Different Antiplatelet Strategies in Patients With New Ischemic Stroke While Taking Aspirin
Background and Purpose—Selecting among different antiplatelet strategies when patients experience a new ischemic stroke while taking aspirin is a common clinical challenge, currently addressed by a paucity of data.
Methods—This study is an analysis of a prospective multicenter stroke registry database from 14 hospitals in South Korea. Patients with acute noncardioembolic stroke, who were taking aspirin for prevention of ischemic events at the time of onset of stroke, were enrolled. Study subjects were divided into 3 groups according to the subsequent antiplatelet therapy strategy pursued; maintaining aspirin monotherapy (MA group), switching aspirin to nonaspirin antiplatelet agents (SA group), and adding another antiplatelet agent to aspirin (AA group). The primary study end point was the composite of stroke (ischemic and hemorrhagic), myocardial infarction, and vascular death up to 1 year after stroke onset.
Results—A total of 1172 patients were analyzed for this study. Antiplatelet strategies pursued in study patients were MA group in 212 (18.1%), SA group in 246 (21.0%), and AA group in 714 (60.9%). The Cox proportional hazards regression analysis showed that, compared with the MA group, there was a reduction in the composite vascular event primary end point in the SA group (hazard ratio, 0.50; 95% confidence interval, 0.27–0.92; P=0.03) and in the AA group (hazard ratio, 0.40; 95% confidence interval, 0.24–0.66; P<0.001).
Conclusions—This study showed that, compared with maintaining aspirin, switching to or adding alternative antiplatelet agents may be better in preventing subsequent vascular events in patients who experienced a new ischemic stroke while taking aspirin.
Aspirin is a first line antiplatelet agent for the secondary prevention of ischemic stroke or transient ischemic attack.1 In addition, aspirin is recommended in national guidelines for primary prevention of vascular events in patients with multiple cardiovascular risk factors.2,3 With its low cost and easy accessibility, prophylactic aspirin use is frequent in the middle-aged and elderly population.4–6
Therefore, patients who suffer a new ischemic stroke while taking aspirin are frequently encountered in a daily practice. Antiplatelet management options in these patients are to maintain aspirin monotherapy, replace aspirin with other antiplatelet agents, such as clopidogrel, or add other antiplatelet agents to aspirin.1,7–10 However, both randomized trial and large-scale registry data to guide this decision are sparse. Accordingly, the most recent American Heart Association/American Stroke Association guideline states that there is no evidence that switching or combining antiplatelet agents reduces the risk of subsequent vascular events in patients who have had stroke while receiving aspirin (Class IIb, Level of Evidence C).1
A post hoc analysis of 838 patients, who have had a recent lacunar stroke while taking aspirin from the Secondary Prevention of Small Subcortical Stroke Trial (SPS3) cohort, showed that vascular events, including ischemic stroke, were not reduced by the addition of clopidogrel compared with the maintenance of aspirin.11 However, the study results could not be extrapolated to other subtypes of ischemic stroke because the study population was restricted to patients with a lacunar infarction. Therefore, questions still remain regarding whether to modify an antiplatelet regimen or not in patients who have had a cerebral ischemic event while receiving aspirin.
Using a multicenter stroke registry database,12 this study aimed to elucidate whether switching aspirin to other antiplatelet agents or adding other antiplatelet agents to aspirin could be more effective in preventing further vascular events than maintaining aspirin monotherapy in patients who had a new ischemic stroke while taking aspirin and whether these effects may differ by ischemic stroke subtype.
This study was an analysis of the Clinical Research Center for Stroke-fifth division (CRCS-5) registry database, a prospective, nationwide, multicenter, acute stroke registry database established in 2008.12,13 The collaborative registry study group consisted of 14 academic and regional tertiary stroke centers. Detailed information on the CRCS-5 registry is given in the online-only Data Supplement.
