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(Stroke. 1996;27:756-760.)
© 1996 American Heart Association, Inc.
Articles |
Aspirin in Ischemic Cerebrovascular Disease
How Strong Is the Case for a Different Dosing Regimen?
From the Departments of Pharmacology and Medicine, University of Chieti "G. D'Annunzio" School of Medicine (Italy) (C.P.), and the Hematology Section, Medical and Research Services, Seattle Veterans Hospital, and the University of Washington, Seattle (G.J.R.).
Correspondence to Professor Carlo Patrono, Cattedra di Farmacologia I, Università degli Studi "G. D'Annunzio," Via dei Vestini, 31, 66013 Chieti, Italy.
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Abstract |
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 Top Abstract IntroductionMechanism of ActionEffects of Aspirin on...Aspirin `Failure' or...Randomized Clinical TrialsAssessment of Benefits and...ConclusionsReferences |
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Background A vast consensus exists in defining a narrow range of recommended daily doses of aspirin, ie, 75 to 160 mg, for the prevention of myocardial infarction, stroke, and vascular death in patients with different manifestations of coronary heart disease. In contrast, for patients with cerebrovascular disease, a much larger degree of uncertainty still exists, with recommendations ranging from 30 to 1300 mg daily.
Summary of Comment The contention that higher doses of aspirin (650 to 1300 mg) are more effective than lower doses in stroke prevention is based on indirect and selective comparisons of different trial data, mini-meta-analyses, or subgroup analyses of individual trials. In the absence of definitive evidence from direct randomized comparisons of low-dose versus high-dose aspirin in trials of adequate size to detect a moderate difference between the two, the biological hypotheses that underpin the suggestion of greater efficacy of higher aspirin doses in cerebrovascular disease patients are reviewed and disputed. Practical implications of the use of higher doses of aspirin are also assessed on the basis of theoretical calculations of absolute benefits and risks.
Conclusions Until additional information from ongoing trials is available, good clinical practice should dictate the use of the lowest dose of aspirin shown effective in the prevention of stroke and death in patients with ischemic cerebrovascular disease, ie, 75 mg daily.
Key Words: antiplatelet therapy • aspirin • stroke prevention
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Introduction |
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TopAbstractIntroductionMechanism of ActionEffects of Aspirin on...Aspirin `Failure' or...Randomized Clinical TrialsAssessment of Benefits and...ConclusionsReferences |
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Aspirin has well-characterized antiplatelet effects of proven clinical value.1 Probably no single cardiovascular drug has a database documenting its efficacy and safety comparable to that derived from more than 50 randomized aspirin trials.2 However, one unique feature of the clinical development of aspirin as an antiplatelet agent, ie, its "academia-driven" nature, has generated a long-standing debate on the "optimal" dose to prevent coronary and cerebral thrombosis. Traditionally, most drugs undergo "industry-driven" clinical development leading to the selection of one particular dose, based on phase II dose-finding studies, that is tested in a limited number of pivotal phase III studies of efficacy and safety. In the case of aspirin, a century-old drug, clinical testing of its antithrombotic efficacy was initiated largely on empirical grounds, and industry-driven clinical development was nil because, at the time, all commercial interest in the product had essentially vanished. Clinical trials were started mostly with doses in the range of 900 to 1500 mg daily, based on dose requirements for other established pharmacological effects of the drug (eg, analgesic) and/or dosing regimens dictated by coadministered drugs (ie, TID for dipyridamole, QID for sulfynpirazone). Soon thereafter, however, studies from academic centers altered this approach with the discovery that aspirin blocked prostaglandin synthesis3 by modifying a key enzyme of platelet arachidonate metabolism, ie, cyclooxygenase, also termed PGH synthase.4 These advances were instrumental in the development of analytical tools to quantitate the dose dependence and time dependence of the effects of aspirin on platelet biochemistry and function. A relatively simple tool, ie, the measurement of TXB2 during whole blood clotting,5 led to a clear understanding of the platelet effect of single oral aspirin doses in both health6 and disease.7 The cumulative effect of the drug in inhibiting platelet cyclooxygenase was also defined by studying the effect of low doses of aspirin given on a daily basis.6 8 This "academic" knowledge eventually led to a progressive reduction in the dose of aspirin used in clinical trials, down to the level of 30 mg daily.9 However, in the case of ischemic cerebrovascular disease and aspirin, questions remain concerning the use of higher versus lower doses of the drug. The debate waxes hot at times, generating strong words and prompting us to offer the following arguments in favor of using low-dose aspirin in patients who are prone to cerebrovascular thrombosis.
