Evaluation of Antiplatelet Agents for Secondary Prevention of Stroke Using Mixed Treatment Comparison Meta-analysis

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1 Original Research Clinical Therapeutics/Volume 35, Number 10, 2013 Evaluation of Antiplatelet Agents for Secondary Prevention of Stroke Using Mixed Treatment Comparison Meta-analysis Rhynn J. Malloy, PharmD; Abir O. Kanaan, PharmD; Matthew A. Silva, PharmD, BCPS; and Jennifer L. Donovan, PharmD MCPHS University, School of Pharmacy, Worcester, Massachusetts ABSTRACT Background: The current guidelines recommend various antiplatelet agents used alone or in combination for secondary prevention of noncardioembolic stroke. Objective: The purpose of this study was to conduct a mixed treatment comparison meta-analysis to determine which antiplatelet or combination of antiplatelet agents is most efficacious and tolerable in patients with prior stroke. Methods: A comprehensive literature search was conducted in MEDLINE (1945 through March 2012), EMBASE (1974 through March 2012), and the Cochrane Controlled Trials Registry (1975 through April 2012) to identify randomized trials evaluating the role of various antiplatelet agents and combinations for the secondary prevention of stroke. Key articles were cross-referenced for additional studies. Data were screened and evaluated to generate direct and indirect comparisons for recurrent stroke and overall hemorrhagic events. Data were reported as rate ratios (RRs) and 95% CIs. Results: A total of 24 articles were included in the analysis. Eleven antiplatelet regimens were compared in 488,000 patients. The combination of acetylsalicylic acid (ASA) plus dipyridamole (DP) was more protective against recurrent stroke than ASA alone (RR ¼ 0.78; 95% CI, ), and no differences were found in all other direct and indirect comparisons with active treatment. ASA plus DP was associated with more overall hemorrhagic events than DP (RR ¼ 1.83; 95% CI, ), cilostazol (RR ¼ 2.12; 95% CI, ), and triflusal (RR ¼ 1.67; 95% CI, ) but fewer events than the combination of ASA plus clopidogrel (RR ¼ 0.38; 95% CI, ). The combination of ASA plus clopidogrel was associated with an excess of overall hemorrhagic events compared with clopidogrel (RR ¼ 2.81; 95% CI, ), cilostazol (RR ¼ 5.56; 95% CI, ), DP (RR ¼ 4.78; 95% CI, ), sarpogrelate (RR ¼ 3.59; 95% CI, ), terutroban (RR ¼ 2.13; 95% CI, ), ticlopidine (RR ¼ 2.80; 95% CI, ), and triflusal (RR ¼ 4.36; 95% CI, ). Conclusion: We found that ASA plus DP was more protective than ASA alone for preventing recurrent stroke; however, no difference was found between most direct and indirect comparisons of antiplatelet agents and combinations. More overall hemorrhagic events seemed to occur with the combination of ASA and clopidogrel than with other treatments. Selection of antiplatelet therapy for the secondary prevention of stroke must be individualized according to patient comorbidities, including risk of stroke recurrence and bleeding. (Clin Ther. 2013;35: ) & 2013 Elsevier HS Journals, Inc. All rights reserved. Key words: antiplatelet, stroke prevention, bleeding, mixed treatment comparison, aspirin, dipyridamole. INTRODUCTION Stroke is a leading cause of morbidity and mortality worldwide and remains a major health care problem with an increasing economic burden. 1,2 Current projections suggest that death caused by stroke will increase exponentially in the next 30 years due to the aging population and inadequate management of risk factors. 3 Furthermore, it is estimated that 25% of strokes that occur each year are recurrent events in which risk is highest during the initial hours to days after a transient ischemic attack (TIA) or ischemic Accepted for publication September 6, /$ - see front matter & 2013 Elsevier HS Journals, Inc. All rights reserved Volume 35 Number 10

2 R.J. Malloy et al. stroke. Thus, a focus on secondary prevention is important in this patient population, and the choice between antiplatelet or anticoagulant therapy often depends on the cause of the stroke and patient-specific risks of recurrence and bleeding. 4 7 Acetylsalicylic acid (ASA) has been an essential drug for secondary prevention of stroke, in conjunction with risk factor modification, such as blood pressure control, management of dyslipidemia, diabetic control, and smoking cessation. In recent years, several antiplatelets and combinations of these antiplatelet agents have become available. The current guidelines on the prevention of thrombotic events in patients with a history of noncardioembolic ischemic stroke or TIA give strong recommendations with high quality of evidence to any one of the following agents: ASA, clopidogrel, cilostazol, or the combination of ASA plus dipyridamole (DP) over no therapy, the combination of ASA plus clopidogrel, or triflusal. 8 However, in a weaker recommendation supported by moderate or low quality of evidence, the preferred agents are clopidogrel or the combination of ASA plus DP over ASA or cilostazol. The weaker recommendation is potentially due to the lack of direct comparisons among all antiplatelet agents. Given the mixed evidence and various antiplatelet options, it becomes challenging for clinicians to select an optimal agent. Therefore, we conducted a mixed treatment comparison (MTC) meta-analysis to evaluate how well antiplatelet therapy protected against recurrent vascular events while minimizing hemorrhagic events in patients with noncardioembolic ischemic stroke in a network of direct and indirect comparisons. METHODS This analysis evaluated the efficacy and tolerability of 11 antiplatelet regimens used in patients with prior noncardioembolic stroke: ASA, cilostazol, clopidogrel, DP, ticlopidine, triflusal, sarpogrelate, and the combination of ASA with cilostazol, clopidogrel, DP, or