Effect of Combined Aspirin and Extended-Release Dipyridamole Versus Clopidogrel on Functional Outcome and Recurrence in Acute, Mild Ischemic Stroke
PRoFESS Subgroup Analysis
Background and Purpose— Long-term antiplatelet therapy is effective at reducing recurrence after ischemic stroke. However, the relative safety and efficacy of combined aspirin-dipyridamole or clopidogrel are not known in patients with acute ischemic stroke.
Methods— The factorial PRoFESS secondary prevention trial assessed antiplatelet and blood pressure–lowering strategies in 20 332 patients, 1360 of whom were randomized within 72 hours of ischemic stroke to combined aspirin (Asp; 25 mg BID) and extended-release dipyridamole (ER-DP; 200 mg BID, n=672) or clopidogrel (75 mg/d, n=688). The primary outcome for this post hoc subgroup analysis was functional outcome at 30 days; secondary outcomes included recurrence and death by 90 days. Analyses were adjusted for baseline prognostic variables and blood pressure treatment assignment.
Results— Patients were representative of the whole trial (age 67 years, National Institutes of Health Stroke Scale score 3, small-artery occlusion 59%), and baseline variables were similar between treatment groups. The mean time from stroke to recruitment was 58 hours. By 90 days, treatment was no longer being taken in 121 (18%) patients randomized to Asp/ER-DP and in 86 (12.5%) assigned to clopidogrel (P=0.006). Combined death or dependency (shift analysis of modified Rankin Scale score at day 30) did not differ between treatment groups (odds ratio [OR]=0.97; 95% CI, 0.79 to 1.19). Nonsignificant trends to reduced recurrence (OR=0.56; 95% CI, 0.26 to 1.18) and vascular events (OR=0.71; 95% CI, 0.36 to 1.37) were present with Asp/ER-DP. Rates of death, major bleeding, and serious adverse events did not differ between treatment groups.
Conclusions— Treatment with combined Asp/ER-DP vs clopidogrel in 1360 patients with acute, mild ischemic stroke did not differ in terms of effects on functional outcome, recurrence, death, bleeding, or serious adverse events. Both treatments were practical to administer.
Patients with ischemic stroke are at increased risk of having another event, and long-term antiplatelet therapy is effective at reducing recurrence.1 Numerous trials of secondary prevention have shown that aspirin (Asp) reduces recurrence by a modest (relative risk reduction 13%2) but worthwhile degree. Other antiplatelet agents are also individually effective, including extended-release dipyridamole (ER-DP) and clopidogrel.3,4 Although combining Asp and DP was more effective than either agent alone,3,5 combined Asp and clopidogrel did not offer additional benefit over either Asp or clopidogrel alone in patients with previous stroke, largely owing to excess bleeding.6,7
Because the risk of stroke recurrence is highest in the first few hours and days after an acute event, early commencement of antiplatelet therapy should be most effective, and this has been confirmed in 2 megatrials for Asp.8,9 However, the safety and efficacy of DP and clopidogrel in acute ischemic stroke have not been explored in large trials, although a small study suggested that combined Asp and clopidogrel might be more effective at reducing recurrence than Asp alone.10 Beneficial effects of early antiplatelet therapy may reflect several mechanisms, including treatment of the index event (eg, salvage of at-risk penumbra) and minimization of deterioration (secondary to thrombus extension) and early recurrence. Differential effects between antiplatelet agents might follow from differences in their antithrombotic activity and propensity to induce hemorrhagic transformation.
The ‘Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is the largest study investigating the prevention of recurrent stroke and compared, in a factorial design, combined Asp and ER-DP with clopidogrel, and telmisartan (angiotensin receptor antagonist) with placebo.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; as a result, 39.9% of patients were recruited within 10 days of the index event.12–14 Furthermore, 1366 (6.7%) patients were recruited within 72 hours of the ictus, thereby providing the opportunity to assess, post hoc, the safety, efficacy, and tolerability of Asp/ER-DP versus clopidogrel in patients with acute ischemic stroke in a randomized design.
Patients and Methods
The PRoFESS trial protocol11 and primary results12,13 have been published. In brief, PRoFESS compared the effect of combined Asp (25 mg BID) and ER-DP (200 mg BID) versus clopidogrel (75 mg daily), and telmisartan (80 mg daily, an angiotensin receptor antagonist) versus placebo in a 2×2 factorial design in patients with recent ischemic stroke. 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. All patients received best medical care independent of treatment assignment.
