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(Stroke. 1996;27:588-592.)
© 1996 American Heart Association, Inc.

Articles

Aspirin Dose in Stroke Prevention

Beautiful Hypotheses Slain by Ugly Facts

H.J.M. Barnett, MD; M. Kaste, MD; H. Meldrum, BA M. Eliasziw, PhD

From the John P. Robarts Research Institute, London, Ontario (H.J.M.B., H.M.), and the Department of Epidemiology and Biostatistics, University of Western Ontario (Canada) (M.E.); and the Department of Neurology, Helsinki (Finland) University Hospital (M.K.).

Correspondence to H.J.M. Barnett, MD, The John P. Robarts Research Institute, PO Box 5015, 100 Perth Dr, London, Ontario, Canada N6A 5K8.

Key Words: aspirin • platelet aggregation • stroke prevention

	Introduction

Top Introduction References

 
Thomas Huxley wrote: "The great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact."¹ Acceptance of several hypotheses has convinced many clinicians to use low-dose aspirin whenever thrombosis or thromboembolism arising in any critical arterial systems threatens vital organs. Two current communications support this concept.^{2 3} This editorial reflects upon the possibility that this insistence on low dose is not based on unassailable data and could have tragic consequences for stroke prevention.

In the 1950s, the role of platelet-fibrin emboli was identified in patients with transient ocular and cerebral ischemic events.⁴ In 1965 and 1967 two drugs, sulfinpyrazone and aspirin, were observed to alter functions of blood platelets.^{5 6} Harrison et al⁷ reported on two patients whose attacks of frequent amaurosis fugax stopped with administration of 600 mg aspirin. Within 2 to 4 days the attacks would recur when the aspirin was replaced by either placebo or 150 mg dypyridamole. The mechanisms of action of aspirin on platelets or endothelial cells were not elucidated when the Canadian Cooperative Study group launched the first randomized trial using aspirin in thrombosis prevention. We selected an arbitrary dose of aspirin based on the dosage commonly used in pain relief and convenient to put in capsule form. The sulfinpyrazone dose used was the same as that for antigout therapy. The study design was double-blind 2x2 factorial; look-alike capsules of 325 mg aspirin, 200 mg sulfinpyrazone, both, or placebo were given four times daily.⁸

Subsequent trials were launched involving patients with TIA and nondisabling stroke and, together with the seminal Canadian and the abbreviated American trials, have recently been reviewed.⁹ They showed a relative risk reduction of stroke and death of 25% to 42% using 900 to 1300 mg aspirin daily. Patients with stable and unstable angina and patients with recent myocardial infarction were included in trials published in the 1970s.

While these studies using a larger dose were nearing completion, it became known that aspirin inhibited the thrombotic thromboxane A₂, derived from platelets. Subsequently, it was found that aspirin inhibited the antithrombotic prostacyclin derived from endothelial cells. Both depended on the cyclooxygenase enzyme. A hypothesis was proposed that arterial thromboses might occur more frequently with the higher dose of aspirin. A second hypothesis was generally accepted that there would be fewer severe gastrointestinal hemorrhages with lower aspirin doses. In light of these hypotheses, many trials tested low-dose aspirin against placebo in patients threatened with myocardial infarction or stroke.

Success rewarded trials of low-dose therapy in patients with symptoms related to coronary artery disease. Doubt clouds the issue of dose in stroke trials. Only three studies used low- or mini-dose aspirin in stroke-threatened patients: first, the UK-TIA trial tested 300 mg against 1200 mg aspirin and placebo in 2435 patients.¹⁰ In the placebo arm, the annual stroke rate was exceptionally low at 3.2% compared with double this risk (5.9% to 7.3%) in the other randomized trials of TIA and stroke patients. In the final report of the UK-TIA trial, the outcome of myocardial infarction, disabling stroke, or vascular death was reduced only 15% when the two dose regimens were combined.¹¹ There was little difference between the two dose regimens, with a trend (as high as 8.9%) favoring the 1200-mg over the 300-mg dose.¹² It is speculation to attribute this modest risk reduction compared with the previous trials to the fact that half of the patients on active treatment were receiving only 300 mg/d aspirin. It is speculative to relate it to the relatively low risk of stroke in this particular population. Nevertheless, the concern cannot be dismissed that this trial may not be presenting the true picture for aspirin benefit as it would apply to a more usual higher-risk population receiving a larger dose. Second, in the SALT trial, an 18% reduction was reported for 75 mg tested against placebo.¹³ Third, the Dutch TIA Trial study reported equal numbers for vascular death, stroke, or myocardial infarction with 30 or 283 mg/d aspirin.¹⁴ They had neither a high-dose group for comparison nor any control population.

