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(Stroke. 1999;30:887-893.)
© 1999 American Heart Association, Inc.

Comments, Opinions, and Reviews

Antiplatelet Therapy in Acute Cerebral Ischemia

Martin M. Bednar, MD, PhD Cordell E. Gross, MD

From the Divisions of Neurosurgery and Surgical Research and the Department of Pharmacology, University of Vermont, Burlington, VT 05405.

Correspondence to Martin M. Bednar, MD, PhD, Associate Professor, Neurosurgery and Pharmacology, Director, Division of Surgical Research, Division of Neurological Surgery, Given D 319, University of Vermont, Burlington, VT 05405. E-mail mbednar{at}zoo.uvm.edu

	Abstract

Top Abstract Introduction Arachidonic Acid Cascade References

 
Background—Improved recognition of stroke signs and symptoms has paralleled the development of pharmacological strategies that may be examined to reduce stroke mortality and morbidity. Presently, tissue plasminogen activator is the only therapy that significantly improves outcome in acute stroke, with no agent demonstrating a significant reduction in mortality.

Summary of Review—Antiplatelet agents are a heterogenous class of drugs that have been successfully used for more than 2 decades in secondary stroke prevention. These agents include aspirin, with or without dipyridamole, and more recently, the adenosine antagonists ticlopidine and clopidogrel. However, studies of the use of antiplatelet agents within 48 hours of the ictus have examined only aspirin. Only 1 study, the Multicentre Acute Stroke Trial–Italy (MAST-I), entered patients within 6 hours of the ictus. These data suggest that an improvement in mortality may be related to the speed of administration. No significant adverse events were noted with early antiplatelet monotherapy. However, MAST-I did note a significant increase in early mortality in patients receiving aspirin plus streptokinase, a finding not adequately explained by an increase in the intracranial hemorrhage rate.

Conclusions—The use of antiplatelet therapy in acute stroke, clinical or experimental, has only recently received attention. It is likely that the use of antiplatelet agents for acute stroke therapy will be less restrictive than that currently seen for thrombolytics. Future studies should include an examination of those agents that have previously demonstrated efficacy in secondary stroke prevention, most notably, aspirin. The recognition that all platelet stimuli share a final common pathway that is dependent on the surface glycoprotein IIb/IIIa (fibrinogen) receptor has resulted in the development of various agents which block this receptor and are currently the focus for clinical trials. The role of nitric oxide in stroke therapy will depend on minimizing the hypotensive side effects of this agent. Stroke models are needed to provide preliminary data on the efficacy of antiplatelet therapy, especially as relates to the interaction of antiplatelet agents with thrombolytics.

Key Words: antiplatelet therapy • aspirin • cerebral infarction • stroke, acute

	Introduction

Top Abstract Introduction Arachidonic Acid Cascade References

 
Pharmacological strategies to reverse or minimize acute ischemic brain injury include "antiplatelet" agents, anticoagulants, and thrombolytics. Historically, antiplatelet therapy is the most recently utilized.^{1 2 3 4} Despite the overwhelming success of this therapy for the treatment of acute myocardial ischemia over the last decade,^{5 6} antiplatelet therapy for acute stroke has received little attention until very recently. The general reluctance to use any therapeutic strategy for the treatment of acute cerebral ischemia likely reflects the long-standing nihilism, which argued that the therapeutic window of time for stroke was too narrow to realistically expect that any intervention could improve the natural history of the disease. This philosophy surfaced in the early 1960s, when attempts to treat stroke with thrombolytics and anticoagulants resulted in an increased mortality rate.¹ At that time, there was both a very limited understanding of the pathophysiology of stroke and an absence of animal stroke models to study the effects of various therapies for the treatment of acute cerebral ischemia. Since these early stroke trials, 3 major advances have allowed the nihilism surrounding stroke therapy in the 1960s to be replaced by the cautious optimism of the 1990s.

The first of these advances was an improved understanding of the pathophysiology of stroke. In the early 1980s, the window of time for neuronal salvage following the initiation of acute cerebral ischemia was established for a nonhuman primate model.⁷ In this study, the concept of intensity-duration of cerebral ischemia was established. That is, the greater the intensity of the ischemic event, the less time is necessary to demonstrate the same degree of permanent injury. In retrospect, the previous clinical treatment of stroke had used time frames as late as 24 to 48 hours, whereas these more current concepts suggested a maximal time frame for treatment in the range of 6 hours. The second advance was the successful use of antiplatelet agents and thrombolytics in acute myocardial infarction (MI).^{5 6} Despite the early failures of thrombolytics in the treatment of acute stroke, the mortality in acute MI was significantly reduced through the use of acute thrombolytic therapy as well as by aspirin monotherapy. Moreover, the combination of the 2 therapies was additively beneficial. Finally, the third major advance was the development of animal stroke models,^{8 9 10 11 12} which greatly assisted in defining acute stroke mechanisms and therapeutic strategies. These animal models also proved useful in refining the therapeutic window of time as well as the overall duration of treatment.

