Recurrent Stroke Prevention Strategies in Patients Receiving Acute Stroke Reperfusion Therapies (CoPrime Study Survey) Open Access

Reperfusion therapy, including intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) has significantly improved outcome in patients with acute ischemic stroke (AIS) [1‒6]. Despite achieving early neurological improvement in up to 59% of patients after EVT and 33% after IVT [7, 8], the risk of recurrent ischemic stroke remains elevated in the early posttreatment period [9, 10]. A meta-analysis of three major EVT trials revealed a higher risk of recurrent ischemic stroke within the first 90 days among patients randomized to the EVT arm compared to those who did not undergo this procedure [11, 12] highlighting the need for effective secondary prevention strategies following reperfusion therapy.

Current guidelines recommend initiating single antiplatelet therapy, most commonly aspirin, in patients with non-cardioembolic ischemic stroke after reperfusion therapy [13]. The Canadian Stroke Best Practices (2022) advice delaying aspirin until 24 h post-IVT, contingent on a follow-up computed tomography (CT) scan confirming no intracranial hemorrhage, while permitting earlier initiation after EVT unless contraindicated [14]. Similar guidance is offered by the American Heart Association and European Stroke Organization, although specific recommendations regarding EVT are less definitive [15, 16].

Dual antiplatelet therapy (DAPT), typically aspirin plus clopidogrel, is recommended for 21 days in patients with minor non-cardioembolic stroke [17, 18]. However, there is increasing interest in the potential benefit of DAPT in broader stroke populations, including those undergoing reperfusion therapy. Despite some observational data suggesting DAPT may be safe and possibly beneficial in this context, current guidelines lack specific recommendations for its use following IVT and/or EVT, and randomized trial data remain absent.

There remains an unmet need for optimal antiplatelet strategies in patients with non-cardioembolic stroke who have undergone reperfusion therapy. Understanding healthcare professionals’ current practices and their willingness to adopt or study DAPT in this setting is essential to guide future clinical trials. To address this, we conducted a multinational survey to assess real-world practices and clinician perspectives on the use of DAPT in patients treated with IVT and/or EVT for AIS.

The CoPrime study was designed as a multinational, cross-sectional, web-based survey targeting healthcare professionals managing non-cardioembolic AIS. The survey was distributed to neurologists and non-neurologist stroke physicians, including neurosurgeons, interventional neuroradiologists, and internal medicine doctors.

Participation was anonymous, and no identifying personal information was collected. All responses were treated as strictly confidential and were accessible only to the study investigators. To ensure data accuracy, IP addresses were recorded by the Qualtrics platform to prevent duplicate submissions; however, these were not used to identify participants. Data were analyzed and reported in aggregate to maintain participant anonymity.

Participants were recruited through professional organizations (Canadian Stroke Consortium, Indian Stroke Association, Canadian Neurological Sciences Federation) and personal networks. The survey targeted healthcare professionals from both academic and nonacademic hospitals to ensure a comprehensive understanding of current practices across different clinical settings. Efforts were made to include diverse respondents to capture a wide range of clinical perspectives. In a worldwide survey to understand stroke care providers, the total number of neurologists and neurosurgeons practicing was estimated at 122,756 in 2017 [19]. In certain regions Internal medicine physicians, emergency department physicians and family physicians also provide stroke care. We estimate approximately 200,000 stroke care providers worldwide in 2024. A sample size of 384 will be adequate for the survey with a 95% confidence interval and a 5% margin of error.

The survey was conducted via Qualtrics^XM (Qualtrics, Provo, UT, USA), a secure, web-based application for data collection in research studies. R.A.A., M.A., A.S., B.B., and M.P.K. developed the questionnaire. Pretesting was conducted with the authors, and a qualitative assessment was done for subject clarity, duration to complete the test, and ease of using the software.

The questionnaire was structured to collect information on participants’ practice settings and admission volumes, followed by 6 case scenarios. Each scenario was designed to evaluate the participants’ approach to antiplatelet therapy in patients with non-cardioembolic stroke who had undergone reperfusion therapy. The survey was conducted via email invitations sent by previously defined professional organizations, which directed participants to a web browser-based questionnaire hosted on the Qualtrics platform. The survey was translated into Mandarin and Cantonese in addition to English.

The survey included demographic and professional background questions, including practice location and years of experience. It also included 6 case scenarios with 14 questions (Fig. 1). Two questions addressed the preference for antiplatelet choice after reperfusion therapy. One asked physicians whether they would administer a loading dose of antiplatelet 24 h postreperfusion therapy. Another inquired about the consideration of DAPT for 21 days post-reperfusion. Four questions focused on the timing of starting antiplatelet therapy after reperfusion.

