American Journal of Cardiology
Volume 103, Issue 8 , Pages 1107-1112, 15 April 2009

Combination Antiplatelet Therapy for Secondary Stroke Prevention: Enhanced Efficacy or Double Trouble?

  • M. Haris U. Usman, MD

      Affiliations

    • Lankenau Institute for Medical Research, Wynnewood, Pennsylvania
    • Mercy Catholic Medical Center, Drexel University College of Medicine, Darby, Pennsylvania
    • ,
  • Lawrence A. Notaro, MD

      Affiliations

    • Lankenau Institute for Medical Research, Wynnewood, Pennsylvania
    • ,
  • Rangadham Nagarakanti, MD

      Affiliations

    • Lankenau Institute for Medical Research, Wynnewood, Pennsylvania
    • ,
  • Eric Brahin, MD

      Affiliations

    • Department of Neurology, Drexel University, Philadelphia, Pennsylvania
    • ,
  • Scott Dessain, MD, PhD

      Affiliations

    • Lankenau Institute for Medical Research, Wynnewood, Pennsylvania
    • Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
    • ,
  • Edward Gracely, PhD

      Affiliations

    • Department of Epidemiology and Biostatistics, Drexel University, Philadelphia, Pennsylvania
    • ,
  • Michael D. Ezekowitz, MBChB, DPhil

      Affiliations

    • Lankenau Institute for Medical Research, Wynnewood, Pennsylvania
    • Corresponding Author InformationCorresponding author: Tel: 610-645-3343; fax: 610-645-3471

Received 8 October 2008; received in revised form 5 January 2009; accepted 5 January 2009. published online 06 March 2009.

Article Outline

The evaluation of antithrombotic agents for secondary stroke prevention has focused on stroke reduction. The aim of this analysis was to focus specifically on the increase in bleeding risk. The annualized rates of total and major bleeding events in secondary stroke prevention trials of antithrombotics were assessed and cross compared. A Medline search for major randomized clinical studies with a follow-up duration of ≥1 year identified 13 studies. Pooled data sets were used to compare mean bleeding rates for aspirin (≤325 mg/day), clopidogrel, anticoagulants (warfarin and other vitamin K antagonists), aspirin plus clopidogrel, and aspirin plus extended-release dipyridamole (ER-DP). Total bleeding occurred at mean rates of 4.8% with aspirin (≤325 mg/day) alone, 2.9% with clopidogrel alone, 3.6% with aspirin plus ER-DP, 10.1% with aspirin plus clopidogrel, and 16.8% with anticoagulation. Major bleeding occurred at mean rates of 1% with aspirin (≤325 mg/day) alone, 0.85% with clopidogrel, 0.93% with aspirin plus ER-DP, 1.7% with aspirin plus clopidogrel, and 2.5% with anticoagulation. In conclusion, the combination of aspirin and clopidogrel is associated with significantly greater bleeding than either aspirin (≤325 mg/day) or clopidogrel alone. Aspirin plus ER-DP has a greater bleeding rate than clopidogrel but a lower rate than aspirin (≤325 mg/day) alone.

 

Aspirin is a very effective antithrombotic agent for secondary stroke prevention, with an estimated risk reduction rate ranging from 15% to 20% compared with placebo.1, 2 Despite this efficacy, its failure to prevent many more events has led to the development of other antiplatelet regimens with additional preventive efficacy.3 Bleeding is a serious complication of all antithrombotic agents and may offset their benefit. A recent review of antithrombotics in patients with acute coronary syndromes directly linked increased bleeding to higher mortality risk.4 However, the assessment of hemorrhage and its impact on the therapeutic efficacy of antiplatelet agents is limited, outdated, and not specifically focused on agents for secondary stroke prevention.5, 6, 7 In addition to the limited awareness of the hemorrhagic risk of current antiplatelet regimens, the continuing evaluation of more potent agents raises concerns about additional hemorrhagic risk that may be overlooked in pursuit of greater efficacy. This review was therefore undertaken to explore and compare the bleeding risk of secondary stroke–prevention regimens for noncardioembolic strokes, with specific focus on recently evaluated combination regimens composed of aspirin plus clopidogrel and aspirin plus extended-release dipyridamole (ER-DP).

