11 - Antiplatelet Therapy | A Primer on Stroke Prevention and Treatment: An overview based on AHA/ASA Guidelines

Editors: Norris, John W.; Hachinski, Vladimir

Title: Stroke Prevention, 1st Edition

> Table of Contents > II - Secondary Prevention > 11 - Antiplatelet Therapy

Antiplatelet Therapy

Donald J. Eastern

Platelet antiaggregation drugs help prevent atherothrombotic events, including transient ischemic attacks (TIA) and strokes. They inhibit the formation of intraarterial platelet aggregates that can form on diseased arteries and induce thrombus formation, occlude the artery, or embolize into distal circulation. Aspirin is the most widely prescribed drug for this purpose. Ticlopidine, clopidogrel, and dipyridamole also are used, though the implications of their efficacy, safety, and cost compared to aspirin are debated.

Because cost is a major factor in prescribing antiplatelet medication, it is important to assess the cost of treatments compared the risk stroke, myocardial infarction (MI), and vascular death. In general, individuals at relatively low risk for these events may be treated with relatively inexpensive medications that may be less beneficial than more expensive ones. High-risk patients may warrant high-risk and expensive procedures medications.

The results of various trials antiplatelet drugs for the prevention stroke and other important vascular outcomes are sometimes confusing and difficult to apply to individual patients at risk. Some studies include all kinds of patients with various atherosclerotic diseases, while others include only patients with a recent stroke or TIA. Common terms used to describe trial results include hazard ratios, odds reductions, absolute and relative risk numbers needed-to-treat to prevent one or more outcomes in one, two, three, or years.

P.196

The primary outcomes, or endpoints, of studies vary enormously, and there may be more than one. The outcomes often include all strokes (including hemorrhagic), ischemic strokes only, major or disabling strokes, all deaths, vascular deaths, MI, and various combinations, or clusters, of these outcomes. The primary analyses of trials may be on an intention-to-treat or an efficacy basis, and the latter excludes various patients and outcomes for various reasons. This chapter reviews, assesses, and discusses the results of the important trials antiplatelet drugs for the prevention of stroke and other important vascular outcomes in patients primarily with prior stroke or TIA and interprets them in a uniform context.

Overview of Antiplatelet Drugs

Aspirin for Secondary Prevention of Vascular Events

Aspirin is the most widely studied antiplatelet agent. Its antiplatelet effect accomplished by acetylating the cyclooxygenase enzyme in platelets. This irreversibly inhibits the formation thromboxane A₂, a platelet aggregating and vasoconstricting prostaglandin. This effect is permanent and lasts for the 7- 10- day life of the platelet. Paradoxically, aspirin also inhibits the formation in endothelial cells of prostacyclin, an antiaggregating and vasodilating prostaglandin. This effect is transient. As soon as the aspirin cleared from the cells, nucleated endothelial cells again produce prostacyclin. Aspirin in low doses given once daily inhibits the production of thromboxane A₂ in platelets without substantially inhibiting prostacyclin formation. Most physicians recommend aspirin in doses of 325 mg or less daily for the prevention atherothrombosis.

The Antiplatelet Trialists¹ conducted a major meta-analysis that assessed the effect of antiplatelet drugs in patients with various manifestations of atherosclerosis, such as unstable angina, MI, TIA and stroke, and other patients at risk for atherothrombotic events. They aggregated the 73,247 high-risk patients who had been in trials lasting longer than 30 days, that is, on long-term antiplatelet therapy. The Antiplatelet Trialists emphasized the composite outcome of stroke, MI, or vascular death. This outcome cluster included hemorrhagic stroke and death due to any hemorrhage. They also analyzed nonfatal stroke, nonfatal MI, vascular death, and death from any cause independently. They expressed the treatment effects for the various vascular outcomes as odds reductions. An ideal outcome cluster to analyze was stroke, MI, or vascular death (along with the individual outcomes of nonfatal stroke, MI, vascular death, and death from all causes) because it included the important outcomes for all patients with atherosclerosis that can be prevented or caused by antiplatelet drugs.

Nevertheless, the final mechanism for stroke may differ from that MI, and stroke patients may differ from MI patients in the pathophysiology of their strokes

P.197

and Mis, although no evidence exists for the latter. Regulatory agencies require that specific outcomes be assessed in groups of patients. Thus, the focus will be on stroke alone, and the cluster of stroke, MI, or vascular death. These vascular outcomes will be considered in all kinds of patients with atherosclerosis, but will focus on patients with prior stroke or TIA.

