Impact of Pre-Stroke Antiplatelet Use on 3-Month Outcome After Ischemic Stroke
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.333484
Source of Support: None, Conflict of Interest: None
Keywords: Antiplatelets, outcome, stroke recurrence, stroke severity
Use of antiplatelet drugs in adults has progressively increased over the last three decades, particularly in persons with diabetes mellitus and cardiovascular disease.,, A study from the United Kingdom reported a more than 10-fold increase in the prevalence of pre-stroke antiplatelet (PAP) use from 2.9% in 1984 to 33.6% in 2004.
Premorbid therapy with antiplatelet medications can potentially influence the severity and course of acute stroke. However, mixed results have emerged from the studies exploring the effect of PAP on stroke severity. A few studies showed decreased odds of severe stroke and disability at discharge with PAP therapy,,,,, whereas others failed to confirm these observations., None of the studies could demonstrate any significant impact of PAP use on the long term outcome of stroke.
All the previous studies focused on the relation of PAP therapy to stroke severity at admission and outcome at discharge. To the best of our knowledge, there are no published studies that have explored its impact on 3-month outcome. The objective of this study was to evaluate the impact of PAP on stroke severity and 3-month outcome of ischemic stroke from the data derived from a prospective multicentre stroke registry in India.
The study data were derived from the Indo-US Collaborative Stroke Project (IUCSP) which is a prospective study of acute ischemic stroke in 5 academic hospitals in India, with a coordinating center in Boston, USA., The study was funded by the U.S. National Institutes of Health and the Department of Biotechnology, India. The study enrolled consecutive patients 18 years and older admitted with a diagnosis of ischemic stroke within two weeks of symptom onset. Patients with primary intracranial hemorrhage, those who were discharged without admission and those who failed to give consent were excluded. The study was approved by the Ethics Committee of each hospital. Written informed consent was obtained from all participants.
Data were collected from January 2012 until December 2014 and entered in a secure web-based electronic database. Information was collected on demographics, risk factors, pre-hospital care, thrombolysis, inpatient management including quality of care, complications, laboratory test results, imaging, medications, and outcomes until 90 days. All investigators were trained and certified on the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS), trained in using the web-based 'Causative Classification of Stroke' tool (https://ccs.mgh.harvard.edu) to assign stroke mechanism, and educated to interpret brain imaging findings.
The current study analyzed the data on prior antiplatelet use among the patients recruited in this study. Patients were divided into 2 groups, PAP and non-PAP, based on documented use of antiplatelet stroke preventive medications (aspirin, dipyridamole, clopidogrel or their combinations) prior to the index stroke. Outcome measures included the 3-month mRS categorized as good (scores 0-2) or poor (scores 3-6), stroke severity at admission (as assessed by NIHSS score 0-4 versus 5+), in-hospital mortality, and symptomatic brain hemorrhage.
Statistical analysis was performed using SPSS, version 21.0 (Armonk, NY: IBM Corp). Continuous variables were expressed as mean (standard deviation) or median (interquartile range). Categorical variables were presented as numbers and percentages. Chi-square and t tests were used as appropriate. A value of P < 0.05 was considered significant. Missing data for variables were considered as being absent for analysis. Variables acquiring significance in the univariate analysis were included in a multivariable model to determine independent predictors of stroke severity, stroke recurrence, and 3-month outcome.
The study recruited 2066 patients of whom 2048 with known pre-stroke medication status were included in this analysis. The mean age of the cohort was 58.25 ± 14.68 years with 1381 (67.43%) males. A total of 336 (16.3%) patients were on one or more antiplatelet medications prior to the index stroke.
[Table 1] compares the baseline clinical data between PAP and non-PAP groups. Significant differences in the vascular risk factor profile were noted between the groups. The PAP group was significantly older, had more men, had a higher prevalence of vascular risk factors, and higher rates of pre-stroke anticoagulant, antihypertensive and cholesterol-lowering medications. However, stroke severity was not significantly different between groups.
[Table 2] shows the treatment and outcomes of the PAP and non-PAP groups. Stroke mechanism was significantly different, with the PAP group having a higher rate of cardiac causes, but not large-artery atherosclerosis. Patients on PAP had a higher frequency of cerebral microbleeds on MRI (performed in 1376 patients), but the rates of post-ischemic hemorrhagic transformation were not significantly different. Intravenous thrombolysis was more commonly administered in the PAP group. There was no significant difference in the rate of symptomatic intracranial hemorrhage associated with thrombolysis (P = 0.884). There were no significant differences in 3-month stroke outcome or in-hospital mortality. However, a higher frequency of recurrent stroke at 90 days was noted with the PAP group.