Information on a fourth low-dose trial comes from an abstract.¹⁵ In the ESPS-2, 25 mg aspirin twice daily was somewhat better than placebo: 17.7% relative risk reduction for stroke, with a similar benefit of 15.8% for dipyridamole alone. A significant benefit is claimed for aspirin added to dipyridamole: a relative risk reduction of 36%. This trial conflicts with three trials in which 900 to 1300 mg aspirin was tested alone or against a combination with dipyridamole. None showed benefit for the combination over aspirin alone.^{16 17 18} Our conclusion is that the dose of aspirin chosen for the ESPS-2 trial was inadequate. The decision of these trialists not to include a higher-dose arm comparable to that used in the previous trials is a mystery.

The usefulness of platelet-inhibiting drugs in stroke prevention was reviewed with meta-analysis.^{19 20} It was hypothesized that all subjects prone to thrombosis in any arterial territory could be lumped together, as could all putative antiplatelet drugs. Trials involving patients known to be at higher and lower risk annually of stroke were combined in a search for a common denominator of benefit. Despite the lack of direct comparisons between low- and high-dose regimens, the Antiplatelet Trialists' Collaboration recommended low doses for all subjects threatened with thrombotic vascular disease.

From these observations, trials, and meta-analyses, three "ugly facts" have emerged. First, the hypothesis that too much aspirin (900 to 1300 mg) has an adverse effect on vascular outcome events has been refuted.^{21 22} Second, in several reviews serious or fatal gastrointestinal hemorrhage has been found not to bear a significant relationship to aspirin dose.^{21 22} In one of his last scientific publications, the late Dr T. Chalmers with his colleagues (Cappelleri et al²² ) conducted a major meta-regression analysis bearing directly on these fundamental issues. From 36 randomized trials designed to compare different doses of aspirin against placebo, they concluded: "For all patients and for subgroups of patients with previous vascular conditions, there was no relationship between dose and vascular events." Furthermore, they added: "For all patients, a dose-response relation was not found with gastro-intestinal hemorrhages and hemorrhagic stroke."

The possibility of an increased number of hemorrhagic strokes with aspirin use was raised in the Physicians' Health Study. Male physicians (n=22 071) received either 325 mg aspirin or placebo every other day. After an average of 57 months of follow-up, 150 strokes had occurred, 80 in the aspirin group and 70 in the placebo group.²³ The reports failed to state the definitions, but 19 events were said to be "hemorrhagic" (12.6%). Seven were classified as mild, 3 in aspirin and 4 in placebo arms; 12 were classified as moderate, severe, or fatal, 10 in aspirin and 2 in placebo arms. This difference in hemorrhagic stroke from secondary analysis was reported as significant. The editor of the New England Journal of Medicine warned against the possibility of aspirin inducing hemorrhagic strokes.²⁴ One year later, the proportion of "hemorrhagic strokes" was similar (35 of 217; 16.5%) but without a statistically significant difference for hemorrhagic stroke between treatment groups.²⁵ In a prospective cohort study of 87 000 women, 146 strokes occurred in 6 years. Hemorrhagic stroke occurred in 26 subjects taking no aspirin, in 20 taking less than 1 tablet per day, in 4 taking 1 or 2 tablets per day, and in 12 taking more than 2 per day.²⁶ In the SPAF trial, hemorrhagic stroke occurred more often with placebo than in patients taking 1 aspirin per day.²⁷ In the severe phase of NASCET, we observed 215 strokes; 96% were evaluated by CT, and 10 (4.6%) were hemorrhagic (NASCET, unpublished data, 1996). Two patients suffered subarachnoid hemorrhage from aneurysm rupture. Of the remaining 8 patients, 2 were taking no aspirin, 5 were taking 325 mg/d, and 1 was taking 1300 mg/d. Data-bank studies made before common prophylactic use of aspirin identified intracerebral and subarachnoid hemorrhage together as the cause of stroke in approximately 15% of patients.^{28 29} The claim that hemorrhagic strokes are increased in the presence of aspirin use is difficult to substantiate. Hemorrhagic strokes affirmed by CT in patients taking aspirin are not dose related.