The Antiplatelet Trialists found that overall (i.e., in all kinds of patients at high risk for vascular outcomes), antiplatelet drugs reduced the odds of the composite outcome of stroke, MI, or vascular death in secondary prevention by about 27% (Table 11.1). The odds reduction attributable to aspirin alone was 25%. They found that antiplatelet drugs reduce the odds of a nonfatal stroke by 31%, nonfatal MI by about 35%, and vascular mortality by 18%.

Whatever patients are analyzed across the spectrum of high risk (e.g., those with recent MI, prior or stroke or TIA), they found a similar risk reduction in stroke, MI or vascular death of about 1/4. That is, no matter what vascular disorder brought these various patients to enter the various clinical trials that were analyzed, the relative effect of antiplatelet drugs on the prevention stroke, MI, or vascular death was similar for all of them.

The Antiplatelet Trialists also analyzed the differences in patients over and under the age of 65 years, and also by gender. While some variation was seen, all patients benefited to a similar degree from antiplatelet therapy. The same was true for patients with and without hypertension with diabetes.

The Antiplatelet Trialists Collaboration meta-analysis concluded that antiplatelet therapy typically prevents about 40 vascular events per 1000 patients with a past history of MI, stroke, or TIA when treated for 2 years. This presentation of the data emphasizes the absolute gain for these patients with various disorders, not just the odds reductions.

TABLE 11.1. The Odds Reductions in Risk of Vascular Outcomes Caused by Antiplatelet Therapy

Vascular Outcome	Odds Reduction
142 randomized trials, 73,247 patients; all antiplatelet drugs in various patients at high risk of vascular events.
Nonfatal stroke	31%
Nonfatal myocardial infarction	35%
Vascular mortality	18%
Overall vascular events	27 %
46 randomized trials; 45,019 patients; aspirin only in various patients at risk of vascular events.
Overall vascular events	25 %

P.198

An important issue arising from the Antiplatelet Trialists' meta-analyses is whether the effect of various antiplatelet drugs on prevention strokes, Mis and vascular deaths is the same in patients entering studies because of prior stroke or TIA as it is for patients entering because of prior MI or other vascular disorders. The Antiplatelet Trialists found that whereas all antiplatelet agents reduced the odds of stroke, MI, or vascular death in all high-risk patients by 27%, the odds reduction in patients with prior stroke or TIA was only 22% (Table 11.2).

Additionally, Algra and van Gijn² performed their own mini-meta-analysis that showed that in the 10 trials evaluating the benefit of aspirin alone only prior stroke or TIA patients, aspirin reduced the odds for stroke, MI, or vascular death by only 16%. When they converted this odds reduction to the more conventional relative risk reduction, the reduction over placebo was only 13% (Table 11.2).

These analyses emphasize that the important points one must assess carefully are whether one is (1) evaluating all patients at high risk for vascular events, or specific patients (e.g., prior stroke or TIA), (2) evaluating the benefit of all antiplatelet drugs, individual drugs, or combinations of drugs, and (3) expressing the result in odds reductions or relative risk reductions. The importance of noting which outcome events are being measured (e.g., stroke, MI, vascular death, various combinations) is addressed below.

The Swedish Aspirin Low-Dose Trial³ compared aspirin at 75 mg daily versus placebo in 1360 patients with minor stroke or TIA. The mean follow-up was 2.7 years, and the primary outcome measure was stroke plus all death. The 18% relative risk reduction of aspirin was statistically significant (p = 0.02). The relative risk reduction of stroke, MI or vascular death was 17% and was statistically significant also. This compares to the 13% that Algre and van Gijn found for all doses of aspirin in similar patients.

The Dutch TIA Trial⁴ compared aspirin at 30 mg per day vs. 283 mg per day in 3131 patients with minor stroke or TIA. The mean follow-up was 2.6 years, and the primary outcome measures were stroke, MI or vascular death. The investigators found that aspirin at 30 mg daily was no less effective than 273 mg, and there were fewer bleeds occurred on the lower dose.