triflusal. Efficacy end points included recurrent stroke, the composite of vascular events, death from any cause, death from vascular causes, and myocardial infarction (Table I). Tolerability end points included any hemorrhagic and major hemorrhagic events and intracranial hemorrhage (Table I). A systematic search was conducted in MEDLINE (1945 through March 2012), EMBASE (1974 through March 2012), and the Cochrane Controlled Trials Registry (1975 through April 2012) for human, English-language, and randomized controlled trials evaluating the role of various antiplatelets used separately or in combination for the secondary prevention of stroke. The following terms were used in the search: aspirin, dipyridamole, Aggrenox, clopidogrel, ticlopidine, triflusal, cilostazol, stroke, transient ischemic attack, secondary stroke prevention, and stroke prevention. Key articles were cross-referenced for additional studies. Studies were included in the analysis if patients had a prior cerebral ischemic event (defined as ischemic stroke, TIA, reversible ischemic neurologic deficit, or any combination thereof) and were using antiplatelet therapy as the primary method for secondary stroke prevention (Table II). Studies were excluded if they (1) did not meet the prespecified population, (2) did not assess efficacy of the intervention, (3) were not an original study, and/or (4) were not a randomized controlled trial. All authors reviewed studies to evaluate methods; to identify patient characteristics; to ascertain randomization, blinding, and allocation concealment; and to assign quality scores. Any identified discrepancies were resolved with additional review and discussion. 9 We used an MTC meta-analysis to create a bayesian evidence network and evaluate direct and indirect treatment effects The Aggregate Data Drug Information System (ADDIS), version , software package was used to build a Markov Chain Monte Carlo analysis using antiplatelet trials in patients with a history of stroke 13 (see the Supplemental Appendix I in the online version at 004). An evidence network was constructed to make direct (A vs B or B vs C) and indirect (A vs C) treatment comparisons along with the number of trials in each node. 14,15 Treatment networks were evaluated to identify heterogeneity and consistency within closed loop evidence structures. 13,16 18 The MTC methods preserved the benefit of within-trial randomization and allowed combinations of direct and indirect evidence because studies had comparable patient characteristics without notable heterogeneity 11,18 (see the Supplemental Appendix II in the online version at ). Data were reported as odds ratios (RRs) and 95% CIs because rates allow for comparisons when multiple events occur in the same individuals. RESULTS Study Demographic Characteristics A total of 661 potentially relevant articles were identified and reviewed, 637 of which were excluded October

3 Clinical Therapeutics Table I. Definition of clinical and safety outcomes. Outcome Recurrent ischemic event Composite of vascular events Myocardial infarction Death from any cause Death from vascular causes Any hemorrhagic event Major hemorrhagic event Intracranial hemorrhage Definition Ischemic stroke, TIA, RIND, or any combination thereof Composite of recurrent ischemic event, MI, vascular death, cerebral hemorrhage, major heart failure, death from any cause, and major hemorrhagic event presented as: Stroke, MI, and vascular death Stroke, MI, HF, TIA, and major hemorrhagic event Stroke, vascular death, MI, and death from any cause Stroke, MI, vascular death, and major hemorrhagic event Stroke, MI, TIA, and cerebral hemorrhage Stroke and death from any cause Stroke, MI, and cerebral hemorrhage Stroke, TIA, and death from any cause Stroke, MI, TIA, and vascular death As reported by each study Death from any reason Death from any vascular event that was recorded in the study, including but not limited to any combination of stroke, MI, TIA, and any hemorrhagic event. Any recorded instance of hemorrhage during follow-up As reported by each study (see the Supplemental Appendix II in the online version at Any hemorrhagic event, including intracerebral hemorrhage, subarachnoid hemorrhage, intraocular hemorrhage, and parenchymal hemorrhage: Intracerebral and subarachnoid Intracerebral and intraocular Intracerebral Intracerebral and parenchyma HF ¼ heart failure; MI ¼ myocardial infarction; RIND ¼ reversible ischemic neurologic disease; TIA ¼ transient ischemic attack. on the basis of study design, duplication, and relevancy. Data from 24 trials were abstracted, entered into ADDIS, and included in the evidence network (Figure) A total of 88,675 patients (range, ,332) with 342,899 person-years of follow-up were represented in the analysis (Table III and Supplemental Appendix I in the online version at /j.clinthera ). All studies included were double-blinded by design. Most patients were male (63.4%). The mean age of the patients was 63.9 years, with a range of 59 to 68 years. All studies reported concurrent history of hypertension, but only 11 reported systolic (range, mm Hg) and diastolic (range, mm Hg) blood pressure. A proportion of patients had a concurrent history of hyperlipidemia (37.9%) or diabetes mellitus (27.4%) (Table III and Supplemental Appendix I in the online version at ). Efficacy Outcomes Recurrent Stroke ASA, clopidogrel, and the combinations of ASA plus DP and ASA plus clopidogrel were more effective than placebo for recurrent stroke. The combination of ASA plus DP was more effective than ASA alone (RR ¼ 0.78; 95% CI, ) (Table IV). All other 1492 Volume 35 Number 10

