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Effect of Combined Aspirin and Extended-Release Dipyridamole Versus Clopidogrel on

Functional Outcome and Recurrence in Acute, Mild Ischemic Stroke : PRoFESS
Subgroup Analysis
Philip M.W. Bath, Daniel Cotton, Reneé H. Martin, Yuko Palesch, Salim Yusuf, Ralph Sacco,
Hans-Christoph Diener, Conrado Estol and Robin Roberts
Stroke. 2010;41:732-738; originally published online February 24, 2010;
doi: 10.1161/STROKEAHA.109.564906
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MD.H. Fla.564906 732 Downloaded from http://stroke. BS. Conclusions—Treatment with combined Asp/ER-DP vs clopidogrel in 1360 patients with acute. PhD.Effect of Combined Aspirin and Extended-Release Dipyridamole Versus Clopidogrel on Functional Outcome and Recurrence in Acute.-C. 2013 . Division of Neurology (R. Martin. Conn.41:732-738. MD.) Key Words: acute stroke 䡲 aspirin 䡲 clopidogrel 䡲 dipyridamole 䡲 ischemic stroke 䡲 outcome 䡲 randomized controlled trial P atients with ischemic stroke are at increased risk of having another event. UK. Other antiplatelet agents are also individually effective.36 to 1. Duisburg-Essen. SC.S. Hamilton.56. death. and long-term antiplatelet therapy is effective at reducing recurrence. largely owing to excess bleeding. Nottingham NG5 1PB. Canada. the relative safety and efficacy of combined aspirin-dipyridamole or clopidogrel are not known in patients with acute ischemic stroke. treatment was no longer being taken in 121 (18%) patients randomized to Asp/ER-DP and in 86 (12. major bleeding. PhD.B.M. Analyses were adjusted for baseline prognostic variables and blood pressure treatment assignment. MB. Biostatistics Group (D. small-artery occlusion 59%).org DOI: 10. 95% CI. Stroke is available at http://stroke.W. Methods—The factorial PRoFESS secondary prevention trial assessed antiplatelet and blood pressure–lowering strategies in 20 332 patients. DPhil. 200 mg BID. FRCP. 95% CI.18) and vascular events (OR⫽0. However. 2010. the safety and efficacy of DP and clopidogrel in acute ischemic stroke have not been explored in large trials. By 90 days. Miami. Hamilton. accepted August 25. Inc. University of Nottingham.bath@nottingham.5 combined Asp and clopidogrel did not offer additional benefit over either Asp or clopidogrel alone in patients with previous stroke.. Bath. and baseline variables were similar between treatment groups. MSc.19).M. 0. ( by guest on May 26.). UK.4 Although combining Asp and DP was more effective than either agent alone. Ralph Sacco.5%) assigned to clopidogrel (P⫽0. Argentina.E. MD.). Canada.). early commencement of antiplatelet therapy should be most effective. and serious adverse events did not differ between treatment Correspondence to Prof Philip Bath. Bioinformatics and Epidemiology (R. 2009.3. Neurologic Center for Treatment and Research (C. n⫽672) or clopidogrel (75 mg/d. Renee´ H. McMaster University. Department of Biostatistics.ahajournals.109. Hans-Christoph Diener. mild ischemic stroke did not differ in terms of effects on functional outcome. 0.1 Numerous trials of secondary prevention have shown that aspirin (Asp) reduces recurrence by a modest (relative risk reduction 13%2) but worthwhile degree. City Hospital Campus. The primary outcome for this post hoc subgroup analysis was functional outcome at 30 days. University of Miami. Division of Stroke Medicine. E-mail © 2010 American Heart Association. 95% CI.97. Conrado Estol. Yuko Palesch. PhD. Y. Population Health Research Institute (S. Daniel Cotton.79 to 1. Medical University of South Carolina. Department of Neurology (H. 0. Robin Roberts.). 1360 of whom were randomized within 72 hours of ischemic stroke to combined aspirin (Asp. Buenos Aires. Combined death or dependency (shift analysis of modified Rankin Scale score at day 30) did not differ between treatment groups (odds ratio [OR]⫽0.71.37) were present with Asp/ER-DP. or serious adverse events.). MD. Results—Patients were representative of the whole trial (age 67 years. bleeding. Boehringer Ingelheim Pharmaceuticals.Y.). 2009. McMaster University.6. University Duisburg-Essen. MS.006).P. The mean time from stroke to recruitment was 58 hours.R. and this has been confirmed in 2 megatrials for Asp. Both treatments were practical to administer. PhD.8. Ridgefield. Nonsignificant trends to reduced recurrence (OR⫽0. although a small Received August 6. and Department of Clinical Epidemiology (R. Columbia. for the PRoFESS Study Group Background and Purpose—Long-term antiplatelet therapy is effective at reducing recurrence after ischemic stroke. Salim Yusuf.7 Because the risk of stroke recurrence is highest in the first few hours and days after an acute event. National Institutes of Health Stroke Scale score 3.D.26 to 1.C. Nottingham. University of Nottingham.1161/STROKEAHA.ahajournals. From the Stroke Trials Unit (P.W. recurrence.). secondary outcomes included recurrence and death by 90 days. Germany. 25 mg BID) and extended-release dipyridamole (ER-DP. n⫽688). including extended-release dipyridamole (ER-DP) and clopidogrel.3. Mild Ischemic Stroke PRoFESS Subgroup Analysis Philip M. Rates of death.9 However.).