TABLE 11.2. Effect of Antiplatelet Therapy on TIA, Myocardial Infarction, and Vascular Death in Various Atherosclerotic Populations

Patient POPULATION	NO. of Trials/Patients/Events			Odds Reduction (95% ci)	Relative Risk Reduction (95% ci)
High-risk, all drugs	142	73,247	9583	27%
High-risk, aspirin	46	45,019	6097	25%
Stroke or TIA, all drugs	18	11,707	2377	22%
Stroke or TIA, aspirin	10	6171	1474	16%	13%

P.199

By the early 1990s, these latter two trials,³^,⁴ along with earlier U.K.-TIA Trial,⁵ provided most of the data that led many clinicians to believe no important differences exist between 30 mg and 1300 of aspirin daily for preventing stroke. Also, low-dose aspirin is less gastrotoxic. Then, in 1996, the European Stroke Prevention Study-2⁶ reported that 50 mg daily of aspirin per day given to patients following stroke or TIA reduced the risk of stroke, and stroke death, by 18% and 13%, respectively. In 1999 the Aspirin in Carotid Endarterectomy (ACE) trial,⁷ involving 2849 patients, investigated appropriate doses of aspirin for prevention of perioperative atherothrombotic events in patients undergoing carotid endarterectomy. ACE found that the risk of stroke, MI, and death between 30 days and 3 months after endarterectomy was lower for patients taking 81 mg or 325 mg of aspirin daily than for those taking 650 mg or 1300 mg. Finally, in 1998, the United States Food and Drug Administration (FDA) published their new recommendation that 50 mg to 325 mg of aspirin per day be used for prevention of ischemic stroke.⁸ Consequently, the majority clinicians worldwide recommend 325 mg or less per day for prevention of stroke.

It would be valuable to conduct a very large clinical trial resolve the question of the ideal dose aspirin for prevention ischemic stroke. While definitive resolution of this question is not an important issue to some, many millions of people worldwide ingest aspirin daily to avoid atherothrombotic events. Small differences in important vascular events and gastrotoxicity could have an important effect on the absolute number of people benefiting from aspirin prophylaxis.

Aspirin gastrotoxicity is dose related, and more indigestion, nausea, heartburn and vomiting occur with higher doses.³^,⁵^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵ Hemorrhages of many types, especially gastrointestinal, are caused by aspirin,³^,¹⁶ but the relationship to dosage is uncertain. It has been estimated conservatively that 16,500 nonsteroidal antiinflammatory drug (NSAID)-related deaths occur among patients with rheumatoid arthritis and osteoarthritis every year in the United States. This figure is similar to the number of deaths from acquired immunodeficiency syndrome.¹⁷ If deaths from the gastrointestinal toxic effects of NSAIDs were tabulated separately in the National Vital Statistics reports, they would constitute the 15th most common cause of death in the United States.¹⁷ Additionally, an increase hemorrhagic stroke has been reported.³^,⁹^,¹⁶ While the optimal dose of aspirin for prevention of stroke remains somewhat unsettled, 325 mg or less daily is effective.

These important data show that aspirin reduces the risk of stroke, MI, and vascular death in all kinds of patients at high risk for these atherothrombotic outcomes. A trend exists toward patients with stroke or TIA benefiting less than other high-risk patients. A trend also exists toward stroke or TIA patients experiencing less reduction in nonfatal stroke than other high-risk patients. More data are necessary to determine if these trends are real. Nevertheless, these possible differences are worth considering as the benefits of ticlopidine, clopidogrel, and dipyridamole are reviewed and analyzed.

P.200

Ticiopidine

Ticlopidine hydrochloride is a thienopyridine. It is an adenosine diphosphate (ADP) receptor antagonist that inhibits ADP-induced fibrinogen binding to platelets, a necessary step in the platelet aggregation process. Ticlopidine is not a cyclo-oxygenase inhibitor (like aspirin) and thus has no effect on prostacyclin production. Also, it is not a phosphodiesterase inhibitor (like dipyridamole) and does not alter cyclic adenosine monophosphate (AMP) in platelets.