4 R.J. Malloy et al. Table II. Summary of inclusion and exclusion criteria for meta-analysis. Study design Population Intervention Outcomes Language of publication Only prospective randomized controlled trials with JADAD score of Z3 were included Adult patients (Z18 years) who had previously experienced an ischemic event (ischemic stroke, TIA, and RIND) and were using antiplatelet therapy as their primary method of stroke prevention. Studies were included if they assessed Z1 of these treatments: Aspirin Clopidogrel Dypiridamole Ticlodipine Triflusal Cilostazol Studies were included if they reported Z1 of the following outcomes: Recurrent ischemic event Composite of vascular events Myocardial infarction Death from any cause Death from vascular cause Any hemorrhagic event Major hemorrhagic event Intracranial hemorrhage Only publications in the English language were included RIND ¼ reversible ischemic neurologic deficit; TIA ¼ transient ischemic attack. direct and indirect comparisons found no difference in the risk of recurrent stroke (See the Supplemental Appendix III in the online version at /j.clinthera ). Composite of Vascular Events ASA, cilostazol, clopidogrel, ticlopidine, and the combinations of ASA plus DP and ASA plus clopidogrel were more effective than placebo in reducing the composite of vascular events (Table IV). Similarly, ASA plus DP was more effective than ASA alone (RR ¼ 0.79; 95% CI, ) and DP (RR ¼ 0.75; 95% CI, ) alone. All other direct and indirect comparisons found no difference in the risk of vascular events (see the Supplemental Appendix IV in the online version at Death From Any Cause and Death From Vascular Causes ASA, clopidogrel, ticlopidine, and the combinations of ASA plus clopidogrel and ASA plus DP were more effective than terutroban in reducing death from vascular causes (Table IV). All other direct and indirect comparisons found no difference in the reduction of death from vascular causes or death Reason for exclusion: Review/editorial Copy/duplicate Study design Intervention Disease/indication Study population Language 661 articles identified as potentially relevant 617 articles excluded based on title and abstract 20 articles excluded based on full text 24 articles were included in the analysis Figure. Study identification and exclusion process. The systematic process of identifying, reviewing, and applying inclusion and exclusion criteria for this mixed treatment comparison meta-analysis. October

5 1494 Volume 35 Number 10 Table III. Study demographic characteristics. Study Study Size Personyears of Followup Primary End point (s) Qualifying Event Age, y Men, No. Women, No. Systolic Blood Pressure, mm Hg Diastolic Blood Pressure, mm Hg Other Concomitant Disease Concomitant Atherosclerotic Disease HTN Hyperlipidemia Diabetes AP MI Stroke PAD TIA Current Smoker Tobacco Use Nonsmoker or Exsmoker AAASPS RS, MI, VD Ischemic stroke ACCSG RS, RI, TIA ACD AICLA RS Ischemic stroke, TIA AITIA RS, VD, TIA ACD, TIA CAPRIE ,724 RS, MI, VD Ischemic stroke, MI, PAD * Culebras et al NFRS, Cerebral NFMI, MB infarction, TIA Danish RS, ACD TIA, RIND Cooperative Study 25 Danish low-dose RS, RI, TIA, Ischemic stroke study 26 VD, ACD, MI ESPRIT ,695 NFRS, VD, TIA, RIND NFMI, MB ESPS RS, ACD Ischemic stroke, TIA, RIND ESPS ,204 RS, ACD Ischemic stroke, TIA Hankey et al ,600 RS Ischemic stroke, TIA Huang et al RS Ischemic stroke MATCH ,531 RS, MI, Ischemic stroke, ACD TIA and IS, MI, AP, DM, and PAD Matias-Guiu NFRS, VD, Ischemic stroke, et al 33 NFMI TIA PERFORM 34 19,100 77,992 RS, NFMI, Ischemic stroke, 67 11, , ,023 VD RIND, TIA PROFESS 35,36 20,332 89,800 RS Ischemic Stroke 65 13, , ,022 S-ACCESS RS Ischemic stroke SALT RS, VD Ischemic stroke, TIA, RIND (continued) Clinical Therapeutics

6 October Table III. (continued) Study Study Size Personyears of Followup Primary End point (s) Qualifying Event Age, y Men, No. Women, No. Systolic Blood Pressure, mm Hg Diastolic Blood Pressure, mm Hg Other Concomitant Disease Concomitant Atherosclerotic Disease HTN Hyperlipidemia Diabetes AP MI Stroke PAD TIA Current Smoker Tobacco Use Shinohara et al ,137 RS Ischemic stroke Swedish RS, ACD Ischemic stroke Cooperative Study 40 TASS ,158 NFRS, ACD Ischemic stroke, RIND, TIA TOPALS RS, MI, Ve Ischemic stroke UK-TIA ,451 RS, MI, Ischemic stroke, ACD TIA Total 88,675 3,42, (mean) 56,267 32, ,585 33,606 24, , ,192 54,950 AASPS ¼ African American Antiplatelet Stroke Prevention Study; ACCSG ¼ American-Canadian Co-Operative Study; ACD ¼ all-cause death; AICLA ¼ Accidents ischémiques cérébraux liés à l athérosclérose; AITIA ¼ Aspirin in Transient Ischemic Attacks; AP ¼ angina pectoris; CAPRIE ¼ Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events; DM ¼ diabetes mellitus; ESPIRIT ¼ European/Australasian Stroke Prevention in Reversible Ischaemia Trial; ESPS ¼ European Stroke Prevention Study; HTN ¼ hypertension; IS ¼ ischemic stroke; MATCH ¼ Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke; MB ¼ major bleeding; MI ¼ myocardial infarction; NFMI ¼ nonfatal myocardial infarction; NFRS ¼ nonfatal recurrent stroke; PAD ¼ peripheral artery disease; PERFORM ¼ Prevention of cerebrovascular and cardiovascular Events of ischemic origin with terutroban in patients with a history of ischaemic stroke or transient ischaemic attack; PRoFESS ¼ Prevention Regimen for Effectively Avoiding Second Strokes Trial; RI ¼ retinal infarction; RIND ¼ reversible ischemic neurologic deficit; RS ¼ recurrent stroke; S-ACCESS ¼ Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction; SALT ¼ Swedish Aspirin Low-Dose Trial; TASS ¼ Ticlopidine Aspirin Stroke Study; TOPALS ¼ Tokai Panaldine Aspirin Long-Term Study; TIA ¼ transient ischemic attack; UK-TIA ¼ United Kingdom transient ischaemic attack aspirin trial; Vep ¼ ; VD¼ vascular death; VE = vascular events. *Only looked at stroke subgroup Includes ischemic stroke, cerebral hemorrhage, and subarachnoid hemorrhage. Excluding hemorrhagic death. Nonsmoker or Exsmoker R.J. Malloy et al.