The eligibility criteria for this study were as follows: (1) acute ischemic stroke with admission to a participating center within 48 hours of stroke onset between April 2008 and July 2013, (2) noncardioembolic ischemic stroke subtype according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria with minor modifications,14,15 and (3) aspirin intake within 7 days before stroke onset for prevention of vascular events. We excluded patients who had anticoagulants during hospitalization or at discharge and who had no antithrombotic therapy at discharge.
Collection of clinical information for the CRCS-5 registry for improving the quality of stroke care was approved by the local institutional review boards (IRBs) of all participating centers with a waiver of informed consent because of study subject anonymity and minimal risk to participants. Also, the use of the registry database and additional review of medical records for this study was approved further by the local IRBs.
Demographic, clinical, imaging, and laboratory data were prospectively collected. Baseline data, including the National Institutes of Health Stroke Scale (NIHSS) score, were collected from all patients, and the stroke subtypes were stratified according to the TOAST criteria after complete diagnostic profiling.14,15 Data collection was described further in the online-only Data Supplement. The study subjects were divided into 3 groups according to antiplatelet therapy regimen at discharge; maintaining aspirin monotherapy (MA group), switching aspirin to nonaspirin antiplatelet agents (SA group), and adding other antiplatelet agents to aspirin (AA group).
For the purpose of monitoring the quality of stroke care and outcomes, occurrences of vascular events, including death, were prospectively captured at discharge, 3 months, and 1 year after stroke through review of medical records or direct or telephone interviews by dedicated stroke coordinators in each center.
The primary outcome measure was a composite of 3 vascular events, including stroke (either ischemic or hemorrhagic), myocardial infarction (MI), and vascular death up to 1 year after stroke. The secondary outcomes were (1) stroke (either ischemic or hemorrhagic) and (2) a composite of stroke (either ischemic or hemorrhagic), MI, and all-cause mortality. Vascular death was defined as death attributable to stroke, MI, and other vascular events, including sudden death. Detailed definitions of the outcome variables have been published elsewhere (Table I in the online-only Data Supplement).13
Baseline characteristics were compared among the MA, SA, and AA groups. Event rates of primary and secondary outcome measures were estimated using Kaplan–Meier product-limit method and were also compared among the MA, SA, and AA groups by log-rank test. Cox proportional hazards regression analysis was used to evaluate the independent effects of antiplatelet regimen modifications on outcome events. Hazard ratios and 95% confidence interval were estimated. To explore the existence of effect modifications by ischemic stroke subtype, an interaction term between antiplatelet therapy regimen and ischemic stroke subtype was generated, and its statistical significance was examined using the Cox proportional hazards models. Details of the statistical analysis are described in the online-only Data Supplement.
Among a total of 25 998 stroke patients, who were registered between April 2008 and July 2013, 13 144 had imaging-confirmed acute ischemic stroke and were hospitalized within 48 hours of stroke onset. Selection of the study population is presented in Figure I in the online-only Data Supplement. Ultimately, 1172 patients (mean age, 69.7±10.9 years; men, 58.7%) were analyzed for this study. Missing values for creatinine (0.1%), initial random glucose (2.4%), first fasting triglyceride (2.9%), and low-density lipoprotein cholesterol (3.8%) were substituted with median values.
Antiplatelet strategies pursued in study patients were (1) continued aspirin monotherapy (MA group) in 212 (18.1%), switch to alternative antiplatelet agents (SA group) in 246 (21.0%), and addition of different antiplatelet agents to aspirin (AA group) in 714 (60.9%). Details of antiplatelet regimens are presented in Table II in the online-only Data Supplement. In the SA group, the most common antiplatelet regimen was clopidogrel monotherapy (80.5%); in the AA group, the most common antiplatelet regimen was aspirin plus clopidogrel (87.1%). In the MA group, the most common loading dose was 300 mg (170/212, 80.2%), and the most common maintenance dose was 100 mg (161/212, 75.9%; Table III in the online-only Data Supplement).