Ticlopidine has been evaluated for the prevention of vascular outcomes in several randomized studies.¹^,¹⁸^,¹⁹^,²⁰^,²¹ Two large trials assessed ticlopidine for the prevention of stroke and other vascular events in patients presenting with cerebrovascular symptoms.¹⁹^,²⁰

The Ticlopidine Aspirin Stroke Study (TASS)²⁰ involved 3069 patients presenting with minor stroke or TIA. Half were treated with 650 mg of aspirin twice daily and half with 250 mg of ticlopidine twice daily. In the three-year event rate, ticlopidine effected a 21% greater relative risk reduction compared to aspirin in the primary endpoint of stroke, and a 13% greater reduction in the endpoint all nonfatal stroke or death. Two percent of patients on ticlopidine were unable to tolerate the medication because of diarrhea and another 2% because skin rash. Serious gastrointestinal adverse effects (e.g., ulcers and bleeding) were 2.5 times more common in the aspirin group, even though patients who had any history of gastrointestinal hemorrhage or dyspeptic symptoms were excluded from the trial. Bleeding from other anatomical sites was infrequent and about equal in the two treatment groups. Severe neutropenias occurred in 0.9% of patients the ticlopidine-treated group. They reversed with cessation of treatment. Most occurred within two months after treatment began. Hence, it is important to perform blood counts at two-week intervals for the first three months on medication, that is, six blood counts in three months.

The Canadian American Ticlopidine Study (CATS)¹⁹ involved 1072 patients with major stroke, rather than a minor stroke or TIA. The patients were randomly allocated to 250 mg of ticlopidine twice daily or placebo. The patients in this study treated with placebo had an event rate for stroke, MI, or vascular death of 15.3% per year, demonstrating the seriousness of stroke as a predictor subsequent vascular events. Ticlopidine reduced the relative risk of stroke, MI, or vascular death, using the efficacy approach, by 30% (p - 0.006), down to 10.8%. The same outcome cluster using the intent-to-treat approach was reduced by about 23% (p = 0.020) in the ticlopidine group. Adverse effects were similar to those in TASS. Ticlopidine reduced the relative risk of ischemic stroke by 33.5% (p 0.008). Bennett et al.²² recently reported that ticlopidine occasionally causes thrombotic thrombocytopenic purpura.

Taken together, these data show that ticlopidine substantially reduces the risk of stroke and other vascular outcomes in patients at risk, TASS showed ticlopidine

P.201

to be better than aspirin. Ticlopidine is likely about 20% aspirin in reducing stroke, and the Antiplatelet Trialists concluded from direct comparisons¹⁹^,²⁰-²³ that, overall, ticlopidine is likely to be about 10% better than aspirin in reducing the composite outcome of stroke, MI, or vascular death.

Clopidogrel

Clopidogrel is a new thienopyridine derivative of the same chemical family as ticlopidine. It is an inhibitor of platelet aggregation induced by ADP. Its antithrombotic effects were recently evaluated in the Clopidogrel versus Aspirine in Patients at Risks of Ischemic Events (CAPRIE) Study.²⁴ CAPRIE was a randomized, blinded, multicenter trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg in reducing the risk of the composite outcome ischemic stroke, MI, or vascular death and to determine their relative safety. The three patient groups studied were those with recent ischemic stroke, recent MI, and symptomatic peripheral arterial disease.

The study involved 19,185 patients, with more than 6000 in each of the three clinical subgroups. They were treated during a mean follow-up of 1.91 years. There were 1960 validated first events in the primary outcome cluster. The intention-to-treat analysis showed that patients treated with clopidogrel experienced an annual 5.32% risk of ischemic stroke, MI, or vascular death, compared to 5.83% with aspirin, for an absolute risk reduction of 0.5% and a relative reduction of 8.7% (95% CI; 0.3 16.5; p = 0.043). The corresponding on treatment analysis showed a relative risk reduction of 9.4%. When serious hemorrhages were considered along with the primary outcome cluster in an intentto-treat analysis, which provides a true net benefit assessment, the relative risk reduction with clopidogrel was 9.5% (95% CI; 1.2 18.5). Finally, when the results in CAPRIE were analyzed using the Antiplatelet Trialists' technique (i.e., intent-to-treat, all stroke, MI, or vascular death [including hemorrhagic]) and by odds reduction, a reduction of 10%, rather than 8.7%, was found favoring clopidogrel. For the 6431 patients entered into CAPRIE with a stroke as the qualifying condition, the relative risk reduction was 7.3% (95% CI; 5.7 18.7), and the odds reduction was 8.5%. For the outcome of stroke only, across the three qualifying conditions (patients with stroke, MI, and peripheral artery disease) a 6.0% relative risk reduction was detected favoring clopidogrel over aspirin. For the outcome of stroke only, in just the patients qualifying with a stroke, an 8.0% relative risk reduction was found favoring clopidogrel over aspirin.