The aim of this post hoc PRoFESS subgroup analysis was to assess the relative safety, efficacy, and tolerability of Asp/ER-DP versus clopidogrel in patients with acute ischemic stroke. Patients were included if they were enrolled in the main trial and had been randomized within 72 hours of stroke onset.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. Some of the PRoFESS inclusion criteria are relevant specifically to assessment of antiplatelet agents in acute stroke: ischemic stroke; symptoms persisting for >24 hours, or if <24 hours, then computed tomographic or magnetic resonance evidence of a new stroke; hospitalized; age >55 years, or 50 to 54 years if 2 additional vascular risk factors were present; seated systolic blood pressure 121 to 180 mm Hg; seated diastolic blood pressure ≤110 mm Hg; and neurologically stable.11
Key exclusion criteria were dysphagia preventing oral medication; severe dependency at time of randomization (modified Rankin Scale score [mRS] >3); hypersensitivity to or intolerance of any of the interventions; currently taking or needing anticoagulation; known current active peptic ulcer disease; known hemostatic disorder or systemic bleeding; thrombocytopenia (platelets <100×109/L or neutropenia [<1.2×109/L]); known severe renal insufficiency or renal artery stenosis; known severe coronary artery disease or recent myocardial infarction (MI); and patient scheduled for carotid endarterectomy.
The primary outcome in this post hoc subgroup analysis was functional outcome measured by the mRS at 30 days after randomization. Functional outcome was chosen because it is the usual measure in acute stroke trials; 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. Secondary outcomes were studied at 7, 30, and 90 days and included symptomatic hemorrhagic transformation of the infarct, cerebral edema, recurrent stroke, MI, composite vascular events (combination of nonfatal stroke, nonfatal MI, and vascular death), death, cognition (Mini Mental State Examination [MMSE]), bleeding, and serious adverse events. Where possible, ordered categorical outcomes were analyzed with ordinal statistical approaches to improve statistical power.16,17 Major bleeding was defined as a hemorrhagic event that resulted in clinically significant disability, symptomatic intracranial hemorrhage, intraocular bleeding causing loss of vision, the need for transfusion of 2 or more units of red cells or the equivalent amount of whole blood, or the need for hospitalization. Tolerability was measured by adherence to therapy in the first 90 days.
Data are shown as the number of subjects (%) or mean (SD). Comparisons were performed with binary logistic regression (dichotomous data), ordinal logistic regression (ordered categorical data), or multiple regression (continuous data). Ordinal regression assumes that treatment effects are “proportional,” ie, constant across the outcome categories. Statistical models were adjusted for the baseline prognostic covariates of age, sex, severity (National Institutes of Health Stroke Scale [NIHSS] score), systolic blood pressure; and assignment to telmisartan or placebo. 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 very early in the trial. Odds ratios (ORs) and (95% CIs) are shown, with an OR <1 favoring Asp/ER-DP and an OR >1 supporting clopidogrel. Statistical significance was set at P<0.05. Analyses were performed with SAS version 9.1.
This subgroup analysis of the PRoFESS trial12,13 examined the effect of Asp/ER-DP versus clopidogrel in 1360 patients (Asp/ED-DP n=672, clopidogrel n=688) randomized within 72 hours of stroke onset (Figure 1). The mean time from stroke to recruitment was 58 hours, with the majority of patients recruited during the third day after stroke onset (Table 1⇓). Treatment was started within 3 days of stroke in 853 patients (63%) and within 4 days in 1250 (92%). The characteristics of patients in this analysis were broadly similar to those of the whole trial (Table 1⇓). The mean age was 67 years, 65% were male, and stroke severity was mild, with an NIHSS score of 3. The treatment groups were similar for demographic and clinical measures (Table 1⇓).
Follow-Up and Adherence
Follow-up at 90 days was completed for 667 (99.3%) patients receiving Asp/DP and for 681 (99.0%) taking clopidogrel (Table 2, Figure 1). At day 30, data were missing for mRS score in 50 patients (Asp/ER-DP n=28, clopidogrel n=22) and for MMSE in 114 patients (Asp/ER-DP n=62, clopidogrel n=52). By 90 days, treatment was no longer being taken in 121 of 672 (18.0%) patients randomized to Asp/ER-DP nor in 86 of 688 (12.5%) of those assigned to clopidogrel (P=0.006); the explanations were treatment never started in 19 (Asp/ER-DP n=9, clopidogrel n=10), adverse reaction in 39 (Asp/ER-DP n=36 [mostly headache], clopidogrel n=3), and other in 22 (Asp/ER-DP n=12, clopidogrel n=10).
There was no interaction between treatment and time of recruitment, ie, “acute” versus “nonacute” (P=0.74), so subsequent analyses focused on the acute patients only. Combined death or dependency (mRS score at 30 days after randomization, with adjustment for the covariates of age, sex, systolic blood pressure, severity, and antihypertensive assignment) did not differ between Asp/ER-DP and clopidogrel, analyzed either as an ordered categorical outcome (ordered mRS categories 0, 1, 2, 3, and 4 to 6 to maintain proportionality)16; OR=0.97; 95% CI, 0.79 to 1.19; P=0.75) (Figure 2) or with dichotomization of the data at the median (mRS 2 to 6; OR=1.14; 95% CI, 0.89 to 1.47; P=0.29; Table 2). For completeness, analysis of potential interactions between the effect of treatment and components of 9 predefined subgroups (by age; sex; baseline systolic blood pressure; prior use of aspirin, dipyridamole, both, or clopidogrel; telmisartan; and TOAST) were performed on functional outcome (Figure 3), but no interactions were present.