A secondary objective of this survey was to assess factors that may influence clinicians’ willingness to randomize patients in a future clinical trial aimed at preventing recurrent stroke after endovascular thrombectomy.

The case scenarios (online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000546654) were formulated based on:

• 1.

  Timing of antiplatelet therapy initiation after reperfusion therapies: within 24 h or 24–36 h from symptom onset

• 2.

  Severity of focal neurological deficits: using the NIHSS scale, categorized as NIHSS 0–4, 5–15, and >15

• 3.

  Infarct volume: based on Alberta Stroke Program Early CT (ASPECTS) score, categorized as ≤7, 6–4, and <4

• 4.

  Hemorrhagic transformation: the presence of either only hemorrhagic transformation or parenchymal hematoma.

These scenarios assessed participants’ treatment choices and willingness to randomize patients for a clinical trial to single versus DAPT for 21 days after follow-up imaging.

We opened the survey from May 4, 2024, to August 2, 2024. All participants could save the survey and complete it over 1 week; after that, it was considered incomplete. Thirty-three incomplete surveys were excluded from analyses. Collecting the internet protocol address and ending the survey with an error message prevented multiple submissions by the same individual. Bot detection was implemented with the help of an embedded data field.

The survey data were analyzed using descriptive statistics to summarize the demographic responses, including the country of practice, specialty, years of practice, type of stroke center, and reperfusion therapy volumes. Differences among proportions were assessed using Microsoft Excel 2016. The findings were reported to highlight current practice patterns and the level of consensus or variability among healthcare professionals regarding the management of stroke patients postreperfusion therapy. We used the Flourish (Canva UK, London, UK) interactive data visualization tool to develop the world map (Projection map v17.6.1) and Sankey Arbitrary Flow diagram (Sankey Diagram v11.6.1). A multinomial logistic regression was performed to assess the relation between willingness to randomize (base outcome was “no”) and demographic characteristics (years of practice [base “>15 years”], annual IVT [base “>200 per year”] and EVT volumes [base “>200 per year”]). The variables, country of practice, area of practice and stroke center practice level were skewed and, hence, were not added to the model. The regression analysis results were expressed as relative risk ratio, 95% confidence interval and p value. All statistical analysis was done with the Stata 18.0 BE version (StataCorp LLC, College Station, TX, USA). A p value <0.05 was considered significant. All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author. This study adheres to the Consensus-Based Checklist for Reporting of Survey Studies (CROSS), and the completed checklist is included as online supplementary material.

A total of 311 individuals from 26 countries participated in the survey. Thirty-three responses were excluded due to either incomplete submissions – defined as not completing a single case scenario – or duplicate entries, resulting in a final analytic sample of 278 participants. Most respondents were from Canada (74/278, 26.6%), India (36/278, 12.9%), and South Korea (26/278, 9.4%) (Fig. 2). A total of 251/278 (90.3%) of the respondents were neurologists or interventional radiologists. A total of 212/278 (76.3%) had at least 5–15 years of practice. A total of 204/278 (73.4%) worked in comprehensive stroke centers. A total of 98/278 (35.3%) worked at centers treating 50–200 patients annually for IVT, while 51/278 (18.3%) worked at centers treating more than 200 cases. For annual EVT treatment volume, 100/278 (35.9%) worked at centers treating 50–200 patients, and 37/278 (13.3%) worked at centers treating more than 200 cases (Table 1).

Regarding antiplatelet therapy, 255/278 (91.7%) participants responded to the first case scenario, which involved a small infarct observed on the follow-up MRI 24 h after IVT and EVT. A total of 194/255 (76.1%) chose aspirin, 49/255 (19.2%) opted for a combination of aspirin and clopidogrel, 10/255 (3.9%) chose clopidogrel alone, and 2/255 (0.8%) considered ticagrelor. In the second case scenario, involving a moderate infarct on the 24-h follow-up MRI after EVT, 241/278 (86.7%) participants responded. A total of 216/241 (89.6%) chose aspirin, 21/241 (8.7%) chose clopidogrel, and 4/241 (1.6%) chose ticagrelor.

In response to the first case scenario, 257/278 (92.4%) participants answered regarding the use of a loading dose of an antiplatelet agent 24 h post-reperfusion, specifically for small infarctions. A total of 98/257 (38.1%) were willing to administer a loading dose, 121/257 (47.1%) would not administer it, and 38/257 (14.8%) were uncertain.