7 Clinical Therapeutics from any cause (see the Supplemental Appendix V and Supplemental Appendix VI in the online version at Table IV. Efficacy outcomes. Outcome RR (95% CI) Myocardial Infarction ASA (RR ¼ 0.75; 95% CI, ) and the combination of ASA plus DP (RR ¼ 0.64; 95% CI, ) were more effective than placebo for the reduction of myocardial infarction (Table IV). All other direct and indirect comparisons revealed no difference (see the Supplemental Appendix VII in the online version at ). Tolerability Outcomes Overall Hemorrhagic Events In direct comparisons, ASA was associated with an excess of overall hemorrhagic events when compared with placebo, cilostazol, DP, and triflusal but was associated with fewer events when compared with the combination of ASA plus clopidogrel (RR ¼ 0.43; 95% CI, ) (Table V). The combination of ASA plus DP had an excess of overall hemorrhagic events when compared with placebo (RR ¼ 2.04; 95% CI, ) or DP (RR ¼ 1.83; 95% CI, ). The combination of ASA plus clopidogrel also had an excess of overall hemorrhagic events than clopidogrel (RR ¼ 2.81; 95% CI, ). The indirect comparisons of the combination of ASA plus clopidogrel were associatedwithanexcessofoverall hemorrhagic events when compared with cilostazol, DP, sarpogrelate, terutroban, ticlopidine, and triflusal. The combination of ASA plus DP resulted in an excess of overall hemorrhagic events when compared with cilostazol (RR ¼ 2.12; 95% CI, ) and triflusal (RR ¼ 1.67; 95% CI, ) but fewer events than the combination of ASA plus clopidogrel (RR ¼ 0.38; 95% CI, ). Cilostazol had fewer instances of overall hemorrhagic events than clopidogrel, terutroban, ticlopidine, and the combination of ASA plus DP. Triflusal was associated with fewer events than terutroban (RR ¼ 0.49; 95% CI, ) or the combination of ASA plus DP (RR ¼ 0.60; 95% CI, ). Placebo was associated with fewer events than clopidogrel, terutroban, ticlopidine, or the combination of ASA plus clopidogrel. All other indirect and direct comparisons revealed no difference (see the Supplemental Appendix VIII in the online version at clinthera ). Recurrent stroke Direct comparison ASA vs placebo 0.79 ( ) ASA-DP vs placebo 0.63 ( ) ASA-DP vs ASA 0.78 ( ) Indirect comparison Clopidogrel vs placebo 0.66 ( ) ASA-clopidogrel vs placebo 0.61 ( ) Composite of vascular events Direct comparison ASA vs placebo 0.75 ( ) ASA-DP vs placebo 0.59 ( ) ASA-DP vs DP 0.75 ( ) ASA-DP vs ASA 0.79 ( ) Indirect comparison Cilostazol vs placebo 0.59 ( ) Ticlodipine vs placebo 0.73 ( ) ASA-clopidogrel vs placebo 0.61 ( ) Death from vascular causes Direct comparison ASA vs terutroban 0.60 ( ) Indirect comparison Clopidogrel vs terutroban 0.52 ( ) Ticlodipine vs terutroban 0.40 ( ) ASA-clopidogrel vs terutroban 0.46 ( ) ASA-DP vs terutroban 0.46 ( ) Myocardial infarction Direct comparison ASA vs placebo 0.75 ( ) ASA-DP vs placebo 0.64 ( ) ASA ¼ acetylsalicylic acid; DP ¼ dipyridamole; RR ¼ rate ratio. Major Hemorrhagic Events Placebo was associated with fewer major hemorrhagic events than the combinations of ASA plus DP and ASA plus clopidogrel, clopidogrel, and terutroban. ASA treatment resulted in more major hemorrhagic events than cilostazol (RR ¼ 3.74; 95% CI, ) and triflusal (RR ¼ 2.57; 95% CI, ). The combination of ASA plus clopidogrel was associated with more major hemorrhagic events than clopidogrel (RR ¼ 2.28; 95% CI, ), cilostazol (RR ¼ 6.33; 95% CI, ), DP (RR ¼ 3.98; 95% CI, ), or triflusal (RR ¼ 4.35; 95% CI, ). The combination of ASA plus DP resulted 1496 Volume 35 Number 10

8 R.J. Malloy et al. Table V. Tolerability outcomes. Outcome RR (95% CI) Overall hemorrhagic event Direct comparison ASA vs placebo 2.32 ( ) ASA vs cilostazol 2.42 ( ) ASA vs DP 2.08 ( ) ASA vs triflusal 1.89 ( ) ASA vs ASA-clopidogrel 0.43 ( ) ASA-DP vs placebo 2.04 ( ) ASA-DP vs DP 1.83 ( ) ASA-clopidogrel vs clopidogrel 2.81 ( ) Indirect comparisons Placebo vs clopidogrel 0.53 ( ) Placebo vs terutroban 0.40 ( ) Placebo vs ticlodipine 0.52 ( ) Placebo vs ASA-clopidogrel 0.19 ( ) Cilostazol vs tetutroban 0.38 ( ) Cilostazol vs ticlodipine 0.51 ( ) Cilostazol vs ASA-DP 0.47 ( ) DP vs terutroban 0.44 ( ) Triflusal vs terutroban 0.49 ( ) Triflusal vs ASA-DP 0.60 ( ) ASA-clopidogrel vs cilostazol 5.56 ( ) ASA-clopidogrel vs DP 4.78 ( ) ASA-clopidogrel vs sarpogrelate 3.59 ( ) ASA-clopidogrel vs terutroban 2.13 ( ) ASA-clopidogrel vs ticlodipine 2.80 ( ) ASA-clopidogrel vs triflusal 4.36 ( ) ASA-DP vs cilostazol 2.12 ( ) ASA-DP vs triflusal 1.67 ( ) ASA-DP vs ASA-clopidogrel 0.38 ( ) Major hemorrhagic events Direct comparison Placebo vs ASA-DP 0.23 ( ) ASA vs cilostazol 3.74 ( ) ASA vs triflusal 2.57 ( ) ASA-clopidogrel vs clopidogrel 2.28 ( ) Indirect comparison Placebo vs clopidogrel 0.28 ( ) Placebo vs terutroban 0.21 ( ) Placebo vs ASA-clopidogrel 0.12 ( ) Cilostazol vs terutroban 0.27 ( ) ASA-DP vs cilostazol 3.42 ( ) ASA-clopidogrel vs cilostazol 6.33 ( ) ASA-clopidogrel vs DP 3.98 ( ) ASA-clopidogrel vs triflusal 4.35 ( ) Intracranial hemorrhage Direct comparison Cilostazol vs ASA 0.28 ( ) Indirect comparison Cilostazol vs terutroban 0.23 ( ) ASA ¼ acetylsalicylic acid; DP ¼ dipyridamole; RR ¼ rate ratio. in