The importance of antiplatelet agents for both the prevention and treatment of ischemic disease was a concept that developed as the consequence of a triad of research breakthroughs in the 1960s: (1) recognition of the contribution of platelets to both cardiac^{13 14} and carotid disease,¹⁵ (2) development of reproducible assays to quantify platelet activation,¹⁶ and (3) demonstration that "anti-inflammatory" agents inhibit platelet aggregation.¹⁷ The mechanism by which aspirin inhibited platelet aggregation awaited further clarification in the mid 1970s with the dual discoveries that (1) platelets, thrombocytes, produce a very potent lipid, an arachidonic acid (AA) metabolite possessing an oxane ring, that results in aggregation and vasoconstriction: thromboxane (TX)¹⁸ and (2) aspirin irreversibly acetylates the cyclooxygenase enzyme responsible for the metabolism of AA to TX and other prostaglandins.¹⁹

It has been nearly 25 years since aspirin therapy was first demonstrated to be clinically efficacious for secondary stroke prevention.²⁰ Although it is now well established that antiplatelet monotherapy using either aspirin^{20 21} or adenosine receptor antagonists such as ticlopidine²¹ is clearly efficacious in reducing neurological sequelae/recurrent events following a TIA or stroke, the examination of antiplatelet agents as monotherapy for the treatment of acute cerebral ischemia has received little attention either clinically⁴ or experimentally.^{22 23 24 25 26} In contrast to the clinical treatment of strokes (acute and subacute), which has focused primarily on aspirin therapy, antiplatelet therapies for animal models of acute cerebral ischemia have generally focused on either (1) very specific alterations of the AA cascade, attempting to either increase levels of the vasodilator/platelet inhibitor prostacyclin (PGI₂)²² or reducing the level/activity of the vasoconstrictor/platelet proaggregant thromboxane A₂ (TXA₂)^{23 24} or (2) serotonin (5-HT₂) receptor antagonism.^{25 26} These therapies have produced variable results. It is also of interest that several studies employing the prophylactic use of aspirin for stroke prevention in "low-risk" patients have reported either no benefit or an increase in stroke incidence.^{27 28} These studies correlate well with earlier clinical observations that aspirin possesses antifibrinolytic²⁹ and/or thrombogenic³⁰ effect(s).

Antiplatelet therapy has also been recently combined with thrombolytics for the treatment of acute cerebral ischemia.⁴ These studies are a logical extension of the therapeutic strategies first examined for the treatment of acute MI nearly a decade earlier.⁶ The use of an adjuvant therapy to thrombolytics appeared to be both necessary (optimal reperfusion with thrombolytic agents occurs in <50%³¹ of treated patients, and the urgency associated with the brief 3-hour window of time for the clinical treatment of acute stroke)³² and, based on the additive benefit seen with these 2 agents in acute MI, very promising, even though the efficacy of aspirin in acute MI may actually relate to the prevention of vessel reocclusion rather than an improvement in the coronary artery patency rate.³³

Experimental studies combining thrombolytic therapy with antiplatelet agents are extremely limited^{34 35 36 37 38 39} and have not demonstrated a consistent effect on brain injury (infarct size or hemorrhage), although 1 study noted an increased rate of intracranial hemorrhage with high-dose (20 mg/kg) aspirin therapy in rabbits.³⁹ Mechanisms to explain the findings in this latter study were not examined, although the dose of tPA used (10 mg/kg) may have been supramaximal.⁴⁰ Specific examination of the effect of antiplatelet therapy on the rate of reperfusion with thrombolytics has been examined by the coadministration of a TX receptor antagonist and a tPA congener in a middle cerebral artery model of photodynamic (nonembolic) injury.³⁸ Dual therapy improved both the patency rate and reduced infarct size when compared with thrombolytic therapy alone; however, the anatomic and pathologic findings following photo-illumination injury are difficult to relate to the clinical state of thromboembolic stroke. Conversely, recent studies in our laboratory have demonstrated that aspirin,^{34 35 36} but not ticlopidine,³⁷ antagonizes tPA-mediated clot lysis in a dose-related manner in a rabbit model of thromboembolic stroke, a finding which was reversed by nitric oxide (NO) donors,³⁶ the prostacyclin mimetic iloprost,³⁵ and both the ß-1 antagonist atenolol and hydralazine (authors' unpublished data, 1998). The specific mechanism by which aspirin may antagonize clot lysis is unclear. However, the common denominator in these studies is the ability of each of these agents to improve regional cerebral blood flow (rCBF) by approximately 20%, whereas the administration of aspirin (20 mg/kg) resulted in an acute reduction in rCBF of approximately 20%. Of great interest, the Multicentre Acute Stroke Trial-Italy (MAST-I),⁴ a clinical trial of streptokinase with or without concomitant aspirin therapy, concluded that the group receiving streptokinase plus aspirin had a marked increase in the 10 day fatality rate that could not be adequately explained by an increase in intracranial hemorrhages.

Thus, the benefit, if any, of antiplatelet therapy for the treatment of acute cerebral ischemia, either clinically or experimentally remains unclear, although it does appear that aspirin monotherapy may result in a modest clinical improvement. Overall, this limited data suggests both (1) an incomplete understanding of and (2) diverse and/or multiple mechanisms of action for "antiplatelet" agents. For example, the 5-HT₂ receptor subtype is found not only on platelets where it is responsible for aggregation, but also in vascular smooth muscle and in cerebral cortex where its actions include vasoconstriction and neuronal excitation, respectively. Thus, any examination of antiplatelet drugs in acute stroke must recognize the heterogeneity of this class of agents. The corollary to the recognition of antiplatelet therapies as a heterogenous class of agents is that outcome variables such as mortality/neurological deficit or the rate/degree of thrombolysis may not be similar, as has been recently noted for experimental cardiac thrombosis.^{41 42 43} Indeed, the term "antiplatelet" as it refers to this class of drugs may not be appropriate, given their broad array of activities both on platelet function and in a variety of other biological systems. A brief summary of the various classes on antiplatelet drugs and their mechanism of antiplatelet action is briefly described.