39.Bath et al Aspirin/Dipyridamole for Acute Ischemic Stroke Table 1. mean (SD) 67.2 (9.7) 5805 (28.0) 105 (15. and telmisartan (angiotensin receptor antagonist) with placebo. 2013 369 (1. as a result.3) Clinical details Blood pressure.4) 73 (10.5) 346 (50.5) … 3 346 (51. Some of the PRoFESS inclusion criteria are relevant specifically to assessment of antiplatelet agents in acute stroke: ischemic stroke.6) 12 231 (60.0) 136 (20.4) 369 (53.7 (8.0) 540 (2. Patients (N⫽20 332) were randomized for 34 months from 695 centers in 35 countries and were followed up for a mean duration of 30 months. post hoc.7) Time from stroke.1) 7352 (36.0) White 398 (59.7) 221 (32.12–14 Furthermore. kg/m2.3) Hyperlipidemia 271 (40. n (%) Previous stroke/transient ischemic attack Atrial fibrillation Hypertension 15 (2.9) 5 (0.3) 3304 (16.3) 22 (3. Patients and Methods The PRoFESS trial protocol11 and primary results12. Differential effects between antiplatelet agents might follow from differences in their antithrombotic activity and propensity to induce hemorrhagic transformation.2) 1159 (5.4) 15 048 (74.7%) patients were recruited within 72 hours of the ictus.2) 79 (11.6) Ethnicity.2) Never 269 (40.5) 26.0) 186 (27. mean (SD) 84 (10.7) 159 (23.7) 13 022 (64.3) Current 163 (24.1) 9493 (46.5) … … Downloaded from http://stroke. n (%) 425 (63.2) 149 (21.8) 26.4 (0.6) 407 (60.1) (Continued) .13 have been published. efficacy.4) 816 (4. and tolerability of Asp/ER-DP versus clopidogrel in patients with acute ischemic stroke in a randomized design.9% of patients were recruited within 10 days of the index event.3) 237 (34.6) 10 168 (50. y. male. efficacy.7) 26.2) 66.0) Other 22 (3. salvage of at-risk penumbra) and minimization of deterioration (secondary to thrombus extension) and early recurrence. including treatment of the index event (eg.0) Ischemic heart disease Smoker Antiplatelet therapy Asp Clopidogrel 90 (13.6) TOAST classification.0) 144 (16.2) 9 (1. the safety. in a factorial design.8) 369 (53.2) 459 (66. hospital- Small-artery occlusion Other determined etiology Undetermined etiology Missing 7 (1.2) 4308 (21. and telmisartan (80 mg daily. PRoFESS compared the effect of combined Asp (25 mg BID) and ER-DP (200 mg BID) versus clopidogrel (75 mg daily).6) 3148 (15.4) 258 (37. and tolerability of Asp/ER-DP versus clopidogrel in patients with acute ischemic stroke.7) 185 (26.9 (4.3) 84 (10.1 (8.7) 26.10 Beneficial effects of early antiplatelet therapy may reflect several mechanisms.3) 23 (3.2) Former 240 (35.5) 13 (1.5) Asian 224 (33.2) 51 (7.1) Diabetes mellitus 188 (28.3) 10 (1.1) 112 ( by guest on May 26.5) 2.ahajournals.7) Hypertension.9) 416 (2.7) 2.5) 6660 (32.6) 401 (58.6) 355 (52. mm Hg. n (%) Figure 1. symptoms persisting for ⬎24 hours.8) 10 578 (52. n (%) Large-artery atherosclerosis Inclusion/Exclusion Criteria Cardioembolism The aim of this post hoc PRoFESS subgroup analysis was to assess the relative safety. treated 359 (53.0) 294 (42. study suggested that combined Asp and clopidogrel might be more effective at reducing recurrence than Asp alone.3) 472 (70.2) 378 (54.3) 6 (0.11 The time of 72 hours was chosen a priori to mirror a parallel study describing a comparison of telmisartan with placebo15 and has the advantage of including a moderately large sample size of 1360 patients. then computed tomographic or magnetic resonance evidence of a new stroke. Patient flow through the trial.0) 5743 (28.6) 84 (10. 