The timing of antiplatelet initiation was assessed in case scenarios 2–5, which involved EVT without IVT (Fig. 3). In case scenario 2, involving a moderate infarction, 246/278 (88.5%) responded. A total of 131/246 (53.3%) preferred to start antiplatelet therapy 24 h post-EVT, while 103/246 (41.9%) considered initiating it immediately post-EVT. Only 12/246 (4.9%) preferred to start antiplatelet therapy after 24 h of symptom onset. In case scenario 3 (contrast staining 24 h after EVT), 243/278 (87.5%) responded. 50/243 (18%) preferred immediate initiation, 83/243 (29.9%) preferred initiation 24 h post-EVT, and 101/243 (36.3%) preferred to wait for an additional scan. In case scenario 4 (HI1), 236/278 (84.9%) responded. A total of 55/236 (23.3%) favored immediate initiation, 91/236 (38.6%) planned to wait for 24 h, and 80/236 (33.9%) planned to base their decision on a repeated CT scan after 24 h. Only 10/236 (4.2%) chose initiation after 24 h of symptom onset. In case scenario 5 (PH1), 232/278 (83.5%) responded. A total of 134/232 (57.7%) preferred to repeat a CT scan after 24 h before deciding, 47/232 (20.3%) preferred to wait 48 h, and 51/232 (22%) considered starting therapy based on the 24-h CT scan.

Willingness to randomize patients to receive single or DAPT for 21 days after follow-up CT or MRI was assessed in all six case scenarios (Fig. 4). In the first scenario, which involved a small infarct following IVT and EVT, 257/278 (92.4%) responded. A total of 175/257 (68.1%) were willing to randomize, and 57/257 (22.2%) were uncertain but considered it. In the second scenario, involving a moderate infarction post-EVT alone, the willingness to randomize dropped to 55.1% (133/241), with 26.7% (64/241) uncertain. In scenarios 3, 4, and 5 (contrast staining, HI1, and PH1), the willingness to randomize further decreased to 41.6% (101/243), 43.8% (103/236), and 31.9% (74/232), respectively, while the response not to randomize increased to 23.9% (58/243), 28.9% (68/236), and 43.5% (101/232), respectively. In case scenario 6, which involved a moderate infarction without hemorrhagic transformation after IVT alone, the willingness to randomize increased to 73.9% (171/232).

Demographic characteristics affected the willingness to randomize. Compared to participants with more than 15 years of practice, those with less than 5 years were less likely to agree to randomization in case scenarios 2, 3, 4, and 5, while participants with 5–15 years of experience were less likely to randomize in case scenarios 2, 4, and 5 (Table 2). Compared to participants practicing at sites performing more than 200 EVT per year, those practicing at sites with fewer than 20 EVT per year were less likely to randomize in case 2.

Our survey findings reflect real-world variability in antiplatelet practices following reperfusion therapy, echoing prior observations in the literature. Despite current guideline recommendations favoring single antiplatelet therapy in most cases, combination therapy remains common in practice. For example, data from the Get With The Guidelines-Stroke program show that DAPT is employed in approximately 42% of patients with moderate-grade neurological deficits (NIHSS >3), regardless of stroke center type or volume [20]. This widespread use underscores clinical uncertainty and the need for more targeted guidance.

Several studies have explored the role of DAPT in acute non-cardioembolic stroke, though patients treated with IVT or EVT were generally excluded. A recent randomized controlled trial involving 3,065 patients with NIHSS scores between 4 and 10 demonstrated that initiating aspirin and clopidogrel within 48 h of symptom onset for 21 days significantly reduced early neurological deterioration (4.8% vs. 6.7% with aspirin alone), with a number needed to treat of 50 [21]. However, the exclusion of reperfusion-treated patients limits the applicability of these findings to the broader stroke population.

A prospective, multicenter registry study (n = 4,461) similarly evaluated early DAPT use (<24 h) in non-minor, non-cardioembolic strokes (NIHSS 4–15) [22]. Although no difference was observed in the composite endpoint of stroke, myocardial infarction, or all-cause mortality at 90 days, DAPT was associated with a significant reduction in all-cause mortality (absolute risk reduction 1.6%; relative risk reduction 31%). Importantly, this study also excluded patients who had received IVT or EVT, further contributing to the evidence gap in this critical population.

In contrast, an observational study involving 712 patients who received IVT and/or EVT found no significant difference in symptomatic intracranial hemorrhage rates between those treated with DAPT and those on single antiplatelet therapy (3.2%) [23]. Antiplatelet initiation timing varied, with nearly 24% starting within 12 h, 40% between 12 and 24 h, and 36% after 24 h of symptom onset, highlighting the absence of consensus regarding optimal timing.