While there were no major differences between aspirin and clopidogrel in terms of safety, and adverse experiences were minimal, more serious hemorrhages occurred in those patients on aspirin. Ten patients (0.10%) the clopidogrel group suffered significant reductions in neutrophils (to <l,200/mm³) compared to 16 (0.17%) in the aspirin group. The numbers of severe neutropenia (<450/mm³)

P.202

numbered 5 and 4, respectively. The overall safety profile of clopidogrel is at least as good as that of 325 mg aspirin per day. Bennett et al. recently reported clopidogrel rarely is associated with thrombotic thrombocytopenic purpura.^24a

The CAPRIE Study data indicated that clopidogrel was more effective than aspirin in reducing the combined risk of ischemic stroke, MI, or vascular death in patients with atherosclerotic vascular disease. Clopidogrel's beneficial effects seem to be comparable ticlopidine's, without the negative adverse effects profile. Its effect on reducing stroke seemed less striking than for ticlopidine. This result may have been simply the play of chance, ticlopidine and clopidogrel could conceivably prevent strokes differently, or perhaps its benefit in TIA patients is greater than that in stroke patients.

Dipyridamole

The Antiplatelet Trialists¹ analyzed trials involving dipyridamole (DP) alone vs. placebo, DP combined with aspirin vs. placebo, and DP vs. aspirin. Ten trials compared DP alone vs. placebo (200 events in 1474 patients) and showed a 23% odds reduction in stroke, MI, or vascular death favoring DP. Thirty-four trials (1741 events in 13,718 patients) compared DP combined with aspirin vs. placebo and showed a 28% odds reduction in stroke, MI, or vascular death favoring the combination. It seemed clear that DP was effective and that the combination of DP plus aspirin might be more effective than either alone. However, more patients were needed to enhance these comparisons in the Antiplatelet Trialists' view.

The Antiplatelet Trialists analyzed 14 trials that compared the combination of DP plus aspirin vs. aspirin alone (628 events in 5317 patients) for prevention of the composite outcome of stroke, MI, or vascular death (Fig. 11.1). One trial involved patients entered because of prior MI, 3 involved patients entered because of prior stroke or TIA, 4 because of post-coronary artery bypass grafting, 3 because of intermittent claudication, 2 because noncoronary grafting, and 1 because of diabetes. The odds reduction for all vascular events was 3%, indicating a slight (statistically nonsignificant) benefit favoring aspirin alone. The only outcome that was reduced by DP combined with aspirin non-fatal stroke. This odds reduction was 12% and not statistically significant. Nevertheless, the Antiplatelet Trialists concluded that a moderate difference between DP combined with aspirin and alone could not be ruled out. They stated,

Any real differences between two antiplatelet regimens are likely to be smaller than the differences between antiplatelet and no antiplatelet treatment. Hence tens of thousands of patients may need to be randomised directly between different antiplatelet regimens to ensure (by large numbers) small enough random errors and to avoid direct randomisation) important biases. Unfortunately, the numbers so far randomised between one antiplatelet regimen and another have been much smaller than this.'

FIGURE 11.1. Direct comparisons of proportional effects on vascular events and nonvascular deaths of dipyridamole plus aspirin vs. aspirin.

P.203

In 1996, the results of the second European Stroke Prevention Study (ESPS-2) were published.⁶ Patients who had experienced either an ischemic stroke or TIA were studied in a multicenter, randomized, blinded, factorial, placebo-controlled study with four treatment groups and a two-year follow-up for all patients. The four treatments were 25 mg aspirin, 200 mg DP, 25 mg aspirin plus and placebo, each given twice daily. DP was given as 200 mg of an extendedrelease formulation. A total of 6602 patients were included in the analysis, and the outcome event clusters were fatal or nonfatal stroke, stroke death from any cause, and all-cause mortality. The investigators found that both extended-release DP at 200 mg twice daily and aspirin at 25 mg had an independent and significant effect in preventing the recurrence of stroke, and that combination of DP plus aspirin was additive and produced highly significant benefits (Table 11.3). DP combined with aspirin vs. aspirin alone reduced the risk of stroke (nonfatal and fatal) by 23%. The absolute risk reduction was 3% at two years, or about 1.5% annually.