1366 (6.3) 276 (40. days 0 … 1 82 (12.9) 4997 (24.3) 1110 (5.3) … 146 (16.2) 147 (16.0) 16 (0. thereby providing the opportunity to assess.5) … 2 238 (35.9 (4.8) Black 28 (4.4 (0.2) 484 (70.9) 11 697 (57.5) DP 29 (4. The ‘Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is the largest study investigating the prevention of recurrent stroke and compared.8) Sex.11 A key intention of the protocol was to recruit patients within 10 days of ischemic stroke at a time when the risk of recurrence was particularly high11.3) 173 (25. mean (SD) Systolic Diastolic Body mass index. In brief. combined Asp and ER-DP with clopidogrel. All patients received best medical care independent of treatment assignment.7) 8663 (42.9 (27.6) 3143 (15. Clinical history.0) 11 (1.7) 114 (16.6) Characteristic Whole Trial Demographics 66. 733 Patient Characteristics at Enrollment Asp/ER-DP (n⫽672) Clopidogrel (n⫽688) Age.7) 94 (14. or if ⬍24 hours. an angiotensin receptor antagonist) versus placebo in a 2⫻2 factorial design in patients with recent ischemic stroke. Patients were included if they were enrolled in the main trial and had been randomized within 72 hours of stroke onset.8 (5.

87) 1.30) 0 (0. n (%) 1 (0. systolic blood pressure. 1.17 Major bleeding was defined as a hemorrhagic event that resulted in clinically significant disability.11 (0.49) 1.94) 9 (1. ordered categorical outcomes were analyzed with ordinal statistical approaches to improve statistical power.3) 16 (2.31) 1. n (%) 7 (1.86.734 Stroke Table 1.77 (0.15) 57 (8.99) 42 (6. and assignment to telmisartan or placebo.3) 2 (slight disability) 184 (27.65. n (%) 6 (0.45) mRS score 2–6.29) … Intracranial bleeding.04) Hemorrhagic transformation.9) Outcomes The primary outcome in this post hoc subgroup analysis was functional outcome measured by the mRS at 30 days after randomization.91) 7. Statistical models were adjusted for the baseline prognostic covariates of age. or 50 to 54 years if 2 additional vascular risk factors were present.31.41 (0.ahajournals. age ⬎55 years.1 (2.24.38) 23 (3. 1.14 (0. n (%) 30 (4.30 (0.89) 4 (0. Analyses were not adjusted for the change in protocol (amendment 2) from combined Asp and clopidogrel to clopidogrel alone (enacted after the MATCH trial was published7) because this affected only 153 (11%) patients recruited 1.64) 20 (2. and 90 After Enrollment Asp/ER-DP (n⫽672) mRS score. currently taking or needing anticoagulation.79) Ceased treatment.32) 7 days 0 (no symptoms) 86 (12. severity (National Institutes of Health Stroke Scale [NIHSS] score).0) 2891 (14.2) 1. n (%) 5 (0. n (%) 88 (13.0) 2.89) 3 (0.0) … 2. Death.41.56 (0.0) … Major bleeding.0) 263 (38. 1.10) MMSE ⬍30. symptomatic intracranial hemorrhage.5) Intracranial bleeding. 3.13 (0.29) 2.58) 1.27) MI. n (%) Clopidogrel (n⫽688) OR (95% CI) 0 (0.4) 189 (27. ordinal logistic regression (ordered categorical data). n (%) 5 (0.17. n (%) 13 (1. 95% CI. 30. the need for transfusion of 2 or more units of red cells or the equivalent amount of whole blood.15) 2 (0. 6.67. Downloaded from http://stroke.66.23) 11 (1.61 (0. 3.87 (0.9) 1 (⬍1.2) Hemorrhagic transformation. 2.46 (0. n (%) 5 (0.37) Hemorrhagic transformation. n (%) 0 (0. n (%) 1 (0.11 Key exclusion criteria were dysphagia preventing oral medication. or the need for hospitalization. n (%) Combined vascular. n (%) 1 (0. sex. a more conventional trial time of 90 days (the usual time point in many acute stroke trials) was not possible because mRS was not measured at this point. *For nonacute patients. or multiple regression (continuous data). nonfatal MI.0) 0 (0. n (%) 0 (0.53. 