	Arachidonic Acid Cascade

Top Abstract Introduction Arachidonic Acid Cascade References

 
Although aspirin is thought to have multiple mechanisms of action,^{44 45 46 47} it has been generally accepted that its effectiveness in ischemic states relates to a directed imbalance of the AA cascade.¹⁹ That is, at low doses (1 mg/kg), aspirin may differentially inhibit the production of the potent vasoconstrictor and platelet activator TXA₂ relative to prostacyclin, a vasodilator and platelet inhibitor.⁴⁸ However, it is of interest that clinical trials examining prostacyclin infusions within 24 hours of the ictus did not improve neurological outcome versus placebo.⁴⁹ The MAST-I study is the only randomized clinical study to date that administered an antiplatelet agent (aspirin) within 6 hours of the ictus. At both 10 days and at 6 months, a trend toward a reduction in mortality was seen with aspirin therapy. Two large-scale, randomized, prospective clinical trials, the International Stroke Trial (IST)² and the Chinese Acute Stroke Trial (CAST),³ have recently been completed in which aspirin (300 and 160 mg daily, respectively) was administered within 48 hours of the ischemic event. These 2 studies reported slight reductions in either recurrent ischemic events or in mortality. Although the benefit seen with aspirin was very modest, its ease of administration, wide availability, and low cost argue for its use in the setting of patients who are not candidates for thrombolytic therapy or of clinical trials examining other antiplatelet agents.

Although aspirin therapy has been conclusively shown to reduce both the incidence of and mortality from MI irrespective of the dose administered,⁵⁰ there is considerable controversy surrounding the optimal dose of aspirin for stroke prevention following TIA.^{51 52 53 54} Indeed, it has been suggested in some, but not all, clinical studies that high-dose (15 to 20 mg/kg) aspirin therapy may be more effective than low-dose aspirin in preventing stroke after TIA, although this finding is counterintuitive to the known effects of aspirin on the AA cascade, since the production of both TXA₂ and prostacyclin is completely inhibited at these higher doses.

Adenosine Receptor Antagonists
The P2 purinoceptor is activated physiologically by adenosine diphosphate, which may be released from red blood cells and the endothelium as well as from the platelet-dense granules (the latter important for amplification of the platelet aggregation process). The development of adenosine receptor antagonists such as ticlopidine and clopidogrel has allowed for a new mechanistic strategy for ischemic disease states.

Ticlopidine and, more recently, clopidogrel have received considerable attention for secondary stroke prevention, demonstrating a trend toward greater efficacy for stroke prophylaxis than aspirin,^{21 54} although the differences in outcome for aspirin therapy versus ticlopidine or clopidogrel are slight. This may also relate to the effects of ticlopidine on the AA cascade, as it may reduce levels of TXA₂ while actually increasing those of prostacyclin.⁵⁵ To date, neither ticlopidine nor clopidogrel has been examined in an acute time frame (<6 hours) in acute ischemic stroke.

Serotonin (5-HT₂) Receptor Antagonists
Serotonin activates platelets via the 5-HT₂ receptor located on the cell surface, contributing to the genesis of arterial thrombi.⁵⁶ Although serotonin is suggested to be a weak agonist in isolation, an amplification process in concert with other agonists has been described, such that inhibition of both the 5-HT₂ and TXA₂ receptors results in an additive benefit in models of coronary thrombolysis. In experimental models of acute cerebral ischemia, 5-HT₂ receptor antagonists have produced variable results.^{25 26} Although not yet examined acutely in clinical stroke, the delayed clinical use of 5-HT₂ receptor antagonists after stroke has resulted in improved functional status.⁵⁷ Despite the success of combined thrombolytic therapy with 5-HT₂ receptor antagonists in both coronary⁴³ and peripheral thrombosis,⁵⁸ this strategy has not yet been examined after stroke.

Phosphodiesterase Inhibition
Adenosine 3',5'-cyclic monophosphate (cAMP) is an important modulator of platelet function. A reduction in cAMP may result in platelet aggregation. A variety of mediators, including prostacyclin and phosphodiesterase inhibitors such as dipyridamole, may function to inhibit platelet aggregation by increasing cAMP. A number of clinical trials have examined dipyridamole in secondary stroke prevention,^{59 60} with the recent European Stroke Prevention Study 2 (ESPS-2) demonstrating improved outcome/event reduction with dipyridamole (400 mg daily) or aspirin (50 mg daily) monotherapy, with the combination of aspirin plus dipyridamole affording additive benefit.

GP IIb/IIIa Receptor Antagonists
Platelet activation and aggregation can occur by pathways independent of the AA cascade, as demonstrated with low-dose thrombin and with platelet activating factor.⁶¹ All of these mechanisms share a final common pathway dependent on the surface glycoprotein IIb/IIIa complex (GP IIb/IIIa). Fibrinogen is the ligand for the GP IIb/IIIa receptor and is responsible for amplification of the aggregation response.⁶² The GP IIb/IIIa receptor may be blocked by either peptides exhibiting the amino acid binding sequence RGDF (arginine-glycine-aspartic acid-phenylalanine⁶³ ; eg, integrelin, tirofiban, lamifiban) or monoclonal antibodies (eg, ReoPro [abciximab]). GP IIb/IIIa receptor interference has demonstrated greater potency than aspirin in preventing thrombosis and rethrombosis in animal models of coronary^{64 65} and carotid⁶⁶ artery stenosis. Recent clinical studies examining integrelin in acute MI have also demonstrated improved reperfusion.⁶⁷ Using the middle cerebral artery model of photodynamic (nonembolic) injury³⁸ described above, antagonism of the GP IIb/IIIa receptor reduced thrombosis and ischemic brain injury.⁶⁸