Are the results of ESPS-2 at odds with earlier trials? When results of ESPS-2 are added to the 14 previous trials DP combined with aspirin vs. aspirin alone in various atherosclerosis patients, one finds a significant 23% reduction for DP plus aspirin in the odds of nonfatal stroke and a nearly significant 10% reduction in the odds of all vascular events, though all of the 10% is attributable to nonfatal strokes.²⁵

TABLE 11.3. Number of Primary Outcome Events and Relative Risk Reductions after Two Years of Treatment in ESPS-2

TREATMENT	NUMBER OF EVENTS/RISK REDUCTION
TREATMENT	STROKE¹	DEATH	STROKE/DEATH
Dipyridamole + aspirin compared to placebo	157/37%	185/8%	286/24%
Dipyridamole compared to placebo	211/16%	188/7%	321/15%
Aspirin compared to placebo	206/18%	182/11%	330/13%
Placebo	250	202	378
Dipyridamole + aspirin compared to aspirin	157/23%	1857 3%	286/13%
¹Nonfatal and fatal.

P.204

ESPS-2 was a cerebrovascular trial (i.e., it entered only patients with stroke or TIA). When the results of ESPS-2 are added to the three earlier cerebrovascular trials (Fig. 11.2 and 11.3),²⁶^,²⁷^,²⁸^,²⁹ one finds a significant 25% reduction in the odds of nonfatal stroke and a significant 18% reduction in the odds of all vascular events, though again all of the 18% is attributable to nonfatal stroke. These data provide evidence that DP combined with aspirin reduces the odds of nonfatal stroke by about 25% over aspirin alone (p = 0.005; CI 0.09 0.42). Also, the risk of stroke was reduced by 37% in ESPS-2 and 38% in ESPS-1.³⁰ This consistency

P.205

is persuasive. It is odd that MI and vascular death were not reduced by DP combined with aspirin in ESPS-2, as they were by all antiplatelet drugs the Antiplatelet Trialists' overview analysis.¹

FIGURE 11.2. Direct comparisons of proportional effects on vascular events and nonvascular deaths of dipyridamole plus aspirin vs. aspirin.

While the primary purpose of this overview is to focus on those antiplatelet trials involving patients with prior stroke or TIA, the totality of the evidence should be considered also. The two largest challenges to accepting combination DP and aspirin as more beneficial than aspirin alone in prevention of stroke (and MI and vascular death) lie in two facts: (1) some clinicians will view the combination's benefit as largely linked to a single trial, namely ESPS-2, and (2) the inconsistency in its effect on stroke, MI, and vascular death. The previous 14 trials were negative (i.e., there was no statistically significant benefit favoring combination DP and aspirin) for all important vascular outcomes, including stroke alone, though there was a trend favoring benefit for stroke alone. The same true for the three cerebrovascular trials.

Nevertheless, these aggregate data provide strong evidence that the combination of DP and aspirin may be substantially better than aspirin alone in preventing strokes. Another trial of similar size to ESPS-2 (about 3,000 patients with stroke or TIA comparing DP plus aspirin at 325 mg to mg alone) may be required to confirm these findings and substantially alter clinical practice. The European and Australian Stroke Prevention in Reversible Ischemia Trial (ESPRIT)³¹ may provide this confirmation. ESPRIT is a randomized clinical trial

P.206

in which patients with cerebral ischemia of arterial origin will be randomized among oral anticoagulation (international normalized ratio [INR]: 2.0 3.0), a combination of aspirin (in any dose between 30 and 325 mg per day) plus DP (400 mg daily), and aspirin only (in any dose between 30 and 325 mg per day). The researchers plan to enroll 4500 patients, with a mean follow-up of three years. The primary outcome is the composite event of vascular death, stroke, myocardial infarction, or major bleeding complication.

FIGURE 11.3. Direct comparisons of proportional effects on nonfatal strokes dipyridamole plus aspirin vs. aspirin.