0.58) Lost to follow-up. seated systolic blood pressure 121 to 180 mm Hg. (%) with ORs and (95% CI).26) 407 (66.0) 86 (12. known severe coronary artery disease or recent myocardial infarction (MI).66 (1. 2.22. composite vascular events (combination of nonfatal stroke.74) 7 (1.15) 2 (0. and patient scheduled for carotid endarterectomy.56) 1 ( by guest on May 26.26.49) 11 (1. 8.4) 103 (15. Values are No. and 90 days and included symptomatic hemorrhagic transformation of the infarct.22 (0. OR⫽1.3) 2.29) … TOAST indicates Trial of ORG 10172 in Acute Stroke Treatment.2) 7580 (37. Ordinal regression assumes that treatment effects are “proportional.10) ized.59. Values are No. n (%) 5 (0. n (%) 2 (0. bleeding.0) … 23 (3.60) 0.51 (1. and assignment to telmisartan or placebo. n (%) 1 (0.29) … Stroke recurrence. constant across the outcome categories.1) Data are shown as the number of subjects (%) or mean (SD).0) … 15 (2. 3. †Treatment-time (acute vs nonacute) interaction.0) … Combined vascular. severity (NIHSS score). April 2010 Continued Characteristic Asp/ER-DP (n⫽672) Clopidogrel (n⫽688) Whole Trial Table 2. 3. (%) or mean (SD) as shown. and neurologically stable.30) 2 (0. intraocular bleeding causing loss of vision. and vascular death).29) … Intracranial bleeding. 30 days Lost to follow-up.0) 1 (no significant disability) 235 (35. Secondary outcomes were studied at 7. Data for the whole trial are given for comparison. Comparison was made by binary logistic regression or multiple regression.60) 1.67) 11 (1. 1. 4.0) 0 (0.77) Any bleeding. n (%) 0 (0. 2.10) 1.0) 0 (0.91 (0.0) 1926 (9.15) … Cerebral edema. Significant findings are in boldface type.0) … SAEs.19) 3 (0. Functional outcome was chosen because it is the usual measure in acute stroke trials.36. 94. Where possible.3) 2853 (14. mean (SD) 2.44) 1. 2. known severe renal insufficiency or renal artery stenosis. systolic blood pressure. and serious adverse events.0) … Major bleeding. thrombocytopenia (platelets ⬍100⫻109/L or neutropenia [⬍1. MI.01. 30.62 (1. 1. n (%)† 90 days Lost to follow-up.5) 1.74. n (%) 10 (1.86 (0.15) … SAEs.15) 1 (0.71 (0.5) 1 (0.44) Stroke recurrence.91 (0. n (%) 47 (6.8 (2. An mRS score of 2– 6 indicates a “poor” outcome.9) 1 (0.39.15) … Any bleeding. n (%)* 229 (35. Stroke recurrence.15) 0 (0.8) 71 (10.7) 442 (69.61). P⫽0.6) 228 (34. cerebral edema.15) 2 (0. recurrent stroke. Tolerability was measured by adherence to therapy in the first 90 days.15) 0 (0.16.0) 0 (0. death.2⫻109/L]).4) 62 (9. 2. known hemostatic disorder or systemic bleeding.76. n (%) MI. Comparisons were performed with binary logistic regression (dichotomous data). n (%) 4 (0.5) 5081 (25. n (%) 4 (moderately severe disability) 70 (10.44) MI.25) Death.60) 2 (0.75.0) … Major bleeding. 2013 .12. 12. known current active peptic ulcer disease.37) Death.34) 0.34) Any bleeding. n (%) 1 (0. 5. with adjustment for age. n (%) 4 (0. severe dependency at time of randomization (modified Rankin Scale score [mRS] ⬎3).8) 3. n (%) Combined vascular. seated diastolic blood pressure ⱕ110 mm Hg. 11. n (%) Analyses 57 (8.96 –1.87) 0. Cumulative Outcome and Safety Measures at Days 7.46) 24 (3. n (%) 121 (18.04) 6 (0.9 (2. n (%) 0 (0.74) 1 (0.51 (0. sex. P⫽0.40.95 (0.” ie.02) 0.44) 2.60) 3 (0. n (%) 8 (1. n (%) 5 (severe disability) … … NIHSS score. hypersensitivity to or intolerance of any of the interventions. n (%) 6 (0.5) 0.56) SAEs.45. n (%) Ceased treatment.18) 2 (0.74) Ceased treatment.76) SAE indicates serious adverse event.0) 3 (moderate disability) 97 (14. n (%) 1 (0. cognition (Mini Mental State Examination [MMSE]).74) 6 (0.15) 1 (0.20 (0.