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Methods 

The primary objective of this analysis was to quantify mean total and major bleeding events and rates for the following 5 drug groups: aspirin, clopidogrel, aspirin plus ER-DP, vitamin K antagonists (warfarin, acenocoumarol, and phenprocoumon), and the combination of aspirin and clopidogrel. Our secondary objective was to compare the chance of major and total bleeding with aspirin plus clopidogrel and aspirin plus ER-DP with that of aspirin alone and clopidogrel alone for the specific clinical setting of secondary stroke prevention. Randomized controlled trials in English evaluating the aforementioned drug groups for secondary stroke prevention specifically were identified using a Medline (National Library of Medicine, Bethesda, Maryland) search. Only trials with mean follow-up durations of ≥1 year were selected (Table 1).

Table 1. Study population characteristics
StudyMean Age (yrs)Study PopulationWomenSmokersHypertensionDiabetesDefinition of Major Bleeding
WARSS863Previous CVA41%29%68%33%IC, IS, or any other bleeding necessitating transfusion
SALT967Previous CVA, TIA, RAO35%27%49%13%ND
ACTIVE W1070AF and = 1 RF34%NP83%21%Fatal, IC, decrease in hemoglobin of 50 g/L, IO, requiring inotropic support, requiring surgery, transfusion of = 4 U of RBCs
ESPS-21667Previous CVA or TIA42%24%62%15%ND
CHARISMA1564History of CAD, CVD, PAD, or multiple atherothrombotic RFs30%20%73%42%Fatal, IC, requiring blood/fluid/inotropic support or surgery
CAPRIE1162Previous CVA, MI, or PAD28%30%52%20%ND
WASID1263Previous CVA or TIA38%22%84%38%Requiring hospitalization, transfusion, or surgery
UK-TIA1459Previous CVA or TIA27%53%27%35%ND
MATCH1366CVA or TIA and = 1 RF37%48%78%68%Disabling, IO, or transfusion =3 U of RBCs
Dutch-TIA1769Previous CVA or TIA30%50%45%18%Requiring hospitalization and treatment
ESPRIT1963Previous CVA or TIA35%37%60%19%IC, fatal or requiring hospitalization
ESPRIT-AC1862Previous CVA or TIA30%41%55%17%IC, fatal or requiring hospitalization
PROFESS2066Previous CVA or TIA36%20%74%28%IC, fatal or requiring ⩾2 U of RBCs

AF = atrial fibrillation; CAD = coronary artery disease; CVA = cerebrovascular accident; CVD = cardiovascular disease; ESPRIT-AC = ESPRIT comparing anticoagulation with aspirin and aspirin combined with ER-DP; IC = intracranial; IO = intraopthalmic; IS = intraspinal; MI = myocardial infarction; ND = not defined; NP = not provided; PAD = peripheral arterial disease; PROFESS = Prevention Regimen for Effectively Avoiding Second Strokes; RAO = retinal artery occlusion; RBC = red blood cell; RF = risk factor; SALT = Swedish Aspirin Low-Dose Trial; TIA = transient ischemic attack; WARSS = Warfarin-Aspirin Recurrent Stroke Study.

All analyzed studies classified bleeding using a 3-tiered system: minor (or mild), moderate, and major (or severe). Despite broad similarity, classification schemes varied significantly across studies. We therefore developed a classification scheme based on 2 classes of bleeding: total and major (Table 2).8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Total bleeding, by definition, was the sum of all (major, moderate, minor, and insignificant) bleeding that occurred throughout the duration of a clinical study. This was either extracted directly from trial published data or calculated from published data. Major bleeding was defined as any bleeding necessitating hospital admission. Thus, any description of “nonminor bleeding,” such as severe, moderate, major, fatal, or life-threatening bleeding, was all included in this definition.

Table 2. Classification of bleeding according to study
StudyMinorModerate⁎Major⁎AnatomicTotal
WARSS+ + Calculated
SALT+ + Published
ACTIVE W+ + Published†
ESPS-2+ + Published
CHARISMA ++ Calculated
CAPRIE+ + Published
WASID + N/A
UK-TIA +Calculated
MATCH+ + Calculated
Dutch TIA+ + Calculated
ESPRIT + N/A
PROFESS+ + N/A

N/A = no calculation because of incomplete published data. Other abbreviations as in Table 1.

⁎All bleeding reported as moderate, major, or life threatening was considered for the present analysis to be major bleeding.

†Total bleeding does not equal the sum of minor, moderate, and major bleeding. This was extracted directly from published data, and the reason for the discrepancy is not stated in the original publication of the ACTIVE W trial.