Nitric Oxide
NO, a short-lived and reactive chemical intermediate, is receiving considerable attention for its contribution to the cerebrovascular circulation during both physiological and pathological states.⁶⁹ Although NO is not specifically an antiplatelet agent, it does possess antiplatelet and vasodilator properties similar to those of prostacyclin.⁷⁰ Both the substrate for NO (L-arginine) and NO donors (3-morpholino-sydnonimine [SIN-1], sodium nitroprusside, nitroglycerine) have reduced ischemic and ischemia-reperfusion injury in a variety of organ systems.^{71 72 73 74 75} Moreover, NO inhibits thrombotic events⁷⁶ and interacts synergistically with thrombolytics to improve outcome during experimental cardiac and peripheral thrombosis.^{76 77} Indeed, the discovery of NO has begun to provide a more mechanistic explanation for the benefit of nitrates and possibly other agents in acute myocardial ischemia, as NO exerts negative inotropic/chronotropic actions and reduces blood pressure.^{69 78} Beta-receptor antagonists^{79 80} have been demonstrated to facilitate NO release, possibly contributing to their benefit in acute MI. Although the efficacy of beta-receptor blockade in acute MI is thought to be afforded through a reduction in the cardiac workload, beta-blockade has been demonstrated to synergize with the thrombolytics, presumably through their ability to improve collateral flow.^{80 81 82 83}

The role of NO in acute stroke has relied almost exclusively on rat models of permanent focal ischemia.^{72 84 85} For acute cerebral ischemia there is a general consensus that endothelial NO is beneficial. Early administration of a NO source within the vascular compartment reduces brain injury, while nonspecific NO synthase (NOS) inhibitors in acute ischemia exacerbate brain injury, perhaps by reducing rCBF. Conversely, the delayed administration of NO has generally resulted in an increase in ischemic brain injury.

Neuronal NO may be deleterious in models of cerebral ischemia, possibly by participating in glutamate-mediated neurotoxicity.⁸⁶ Of interest, NO sensors have demonstrated increased levels of intracerebral NO in acute stroke, particularly during the ischemic episode, with smaller elevations noted during reperfusion.⁸⁷ Moreover, inhibitors directed at either neuronal NOS (7-nitroindazole)⁸⁸ or inducible NOS (iNOS; aminoguanidine)⁸⁹ reduce brain injury in models of permanent focal cerebral ischemia. Supporting the concept that eNOS and nNOS may serve as a contrast for reducing and exacerbating ischemic tissue injury, respectively, is the recent development of "knock-out" mice. In each circumstance, the deletion of the enzyme results in the predicted outcome: greater ischemic injury in mice devoid of eNOS and less-than-anticipated injury in mice without nNOS.⁹⁰

The production of NO and the cyclooxygenase products of the AA cascade, prostaglandins (particularly prostacyclin), appear to be closely linked in many biological systems.^{91 92} That is, in many^{91 92} but not all⁹³ experimental models, the upregulation/stimulation of NO will result in an increase in eicosanoid production, such as prostacyclin. Conversely, changes in prostacyclin levels result in similar effects on NO production or activity. Of great interest, aspirin and, to some extent, other cyclooxygenase inhibitors, have demonstrated inhibition of inducible NOS activity.⁴⁴ Thus, previous studies focusing on either NO or the AA cascade in isolation may need to reexamine these findings in order to gain a more comprehensive understanding of the mechanism of action. Specifically, aspirin inhibition of both NO and prostacyclin could result in adverse effects on thrombolysis, such as the antagonism of clot lysis recently demonstrated in a rabbit model of thromboembolic stroke.^{34 35 36} It was hypothesized that the antagonism of clot lysis seen in this model may be abrogated by the concomitant administration of agents that either stimulate or provide a source of NO.³⁶ These studies demonstrated that addition of NO donors to aspirin therapy reversed the antagonism of tPA-mediated clot lysis seen with aspirin administration. This finding may help to explain the disparate results obtained among the various ischemic models and clinical scenarios that have included aspirin, particularly cardiac versus cerebral ischemia.

Future Directions
Recognizing that the timing of therapy will impact efficacy, future studies should emphasize treatment initiated within 6 hours of the ictus. To date, MAST-I is the only prospective, randomized clinical study to examine an antiplatelet agent, aspirin, within this time frame. Although the results demonstrate a promising and persistent trend in reducing mortality, larger studies are needed to confirm these findings. Based on the success of ESPS-2 in secondary stroke prevention, a logical extension of these studies includes the combination of aspirin plus dipyridamole. Alternatively, MAST-I emphasizes that combining therapeutic strategies such as aspirin and streptokinase may adversely affect outcome and should first be carefully studied in appropriate animal models.