Asp/ER-DP did not alter functional outcome (assessed with the mRS) at 30 days.30. For completeness. clopidogrel n⫽10).41 to 1. The overall PRoFESS trial reported that recurrence rates were comparable between Asp/ER-DP and clopidogrel. analysis of potential interactions between the effect of treatment and components of 9 predefined sub- groups (by age. respectively. and 4 to 6 to maintain proportionality)16. 1 versus 0. Statistical significance was set at P⬍0. 95% CI. OR⫽0.75) (Figure 2) or with dichotomization of the data at the median (mRS 2 to 6. Similarly. Follow-Up and Adherence Follow-up at 90 days was completed for 667 (99. and transfusions.19. sex. Discussion The aim of the present post hoc subgroup analysis was to investigate the relative safety. did not differ between treatment groups at 90 days. efficacy.37. 95% CI. clopidogrel n⫽22) and for MMSE in 114 patients (Asp/ER-DP n⫽62. Table 2). gastrointestinal bleeding. OR⫽1. death. Although there were nonsignificant trends to lower rates of recurrence and composite vascular outcomes with Asp/ER-DP at 90 days.74). By 90 days. No serious adverse events were reported as edema extension or cerebral hemorrhage during the 90 days.36 to 1.12. 95%.1. though few. 1. In comparison with clopidogrel. prior use of aspirin. The treatment groups were similar for demographic and clinical measures (Table 1). although it is important to note that Asp-ER-DP failed to show noninferiority to clopidogrel. independent stroke [mRS 0. 95% CI. Treatment was started within 3 days of stroke in 853 patients (63%) and within 4 days in 1250 (92%). and antihypertensive assignment) did not differ between Asp/ER-DP and clopidogrel. both. CI 0. so subsequent analyses focused on the acute patients only. 1].26 to 1. Asp/ER-DP was associated with increased intracranial bleeding and trends in major and Downloaded from http://stroke. data were missing for mRS score in 50 patients (Asp/ER-DP n⫽ by guest on May 26.79 to 1. very early in the trial. 1 versus 2. with the majority of patients recruited during the third day after stroke onset (Table 1). P⫽0. Odds ratios (ORs) and (95% CIs) are shown. and other in 22 (Asp/ER-DP n⫽12. clopidogrel n⫽688) randomized within 72 hours of stroke onset (Figure 1). Patients (n⫽1360) were randomized within 72 hours of the onset of ischemia. clopidogrel n⫽10).5%) of those assigned to clopidogrel (P⫽0. A trend to a reduction in stroke recurrence with Asp/ ER-DP compared with clopidogrel was present at 90 days. 95% CI. 5 versus 6 and nonfatal. 0. The rates of serious adverse events were low and similar between Asp/ER-DP and clopidogrel groups during the first 90 days: fatal. the primary outcome for the whole trial. At day 30. baseline systolic blood pressure. The mean time from stroke to recruitment was 58 hours. Figure 1). 3. telmisartan. 0. systolic blood pressure. there were no differences between the treatment groups for MI.006). ie. mRS scores at day 30. 95% CI.19. 2013 . Comparison was made by ordinal logistic regression. P⫽0.79 to 1. with adjustment for the covariates of age. the rate of vascular events was nonsignificantly lower with Asp/ ER-DP than with clopidogrel at 90 days (OR⫽0. minor bleeding. dependent stroke [mRS 2 to 5]. adverse reaction in 39 (Asp/ER-DP n⫽36 [mostly headache]. Figure 5).ahajournals.75.89 to 1.13 examined the effect of Asp/ER-DP versus clopidogrel in 1360 patients (Asp/ED-DP n⫽672. Figure 4) or as a shift in the distribution of ordered categorical events (fatal stroke. analyzed either as an ordered categorical outcome (ordered mRS categories 0. 