Comparisons of demographics and other clinical characteristics are shown in Table 1. The SA group trended to be older than the other 2 groups. Ischemic stroke subtypes were different among the 3 groups. Coronary artery disease and prior statin use were most frequently observed in the AA group. Dyslipidemia was most common in the SA group. Relevant arterial stenosis was most frequently observed in the AA group and occlusion in the MA group. Statin use at discharge was highest in the AA group and lowest in the MA group.
The mean follow-up duration was 278±129 days. The primary outcome event, a composite of stroke, MI, and vascular death occurred in 86 patients (Table IV in the online-only Data Supplement). The 1-year cumulative event rate was 8.2%, and 73.3% of the primary outcome events occurred within 3 months after stroke onset. The 1-year stroke recurrence rate was 6.2% (n=64). Recurrent stroke was fatal in 7 (11%). The composite of stroke, MI, and all-cause mortality occurred in 136 patients, and its 1-year cumulative rate was 13.1%.
In unadjusted analysis, the rates of all primary and secondary outcome events at 1 year differed significantly according to antiplatelet therapy regimen (Table 2; Figures 1 and 2). The 1-year event rates of (1) the composite of stroke, MI, and vascular death, (2) stroke recurrence, and (3) the composite of stroke, MI, and all-cause mortality were higher in the MA group (14.5%, 9.0%, and 21.2%, respectively) than in the SA group (7.4%, 7.4%, and 11.7%, respectively) and in the AA group (6.7%, 5.0%, and 11.2%, respectively).
The Cox proportional hazards regression analysis revealed that, compared with maintaining aspirin monotherapy, switching aspirin to nonaspirin antiplatelet agents and adding other antiplatelet agents to aspirin were independently associated with the reduction of the composite of stroke, MI, and vascular death (Table 3). The adjusted hazard ratio (95% confidence interval) was 0.50 (0.27–0.92) in Model 1 and 0.51 (0.27–0.94) in Model 2 for the SA group and 0.40 (0.24–0.66) in Model 1 and 0.43 (0.26–0.72) in Model 2 for the AA group. In addition, antihypertensive (both of model 1 and 2) and statin (both of model 1 and 2) use at discharge and prior statin use (model 1) were independently associated with the reduction of the composite of stroke, MI, and vascular death.
Similarly, switching to other nonaspirin antiplatelet agents and adding other antiplatelet agents to aspirin reduced about half of the composite of stroke, MI, and all-cause mortality (Table VA in the online-only Data Supplement). However, with respect to stroke recurrence alone, switching to other antiplatelet agents did not significantly reduce stroke recurrence (hazard ratio, 0.85; 95% confidence interval, 0.43–1.69), although addition of other antiplatelet agents to aspirin was effective (hazard ratio, 0.45; 95% confidence interval, 0.25–0.83; Table VB in the online-only Data Supplement).
The unadjusted 1-year event rates of the composite of stroke, MI, and vascular death did not differ by antiplatelet therapy regimen in patients with small vessel occlusion (P=0.63 on log-rank test) but did differ in patients with other etiology or undetermined causes (P<0.001; Table 4). However, the interaction between antiplatelet therapy regimen and ischemic stroke subtype was not statistically significant in the multivariable model for the primary outcome (P for interaction=0.19). Similar patterns were observed for the other secondary outcomes; P for interaction=0.18 for stroke recurrence; P for interaction=0.18 for the composite of stroke, MI, and all-cause mortality. The unadjusted post hoc comparisons of outcome events showed no significant difference according to the maintenance aspirin dose in the MA group (Table III in the online-only Data Supplement).
This study found that switching to or adding alternative antiplatelet agents was associated with reduction in future vascular events compared with maintaining aspirin monotherapy in patients who experience a new ischemic stroke while taking aspirin. The hazard of the composite of stroke, MI, and vascular death was reduced by half by switching to alternative antiplatelet agents and ≈60% by adding alternative agents to aspirin compared with maintaining aspirin monotherapy during the first year of ischemic stroke.