The development of GP IIb/IIIa antagonists and inhibitors has demonstrated efficacy in myocardial ischemia without the side effect of significant bleeding. Future directions in acute stroke management should include an examination of this promising antiplatelet therapy. There is also much interest in understanding the role of NO in acute stroke therapy. Similar to prostacyclin, NO may reduce ischemic injury through suppression of platelet and/or neutrophil activation. The vasodilator and hypotensive effects of prostacyclin likely contributed to its lack of efficacy in earlier stroke trials and raise appropriate concerns about the role of NO in this setting. However, the ability to deliver NO by inhalation may abrogate its hemodynamic side effects and allow further examination of this novel therapy in acute stroke.⁹⁴

In summary, antiplatelet drugs represent a diverse group of agents that share the ability to reduce platelet activity through a variety of mechanisms. Their biological activities go well beyond the platelet and include effects both locally on other blood elements and within the vessel wall as well as more remote effects on other cell types throughout the body. It is recognized that the intact endothelium produces a variety of substances, including NO, tPA and prostacyclin, that are physiologically important to the local blood flow, as well as ensuring both the maintenance of a nonthrombogenic surface and facilitating local clot lysis.^{92 95 96} As noted, "antiplatelet" agents such as aspirin may affect both NO and prostacyclin levels, with resultant adverse effects on exogenous tPA therapy. It is also recognized that the clinical use of tPA as a monotherapy for acute stroke will remain limited. However, it is also clear from the cardiac literature that adjuvant therapy, particularly antiplatelet agents, can enhance the efficacy of thrombolysis and improve outcome. The future use of antiplatelet therapy for the treatment of acute cerebral ischemia is dependent on a greater understanding of the activity of these agents not only on platelet function but also on the cerebrovasculature and within the brain parenchyma, especially as they relate to cerebral blood flow, the blood-brain barrier, and neuronal function. These examinations will assist in determining the most beneficial pharmacological regimen that will minimize brain injury in acute stroke.

Received September 18, 1998; revision received January 4, 1999; accepted January 4, 1999.

	References

Top Abstract Introduction Arachidonic Acid Cascade References

 
1. Meyer JS, Gilroy J, Barnhart MI, Johnson JF. Anticoagulants plus streptokinase therapy in progressive stroke. JAMA. 1963;189:373.

2. International Stroke Trial Collaborative Group (IST). A randomized trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet. 1997;349:1569–1581.[Medline] [Order article via Infotrieve]

3. Chinese Acute Stroke Trial Collaborative Group (CAST). Randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke. Lancet. 1997;349:1641–1649.[Medline] [Order article via Infotrieve]

4. Multicentre Acute Stroke Trial–Italy Group (MAST-I). Randomized controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke [see comment]. Lancet. 1995;346:1509–1514.[Medline] [Order article via Infotrieve]

5. Verstraete M. Risk factors, interventions and therapeutic agents in the prevention of atherosclerosis-related ischaemic diseases. Drugs. 1991;42(suppl 5):22–38.

6. Second International Study of Infarct Survival Collaborative Group (ISIS-2). Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet. 1988;2:349–360.[Medline] [Order article via Infotrieve]

7. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg. 1981;54:773–782.[Medline] [Order article via Infotrieve]

8. Bednar MM, McAuliffe T, Raymond S, Gross CE. Tissue plasminogen activator reduces brain injury in a rabbit model of thromboembolic stroke. Stroke. 1990;21:1705–1709.[Abstract/Free Full Text]

9. Gross CE, Raymond SJ, Howard DB, Bednar MM. Delayed tissue-plasminogen activator therapy in a rabbit model of thromboembolic stroke. Neurosurgery. 1995;36:1172–1177.[Medline] [Order article via Infotrieve]

10. Overgaard K, Sereghy T, Pedersen H, Boysen G. Effect of delayed thrombolysis with rt-PA in a rat embolic stroke model. J Cereb Blood Flow Metab. 1994;14:472–477.[Medline] [Order article via Infotrieve]

11. Morawetz RB, DeGirolami U, Ojemann RG, Marcoux FW, Crowell RM. Cerebral blood flow determined by hydrogen clearance during middle cerebral artery occlusion in unanesthetized monkeys. Stroke. 1978;9:143–149.[Free Full Text]

12. Zivin JA, Fisher M, DeGirolami U, Hemenway CC, Stashak JA. Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science. 1985;230:1289–1292.[Abstract/Free Full Text]

13. Mustard JF, Rowsell HC, Murphy EA. Reversible platelet aggregation and myocardial ischemia. Circulation. 1964;30(suppl III):III-23. Abstract.

14. Badimon L, Badimon JJ. Mechanism of arterial thrombosis in non-parallel streamlines: platelet growth at the apex of stenotic severely injured vessel wall: experimental study in the pig model. J Clin Invest. 1989;84:1134–1144.

15. Fisher CM. Concerning recurrent transient cerebral ischemic attacks. Can Med Assoc. 1962;86:1091–1099.

16. Born GVR, Cross MJ. The aggregation of blood platelets. J Physiol. 1963;168:178–195.

17. Weiss HJ, Aledort LM. Impaired platelet/connective-tissue reaction in man after aspirin ingestion. Lancet. 1967;2:495–497.[Medline] [Order article via Infotrieve]

18. Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci U S A. 1975;2:2994–2998.

19. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232–235.[Medline] [Order article via Infotrieve]

20. Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia. Stroke. 1977;8:301–314.[Abstract/Free Full Text]

21. Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, Kamm B. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients [see comments]. N Engl J Med. 1989;321:501–507.[Abstract]

22. Dogan A, Temiz C, Turker RK, Egemen N, Baskaya MK. Effect of the prostacyclin analogue, iloprost, on infarct size after permanent focal cerebral ischemia. Genl Pharmacol. 1996;27:1163–1166.[Medline] [Order article via Infotrieve]

23. Moufarrij NA, Little JR, Skrinska V. Thromboxane synthetase inhibition in acute focal cerebral ischemia in cats. J Neurosurg. 1984;61:1107–1112.[Medline] [Order article via Infotrieve]

24. Imura Y, Kiyota Y, Nagai Y, Nishikawa K, Terashita Z. Beneficial effect of CV-4151 (Isbogrel), a thromboxane A2 synthase inhibitor, in a rat middle cerebral artery thrombosis model [published errata appear in Thromb Res.. 1996;83:111–112 and 1996;84:143]. Thromb Res. 1995;79:95–107.

