials in the early 1970s failed to show a significant benefit of the use of ASA in the setting of an acute MI. These trials were generally plagued, however, by relatively smaller sample sizes, a more pure clinical recognition of an acute infarction, and limited follow-up. Perhaps the most convincing evidence to date remains the ISIS-2 15 study. ISIS-2 was a randomized placebo controlled study involving over 17,000 patients. Patients were given streptokinase, streptokinase + ASA 160 mg/day for 30 days, both, or neither. ASA was found to be as important as streptokinase in reducing mortality (13.2 % ASA vs. 8 % no ASA) at 5 weeks follow-up. Additionally, in those patients given both ASA and SK there was a significant reduction in re-infarction. There was no increased risk of hemorrhagic strokes in those patients given SK, ASA, or both. The current ACCP recommendations for patients with an acute infarction to immediately chew 160 to 325 mg of ASA and continue taking a similar dose on a daily basis 8.
Interventional Cardiology
Procedurally Related Events. Several studies have examined the utility of ASA prior to angioplasty. Barnathan et al. reported a reduction of clinically significant thrombus (requiring emergent CABG, requiring the use of thrombolytics, or causing a 100 % occlusion) formation from 5.7 % to 1.4 % (p = 0.001) 16. Additionally, the risk of Q-wave infarction has been shown to be reduced with the use of ASA prior to PTCA (6.9 % placebo vs. 1.6 % ASA + persantine) 17.
Restenosis. Several studies have examined the use of ASA in reducing the restenosis rate of angioplasty (prior to the stent era). The hypothesis was that subclinical deposition of activated platelets would occur at the site of angioplasty. These activated platelets would set up a cascade of events leading to recruitment and proliferation of smooth muscle cells. To date there has been no convincing evidence that ASA reduces restenosis in stand-alone angioplasty. However, the ATC combined three randomized trials of the use of ASA in angioplasty and found a significant absolute reduction of complete re-occlusions (8.0 % vs. 4.1 %) 18. Based upon a review of these trials, the current ACCP guidelines suggest that patients receive 80 to 325 mg of ASA within 24 hours prior to angioplasty and 160 to 325 mg/day thereafter for the secondary prevention of ischemic heart disease 8.
CABG. Several studies have explored the use of ASA in maintaining saphenous vein bypass graft patency (IMA grafts generally have an occlusion rate so low as to preclude ASA from having a demonstrable effect on patency). These studies have produced conflicting results but this may be due to protocol differences. For example, although most authors agree that a substantial (between 10 and 20 %) of vein grafts occlude within the first few postoperative days, some studies did not start ASA until several days after surgery. Others were more restrictive on entry criteria by excluding diabetics. Angiographic follow-up varied between 50-90 % at one year. The ATC examined 20 randomized-control trials and demonstrated a significant benefit in graft patency (30.3 % vs. 21.1 %) for those patients given ASA 18. The ACCP consensus panel concluded that ASA, given either prior to or early in the post-operative coarse, has a beneficial effect on patency during the first post-operative year. Although there is no apparent benefit of ASA in terms of graft patency beyond the first year, the authors argued that patients post-CABG should be maintained on ASA for secondary prevention 8.
References
1. Collins R, Peto R, Baigent C and P Sleight (1997). Aspirin, heparin and fibrinolytic therapy in suspected acute myocardial infarction. NEJM 336: 847-60.
2. The Dutch TIA Study Group (1991). A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor stroke. NEJM 325:1261-6.
3. Antiplatelet Trialists' Collaboration (1994). Collaborative overview of randomized trials of antiplatelet therapy: I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 308:81-106.
4. Kelly JP, Kaufman DW, Jurgelon JM, et al (1996). Risk of aspirin-ass0ciated major upper gastrointestinal bleeding with enteric-coated or buffered product. Lancet 348:1413-6.
5. Steering Committee of the Physician's Health Study Research Group (1989). Final report on the aspirin component of the ongoing Physician's Health Study. NEJM 321:129-35.
6. Peto R, Gray R, Collins R et al (1988). Randomised trial of prophylactic daily aspirin in British male doctors. BMJ 296:313-6.
7. (1998). Thrombosis Prevention Trial: randomized trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 351:231-41.
8. Fifth ACCP Consensus Conference on antithrombotic therapy (199?). Chest 114(5):626-8S.
9. Juul-Moller S, Edvardsson N, Jahnmatz B et al (1992). Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet 340:1421-5.
10. Ridker PM, Manson JAE, Gaziano JM et al (1991). Low-dose aspirin therapy for chronic stable angina: a randomized, placebo-controlled clinical trial. Ann Int Med 114:835-9.
11. The Persantine-Aspirin Reinfarction Study Research Group (1980). Persantine and aspirin in coronary heart disease. Circulation 62:449-61.
12. Aspirin Myocardial Infarction Research Group (1980). A randomised, controlled trial of aspirin in persons recovered from myocardial infarction. JAMA 243:661-9.
13. The RISC Group (1990). Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary disease. Lancet 336:827-30.
14. Lewis HD, David JW, Archibald DG et al (1983). Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration cooperative study. NEJM 309:396-403.
15. ISIS-2 Collaborative Group (1988). Randomised trial of intravenous streptokinase, oral aspirin, both, or neither amongst 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2:349-60.
16. Barnathan ES, Schwartz JS, Taylor L et al (1987). Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation 76:125-34.
17. Schwartz L, Bourassa MG, Lesperance J et al (1988). Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal angioplasty. NEJM 319:1714-9.
18. Antiplatelet Trialists' Collaboration (1994). Collaborative overview of randomized trials of antiplatelet therapy: II. Maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ 308:159-68.
Steven D. Filardo, M.D., M.P.H.