Of the 13 trials identified and used in our analysis, 11 classified bleeding as either major or severe or as minor, nonmajor, or nonsevere, and 1 (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA]) categorized bleeding as major or moderate.15 Because major and moderate bleeding types necessitated transfusion, for our analysis, they were combined to constitute “major” bleeding. The United Kingdom Transient Ischaemic Attack (UK-TIA) trial classified bleeding on the basis of anatomic location rather than according to severity, precluding the reporting of major bleeding.14 Data on “nonmajor” bleeding events was not reported for 3 trials: CHARISMA, the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT), and the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial.12, 15, 18, 19 Therefore, “total” bleeding could not be computed for these studies. Table 2 summarizes bleeding types as defined in each trial.

Bleeding events were initially tabulated for all studies as gross rates and then annualized rates (per 100 patient-years; Table 3). Bleeding rates for each category (total and major) were pooled together for each of the 5 drug groups. Because studies were heterogenous, and all had reasonably large sample sizes, a simple average of rates rather than a weighted average (by sample size) was calculated. To estimate the standard error, we first computed a variance for each study (using patient-years as the denominator). The sum of these variances was then obtained for each drug group. Ninety-five percent confidence intervals (CIs) were calculated for each estimated group using the sum of the variance estimates. The standard error for the average rate of total or major bleeding was then calculated using the following formula: √[sum of variances/(number of studies)2]. A p value ≤0.05 was considered statistically significant. All analysis was done using SPSS version 15 (SPSS, Inc., Chicago, Illinois).

Table 3. Summary of bleeding rates
ComparatorsNameStudy Drug (Dose)nMean Follow-Up (yrs)Patient-YearsBleeding (n)Bleeding Rate/100 Patient-Years
TotalMajorTotalMajor
Aspirin vs placeboSALTAspirin (75 mg/day)6762.71,82549202.621.11
Placebo6842.71,8462291.120.49
UK-TIAAspirin (300 mg/day)80643,22448NR1.49NR
Aspirin (1,200 mg/day)81543,25664NR1.96NR
Placebo81443,26025NR0.76NR
High- vs low-dose aspirinDutch TIAAspirin (30 mg/day)1,5552.64,04389402.221.00
Aspirin (283 mg/day)1,5762.64,097137533.361.30
Aspirin vs clopidogrelCAPRIEClopidogrel (75 mg/day)9,5991.9118,3348901325.050.75
Aspirin (325 mg/day)9,5861.9118,3098901495.080.85
Anticoagulation vs aspirinWARSSWarfarin (target INR 1.4–2.8)1,10322,2064574420.721.99
Aspirin (325 mg/day)1,10322,2062893013.101.36
WASIDWarfarin (target INR 2.0–3.0)2891.90549NR24NR1.78
Aspirin (1,300 mg/day)2801.90532NR9NR4.46
ESPRITWarfarin (target INR 2.0–3.0)5364.602,466NR45NR1.81
Aspirin (30–325 mg/day)5324.602,447NR18NR0.73
ESPRIT-ACWarfarin (target INR 2.0–3.0)5364.602,466NR45NR1.81
Aspirin (30–325 mg/day)5324.602,447NR18NR0.73
Aspirin + ER-DP vs aspirin alone, clopidogrel alone, dipyridamole alone, placebo, or anticoagulationESPRITAspirin (30–325 mg/day) + ER-DP (400 mg/day)1,3633.54,771206354.30.7
Aspirin (30–325 mg/day)1,3763.54,816221534.51.1
ESPRIT-ACAspirin (30–325 mg/day) + ER-DP (400 mg/day)5094.62,406NR11NR0.46
Warfarin (target INR 2.0–3.0)5234.62,341NR47NR1.95
ESPS-2Aspirin (50 mg/day) + ER-DP (400 mg/day)1,65023,300144274.360.81
Aspirin (50 mg/day)1,64923,298135204.090.61
ER-DP (400 mg/day)1,6542.3,3007762.320.18
Placebo1,64923,2987472.240.21
PROFESSAspirin (50 mg/day) + ER-DP (400 mg/day)10,1812.424,4345354192.21.72
Clopidogrel (75 mg/day)10,1512.424,3624943652.01.50
Clopidogrel + aspirin vs aspirin or clopidogrel or anticoagulationCHARISMAClopidogrel (75 mg/day) + aspirin (75–162 mg/day)7,8022.3317,945NR294NR1.64
Aspirin (75–162 mg/day)7,8012.3317,942NR205NR1.14
MATCHClopidogrel (75 mg/day) + aspirin (325 mg/day)3,7591.505,639289735.101.29
Clopidogrel (75 mg/day)3,7811.505,672110221.950.39
ACTIVE-WClopidogrel (75 mg/day) + aspirin (75–100 mg/day)3,3351.284,26964410112.82.36
Warfarin (target INR 2.0–3.0)3,3711.284,3155559315.12.15

INR = international normalized ratio; NR = not reported. Other abbreviations as in Table 1.