An important reason for wanting the lowest effective quantity of aspirin is the dose-related gastric upset. It interferes with compliance. Enteric coating substantially reduces the distress of indigestion and gastric discomfort of regular aspirin ingestion. Enteric coating reduces but does not entirely eliminate gastrointestinal blood loss.³⁰ The earlier trials in stroke prevention usually involved the noncoated variety. More observations are needed here. Meanwhile, aspirin at any dose should be avoided in the presence of active symptoms of peptic ulceration.³¹

The third "ugly fact" is the spread of enthusiasm to embrace a low dose for all potential thrombotic events. The literature favoring it overlooks the evidence refuting the two hypotheses that appeared to make low doses imperative. Furthermore, it ignores serious problems in stroke prevention that endorsement of low-dose aspirin creates. Conclusions are premature, but the reasons we cannot write finis to this debate are not trivial. First, direct comparisons of the minidose (30 to 80 mg) and low dose (165 to 300 mg) with the higher dose (650 to 1300 mg) are lacking. SALT and the Dutch trial eschewed the opportunity to do this.^{13 14} The UK-TIA trial found no difference between 300 and 1200 mg.^{10 12}

Second, the placebo-controlled trials of patients who had TIA or nondisabling stroke are divisible into those that used a minidose or low dose (SALT, 75 mg; UK-TIA, either 300 or 1200 mg) and those in which a high dose (900 to 1300 mg) was administered. The relative risk reduction for stroke and death was 7% to 18% for the lower-dose trials. This compares unfavorably with the 25% to 42% reduction in the higher-dose trials.⁹ These trials did not have comparable patients, and the statistical differences between these relative risk reductions cannot be considered robust. Nevertheless, the striking differences are impressive. If they had been direct comparisons, no one would prefer low-dose therapy for stroke prevention.

Third, the theoretical arguments favoring the low dose are based on the measurable impact that very small amounts of aspirin have on platelet aggregation through cyclooxygenase inhibition. If this effect on platelet aggregation was all that mattered and other clinical and experimental data could be comfortably ignored, the case would be closed. However, there are a number of other recent observations that must be weighed carefully. (1) There are disturbing reports of nonresponsiveness and of dose-related response.^{32 33 34 35 36} In a study of 180 poststroke patients, the majority of thrombotic events occurred in aspirin nonresponders as determined by the inhibition or lack of it in platelet reactivity.³⁶ The ratio of responders to nonresponders in this study was 2:1. The nonresponders had a 40% risk of secondary stroke, but the responders had a minimal risk. Nonresponsiveness cannot be attributed entirely to an unusual lack of effect of aspirin on the cyclooxygenase system. The production of thromboxane A₂ is effectively blocked in most subjects by 325 mg/d aspirin. There is, however, a simultaneous metabolism of the platelet arachidonic acid by another platelet enzyme, lipoxygenase, and individual variations occur in the effect of aspirin on this pathway.³⁷ The differential effect on these two pathways may be an important explanation for nonresponsiveness. Low-dose aspirin may not be adequate to inhibit this alternative breakdown product (12 hydroxyeicosatetraenoic acid).³⁸ Low-dose aspirin may provide a limited antithrombotic effect or even increase thrombosis, accounting for clinical failures.

Doses of aspirin varying from 325 to 1300 mg/d were required to maintain complete platelet inhibition in 306 patients with cerebral ischemic events.³⁹ Initially, 34% had only partial inhibition. Throughout the 33 months of follow-up, increasing doses were needed to maintain complete inhibition in the imperfect responders, and the response fluctuated in some individuals. Even at 1300 mg/d, 8% of subjects were resistant. It is suggested that ongoing monitoring of aggregation tests may be important for the long-term use of aspirin in patients with cerebral ischemic events (C.M. Helgason, verbal communication, 1996).

(2) Aspirin has been observed to alter many thrombogenic phenomena. Among the variables studied with a differential effect from differing doses are the strength of the agonist collagen,³⁴ aspirin hydrolysis,⁴⁰ hyperreactivity to shear stress in patients with vascular disease,^{41 42 43} disaggregation response,⁴⁴ decreased platelet membrane fluidity,⁴⁵ generation of thrombin,⁴⁶ inhibition of smooth muscle cell growth,⁴⁷ and inhibition of megakaryocyte cyclooxygenase.⁴⁸ The variability of these responses in different arterial systems raises questions about the wisdom of lumping together trial results for all arteries.⁴⁹ (3) Studies of experimental arterial injury have reported clear aspirin dose-dependency on the inhibition of thrombus formation, on the number of emboli, and on the length of time over which emboli will recur after injury.^{50 51}