Discussion

Stroke is a major health problem, especially in terms of disability for patients and expense to patients and society. Ischemic strokes due to atherothrombosis and cardioembolism are the commonest causes of stroke. Additionally, patients at high risk for stroke are also at MI. Many of the atherothrombotic events resulting from these arterial and cardiac disorders are preventable.

Based on the clinical trial results available so far, the following statements seem reasonable:

Aspirin reduces the odds of the composite outcome stroke, MI, or vascular death in patients with symptomatic atherosclerosis by about 25%, and it reduces the odds of stroke by about 30%.¹ In stroke or TIA patients, aspirin reduces the odds of the composite outcome of stroke, MI, or vascular death by about 16% (the relative risk reduction is 13%).² Many patients have difficulty taking aspirin because of gastrointestinal discomfort, especially when high doses are taken, and aspirin sometimes causes serious bleeding.
Ticlopidine appears to reduce the same composite outcome by about a third in stroke or TIA patients, but there is a 5% incidence of bothersome adverse effects, a 0.9% incidence of severe neutropenia, and occasional thrombotic thrombocytopenic purpura.
Clopidogrel produces a benefit similar to ticlopidine but virtually without serious adverse effects. Clopidogrel is at least as safe aspirin.
DP in combination with aspirin vs. placebo appears to reduce the risk of the composite outcome of stroke, MI, or vascular death in patients with symptomatic atherosclerosis by about 28%¹ DP in combination with aspirin vs. placebo reduced the risk of stroke alone in patients with symptomatic atherosclerosis by 38% and 37% in ESPS-1 and -2, respectively. Finally, DP in combination with aspirin versus aspirin alone reduces the risk of the composite outcome stroke, MI, or vascular death in patients with symptomatic atherosclerosis by about 10%;²⁵ it reduces the risk of (ischemic) stroke by about 23% over aspirin alone.⁶^,²⁵

P.207

Conclusion

Aspirin is inexpensive, can be given in low doses as infrequently every other day, and could be recommended for all adults to prevent both stroke ML However, it causes adverse effects, including epigastric discomfort, gastric ulceration, and gastrointestinal hemorrhage. The gastric bleeding may be asymptomatic and detectable only by regular stool examinations. A life-threatening hemorrhage may occur without warning. Consequently, not every 40- or 50-yearold should be advised to take aspirin regularly because the risk of atherothrombotic stroke (and MI) is low and may be outweighed by the risk of adverse side effects. Conversely, every patient who has experienced an atherothrombotic stroke and has no contraindication should be taking an antiplatelet agent regularly because the average annual risk of another stroke is 5% to 15%, and the risk another few percent higher for MI and vascular death. In this setting, the likelihood of benefit far outweighs the risks of treatment. The choice antiplatelet agent and dose similarly must balance the risk of stroke against benefit, risk, and cost of the treatments. These data are less definitive, and opinions therefore vary.

Aspirin reduces the odds of stroke, MI, or vascular death by about 25% in an aggregate group of high-risk patients. In patients with prior stroke or TIA, aspirin may reduce the relative risk of the same outcome cluster by only about 13%. Low-dose (30 75 mg daily) and high-dose (650 1300) aspirin appear to be comparably effective, and low-dose is less gastrotoxic.

Ticlopidine is more effective than aspirin by about 10% for preventing stroke, MI, or vascular death and about 20% more effective for reducing stroke. The cost and risk of adverse effects of ticlopidine are higher, and it is given twice daily. Clopidogrel's benefit appears to be similar ticlopidine's, but it has an excellent adverse-effect profile and is given once daily. Clopidogrel at 75 mg daily may be less effective for preventing stroke than ticlopidine at 250 mg twice daily.

The combination of DP and aspirin also is more effective than aspirin alone. Most of the benefit shown for this combination has been limited to stroke prevention in patients with prior stroke or TIA. It is given twice daily and the adverse-effect profile is good. In order to compare the relative benefits (efficacy and safety) of aspirin, ticlopidine, clopidogrel, and DP, it will be necessary to obtain more data from randomized clinical trials.

References

1. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials antiplatelet therapy I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81 106.

2. Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neural Neurosurg Psychiatry 1996;60:197 199.

P.208

3. The SALT Collaborators Group. Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338:1345 1349.

4. The Dutch TIA Trial Study Group. A comparison of two doses aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N EnglJ Med 1991;325:1261 1266.