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Results 

Thirteen studies including 87,205 patients met the search criteria.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Table 3 lists the bleeding outcomes reported in each trial as the number of events and the annualized bleeding rates for total and major bleeds in each study. Figure 1, Figure 2 summarize the annualized total and major bleeding rates for each drug group, respectively.

The mean annualized total bleeding rate for aspirin (≤325 mg/day) was 4.8% (95% CI 4.5% to 5.1%). This was significantly lower than for aspirin plus clopidogrel (mean rate 10.1%, 95% CI 9.5% to 10.7%, p <0.0001) and significantly higher than for aspirin plus ER-DP (mean rate 3.6%, 95% CI 3.3% to 3.9%, p <0.0001). Although bleeding rates were dose dependent in the 2 studies incorporating >1 aspirin dose (the Dutch Transient Ischemic Attack [Dutch TIA] and UK-TIA trials), there was substantial interstudy variability in bleeding rates associated with aspirin at comparable doses. For instance, rates for aspirin at 325 mg/day in the Warfarin-Aspirin Recurrent Stroke Study (WARSS) were higher than the same dose of aspirin in the Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial. Similarly, bleeding rates were higher for 283 mg/day in the Dutch TIA study than for 300 mg/day in the UK-TIA trial. Some of this variability may be attributable to differences in study populations, but an incremental effect of dose on bleeding could not be substantiated in our analysis. Clopidogrel had a mean total bleeding rate of 2.9% (95% CI 2.8% to 3.1%). This was significantly lower than for aspirin plus clopidogrel (mean rate 10.1%, 95% CI 9.5% to 10.7%, p <0.0001) and aspirin plus ER-DP (mean rate 3.6%, 95% CI 3.3% to 3.9%, p <0.0001).

The mean major bleeding rate for aspirin (≤325 mg/day) was 1% (95% CI 0.89% to 1.1%). This was significantly lower than for aspirin plus clopidogrel (mean rate 1.76%, 95% CI 1.58% to 1.96%, p <0.0001). Aspirin plus ER-DP had a lower bleeding rate than aspirin alone, but this was statistically insignificant (mean rate 0.93%, 95% CI 0.81% to 1.06%). Clopidogrel had an annual major bleeding rate of 0.85% (95% CI 0.77% to 0.93%). This was significantly lower than for aspirin plus clopidogrel (mean rate 1.76%, 95% CI 1.58% to 1.96%, p <0.0001) but not significantly lower than for aspirin plus ER-DP (mean rate 0.93%, 95% CI 0.81% to 1.06%).

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Discussion 

In this analysis, we found that clopidogrel monotherapy has a lower bleeding rate than aspirin plus ER-DP and aspirin plus clopidogrel. Aspirin (≤325 mg/day) has a lower bleeding rate than aspirin plus clopidogrel but a higher bleeding rate than aspirin plus ER-DP.

Evidence from placebo-controlled studies clearly shows that there is an important risk for hemorrhagic complications of approximately 1% after ischemic stroke or transient ischemic attack in the absence of active antithrombotic treatment.21 The high rates of microhemorrhage and of hemorrhagic transformation after ischemic stroke (even in the absence of thrombolytic therapy) suggest that ischemic events may render the cerebral and peripheral vasculature more sensitive to hemorrhage.22 The use of antithrombotic agents increases this risk further. Studies of aspirin consistently show that the risk reduction for ischemic stroke substantially outweighs the increase in bleeding risk. The question is whether this benefit is maintained with other antiplatelet agents, whether alone or in combination with aspirin.