A trend to a reduction in stroke recurrence with Asp/ER-DP compared with clopidogrel was present at 90 days, whether assessed as time to event (OR=0.56; 95%, CI 0.26 to 1.18; P=0.12; Figure 4) or as a shift in the distribution of ordered categorical events (fatal stroke, dependent stroke [mRS 2 to 5], independent stroke [mRS 0, 1], transient ischemic attack, or no cerebrovascular event)17 (OR=0.75; 95% CI, 0.41 to 1.35; P=0.33; Figure 5). Similarly, the rate of vascular events was nonsignificantly lower with Asp/ER-DP than with clopidogrel at 90 days (OR=0.71; 95% CI, 0.36 to 1.37; P=0.30; Table 2). Other events, ie, MI and death, though few, did not differ between treatment groups at 90 days. There was no difference in the MMSE score at 30 days.
The rates of serious adverse events were low and similar between Asp/ER-DP and clopidogrel groups during the first 90 days: fatal, 5 versus 6 and nonfatal, 42 versus 36. Selected serious adverse events relevant to antiplatelet treatment included major bleeding, 6 versus 4; minor bleeding, 1 versus 2; gastrointestinal bleeding, 0 versus 0; and transfusions, 1 versus 0, respectively. No serious adverse events were reported as edema extension or cerebral hemorrhage during the 90 days.
The aim of the present post hoc subgroup analysis was to investigate the relative safety, efficacy, and tolerability of 2 antiplatelet regimens when started in the acute phase of ischemic stroke. Patients (n=1360) were randomized within 72 hours of the onset of ischemia, and data for these subjects form the basis of this report. In comparison with clopidogrel, Asp/ER-DP did not alter functional outcome (assessed with the mRS) at 30 days. Although there were nonsignificant trends to lower rates of recurrence and composite vascular outcomes with Asp/ER-DP at 90 days, there were no differences between the treatment groups for MI, death, or cognition (MMSE). When adverse events were considered, no significant differences were observed, in particular for the rates of all serious adverse events and for major bleeding.
The overall PRoFESS trial reported that recurrence rates were comparable between Asp/ER-DP and clopidogrel, although it is important to note that Asp-ER-DP failed to show noninferiority to clopidogrel, the primary outcome for the whole trial.12 In addition, Asp/ER-DP was associated with increased intracranial bleeding and trends in major and life-threatening bleeding compared with clopidogrel.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.
Very limited data have been published on the short-term use of DP or clopidogrel in stroke. The FASTER pilot trial compared combined Asp and clopidogrel with Asp alone in 392 patients with transient ischemic attack or minor ischemic stroke.10 Compared with Asp alone, combined Asp and clopidogrel were associated with a nonsignificant reduction in recurrent stroke at 90 days (risk ratio=0.7; 95%, CI, 0.3 to 1.2; P=0.19)10; the rate of intracranial hemorrhage did not differ between the groups (clopidogrel 1% vs placebo 0%, P=0.5). Earlier trials involving DP (ESPS, ESPS II, ESPRIT, and Sprigg et al3,5,18,19) or clopidogrel (CAPRIE, MATCH, CARESS, and CHARISMA4,6,7,20) focused on patients with subacute or chronic stroke, and very few patients were enrolled during the acute phase (Figure 2 in Kennedy et al10). Hence, the present subgroup analysis represents the largest analysis of the safety, efficacy, and tolerability of both Asp/ER-DP and clopidogrel in acute ischemic stroke.