25. Szabo L, Hofmann HP. (S)-Emopamil, a novel calcium and serotonin antagonist for the treatment of cerebrovascular disorders, 3rd communication: effect on postischemic cerebral blood flow and metabolism, and ischemic neuronal cell death. Arzneimittelforschung. 1989;39:314–319.[Medline] [Order article via Infotrieve]

26. Takagi K, Ginsberg MD, Globus MY, Busto R, Dietrich WD. The effect of ritanserin, a 5-HT2 receptor antagonist, on ischemic cerebral blood flow and infarct volume in rat middle cerebral artery occlusion. Stroke. 1994;25:481–485.[Abstract]

27. Kronmal RA, Hart RG, Manolio TA, Talbert RL, Beauchamp NJ, Newman A. Aspirin use and incident stroke in the Cardiovascular Health Study. Stroke. 1988;29:887–894.[Abstract/Free Full Text]

28. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321:129–135.[Abstract]

29. Levin RI, Harpel PC, Weil D, Chang TS, Rifkin DB. Aspirin inhibits vascular plasminogen activator activity in vivo: studies utilizing a new assay to quantify plasminogen activator activity. J Clin Invest. 1984;74:571–580.

30. Kelton JG, Hirsh J, Carter CJ, Buchanan MR. Thrombogenic effect of high-dose aspirin in rabbits: relationship to inhibition of vessel wall synthesis of prostaglandin I2-like activity. J Clin Invest. 1978;62:892–895.

31. Sasaki O, Shigekazu T, Koike T, Koizumi T, Tanaka R. Fibrinolytic therapy for acute embolic stroke: intravenous, intracarotid, and intra-arterial local approaches. Neurosurgery. 1995;36:246–253.[Medline] [Order article via Infotrieve]

32. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke [see comment]. N Engl J Med. 1995;333:1581–1587.[Abstract/Free Full Text]

33. Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction: Heparin-Aspirin Reperfusion Trial (HART) Investigators [see comments]. N Engl J Med. 1990;323:1433–1437.[Abstract]

34. Bednar MM, Quilley J, Thomas GR, Raymond-Russell SJ, Fuller SP, Booth C, Howard D, Gross CE. The effect of oral antiplatelet agents on t-PA-mediated thrombolysis in a rabbit model of thromboembolic stroke. Neurosurgery. 1996;39:352–359.[Medline] [Order article via Infotrieve]

35. Thomas GR, Thibodeaux H, Errett CJ, Bednar MM, Gross CE, Bennett WF. Intravenous aspirin causes a paradoxical attenuation of cerebrovascular thrombolysis. Stroke. 1995;26:1039–1046.[Abstract/Free Full Text]

36. Bednar MM, Gross CE, Howard DB, Russell SR, Thomas GR. Nitric oxide reverses aspirin antagonism of t-PA thrombolysis in a rabbit model of thromboembolic stroke. Exp Neurol. 1997;146:513–517.[Medline] [Order article via Infotrieve]

37. Bednar MM, Raymond-Russell SJ, Booth CL, Gross CE. Combination tissue plasminogen activator and ticlopidine therapy in a rabbit model of acute thromboembolic stroke. Neurol Res. 1996;18:45–48.[Medline] [Order article via Infotrieve]

38. Umemura K, Wada K, Uematsu T, Nakashima M. Evaluation of the combination of a tissue-type plasminogen activator, SUN9216, and a thromboxane A2 receptor antagonist, vapiprost, in a rat middle cerebral artery thrombosis model. Stroke.. 1993;24:1077–1081; discussion, 1081–1082.[Abstract/Free Full Text]

39. Clark WM, Madden KP, Lyden PD, Zivin JA. Cerebral hemorrhagic risk of aspirin or heparin therapy with thrombolytic treatment in rabbits. Stroke. 1991;22:872–876.[Abstract/Free Full Text]

40. Thomas GR, Thibodeaux H, Bennett WF, Refino CJ, Badillo JM, Errett CJ, Zivin JA. Optimized thrombolysis of cerebral clots with tissue-type plasminogen activator in a rabbit model of embolic stroke. J Pharmacol Exp Ther. 1993;264:67–73.[Abstract/Free Full Text]

41. Haskel EJ, Prager NA, Sobel BE, Abendschein DR. Relative efficacy of antithrombin compared with antiplatelet agents in accelerating coronary thrombolysis and preventing early reocclusion. Circulation. 1991;83:1048–1056.[Abstract/Free Full Text]

42. Yasuda T, Gold HK, Yaoita H, Leinbach RC, Guerrero JL, Jang IK, Holt R, Fallon JT, Collen D. Comparative effects of aspirin, a synthetic thrombin inhibitor and a monoclonal antiplatelet glycoprotein IIb/IIIa antibody on coronary artery reperfusion, reocclusion and bleeding with recombinant tissue-type plasminogen activator in a canine preparation [see comments]. J Am Coll Cardiol. 1990;16:714–722.[Abstract]

43. McAuliffe SJ, Moors JA, Jones HB. Comparative effects of anti-platelet agents as adjuncts to tissue plasminogen activator in a dog model of occlusive coronary thrombosis. Br J Pharmacol. 1994;112:272–276.[Medline] [Order article via Infotrieve]

44. Aeberhard EE, Henderson SA, Arabolos NS, Griscavage JM, Castro FE, Barrett CT, Ignarro LJ. Nonsteroidal anti-inflammatory drugs inhibit expression of the inducible nitric oxide synthase gene. Biochem Biophys Res Commun. 1995;208:1053–1059.[Medline] [Order article via Infotrieve]

45. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994;265:956–59.[Abstract/Free Full Text]

46. Ratnatunga CP, Edmondson SF, Rees GM, Kovacs IB. High-dose aspirin inhibits shear-induced platelet reaction involving thrombin generation. Circulation. 1992;85:1077–1082.[Abstract/Free Full Text]

47. Riepe MW, Kasischke K, Raupach A. Acetylsalicylic acid increases tolerance against hypoxic and chemical hypoxia. Stroke. 1997;28:2006–2011.[Abstract/Free Full Text]

48. FitzGerald GA, Oates JA, Hawiger J, Maas RL, Roberts LJD, Lawson JA, Brash AR. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983;71:676–688.