more major hemorrhagic events than cilostazol (RR ¼ 3.42; 95% CI, ). Treatment with cilostazol resulted in fewer major hemorrhagic events than terutroban (RR ¼ 0.27; 95% CI, ). All other indirect and direct comparisons revealed no difference (see the Supplemental Appendix IX intheonlineversion at Intracranial Hemorrhage Cilostazol was associated with less intracranial hemorrhage than ASA (RR ¼ 0.28; 95% CI, ) and terutroban (RR ¼ 0.23; 95% CI, ). All other indirect and direct comparisons revealed no difference (see the Supplemental Appendix X in the online version at DISCUSSION In this MTC analysis, we were able to compare 11 antiplatelet regimens in 488,000 patients with prior stroke, thereby allowing for several comparisons among agents not directly evaluated using a clinical trial. The combination of ASA plus DP was consistently more protective against stroke than ASA alone and against vascular events than ASA or DP individually. However, this combination was associated with more overall hemorrhagic events than DP alone. Most antiplatelets (ASA, clopidogrel, ticlopidine, and the combinations of ASA plus clopidogrel and ASA plus DP) were more protective than terutroban in reducing death from vascular causes. ASA individually and in combination with DP was more effective in reducing the rate of myocardial infarction than placebo. The combination of ASA plus clopidogrel was associated with an excess of overall hemorrhagic events compared with most of the other antiplatelets (clopidogrel, cilostazol, DP, sarpogrelate, terutroban, ticlopidine, triflusal, and the combination of ASA plus DP). To our knowledge, this is the first MTC meta-analysis comparing the tolerability and efficacy of all antiplatelet agents worldwide for the secondary prevention of stroke. The previous network meta-analysis published by Thijs et al 44 excluded triflusal and sarpogrelate and did not report tolerability data. In this earlier network metaanalysis, 24 trials and subset analyses were evaluated and included 442,000 patients with TIA or stroke. Using indirect and direct comparisons, they compared placebo, ASA, thienopyridines (clopidogrel and ticlopidine), and October

9 Clinical Therapeutics the combinations of ASA plus DP and ASA plus clopidogrel for the prevention of serious vascular events. Similar to our results, the combination of ASA plus DP was more effective than ASA alone (RR ¼ 0.78; 95% CI, ). However, the authors also concluded that the combination of ASA plus DP was also more effective than clopidogrel or ticlopidine individually (RR ¼ 0.84; 95% CI, ), although this finding was not consistent with our analysis. Other pooled analyses have been conducted to assess the effects of various antiplatelet agents when used alone or in combination. 45,46 Verro et al 45 compared the combination of ASA plus DP with ASA alone using data from 6 trials that included 7649 patients with TIA or stroke. The combination of ASA plus extendedrelease DP was found to be more protective against nonfatal stroke than ASA (relative risk [RR] ¼ 0.77; 95% CI, ) and against the composite of stroke, myocardial infarction, or vascular death (RR ¼ 0.85; 95% CI, ). The immediate-release formulation of DP in combination with ASA was found to be similar to ASA alone in reference to nonfatal stroke (RR ¼ 0.83; 95% CI, ) and to the composite of stroke, myocardial infarction, or vascular death (RR ¼ 0.95; 95% CI, ). Geeganage et al 46 conducted a meta-analysis of 12 different controlled trials specifically evaluating the efficacy of monotherapy (ASA, DP, or clopidogrel) to dual (ASA plus clopidogrel or ASA plus DP) antiplatelet therapy in 3766 patients. Dual antiplatelet therapy was more protective in reducing the rate recurrent stroke (RR ¼ 0.67; 95% CI, ) and in the composite of vascular events (stroke, myocardial infarction, or vascular death) (risk ratio ¼ 0.75; 95% CI, ) than antiplatelet monotherapy; however, dual therapy was associated with a trend to more bleeding events (risk ratio ¼ 2.09; 95% CI, ). These efficacy and tolerability findings are consistent with our direct comparison analysis. Although ASA has been the mainstay of treatment for secondary prevention of ischemic stroke, patient-specific factors, such as the presence of risk factors or comorbidities, the development of adverse events, and inadequate response or resistance to its antiplatelet effects, necessitate the use of other antiplatelet agents or combination therapy. 47 Combination antiplatelet therapy is postulated to enhance the secondary prevention of stroke through multiple pharmacologic mechanisms; however, its utility may be limited by adverse events, such as bleeding, as seen in our analysis. Thus, combination antiplatelet therapy, mainly ASA plus clopidogrel, should be reserved in specific clinical scenarios, such as coronary stenting. 8 Our data suggest similar efficacy between cilostazol and ASA plus clopidogrel in respect to vascular events, although cilostazol had fewer overall and major hemorrhagic events, which suggests lower bleeding risks with this agent. Patients who are unresponsive to antiplatelet therapy require reevaluation of antiplatelet therapy by considering patient features, treatment tolerance, drug metabolism, and potential drug interactions. Treatment failure, resulting in TIAs or stroke recurrence, can be attributed to various reasons, including nonadherence and antiplatelet resistance. 