The magnitudes of the effects observed are substantial. For example, the absolute difference in the 1-year event rate of the composite of stroke, MI, and vascular death between the MA and SA groups was 7.1% (14.5% versus 7.4%), which indicates a number needed to treat of 14 to prevent 1 subsequent vascular event. Both discontinuing aspirin and switching to a different antiplatelet regimen and adding additional antiplatelet agents to aspirin showed comparable degrees of event reduction versus continuing aspirin alone.
However, we could not investigate most of relevant safety outcomes, including major systemic bleeding. Because the benefit of antiplatelet therapy should be weighed against its safety, especially related to its long-term use, it is difficult to estimate the net benefits of switching to or adding alternative antiplatelet agents in comparison with maintaining aspirin in this study. Furthermore, because the dual antiplatelet agents (such as aspirin and clopidogrel) may have increased systemic bleeding complications long-term compared with nonaspirin monotherapy,16–18 switching to an alternative monotherapy agent might be a better option than dual antiplatelet therapy for those patients. A recent retrospective cohort study based on a nationwide insurance claim database also reported that in the event of ischemic stroke while on aspirin, switching to clopidogrel might be better than aspirin reinitiation for the prevention of recurrent vascular events.10
Clopidogrel (80.5%) was the most commonly used alternative antiplatelet agent in this study. In a clinical trial to compare the treatment effect of clopidogrel and aspirin for the prevention of the composite of stroke, MI, and vascular death,8 point estimates showed an absolute difference of 0.56% and a relative risk reduction of 7.3% in favor of clopidogrel was observed in the subgroup of 12 033 patients who had recent ischemic stroke as their qualifying event. Cilostazol was the second commonly used alternative antiplatelet agent (9.8%) in the SA group. Cilostazol is a phosphodiesterase inhibitor that was reported to be superior to aspirin for the prevention of stroke recurrence after an initial ischemic stroke in an Asian population.19
Our study provides support for the view that alternative antiplatelet strategies are more effective than continuing aspirin monotherapy in aspirin failure patients—patients in whom an ischemic stroke occurred on aspirin. However, it should be noted that, although composite vascular event rates were reduced, with respect to stroke recurrence alone, switching to other antiplatelet agents was only nominally, not statistically, more effective than maintaining aspirin monotherapy. The low statistical power because of small number of stroke events (n=64) may explain the lack of effect on stroke prevention in contrast to clear effect on preventing the composite vascular events.
More than 60% of the study subjects were treated with the combination antiplatelet therapy, including aspirin, most commonly with aspirin plus clopidogrel (87%), and the analysis results suggest the superiority of the combination therapy over aspirin monotherapy. These results accord with the findings of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) and the Clopidogrel in high-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) randomized trials.20,21 In the SAMMPRIS trial, a lower than expected risk of recurrent stroke was reported in patients who were enrolled into a large intracranial stenting trial for symptomatic intracranial stenosis (70% to 99%) and who were treated with a combination of aspirin and clopidogrel.20 Superiority of aspirin plus clopidogrel over aspirin was found in the CHANCE trial; the reduction of early recurrent stroke by ≈30% after 3 months of follow-up.21 A recent meta-analysis demonstrated that early and short-term use of dual antiplatelet therapy might be better than monotherapy for preventing subsequent ischemic events in patients with noncardioembolic stroke or transient ischemic attack.22
The findings of this study contrast with those of the Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) and SPS3 trials, which did not demonstrate superiority of double antiplatelet therapy over antiplatelet monotherapy for secondary prevention after initial ischemic stroke.17,18 However, MATCH differed from the current study in not including the early postqualifying stroke period in the great preponderance of patients, using clopidogrel rather than aspirin as the monotherapy agent, and enrolling a largely non-Asian population. Similarly, SPS3 differed in not including the early postqualifying stroke period in the great preponderance of patients and enrolling a largely non-Asian population. SPS3 also was confined to patients with lacunar stroke presumed because of intrinsic small vessel disease. In our study, statistical tests for heterogeneity of treatment effect failed to show an influence of ischemic stroke subtype on benefit of double over single antiplatelet therapy. Nonetheless, the difference in 1-year event rates according to antiplatelet regimen was or tended to be more significant in patients with noncardioembolic and nonlacunar stroke than in lacunar stroke, consistent with SPS3.