Fourth, a dose that may be "adequate for most people" but uncertain in its efficacy for others is not the best benchmark for comparative trials. With hard data lacking about the best dose of aspirin, it is difficult to choose a dose for comparison against novel antiplatelet drugs. CAPRIE trialists selected 325 mg/d aspirin in evaluating this putative successor to ticlopidine.⁵² If further studies establish that 325 mg is not the optimum dose, the results could be misleading. The same worry applies to the decision to use 300 and 325 mg, respectively, in the International Stroke Trial⁵³ and the Warfarin/Aspirin Recurrent Stroke Study (J.P. Mohr, verbal communication, 1996) and to use 30 mg [sic] in the SPIRIT Study.⁵⁴ Anticoagulants erroneously may be claimed to be better than aspirin. The ESPS-2 trial selected 50 mg/d aspirin.¹⁵ For this dose, there are no previous data from clinical trials in stroke prevention. The only valid conclusion from the ESPS-2 trial may be that a daily dose of 50 mg aspirin is a little better than placebo and not much better than dipyridamole alone. In a recent negative trial of aspirin in asymptomatic patients, 325 mg/d aspirin was administered to 372 patients. The lack of benefit might be attributed to too small a dose or too small a sample size.⁵⁵

Fifth, in primary prevention trials no benefit of aspirin for the outcome of stroke was observed. In 22 071 male physicians, 325 mg every other day reduced myocardial infarction, not stroke. In the observational study of 87 000 nurses, benefit was observed in myocardial infarction but not stroke. Approximately 75% used 325 mg/d aspirin or less. Prophylactic benefit of a larger dose is not known for either sex. The British Doctors Study of 5000 subjects was terminated early. With 500 mg/d, neither myocardial infarction nor stroke outcome benefited.⁵⁶

Sixth, a post hoc analysis of the perioperative stroke risk in NASCET detected a fivefold increase in stroke for patients taking 325 mg/d aspirin or less compared with those taking 650 mg/d or more. It is speculated that endarterectomy, with its exposure of large amounts of subendothelial collagen tissue, may expose a greater thrombogenic surface than the lower dose of aspirin can cope with.³⁵ Postoperative inflammatory differences may add to this failure. A second cyclooxygenase pathway operates in the presence of inflammation.^{57 58} This pathway is "not consistently inhibited by aspirin in lower therapeutic doses" (A.G.G. Turpie, verbal communication, 1996). A major trial is under way, randomly assigning endarterectomy patients to either 80, 325, 650, or 1300 mg aspirin for a perioperative period of 90 days. This trial, funded by the National Institute of Neurological Disorders and Stroke and known as Aspirin in Carotid Endarterectomy (ACE), is being conducted in NASCET centers. The condition of the artery after carotid endarterectomy differs from most other situations in patients with threatened stroke. Nevertheless, if this randomized trial directly testing one dose against another verifies our hypothesis, then we have one clear indication where more is better.

Last, in an angiographic study of restenosis after coronary angioplasty, a randomized trial detected less stenosis and larger lumen in patients randomly assigned to 500 mg/d aspirin compared with either 100 or 40 mg/d.⁵⁹

In conclusion, no scientific data are available to advocate with assurance either high-dose or low-dose aspirin in stroke prevention. There is neither adequate evidence nor compelling scientific data to support the statement of Patrono and Roth² that good clinical practice should dictate the use of 75 mg aspirin in the prevention of ischemic cerebrovascular disease. We postulate that the evidence is uncertain and available only from indirect comparisons but that it leans toward the moderate- to higher-dose regimens. A clinical trial making a direct comparison is the only way to obtain an answer. In the meantime, physicians should continue to use aspirin for stroke prevention. Aspirin is the least toxic and most readily available platelet inhibitor known to prevent stroke. There is a larger body of evidence supporting its use than that of other preparations. It is not perfect, many patients do not appear to benefit, and some have side effects. To quote Francis Bacon: "There is no excellent beauty that hath not some strangeness in the proportion."⁶⁰

	Selected Abbreviations and Acronyms

 

CAPRIE = Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events ESPS-2 = European Stroke Prevention Study NASCET = North American Symptomatic Carotid Endarterectomy Trial SALT = Swedish Aspirin Low Dose Trial SPAF = Stroke Prevention in Atrial Fibrillation SPIRIT = Stroke Prevention in Reversible Ischemia Trial TIA = transient ischemic attack

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association, Inc.

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