48 One factor leading to nonadherence is the development of adverse effects, such as headaches and gastrointestinal intolerance, as reported with the combination of ASA plus DP. Antiplatelet resistance occurs when antiplatelet therapy fails to adequately inhibit platelet activation due to drug-drug interactions or genetic polymorphism that affect drug metabolism and drug receptor binding. 48,49 For example, nonsteroidal anti-inflammatory drugs can decrease the antiplatelet effects of ASA by competing with the cyclooxygenase-2 receptor site to which aspirin binds. 50 Moreover, inhibition or polymorphism of the CYP3A4 and CYP2C19 enzyme systems can decrease the bioactivation of clopidogrel from its prodrug state, thus decreasing its clinical benefit. 50 Some limitations exist when evaluating the data in this analysis. A meta-analysis accepts the assumptions and definitions of the studies included. In addition, a network meta-analysis evaluates and then accepts studies with normally distributed heterogeneity. All comparisons involving terutroban are tenuous given that there is only one study in our analysis. Moreover, concomitant atherosclerotic disease, other comorbidities, and other medications used, such as β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitors, were not consistently reported in all trials. Although the scope of our study is limited to antiplatelet use, anticoagulant therapy has been the subject of other published analyses and should be compared with antiplatelet therapy for the prevention of noncardioembolic stroke. In conclusion, our MTC meta-analysis of direct and indirect comparisons found comparable efficacy among most antiplatelet agents. When compared with ASA alone, the combination of ASA plus DP was more effective in reducing recurrent stroke and vascular events. There was an increase in bleeding with combination 1498 Volume 35 Number 10

10 R.J. Malloy et al. therapy and with ASA when compared with cilostazol and triflusal. Given the comparable efficacy and tolerability among most antiplatelet options, selection of antiplatelet therapy for the secondary prevention of stroke must be individualized according to patient needs and bleeding risks from existing comorbidities. ACKNOWLEDGEMENTS Dr. Malloy was responsible for the literature search, figure and table creation, data collection, and data interpretation. Drs. Silva, Kanaan, Donovan were responsible for the study design, literature search, data interpretation, writing of the manuscript CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article. SUPPLEMENTAL MATERIAL Supplemental appendixes accompanying this article can be found in the online version at /j.clithera REFERENCES 1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:e21 e Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367: Elkins JS, Johnston SC. Thirty-year projections for deaths from ischemic stroke in the United States. Stroke. 2003;34: Johnston SC, Fayad PB, Gorelick PB, et al. Prevalence and knowledge of transient ischemic attack among US adults. Neurology. 2003;60: Johnston SC, Gress DR, Browner WS, Sidney S. Shortterm prognosis after emergency department diagnosis of TIA. JAMA. 2000;284: Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson LW, Schopflocher DP. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology. 2004;62: Coull AJ, Lovett JK, Rothwell PM, Oxford Vascular S. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ. 2004;328: Lansberg MG, O Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e601S e636s. 9. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17: Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004;23: Lu G, Ades AE. Assessing evidence inconsistency in mixed treatment comparisons. JAmStatAssoc. 2006;101: Woods BS, Hawkins N, Scott DA. Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial. BMC Med Res Methodol. 2010;10: van Valkenhoef G, Tervonen T, Zwinkels T, de Brock B, Hillege H. ADDIS: a decision support system for evidencebased medicine. Decis Support Syst. 2013;55: Lumley T. Network meta-analysis for indirect treatment comparisons. Stat Med. 2002;21: Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ. 2005;331: Salanti G, Higgins JP, Ades AE, Ioannidis JP. Evaluation of networks of randomized trials. Stat Methods Med Res. 2008;17: Salanti G, Kavvoura FK, Ioannidis JP. Exploring the geometry of treatment networks. AnnInternMed. 2008;148: Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010;29: Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA. 2003;289: The American-Canadian Co-Operative Study Group. Persantine Aspirin Trial in cerebral ischemia, part II: endpoint results. Stroke. 1985;16: Bousser MG, Eschwege E, Haguenau M, et al. AICLA controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. Stroke. 1983;14: Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia. Stroke. 1977;8: CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348: Culebras A, Rotta-Escalante R, Vila J, et al. Triflusal vs aspirin for prevention of cerebral infarction: a randomized stroke study. Neurology. 2004;62: Sorensen PS, Pedersen H, Marquardsen J, et al. Acetylsalicylic acid in the prevention of stroke in patients with reversible cerebral ischemic attacks: a Danish cooperative study. Stroke. 1983;14: October