5. UK-TIA Study Group. United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: Final results. J N enrol euro surg Psychiat 1991;54:1044 1054.

6. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J N enrol Sci 1996;143:1 13.

7. Taylor DW, Barnett HJ, Haynes RB, et al. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: A randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators. Lancet 1999;353:2179 2184.

8. U.S. Food and Drug Administration. Internal analgesic, antipyretic, antirheumatic drug products for over-the-counter human use: Final Rule professional labelling of aspirin, buffered and aspirin in combination with antacid drug products. Federal Register 1998;63:56802 56819,66015 66017.

9. 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.

10. Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995;310:827 830.

11. Soil AH, Weinstein WM, Kurata J, McCarthy D. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med 1991; 14:307 319.

12. Kelly JP, Kaufman DW, Jurgelon JM, Sheehan J, Koff RS, Shapiro S. Risk of aspirinassociated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996;348:1413 1416.

13. Fuster V, Dyken ML, Vokonas PS, Hennekens C. Aspirin as a therapeutic agent in cardiovascular disease: Special Writing Group. Circulation 1993;87:659 675.

14. Laporte JR, Carne X, Vidal Moreno V, Juan J. Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs: Catalan Countries Study on Upper Gastrointestinal Bleeding Lancet 1991;337:85 89.

15. Levy M, Miller DR, Kaufman DW, et al. Major upper gastrointestinal tract bleeding: Relation to the use of aspirin and other nonnarcotic analgesics. Arch Intern Med 1988; 148:281 285.

16. Peto R, Gray Collins et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ 1988; 1:313 316.

17. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. New Engl J Med 1999;340:1888 1899.

18. Balsano F, Rizzon P, Violi et al. Antiplatelet treatment with ticlopidine in unstable angina: A controlled multicenter clinical trial. Circulation 1990;82:17 26.

19. Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989;1:1215 1220.

20. Hass WK, Easton JD, Adams HP, Jr., et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients: Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989;321:501 507.

P.209

21. Janzon L, Bergqvist D, Boberg J, et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication: Effect of ticlopidine. Results from STEMS, the Swedish Ticlopidine Multicentre Study. J Intern Med 1990;227:301 308.

22. Bennett CL, Weinberg PD, Rozenberg-Be-Dror K, Yarnold PR, Kwaan HC, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine: A review of 60 cases. Ann Intern Med 1998;128:541 544.

23. Murakami M, Toyokura T, Omae Gotoh F, Tazaki Y, Ohtomo E. Effects of ticlopidine and aspirin on TIAs a twelve month, double blind, comparative study. Igaku noAyumi 1983;127:950 971.

24. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329 1339.

24a. Bennett CL, Connors JM, Carwile Moake JL, Bell WR, Tarantolo SR, McCarthy LJ, Sarode R, Hatfield AJ, Feldman MD, Davidson CJ, Tsai HM. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000;342:1773 1777.

25. Wilterdink JL, Easton JD. Dipyridamole plus aspirin in cerebrovascular disease. Arch Neural 1999;56:1087 1092.

26. Bousser MG, Eschwege E, Haguenau M, et al. AICLA controlled trial of aspirin and dipyridamole in the secondary prevention of atherothrombotic cerebral ischemia. Stroke 1983;14:5 14.

27. Fields WS, American-Canadian Co-operative Study Group. Persantine aspirin trial in cerebral ischemia. Stroke 1983;14:99 103.

28. Fields WS, American-Canadian Co-operative Study Group. Persantine aspirin trial in cerebral ischemia. Part III: Risk factors for stroke. Stroke 1986;17:12 18.

29. Guiraud-Chaumeil B, Rascol A, David J, Boneu B, Clanet M, Bierme R. Prevention des recidives des accidents vasculaires cerebraux ischemiques par les anti-agregants plaquettaires. Rev Neural (Paris) 1982; 138:367 385.

30. The ESPS Group. The European Stroke Prevention Study (ESPS): Principal endpoints. Lancet 1987;2:1351 1354.

31. Goiter JW, De Schryver EL, Algra A. Secondary prevention after ischemic cerebral infarct. The ESPRIT Study: Low dose anticoagulation, combined therapy with acetylsalicylic acid/dipyridamole or monotherapy with acetylsalicylic acid? Nervenarzt 1999;70:368 370.