49. Hsu CY, Faught RE Jr, Furlan AJ, Coull BM, Huang DC, Hogan EL, Linet OI, Yatsu FM. Intravenous prostacyclin in acute nonhemorrhagic stroke: a placebo-controlled double-blind trial. Stroke. 1987;18:352–358.[Abstract/Free Full Text]

50. Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. BMJ. 1988;296:320–331.

51. Barnett HJ, Kaste M, Meldrum H, Eliasziw M. Aspirin dose in stroke prevention: beautiful hypotheses slain by ugly facts. Stroke. 1996;27:588–592.[Free Full Text]

52. Hart RG, Harrison MJ. Aspirin wars: the optimal dose of aspirin to prevent stroke. Stroke. 1996;27:585–587.[Free Full Text]

53. Dyken ML, Barnett HJ, Easton JD, Fields WS, Fuster V, Hachinski V, Norris JW, Sherman DG. Low-dose aspirin and stroke. "It ain't necessarily so" [editorial] [see comments]. Stroke. 1992;23:1395–1399.[Free Full Text]

54. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events [see comments]. Lancet. 1996;348:1329–1339.[Medline] [Order article via Infotrieve]

55. Lagarde M, Ghazi I, Dechavanne M. Effects of ticlopidine on platelet prostaglandin metabolism: possible consequences for prostacyclin production. Prostaglandins Med. 1979;2:433–439.[Medline] [Order article via Infotrieve]

56. De Clerck F, Janssen PAJ. 5-Hydroxytryptamine and thromboxane A₂ in ischemic heart disease. Blood Coagul Fibrinolysis. 1990;1:201–210.[Medline] [Order article via Infotrieve]

57. Dam M, Tonin P, DeBoni A, Pizzolato G, Casson S, Ermani M, Freo U, Piron L, Battistin L. Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke. 1996;27:1211–1214.[Abstract/Free Full Text]

58. Herbert JM, Bernat A, Sainte-Marie M, Dol F, Rinaldi M. Potentiating effect of clopidogrel and SR 46349, a novel 5-HT2 antagonist, on streptokinase-induced thrombolysis in the rabbit. Thromb Haemost. 1993;69:268–271.[Medline] [Order article via Infotrieve]

59. Easton JD. Antiplatelet therapy in the prevention of stroke. Drugs. 1991;42(suppl 5):39–50.

60. ESPS-2. Primary endpoints. J Neurol Sci. 1997;151:S13–S26.

61. Yardumian DA, Mackie IJ, Machin SJ. Laboratory investigation of platelet function: a review of methodology. J Clin Pathol. 1986;39:701–712.[Abstract/Free Full Text]

62. Gartner TK, Bennett JS. The tetrapeptide analogue of the cell attachment site of fibronectin inhibits platelet aggregation and fibrinogen binding to activated platelets. J Biol Chem. 1985;160:11891–11894.

63. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med. 1995;332:1553–1559.[Free Full Text]

64. Yasuda T, Gold HK, Fallon JT, Leinbach RC, Guerrero JL, Scudder LE, Kanke M, Shealy D, Ross MJ, Collen D, Coller BS. Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. J Clin Invest. 1988;81:1284–1291.

65. Schror K. Antiplatelet drugs: a comparative review. Drugs. 1995;50:7–28.[Medline] [Order article via Infotrieve]

66. Rote WE, Werns SW, Davis JH, Feigen LP, Kilgore KS, Lucchesi BR. Platelet GPIIb/IIIa receptor inhibition by SC-49992 prevents thrombosis and rethrombosis in the canine carotid artery. Cardiovasc Res. 1993;27:500–507.[Abstract/Free Full Text]

67. Ohman EM, Kleiman NS, Gacioch G, Worley SJ, Navetta FI, Talley JD, Anderson HV, Ellis SG, Cohen MD, Spriggs D, Miller M, Kereiakes D, Yakubov S, Kitt MM, Sigmon KN, Califf RM, Krucoff MW, Topol EJ. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIB/IIIa integrin receptor blockade with integrilin in acute myocardial infarction: Results of a randomized, placebo-controlled, dose-ranging trial: IMPACT-AMI Investigators. Circulation. 1997;95:846–854.[Abstract/Free Full Text]

68. Kaku S, Umemura K, Mizuno A, Kawasaki T, Nakashima M. Evaluation of the disintegrin, triflavin, in a rat middle cerebral artery thrombosis model. Eur J Pharmacol. 1997;321:301–305.[Medline] [Order article via Infotrieve]

69. Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease [review]. Annu Rev Med. 1997;48:489–509.[Medline] [Order article via Infotrieve]

70. Radomski MW, Palmer RM, Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol. 1987;92:181–187.[Medline] [Order article via Infotrieve]