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Mechanism of Action |
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Although several "cyclooxygenase-independent" actions of aspirin have been subsequently described,10 11 12 the effect of aspirin on cyclooxygenase has been exceptionally well defined and shown to involve the acetylation of a single amino acid residue (serine 529) in the polypeptide chain. This cyclooxygenase-dependent effect has several distinct features that are worth mentioning vis-à-vis other mechanisms. First, the aspirin-sensitive platelet cyclooxygenase enzyme has been identified, sequenced, and cloned.13 Second, this enzyme is responsible for the generation of a labile eicosanoid, TXA2,14 which amplifies the response of platelets to a variety of agonists.15 Third, increased TXA2 biosynthesis has been characterized in patients with acute coronary16 or cerebral17 ischemic syndromes as well as in conjunction with a variety of cardiovascular risk factors associated with enhanced thrombotic risk.18 Fourth, platelet cyclooxygenase is completely and permanently inhibited by aspirin, thus accounting for the persistent antiplatelet effect of a drug with a 15- to 20-minute half-life.19 Fifth, the dose requirement and single daily dosing for complete inactivation of platelet cyclooxygenase activity6 are consistent with the minimum effective dose of aspirin as an antithrombotic agent in a variety of disease states1 2 (Table 1
). These five points imply that aspirin exerts
its antithrombotic action by inhibiting platelet
cyclooxygenase.
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None of these five features have been characterized for the cyclooxygenase-independent effects of aspirin on hemostasis. Although aspirin, in higher doses, acetylates a number of proteins besides platelet cyclooxygenase (eg, fibrinogen10 and prothrombin12 ), the dose-response relationship, duration, occurrence in the clinical setting, and relevance to the antithrombotic effect of aspirin have not been established. In a sense, these findings are only descriptive phenomenology because they do not define clear-cut molecular mechanisms that correlate with clinical findings. We can and should demand more substantial evidence for these cyclooxygenase-independent mechanisms before accepting them as relevant to aspirin's ability to prevent thrombosis.
One obvious consequence of the largely academia-driven clinical development of aspirin as an antiplatelet agent has been a marked degree of individualism in the choice of doses being tested in different clinical trials, tempered only by the size of tablets commercially available in different countries. While trials using daily doses equal to or lower than 2 mg/kg clearly tested a mechanism-based hypothesis (ie, platelet cyclooxygenase inhibition), it is not immediately apparent which specific hypotheses were tested in trials using 300 to 325 mg given every other day, daily, BID, TID, or QID. However, the results of these trials have been reviewed recently,1 2 19 and it is not the intent of this article to discuss them in any detail. Rather, we wish to address, in a sequential fashion, a single hypothesis that relates to ischemic cerebrovascular disease and aspirin, ie, the idea that a specific vascular district, such as the cerebral circulation, is a major determinant in the effectiveness of an antithrombotic drug such as aspirin. We do not discuss the possible antiatherogenic effect of aspirin since data in this area are limited.20
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Effects of Aspirin on the Coronary and Cerebral Circulation |
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TopAbstractIntroductionMechanism of ActionEffects of Aspirin on...Aspirin `Failure' or...Randomized Clinical TrialsAssessment of Benefits and...ConclusionsReferences |
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Starting from the vantage point of knowledge about patients with different manifestations of coronary heart disease, a vast consensus exists in defining a rather narrow range of recommended daily doses, ie, 75 to 160 mg, for the prevention of myocardial infarction, stroke, and vascular death.19 21 22 This is supported by separate trial data in more than 20 000 patients randomized to low-dose aspirin or placebo as well as by an overview of all antiplatelet trials showing no obvious dose dependence for the protective effects of aspirin.2
In contrast, for patients with cerebrovascular disease, a much larger degree of uncertainty still exists, with recommendations ranging from 30 to 1300 mg daily. In particular, a strong case has been put forward by some members of the North American neurological community for higher doses of aspirin (650 to 1300 mg) being more effective than lower doses. This has been reported in several recent reviews and editorials.22 23 24 The evidence supporting this contention is based largely on indirect and selective comparisons of different trial data, mini-meta-analyses, or subgroup analyses of individual trials. In the absence of definitive evidence from direct randomized comparisons of low-dose versus high-dose aspirin in trials of adequate size to detect a moderate difference (one way or the other) between the two, one can only discuss the likelihood of the biological hypothesis that underpins the suggestion of greater efficacy of higher aspirin doses in cerebrovascular disease patients.