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12 October e1 Supplemental Appendix I. Studies identified by the systematic review and considered for direct and indirect comparison, where interventions and outcomes are evaluated. Study Intervention Recurrent Ischemic Event Composite of Events Myocardial Infarction Death From Any Cause Death From Vascular Cause Overall Hemorrhagic Event Intracranial Hemorrhagic Event Major Hemorrhagic Event AAASPS 19 ASA a vs TC X X X X X X X ACCSG 20 ASA/DP vs ASA X X X X X X X AICLA 21 ASA vs ASA-DP vs X X X X X X X X placebo AITIA 22 ASA vs placebo X X X X X X X X CAPRIE 23 ASA vs clopidogrel X X X X Culebras et al 24 ASA vs triflusal X X X X X X X X Danish Cooperative ASA vs placebo X X X X X X X X Study 25 Danish low-dose ASA vs placebo X X X X study 26 ESPRIT 27 ASA vs ASA-DP X X X X X X X X ESPS 28 ASA-DP vs placebo X X X X X ESPS 2 29 ASA vs DP vs ASA- X X X X X X DP vs placebo CHARISMA 30 ASA vs ASAclopidogrel X X X X X X X Huang et al 31 ASA vs cilostazol X X X X MATCH 32 ASA-clopidogrel vs X X X X X X X clopidogrel Matias-Guiu et al 33 ASA vs triflusal X X X X X X X X PERFORM 34 ASA vs terutroban X X X X X X X X PRoFESS 35,36 ASA-DP vs X X X X X X X X clopidogrel S-ACCESS 37 ASA vs sarpogrelate X X X X X X SALT 38 ASA vs placebo X X X X X X X X Shinohara et al 39 ASA vs cilostazol X X X X X Swedish Cooperative ASA vs. placebo X X X X X X X Study 40 TASS 41 ASA vs TC X X X X X X (continued) R.J. Malloy et al.

13 1500.e2 Volume 35 Number 10 Supplemental Appendix I. (continued) Study Intervention Recurrent Ischemic Event Composite of Events Myocardial Infarction Death From Any Cause Death From Vascular Cause Overall Hemorrhagic Event Intracranial Hemorrhagic Event TOPALS 42 ASA-TC vs TC X X X X X UK-TIA 43 ASA vs placebo X X X X X X X X Major Hemorrhagic Event AASPS ¼ African American Antiplatelet Stroke Prevention Study; ACCSG ¼ American-Canadian Co-Operative Study; AICLA ¼ Accidents ischémiques cérébraux liés à l athérosclérose; AITIA ¼ Aspirin in Transient Ischemic Attacks; ASA ¼ acetylsalicylic acid; CAPRIE ¼ Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events; ESPIRIT ¼ European/Australasian Stroke Prevention in Reversible Ischaemia Trial; ESPS ¼ European Stroke Prevention Study; MATCH ¼ Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke; PERFORM ¼ Prevention of cerebrovascular and cardiovascular Events of ischemic origin with terutroban in patients with a history of ischaemic stroke or transient ischaemic attack; PRoFESS ¼ Prevention Regimen for Effectively Avoiding Second Strokes Trial; S-ACCESS ¼ Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction; SALT ¼ Swedish Aspirin Low-Dose Trial; TASS ¼ Ticlopidine Aspirin Stroke Study; TOPALS ¼ Tokai Panaldine Aspirin Long-Term Study; UK- TIA ¼ United Kingdom transient ischaemic attack aspirin trial. Clinical Therapeutics

14 October e3 Supplemental Appendix II. Definition of major bleeding across included studies.* Study Fatal Hemorrhage Moderate or Severe Hemorrhage Life- Threatening Bleed Hospital Admission Significantly Disabling Intracranial Hemorrhage All Causes of Withdrawal RBC Transfusion Inotropic Support Decrease in Hemoglobin of Z50 g/l Intraocular BþL21leeding AAASPS 19 X X X X ACCSG 20 X X AICLA 21 X X X AITIA 22 X X Culebras et al 24 X X Danish Cooperative Study 25 X X ESPRIT 27 X X X ESPS 2 29 X X CHARISMA 30 X X X X Huang et al 31 X MATCH 32 X X X X X X X Matias-Guiu et al 33 X X PERFORM 34 X X X X X X PRoFESS 35,36 X X X X X X X S-ACCESS 37 X SALT 38 X Swedish Cooperative Study 40 X TOPALS 42 UK-TIA 43 X X X AASPS A10 ¼ African American Antiplatelet Stroke Prevention Study; ACCSG ¼ American-Canadian Co-Operative Study; AICLA ¼ Accidents ischémiques cérébraux liés à l athérosclérose; AITIA ¼ Aspirin in Transient Ischemic Attacks; CAPRIE ¼ Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events; ESPIRIT ¼ European/Australasian Stroke Prevention in Reversible Ischaemia Trial; ESPS ¼ European Stroke Prevention Study; MATCH ¼ Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke; PERFORM ¼ Prevention of cerebrovascular and cardiovascular Events of ischemic origin with terutroban in patients with a history of ischaemic stroke or transient ischaemic attack; PRoFESS ¼ Prevention Regimen for Effectively Avoiding Second Strokes Trial; RBC ¼ red blood cell; S-ACCESS ¼ Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction; SALT ¼ Swedish Aspirin Low-Dose Trial; TASS ¼ Ticlopidine Aspirin Stroke Study; TOPALS ¼ Tokai Panaldine Aspirin Long-Term Study; UK-TIA ¼ United Kingdom transient ischaemic attack aspirin trial. *Trials CAPRIE, Danish low-dose study, ESPS, and TASS do not have outcomes for major bleeding and are not included in this table. TOPALS listed major bleeding events but no clinical definition. R.J. Malloy et al.