Studies and guidelines show that aspirin at doses up to 100 mg/day is sufficient to suppress platelet aggregation through thromboxane inhibition.3, 23 Although the association between aspirin doses >100 mg/day and risk for adverse events has been confirmed in multiple studies, no such dose relation has been identified for efficacy.24 In fact, evidence suggests that further increasing the dose may enhance prostacyclin suppression in the vascular mucosa, which may promote bleeding without further beneficially decreasing platelet aggregation.25, 26, 27

Clopidogrel permanently blocks binding between adenosine diphosphate and its platelet membrane-bound receptor, thereby irreversibly inhibiting platelet aggregation for its entire life span.28 The mechanistic approach of combining aspirin with clopidogrel was assumed to have greater therapeutic efficacy than each agent alone in the Management of Atherothrombosis With Clopidogrel in High-Risk Patients With Recent TIA or Ischemic Stroke (MATCH), CHARISMA, and Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W) studies for secondary stroke reduction.10, 13, 15 This hypothesis was extrapolated from earlier trials that had proved this combination significantly more efficacious than each agent alone, despite significantly greater hemorrhage, in the setting of acute coronary syndromes and percutaneous intervention.29, 30 For stroke prevention, this attempt was counterproductive because of a lack of greater preventive efficacy than with either agent alone.10, 13, 15 Our study reconsolidated the finding that the combination still carried a significantly greater hemorrhagic impact, which when combined with lack of therapeutic efficacy makes it detrimental in the setting of stroke prevention.

Dipyridamole inhibits adenosine uptake and acts on the vascular endothelium by increasing endothelial production of nitric oxide.31 Increased nitric oxide may facilitate aspirin's platelet inhibition by parallel mechanisms that inhibit the proliferation of vascular smooth muscle and vasoconstriction.32, 33, 34 This enhanced vasodilatation has been shown to decrease endothelial inflammation by inhibiting endothelial leukocyte adhesion and may have accounted for increased “platelet sparing,” with a resultant increase in efficacy and a decrease in bleeding compared with aspirin alone, in ESPRIT and the Second European Stroke Prevention Study (ESPS-2).16, 18, 19, 35 Although the reason for the failure of this mechanistic approach to demonstrate a similar advantage against clopidogrel cannot be fully elucidated, the more likely explanation could be a greater suppression of platelet aggregation by the combination, with a resultant increase in hemorrhagic outcomes.

This analysis raises concerns about the utility of combining 2 antiplatelet agents to achieve superior therapeutic efficacy by highlighting its bleeding impact. For aspirin plus clopidogrel, this bleeding risk approached that of oral anticoagulation without any stroke reduction benefit. Although aspirin plus ER-DP was not as severe, it did not provide greater therapeutic benefit than clopidogrel, with an added hemorrhagic risk. A recent meta-analysis supported our findings that combination antiplatelet therapy carries a greater bleeding risk than monotherapy but failed to stratify therapy according to disease state or type of combination agent.36 This analysis does not serve as a surrogate to currently available guidelines but highlights the detrimental impact of combining aspirin and clopidogrel for stroke reduction while emphasizing that among the 3 currently approved agents for secondary stroke prevention, clopidogrel alone, carries the lowest hemorrhagic profile and may therefore be safer than aspirin plus ER-DP.

The studies reported in this review are similar, but not identical, with respect to patient populations and study designs. This heterogeneity arises principally because of variation in reported rates and terminologies in individual trials. If these trials are entirely unrepresentative of one another, then the CIs in our analysis would bear no relation. However, these barriers are ubiquitous to all meta-analyses, and the true purpose of our analysis was to highlight an understated observation of the original trials.

The current limitation in reporting bleeding rates stems principally from the lack of a common classification scheme. The principal classification schemes used by trials analyzed in our study were extrapolated from the Thrombolysis In Myocardial Infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria.37, 38 These criteria have been useful for assessing bleeding outcomes related to thrombolytic and more potent antiplatelet agents, and they may be insufficient to quantify the risks and outcomes of present day long-term agents. More precise definitions reflecting clinical features specific to these agents are necessary.

A promising potential tool is the BleedScore, recently proposed by Serebruany and Atar,39 which covers a spectrum of bleeding categories specific to these antiplatelet agents. BleedScore also incorporates the severity and location of bleeding, 2 parameters overlooked by conventional bleeding classifications. In addition, we propose that bleeding requiring transfusion and bleeding necessitating the modification of study drugs (dosage adjustments or discontinuation) should be included as important items in a new classification scheme. These items would account for a potential increase in transfusion requirements and “insignificant” bleeding, which are often responsible for the premature termination of therapy. Premature termination itself is a significant outcome because it could inadvertently lead to rebound platelet activation and a greater propensity for secondary vascular events, thus further doubling the existing trouble.

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PII: S0002-9149(09)00033-2

doi:10.1016/j.amjcard.2009.01.003

American Journal of Cardiology
Volume 103, Issue 8 , Pages 1107-1112, 15 April 2009

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