6 versus 4.Bath et al Aspirin/Dipyridamole for Acute Ischemic Stroke 735 Figure 2. but no interactions were present. whether assessed as time to event (OR⫽0.18.3%) patients receiving Asp/DP and for 681 (99. treatment was no longer being taken in 121 of 672 (18. 42 versus 36.33. Selected serious adverse events relevant to antiplatelet treatment included major bleeding. 0 versus 0.56.12 In addition. Analyses were performed with SAS version 9.05. with an NIHSS score of 3. Combined death or dependency (mRS score at 30 days after randomization. P⫽0. dipyridamole. P⫽0.35. and stroke severity was mild. Other events.0%) taking clopidogrel (Table 2. or cognition (MMSE). P⫽0. 65% were male.14.0%) patients randomized to Asp/ ER-DP nor in 86 of 688 (12. 0. and tolerability of 2 antiplatelet regimens when started in the acute phase of ischemic stroke.97. ie. the explanations were treatment never started in 19 (Asp/ER-DP n⫽9. Table 2). or clopidogrel. or no cerebrovascular event)17 (OR⫽0. When adverse events were considered. 0. in particular for the rates of all serious adverse events and for major bleeding. There was no difference in the MMSE score at 30 days. MI and death. OR⫽0. and TOAST) were performed on functional outcome (Figure 3). no significant differences were observed.75.47. P⫽0. clopidogrel n⫽3).97. transient ischemic attack. sex. Outcome There was no interaction between treatment and time of recruitment. 2. with an OR ⬍1 favoring Asp/ER-DP and an OR ⬎1 supporting clopidogrel. The mean age was 67 years. The characteristics of patients in this analysis were broadly similar to those of the whole trial (Table 1). “acute” versus “nonacute” (P⫽0.29. and data for these subjects form the basis of this report. clopidogrel n⫽52). Results This subgroup analysis of the PRoFESS trial12.71. 0. severity.

DP. other.7. CI.736 Stroke April 2010 Figure 3.ahajournals. 1) at day 30 in prespecified subgroups of patients categorized at baseline according to the following variables: age (⬎70. systolic blood pressure (⬎150. ⱕ70 years). sex. Downloaded from http://stroke. premorbid history of by guest on May 26. combined Asp and clopidogrel were associated with a nonsignificant reduction in recurrent stroke at 90 days (risk ratio⫽0. placebo). 95%. Kaplan–Meier plot for stroke recurrence during the first 90 days. and treatment assignment (telmisartan.12 These differences between the results of the main trial and the present subgroup analysis may be due to the fact that either the subgroup analysis was of modest size and was relatively underpowered to compare Asp/ER-DP and clopidogrel and/or patients with acute stroke with short-term follow-up may differ in their responses to antiplatelet agents. 2013 . combined Asp/DP. *All other etiologic subtypes included large-artery atherosclerosis. life-threatening bleeding compared with clopidogrel. cardioembolism. Very limited data have been published on the short-term use of DP or clopidogrel in stroke. ⱕ150 mm Hg). 0. Forrest plot showing a good functional outcome (mRS score⫽0. and clopidogrel use.3 to Figure 4. The FASTER pilot trial compared combined Asp and clopidogrel with Asp alone in 392 patients with transient ischemic attack or minor ischemic stroke. and undetermined etiologies.10 Compared with Asp alone.