15 1500.e4 Volume 35 Number 10 Supplemental Appendix III. Recurrent stroke.* Rate Ratio (95% CI)þB2 Intervention Cilostazol DP ASA-DP Placebo Sarpogrelate Terutroban TC ASA-TC ASA ASA-Clopidogrel Clopidogrel Triflusal Cilostazol 1 DP 1.30 ( ) 1 ASA-DP 0.99 ( ) 0.77 ( ) 1 Placebo 1.58 ( ) 1.24 ( ) 1.60 ( ) 1 Sarpogrelate 1.58 ( ) 1.22 ( ) 1.58 ( ) 0.98 ( ) 1 Terutroban 1.29 ( ) 0.98 ( ) 1.28 ( ) 0.80 ( ) 0.81 ( ) 1 TC 1.22 ( ) 0.93 ( ) 1.22 ( ) 0.76 ( ) 0.76 ( ) 0.94 ( ) 1 ASA-TC 1.08 ( ) 0.85 ( ) 1.12 ( ) 0.70 ( ) 0.69 ( ) 0.85 ( ) 0.91 ( ) 1 ASA 1.27 ( ) 0.97 ( ) 1.28 ( ) 0.79 ( ) 0.80 ( ) 0.99 ( ) 1.05 ( ) 1.15 ( ) 1 ASA-clopidogrel 0.99 ( ) 0.75 ( ) 0.99 ( ) 0.61 ( ) 0.62 ( ) 0.77 ( ) 0.81 ( ) 0.89 ( ) 0.77 ( ) 1 Clopidogrel 1.05 ( ) 0.81 ( ) 1.06 ( ) 0.66 ( ) 0.67 ( ) 0.83 ( ) 0.87 ( ) 0.95 ( ) 0.83 ( ) 1.08 ( ) 1 Triflusal 1.30 ( ) 1.00 ( ) 1.30 ( ) 0.82 ( ) 0.82 ( ) 1.01 ( ) 1.07 ( ) 1.18 ( ) 1.02 ( ) 1.34 ( ) 1.23 ( ) 1 ASA ¼ acetylsalicylic acid; DP ¼ dipyridamole; TC ¼ triclopidine. *Direct comparisons are in bold. Supplemental Appendix IV. Composite of vascular events.* Rate Ratio (95% CI) Intervention Cilostazol DP ASA-DP Placebo Sarpogrelate Terutroban TC ASA-TC ASA ASA-Clopidogrel Clopidogrel Triflusal Cilostazol 1 DP 1.34 ( ) 1 ASA-DP 1.00 ( ) 0.75 ( ) 1 Placebo 1.69 ( ) 1.26 ( ) 1.68 ( ) 1 Sarpogrelate 1.47 ( ) 1.09 ( ) 1.46 ( ) 0.87 ( ) 1 Terutroban 1.32 ( ) 0.97 ( ) 1.30 ( ) 0.78 ( ) 0.90 ( ) 1 TC 1.24 ( ) 0.92 ( ) 1.23 ( ) 0.73 ( ) 0.84 ( ) 0.94 ( ) 1 ASA-TC 1.17 ( ) 0.86 ( ) 1.15 ( ) 0.69 ( ) 0.79 ( ) 0.88 ( ) 0.93 ( ) 1 ASA 1.28 ( ) 0.95 ( ) 1.27 ( ) 0.75 ( ) 0.87 ( ) 0.97 ( ) 1.03 ( ) 1.10 ( ) 1 ASA-clopidogrel 1.03 ( ) 0.76 ( ) 1.02 ( ) 0.61 ( ) 0.70 ( ) 0.78 ( ) 0.83 ( ) 0.89 ( ) 0.81 ( ) 1 Clopidogrel 1.08 ( ) 0.80 ( ) 1.07 ( ) 0.64 ( ) 0.74 ( ) 0.82 ( ) 0.87 ( ) 0.93 ( ) 0.84 ( ) 1.05 ( ) 1 Triflusal 1.31 ( ) 0.97 ( ) 1.30 ( ) 0.77 ( ) 0.89 ( ) 0.99 ( ) 1.05 ( ) 1.12 ( ) 1.02 ( ) 1.27 ( ) 1.21 ( ) 1 ASA ¼ acetylsalicylic acid; DP ¼ dipyridamole; TC ¼ triclopidine. *Direct comparisons are in bold. Clinical Therapeutics