71. Zhang F, White JG, Iadecola C. Nitric oxide donors increase blood flow and reduce brain damage in focal ischemia: evidence that nitric oxide is beneficial in the early stages of cerebral ischemia. J Cereb Blood Flow Metab. 1994;14:217–226.[Medline] [Order article via Infotrieve]

72. Morikawa E, Moskowitz MA, Huang Z, Yoshida T, Irikura K, Dalkara T. L-arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat. Stroke. 1994;25:429–435.[Abstract]

73. Nagafuji T, Sugiyama M, Matsui T, Koide T. A narrow therapeutical window of a nitric oxide synthase inhibitor against transient ischemic brain injury. Eur J Pharmacol. 1993;248:325–328.[Medline] [Order article via Infotrieve]

74. Lefer AM, Lefer DJ. Pharmacology of the endothelium in ischemia-reperfusion and circulatory shock. Annu Rev Pharmacol Toxicol. 1993;33:71–90.[Medline] [Order article via Infotrieve]

75. Johnson GD, Tsao PS, Lefer AM. Cardioprotective effects of authentic nitric oxide in myocardial ischemia with reperfusion. Crit Care Med. 1991;19:244–252.[Medline] [Order article via Infotrieve]

76. Yao SK, Akhtar S, Scott-Burden T, Ober JC, Golino P, Buja LM, Casscells W, Willerson JT. Endogenous and exogenous nitric oxide protect against intracoronary thrombosis and reocclusion after thrombolysis. Circulation. 1995;92:1005–1010.[Abstract/Free Full Text]

77. Kornowski R, Chernine A, Hasdai D, Ovadia Z, Battler A. Beneficial effect of nitroglycerin on arterial rethrombosis after thrombolysis: results from a rabbit thrombosis model. Eur Heart J. 1995;16:177–183.[Abstract/Free Full Text]

78. Hare JM, Colucci WS. Role of nitric oxide in the regulation of myocardial function. Prog Cardiovasc Dis. 1995;38:155–166.[Medline] [Order article via Infotrieve]

79. Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CP, Dupont AG, Van Nueten L, Wooding SJ, Ritter JM. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995;274:1067–1071.[Abstract/Free Full Text]

80. Mehta JL, Lopez LM, Chen L, Cox OE. Alterations in nitric oxide synthase activity, superoxide anion generation, and platelet aggregation in systemic hypertension, and effects of celiprolol. Am J Cardiol. 1994;74:901–905.[Medline] [Order article via Infotrieve]

81. Becker RC. Beta-adrenergic blockade following thrombolytic therapy: is it helpful or harmful? Clin Cardiol. 1994;17:171–174.[Medline] [Order article via Infotrieve]

82. Roberts R, Rogers WJ, Hiltrud S, Mueller HS, Lambrew CT, Diver DJ, Smith HC, Willerson JT, Zaret BL, Wackers F, Braunwald E. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) II-B study [see comments]. Circulation. 1991;83:422–437.[Abstract/Free Full Text]

83. Zmudka K, Aubert A, Dubiel J, Vanhaecke J, Flameng W, Kaczmarek J, De Geest H. Early intravenous administration of metoprolol enhances myocardial salvage by thrombolysis with recombinant tissue-type plasminogen activator after thrombotic coronary artery occlusion in the dog by improvement of the collateral blood flow to the area at risk. J Am Coll Cardiol. 1994;23:1499–1504.[Abstract]

84. Iadecola C. Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci. 1997;20:132–139.[Medline] [Order article via Infotrieve]

85. Samdani AF, Dawson TM, Dawson VL. Nitric oxide synthase in models of focal ischemia. Stroke. 1997;28:1283–1288.[Abstract/Free Full Text]

86. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A. 1991;88:6368–6371.[Abstract/Free Full Text]

87. Sato S, Tominaga T, Ohnishi T, Ohnishi ST. Role of nitric oxide in brain ischemia. Ann N Y Acad Sci. 1994;38:369–373.

88. Dalkara T, Yoshida T, Irikura K, Moskowitz MA. Dual role of nitric oxide in focal cerebral ischemia. Neuropharmacology. 1994;33:1447–1452.[Medline] [Order article via Infotrieve]

89. Iadecola C, Zhang F, Xu X. Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am J Physiol. 1995;268:R286–R292.[Abstract/Free Full Text]

90. Huang Z, Huang PL, Fishman MC, Moskowitz MA. Focal cerebral ischemia in mice deficient in either endothelial (eNOS) or neuronal nitric oxide (nNOS) synthase. Stroke. 1996;27:173. Abstract.

91. Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A. 1993;90:7240–7244.[Abstract/Free Full Text]

92. Gryglewski RJ. Interactions between endothelial secretogogues. Ann Med. 1995;27:421–427.[Medline] [Order article via Infotrieve]

93. Xu X, Tanner MA, Myers PR. Prostaglandin-mediated inhibition of nitric oxide production by bovine aortic endothelium during hypoxia. Cardiovasc Res. 1995;30:345–350.[Medline] [Order article via Infotrieve]

94. Adrie C, Block KD, Moreno PR, Hurford WE, Guerrero JL, Holt R, Zapol WM, Gold HK, Semigran MJ. Inhaled nitric oxide increases coronary artery patency after thrombolysis. Circulation. 1996;94:1919–1926.[Abstract/Free Full Text]

95. Gryglewski RJ. Interactions between nitric oxide and prostacyclin. Semin Thromb Hemost. 1993;19:158–166.[Medline] [Order article via Infotrieve]

96. Vane JR, Botting RM. Formation by the endothelium of prostacyclin, nitric oxide and endothelin. J Lipid Med. 1993;6:395–404.

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