Antihypertensive and statin uses at discharge were highest in the AA group, the second highest in the SA group, and lowest in the MA group. Changing antiplatelet regimen may be a marker for more intensive treatment of vascular risk factors or patients’ willing to make changes in management. However, despite including these variables into the models, switching to or adding alternative antiplatelet agents were independently associated with the reduction of subsequent vascular events. Interestingly, antihypertensive and statin uses at discharge significantly reduced the primary outcome events in this study, indicating the known importance of risk factor controls for preventing vascular events in stroke survivors.1 It should be noted that the rates of antihypertensive and statin uses at discharge in this study were much higher than those at 3 months in the CHANCE trial (≈35% and 42%, respectively).21
Because our registry was based on stroke patients admitted to university hospitals or regional stroke centers and, in addition, this study included those who had aspirin for the prevention of vascular events, the study subjects might have relatively higher risk for vascular events other than stroke recurrence compared with the general stroke population, which might explain the unusual stronger impact of antiplatelet strategies on stroke recurrence than vascular events in general.
We did not investigate mechanisms of aspirin failure, such as aspirin resistance, on platelet function test. It remains controversial whether antiplatelet regimen should be changed when aspirin resistance is suspected on platelet function test. A recent clinical trial reported no significant improvement in clinical outcomes by modification of antiplatelet regimen according to platelet function monitoring in patients scheduled for coronary stenting.23 With respect to stroke prevention, the lack of evidence necessitates further research on this topic.
Our study has several limitations. First, it has the inherent limitation of a registry-based study on a patient cohort restricted to South Korea. Second, compliance and duration of antiplatelet therapy could not be ascertained by pill count or direct interview in our study. Furthermore, the heterogeneity of antiplatelet therapy regimen limits the interpretation of the study results, although the predominant regimen was clopidogrel in the SA group and aspirin plus clopidogrel in the AA group. In addition, the combination of aspirin and extended release dipyridamole was not commercially available for ischemic stroke in Korea. Third, as mentioned above, inadequate evaluation of safety outcome related to antiplatelet therapy should be noted. Finally, it should be noted that inability to exclude reverse causation and residual confounding related to imbalances of baseline characteristics do not allow us to accept the study results as conclusive.
In conclusion, this study showed that switching to or adding alternative antiplatelet agents could be associated with reduction in future vascular events than maintaining aspirin monotherapy in patients who suffer a new ischemic stroke while taking aspirin. Because of the nature of the nonrandomized, registry-based study and the inevitable baseline imbalances according to antiplatelet strategies, the results of this study should be interpreted with caution, and the findings should be confirmed in randomized clinical trials.
Sources of Funding
This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020).
Dr Bae is involved in the principal investigator, a member of steering committee, and a site investigator of multicenter clinical trials or clinical studies sponsored by Otsuka Korea, Bayer Korea, Boehringer Ingelheim Korea, Handok Pharmaceutical Company, SK Chemicals, ESAI-Korea, Daewoong Pharmaceutical Co. Ltd, Daichi Sankyo, AstraZeneca Korea, Dong-A Pharmaceutical, and Yuhan Corporation; served as the consultant or scientific advisory board for Bayer Korea, Boehringer Ingelheim Korea, BMS Korea, and Pfizer Korea; and received lecture honoraria from AstraZeneca Korea, Bayer Korea, BMS Korea, Coviden Korea, and Daichi Sankyo Korea (modest). Dr Hong received lecture honoraria from Sanofi Korea (modest). Dr Saver receives funding for services as a scientific consultant regarding trial design and conduct to Boehringer Ingelheim (prevention only). The authors report no conflicts.
Guest Editor for this article was Seemant Chaturvedi, MD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.011595/-/DC1.
- Received September 22, 2015.
- Revision received September 22, 2015.
- Accepted October 13, 2015.
- © 2015 American Heart Association, Inc.
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