8. 1. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. 1996. and stroke in high risk patients. Comparison was made by ordinal logistic regression.tardistrial. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient Downloaded from http://stroke.20) focused on patients with subacute or chronic stroke. Weber MA. and Roberts were members of the trial steering committee.19) or clopidogrel (CAPRIE. Mas J-L. and Vicky Hinstridge for technical assistance. and Roberts have received consulting and/or lecture fees from Boehringer Ingelheim. thus explaining why patients had very mild stroke (mean NIHSS score⫽3). Cohen EA. a stroke complication that can limit administration of oral medications. Rupprecht HJ. Cimminiello C.41 to 1. Forbes C. Black HR. efficacy. indeed. Matias-Guiu J. Bogousslavsky J. Topol EJ. so the exclusion of dysphagic patients. As a result. Hence. 60:197–199. the results come from a subgroup of patients entered into a very large secondary prevention trial. Drs Martin and Palesch have received consulting fees from Boehringer Ingelheim. such that patient characteristics reflected the inclusion criteria for a study of vascular prophylaxis rather than acute intervention. A randomised. Creager MA. 2002. The ongoing FASTER 2 (Asp-clopidogrel vs Asp) and TARDIS (Aspclopidogrel-DP vs Asp-DP.Bath et al Aspirin/Dipyridamole for Acute Ischemic Stroke 737 Figure 5. myocardial infarction. P⫽0.33. Drs Yusuf. J Neurol Neurosurg Psychiatry. The findings should not influence clinical practice or guidelines because they were based on a modestly sized and selected sample of patients. Fox KAA. MATCH.35. a lower dose of Asp was used than was tested in the IST and CAST megatrials (50 mg vs 160 to 300 mg/d). Pearson TA.9 Whether this difference is important in acute stroke is unclear. and Diener were co-chief investigators of PRoFESS. Brass LM. Several comments need to be made about this PRoFESS analysis. Sacco. the results do not apply to patients with moderate to severe stroke because no such patients were included. Brennan DM.18. Lowenthal A.13) who enrolled patients shortly after stroke into PRoFESS. and Drs Martin and Palesch and Daniel Cotton were biostatisticians supporting the trial. P⫽0. The ESPRIT Study Group.2 Fourth. Antithrombotic Trialists Collaboration.2. the sample size was too small to reliably detect any differences between antiplatelet strategies on functional outcome. European Stroke Prevention Study 2. Third. OR⫽0. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. and Sprigg et al3. and Daniel Cotton is an employee of Boehringer Ingelheim. as in PRoFESS. 3. need not occur in routine clinical practice.19)10. and very few patients were enrolled during the acute phase (Figure 2 in Kennedy et al10). in this respect.5.5). Importantly. Boden WE. Cacoub P. Haffner SM. Cunha L. Claiborne Johnston S. available at www.8. van Gijn J. Hankey GJ. Hamm CW. Drs Bath. Steg PGD. 7.7. ESPRIT. most patients entered the trial on day 3 (mean time to recruitment⫽58 hours). Sivenius J. Berger PB. P⫽0. this post hoc subgroup analysis of the PRoFESS trial involving 1360 patients was neutral and did not identify any significant differences between Asp/ER-DP and clopidogrel on functional outcome in patients with acute ischemic stroke.367:1665–1673. no patients were recruited during the hyperacute phase (⬍6 hours of onset) of stroke. 95% CI. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. although it is not in secondary prevention. Csiba L. Steinhubl SR.75.348:1329 –1339. however. both of the antiplatelet strategies appear to be safe when given in the short term after mild stroke (and possibly transient ischemic attack) and their administration is feasible. As a result. 0. First. it is worth noting that it took 2 megatrials of 20 000 patients each to demonstrate that Asp improved functional outcome after stroke. the inclusion criteria included neurologic stability and absence of severe dependency (mRS ⬎3). 6. Booth J. Algra A. Source of Funding Boehringer Ingelheim sponsored and funded PRoFESS and reviewed the manuscript. Disclosures Drs Bath. Fabry-Ribaudo L. trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Last. Acknowledgments We thank the patients included in this substudy. the present subgroup analysis represents the largest analysis of the safety. 2006.324:71– 86. largely through reducing early recurrence.6. J Neurol Sci. for the CHARISMA Investigators. N Engl J Med. the rate of intracranial hemorrhage did not differ between the groups (clopidogrel 1% vs placebo 0%. BMJ. 2013 . ESPS trials are examining the question of antiplatelet intensity in patients with acute transient ischemic attack or ischemic stroke. 2. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death. Bhatt DL. the trial was not designed to explicitly test the comparison of antiplatelet agents in acute ischemic stroke. Estol. CARESS. 1996. Diener HC. 5. Werner Hacke CB. Although ER-DP cannot be administered via nasogastric tube. Smets P. Kaste M. Mak K-H. Yusuf.354:1706 –1717. Estol. blinded. Diener HC. CAPRIE Steering Committee. Diener. Note that the majority of patients who did not have stroke or transient ischemic attack (95% of all patients) are not shown to improve visualization of the relevant part of the figure. Lancet.9 In summary. 2006. 1996. liquid DP can be used in its place during tube feeding. Sacco. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. 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