The hypothesis dictates a number of essential conditions: (1) that the mechanism(s) through which aspirin prevents stroke is different from that through which the drug prevents myocardial infarction; (2) that the mechanism(s) through which aspirin prevents stroke in patients with cerebrovascular disease is different from that through which it prevents stroke in patients with coronary heart disease; and (3) that the dose dependence and time dependence of the antiplatelet effects of aspirin are clearly different in the two clinical settings. Although each of these arguments can be entertained on theoretical grounds, lack of direct evidence supporting any of these conditions concerns us and prompts the following comments. The strongest evidence of a differential effect of aspirin on the coronary versus cerebral circulation is the data from the Physicians' Health Study.25 In this primary prevention trial among 22 071 healthy male physicians, there was a 44% reduction in the risk of myocardial infarction (RR, 0.56; 95% CI, 0.45 to 0.70; P<.00001) and an 11% increase in the risk of ischemic stroke (RR, 1.11; 95% CI, 0.82 to 1.50; P=.50) associated with long-term aspirin administration. Two facts should be noted: (1) the absolute risk of these apparently healthy physicians to develop a first myocardial infarction during the 5-year follow-up was threefold higher than the absolute risk of experiencing a first ischemic stroke, and (2) the 95% CI for the RR of ischemic stroke if treated with aspirin versus placebo does include the possibility of an 18% risk reduction, ie, the kind of risk reduction suggested by an overview24 of aspirin trials in patients with cerebrovascular disease using doses in the range of that used in the Physicians' Health Study. While we freely admit the possibility that a particular mechanism of platelet activation might be dependent on the vascular district involved, the fact remains that, to the best of our knowledge, the determinants of the hemostatic response to vascular injury do not appear to vary substantially in different clinical settings. In fact, the same mechanisms of platelet function and plasma coagulation apply to both normal hemostasis and abnormal thrombosis. Nature uses exactly the same materials and methods to form the life-saving hemostatic plug and the life-threatening thrombus. Current information does not resolve the question of whether aspirin's effect on platelets will vary from one vascular region to another. However, aspirin appears to exert exactly the same effect on platelet cyclooxygenase regardless of the setting in which it occurs, normal or abnormal; also, it seems reasonable to expect that aspirin exerts its noncyclooxygenase effects in the same even-handed way. If acetylation processes are involved, it is difficult to envisage how the cerebral circulation, the underlying disease, or the mechanism of stroke would lead to a novel requirement for markedly higher concentrations of aspirin and convergent changes in the stoichiometry of the acetylation reaction, its dose dependence, and its duration.
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Aspirin `Failure' or `Resistance' |
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TopAbstractIntroductionMechanism of ActionEffects of Aspirin on...Aspirin `Failure' or...Randomized Clinical TrialsAssessment of Benefits and...ConclusionsReferences |
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It has been claimed that the dose of aspirin needed to fully suppress platelet aggregation may be higher in patients with cerebrovascular disease than in healthy subjects and may vary from time to time in the same patient. Terms like "aspirin failure" or "aspirin resistance" have been used in these studies26 27 to designate less than complete inhibition of platelet aggregation. One important caveat in the interpretation of these measurements of platelet function is represented by the uncontrolled nature of the studies, which does not recognize the contribution of (1) intrasubject variability of the aggregation measurements, (2) lack of compliance with study medication, or (3) drug interactions potentially preventing acetylation of platelet cyclooxygenase by aspirin. A recent controlled study clearly demonstrated the contribution of poor compliance in 10% of outpatients with ischemic cerebrovascular disease being treated with low-dose aspirin or ticlopidine.28 Both biochemical and molecular tools are now available to address the issue of an alleged aspirin resistance. These should be used to upgrade the quality of these observations.
Certainly, questions about the effectiveness of aspirin therapy in blocking platelet and nonplatelet sources of prostanoid synthesis should continue to be raised. For example, enhanced TXB2 metabolite excretion has been described in some patients with unstable angina while on an intravenous low-dose aspirin regimen.29 This may reflect the contribution of extraplatelet sources of TXA2 biosynthesis, including the inducible expression of PGH synthase 2 in monocytes/macrophages.30 This same type of scrutiny will need to be applied to the use of aspirin in other clinical syndromes.