Several comments need to be made about this PRoFESS analysis. First, the results come from a subgroup of patients entered into a very large secondary prevention trial, such that patient characteristics reflected the inclusion criteria for a study of vascular prophylaxis rather than acute intervention. As a result, the trial was not designed to explicitly test the comparison of antiplatelet agents in acute ischemic stroke. Importantly, the inclusion criteria included neurologic stability and absence of severe dependency (mRS >3), thus explaining why patients had very mild stroke (mean NIHSS score=3). Second, no patients were recruited during the hyperacute phase (<6 hours of onset) of stroke; indeed, most patients entered the trial on day 3 (mean time to recruitment=58 hours). Third, a lower dose of Asp was used than was tested in the IST and CAST megatrials (50 mg vs 160 to 300 mg/d).8,9 Whether this difference is important in acute stroke is unclear, although it is not in secondary prevention.2 Fourth, no patient had dysphagia, a stroke complication that can limit administration of oral medications. Although ER-DP cannot be administered via nasogastric tube, liquid DP can be used in its place during tube feeding, so the exclusion of dysphagic patients, as in PRoFESS, need not occur in routine clinical practice. Last, the sample size was too small to reliably detect any differences between antiplatelet strategies on functional outcome; in this respect, it is worth noting that it took 2 megatrials of 20 000 patients each to demonstrate that Asp improved functional outcome after stroke, largely through reducing early recurrence.8,9
In summary, 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. As a result, 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; however, the results do not apply to patients with moderate to severe stroke because no such patients were included. The findings should not influence clinical practice or guidelines because they were based on a modestly sized and selected sample of patients. The ongoing FASTER 2 (Asp-clopidogrel vs Asp) and TARDIS (Asp-clopidogrel-DP vs Asp-DP; available at www.tardistrial.org/) trials are examining the question of antiplatelet intensity in patients with acute transient ischemic attack or ischemic stroke.
We thank the patients included in this substudy; the investigators (listed in the primary trial publications12,13) who enrolled patients shortly after stroke into PRoFESS; and Vicky Hinstridge for technical assistance. Drs Yusuf, Sacco, and Diener were co-chief investigators of PRoFESS; Drs Bath, Estol, and Roberts were members of the trial steering committee; and Drs Martin and Palesch and Daniel Cotton were biostatisticians supporting the trial.
Source of Funding
Boehringer Ingelheim sponsored and funded PRoFESS and reviewed the manuscript.
Drs Bath, Yusuf, Sacco, Diener, Estol, and Roberts have received consulting and/or lecture fees from Boehringer Ingelheim; Drs Martin and Palesch have received consulting fees from Boehringer Ingelheim; and Daniel Cotton is an employee of Boehringer Ingelheim.
- Received August 6, 2009.
- Accepted August 25, 2009.
Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71–86.
Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry. 1996; 60: 197–199.
Bhatt DL, Fox KAA, Werner Hacke CB, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Claiborne Johnston S, Mak K-H, Mas J-L, Montalescot G, Pearson TA, Steg PGD, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ, for the CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006; 354: 1706–1717.
Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004; 364: 331–337.
Diener H-C, Sacco RL, Yusuf S, for the Steering Committee and PRoFESS Study Group. Rationale, design and baseline data of a randomized, double-blind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: the prevention regimen for effectively avoiding second strokes trial (PRoFESS). Cerebrovasc Dis. 2007; 23: 368–380.
Sacco RL, Diener H-C, Yusuf S, Cotton D, Ounpuu S, Lawton W, Palesch Y, Martin R, Albers GW, Bath PM, Bornstein N, Chan BPL, Chen S-T, Cunha L, Dahlof B, De Keyser J, Donnan GA, Estol C, Gorelick PB, Gu V, Hermansson K, Hillbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voight T, Weber M, Yoon B-W, the PROFESS Study Group. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008; 359: 1238–1251.
Yusuf S, Diener H-C, Sacco RL, Cotton D, Ounpuu S, Lawson WA, Palesch Y, Martin RH, Albers GW, Bath PM, Bornstein N, Chan BPL, Chen S-T, Cunha L, Dahlof B, De Keyser J, Donnan GA, Estol C, Gorelick PB, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig G, PP, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voight T, Weber M, Yoon B-W, for the PROFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008; 359: 1225–1237.
Diener H-C, Sacco RL, Yusuf S, Cotton D, Ounpuu S, Lawton W, Palesch Y, Martin R, Albers GW, Bath PM, Bornstein N, Chan BPL, Chen S-T, Cunha L, Dahlof B, De Keyser J, Donnan GA, Estol C, Gorelick PB, Gu V, Hermansson K, Hillbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voight T, Weber M, Yoon B-W, for the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol. 2008; 7: 875–884.
Bath PM, Martin RH, Palesch Y, Cotton D, Yusuf S, Sacco R, Diener HC, Toni D, Estol C, Roberts R; PRoFESS Study Group. Effect of telmisartan on functional outcome, recurrence, and blood pressure in patients with acute mild ischemic stroke: a PRoFESS subgroup analysis. Stroke. 2009; 40: 3541–3546.
The Optimising Analysis of Stroke Trials (OAST) Collaboration. Can we improve the statistical analysis of stroke trials? statistical re-analysis of functional outcomes in stroke trials. Stroke. 2007; 38: 1911–1915.
Bath PMW, Geeganage CM, Gray LJ, Collier T, Pocock S. Use of ordinal outcomes in vascular prevention trials: comparison with binary outcomes in published stroke trials. Stroke. 2008; 39: 2817–2823.
Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, Ringelstein EB. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection; the clopidogrel and aspirin for reduction of emboli in symptomatic carotid stenosis (CARESS) trial. Circulation. 2005; 111: 2233–2240.