[Table 3],[Table 4],[Table 5] show the results of multivariate analysis adjusting for age, sex, stroke mechanism, and vascular risk factors on outcome measures (stroke severity, 3-month outcome, and stroke recurrence). PAP therapy was not an independent predictor of stroke severity or poor outcome at 90 days, and no longer remained significant for stroke recurrence (P = 0.065, OR = 1.807, 95% CI 0.965 to 3.386).
A substantial part of functional recovery following stroke is achieved within three months of stroke onset and the clinical status at three months is considered a reliable predictor of the final stroke outcome. Our study, which specifically addressed 3-month stroke outcome in relation to PAP use, did not demonstrate any significant effect of PAP on this measure. We also did not find any association between initial stroke severity and PAP use in our cohort. Previous studies that addressed short and long term mortality in stroke also failed to show any positive impact of PAP therapy., A recent study observed that the use of PAP reduced the 30-day mortality due to ischemic stroke only when dual, and not single, antiplatelet therapy was used. We did not have an adequate sample size to investigate the effect of dual antiplatelet therapy in our cohort.
Predictably, the group on PAP had a significantly higher prevalence of vascular risk factors such as diabetes mellitus, hypertension, and dyslipidemia as well as higher incidence of prior stroke and myocardial infarction. These factors confer a higher risk for ongoing vascular damage and worse outcome after stroke. The higher prevalence of risk factors in the PAP group may have reduced any possible benefit of PAP therapy; however, despite adjusting for vascular risk factors we did not find any effect of PAP on stroke severity, recurrence rates and 3-month outcome. Some of the earlier studies used propensity score matching and found that the PAP use became significant for stroke severity only after accounting for the effect of risk factors.,, Although risk factors account for 90% of the stroke occurrence, the propensity to develop these risk factors varies between and within population groups as does the risk of recurrence. Additional factors including genetic predispositions need to be explored to more definitely quantitate this risk.
The trials of low dose aspirin for primary prevention of cardiovascular diseases have shown mixed results.,,, A consistent finding was an increased risk for hemorrhagic strokes with aspirin.,,, Interestingly, in our cohort, those with a history of hemorrhagic stroke were also more likely to use PAP, though the absolute numbers were low, and it is possible that the past history concerning prior stroke subtype was not reliable. Both hemorrhagic and ischemic strokes share vascular risk factors like older age, male sex, and hypertension and persons with intracerebral bleed may be more prone to have concomitant vascular diseases like coronary artery disease and ischemic strokes. Intracerebral hemorrhage may, therefore, be a strong marker of vascular injury.
Previous studies had noted a differential effect for PAP therapy for the various etiological subtypes of stroke., PAP therapy was useful in reducing the frequency and severity of strokes related to large artery atherosclerotic disease but did not significantly impact the profile of small vessel and cardioembolic strokes., The low number of subjects using PAP limited a subgroup analysis in this study.
As was observed in our study, previous studies also noted a significantly higher occurrence of cerebral microbleeds in antiplatelet users., A Japanese study had reported an association for the presence of microbleeds with dual, but not single, antiplatelet therapy. A pooled analysis of similar studies did not show a difference in the number of microbleeds in antiplatelet users who developed intracerebral hemorrhage compared to those who had an ischemic stroke. In this respect, antiplatelet associated microbleeds differ from those associated with warfarin therapy in that the latter portends an increased risk of an intracranial hemorrhage. Our observations on cerebral microbleeds are limited by the non-availability of MRI in 32.8% of the patients and the lack of information on single versus dual antiplatelet therapy.
Our study has limitations. Some details concerning antiplatelet therapy such as the specific drug, doses of the drugs, and the number of drugs used were not available. Secondly, at the baseline, there were statistically significant differences in the risk factor profile of the PAP and non-PAP groups which could contribute to the inability to demonstrate a protective effect for PAP in these patients despite multivariable adjustment. The relatively low number of patients on PAP therapy could also have dictated the lack of significant differences in the protective effects. The low sample size also prevented us from including other potential influencers of outcome like anticoagulant and statin use and in-hospital complications in the multivariable model. Follow-up until 3 months may not be adequate to show the effects of PAP on stroke recurrence. The strength of the study was the meticulous collection of the data prospectively by trained staff with accurate documentation of the information on the risk factors, severity, and outcome of stroke. In all the centers, the NIHSS at admission and mRS on follow-up were scored by research associates with training and certification in the scoring systems.
In conclusion, our analysis did not reveal an association of PAP use with the three-month functional outcome of acute ischemic stroke. Furthermore, the higher risk for stroke recurrence in the PAP group was nullified after correcting for traditional vascular risk factors. The negative effects on the group on antiplatelet drugs may largely be related to the higher burden of vascular risk factors, but other factors such as ethnicity and genetic factors in relation to the drug effect also need to be explored.
Financial support and sponsorship
This study was supported by the US National Institutes of Health (R21NS077442) and the Department of Biotechnology, Government of India.
Conflicts of interest
Dr Singhal is consultant at Partners HealthCare International. The other authors have no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]