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Randomized Clinical Trials |
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TopAbstractIntroductionMechanism of ActionEffects of Aspirin on...Aspirin `Failure' or...Randomized Clinical TrialsAssessment of Benefits and...ConclusionsReferences |
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If we now turn to randomized clinical trial data, the only study that compared aspirin alone versus placebo in patients with cerebrovascular disease and showed a statistically significant difference between the two in prespecified primary end points analyzed according to the intention-to-treat principle is SALT,31 which used 75 mg daily in 1360 patients with TIA or minor ischemic stroke. This study demonstrated an 18% reduction in the risk of stroke or death in patients treated with low-dose aspirin (RR, 0.82; 95% CI, 0.67 to 0.99; P=.02). The study also reported intention-to-treat analyses for secondary outcome events. For the combined end point of "stroke, or two or more TIAs within a week necessitating a change of therapy," aspirin significantly reduced the probability (RR, 0.80; 95% CI, 0.63 to 1.01; P=.03). For the two other secondary end points, similar point estimates of risk reduction were obtained for stroke (RR, 0.84; 95% CI, 0.65 to 1.08; P=.11) and for myocardial infarction (RR, 0.80; 95% CI, 0.57 to 1.13; P=.13), although the differences between the two treatment groups were not statistically significant. The CI for the 18% reduction in the risk of stroke or death is wide because it includes the extremes of a trivial 1% benefit as well as a more substantial 33% risk reduction. However, this is as good a piece of evidence as we have today for any antiplatelet agent including ticlopidine, which yielded a 23% reduction in primary outcome events in CATS,32 with a 95% CI of 1% to 40%.
A recent meta-analysis performed by Barnett et al24 clearly shows that higher doses of aspirin, when used alone, do not produce any greater risk reduction than that recorded in SALT. Individual trial results as well as the meta-analysis performed by Barnett et al suggest that when high-dose aspirin is combined with dipyridamole33 34 or sulfinpyrazone,35 a somewhat higher risk reduction can be obtained, ie, 30% to 35%. These studies, however, did not have the statistical power (because of limited sample size) to detect a modest difference between aspirin alone and the combination. Thus, whether sulfinpyrazone or dipyridamole acts synergistically when combined with high-dose aspirin in patients with cerebrovascular disease remains an open question. Therefore, the results of these trials cannot be interpreted unequivocally and cannot be used as a basis for recommending high-dose aspirin alone.
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Assessment of Benefits and Risks |
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TopAbstractIntroductionMechanism of ActionEffects of Aspirin on...Aspirin `Failure' or...Randomized Clinical TrialsAssessment of Benefits and...ConclusionsReferences |
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What does a 30% rather than 20% risk reduction mean in terms of absolute benefits? It depends on the absolute level of risk in the patient group. Thus, in a high-risk situation (10% risk of stroke or death in 1 year), the number of patients who need to be treated to avoid one additional event is 100. In a low-risk situation (1% risk of stroke or death in 1 year), the same number is 1000 patients. Assuming that high-dose aspirin can indeed produce a 30% risk reduction in patients with cerebrovascular disease rather than the 20% reduction suggested by SALT, one should consider that even in a high-risk setting, 99 of 100 patients need to be exposed to a 15-fold excess of drug intake for nothing because stroke or death would have been avoided by low-dose aspirin (n=2), would have occurred despite high-dose aspirin (n=7), or would never have occurred in any case (n=90). Since the risk of gastrointestinal damage and bleeding increases as a function of the aspirin dose9 36 (perhaps decreased by enteric coating), number of daily administrations, and duration of treatment, one should balance the potential for additional benefit with the risk of enhanced harm. Only a randomized head-to-head comparison of high-dose versus low-dose aspirin can properly assess such benefit-risk ratio under controlled conditions.
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Conclusions |
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TopAbstractIntroductionMechanism of ActionEffects of Aspirin on...Aspirin `Failure' or...Randomized Clinical TrialsAssessment of Benefits and...ConclusionsReferences |
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Several large antiplatelet trials are currently ongoing (Table 2
), and we await their findings with great
interest. Neurologists participating in these trials all over the world
are currently randomizing patients at risk of or experiencing an acute
ischemic stroke to aspirin doses ranging between 30 and 325 mg
daily, indicating that such lower doses of aspirin are considered to be
effective and worthy of study by these investigators. In addition, a
relatively small prospective study in patients undergoing carotid
endarterectomy is currently examining the
dose-related hypothesis generated by a subgroup analysis of
NASCET.24 Until such additional information is available,
good clinical practice should dictate the use of the lowest dose of
aspirin shown effective in the prevention of stroke and death in
patients with ischemic cerebrovascular disease, ie, 75 mg
daily. Of course, in a very high-risk setting the physician may
want to consider the possibility of increased efficacy related to more
elaborate and combined dosing regimens vis-à-vis the risk of
treatment-related side effects. At this stage, however, the burden
of proof should be on demonstrating that high-dose aspirin is more
effective than low-dose aspirin to justify the inherently increased
long-term toxicity.
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Although there might be "50 ways to leave your lover," as predicated by singer-composer Paul Simon in the 1970s, it is perhaps time for modern medicine to come to a more limited number of ways to use aspirin!
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The expert editorial assistance of Alessandra Migliavacca is gratefully acknowledged.
Received June 27, 1995; revision received October 9, 1995; accepted November 8, 1995.
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