Together, these studies reinforce the uncertainty that our survey aimed to address. While DAPT may hold promise for reducing early ischemic events in selected stroke populations, definitive data in the post-reperfusion setting are lacking. Overwhelmingly, three-fourths of participants were either willing or would consider randomization to dual antiplatelet or single antiplatelet strategy in a clinical trial for secondary stroke prevention after reperfusion therapy.

The survey results reveal that while aspirin 81 mg once daily remains the predominant choice of antiplatelet therapy, DAPT with clopidogrel is also considerable, particularly in cases of small to moderate infarcts. However, few preferred clopidogrel or ticagrelor alone. This preference pattern aligns with existing practices but underscores the need for more robust evidence to guide antiplatelet choices in various clinical scenarios [17, 18, 24].

Regarding timing for initiating antiplatelet therapy, most respondents preferred starting antiplatelets 24 h post-EVT in line with current guidelines recommendations [14, 15]. However, immediate initiation post-EVT was also a common consideration, especially in cases without hemorrhagic transformation. Interestingly, when faced with scenarios involving contrast uptake or hemorrhagic infarction, clinicians had greater caution, with many opting to delay antiplatelet initiation or base their decisions on follow-up imaging results. This cautious approach likely reflects concerns about hemorrhagic risks and the need for more definitive imaging before making therapeutic decisions.

The variability in responses, particularly regarding the timing and choice of antiplatelet therapy, highlights a substantial area of uncertainty and the absence of clear, evidence-based guidelines [14, 15]. For instance, the decision to administer a loading dose of antiplatelet therapy 24 h post-reperfusion shows a split, with nearly equal proportions of respondents for and against it and a notable number remaining undecided. This division indicates the need for further research and consensus-building to establish more concrete guidelines.

The willingness to randomize patients for single versus DAPT for 21 days after follow-up imaging also varied significantly across different clinical scenarios. High willingness was observed in scenarios involving small infarcts post-IVT and EVT and moderate infarcts without hemorrhagic transformation, suggesting a perceived equipoise in these situations. However, in scenarios involving contrast staining or hemorrhagic transformations, the willingness to randomize decreased, likely due to concerns over safety and the complexity of these cases. This was further influenced by years of practice and EVT volumes. This trend underscores the challenges in designing and implementing clinical trials in these high-risk groups and highlights the need for tailored approaches to study these populations.

The findings from this survey underscore the pressing need for more definitive clinical trials and evidence-based guidelines to standardize the management of antiplatelet therapy post-reperfusion. The diversity in practice patterns and the areas of uncertainty highlighted by this study point to critical gaps in knowledge that must be addressed to improve patient outcomes. Future research should focus on high-risk groups, such as those with hemorrhagic transformations, to develop tailored guidelines that clinicians can confidently apply in practice. We are currently exploring the safety and feasibility of the role of DAPT 24 h after reperfusion therapy in patients with non-cardioembolic stroke in a clinical trial (ClinicalTrials.gov ID: NCT06638151).

This study has several limitations that may affect the interpretation and generalizability of the findings. Participation was based on professional networks, introducing potential response bias and limiting the representativeness of the broader stroke care community. Although we aimed for international diversity, the sample was disproportionately composed of clinicians from a few countries, primarily Canada, India, and South Korea, and mostly neurologists or interventional radiologists. This may not fully reflect practices in other regions or among other specialties. The cross-sectional, self-reported nature of the survey captures practices at a single time point and may be subject to recall or perception bias. Additionally, the lack of broader language translation, exclusion of incomplete surveys without comparative analysis, and omission of key variables from regression models due to skewed distributions further limit the scope of our findings. These factors highlight the need for cautious interpretation and further prospective research to validate these results.

In conclusion, our study highlights significant variability and uncertainty in the management of antiplatelet therapy following reperfusion therapy for secondary stroke prevention. While aspirin remains the predominant choice, the timing of initiation and the use of dual therapy are areas marked by diverse practices and a lack of consensus. These findings call for more robust clinical trials and the development of clear, evidence-based guidelines to ensure consistent and effective patient care.

This study was performed in accordance with the World Medical Association Declaration of Helsinki. This human study protocol was reviewed and approved by Research Ethics Board 2 at University of Alberta – approval: Pro00141810. Written informed consent to participate was not directly obtained but inferred by completion of the questionnaire/participation in the interview.

Dr. PN Sylaja and Prof. Mohammad Wasay were members of the Journal’s Editorial Board at the time of submission. The other authors declare no conflict of interest.

No funding was received for this study.

R.A.A. contributed to the writing of the original draft and provided resources. M.P.K. was responsible for the conceptualization, formal analysis, supervision, and review and editing of the manuscript. A.S. and B.B. were involved in the conceptualization and review and editing of the manuscript. M.A., P.S., A.D., J.D., A.P., M.S.H., Y.Z., N.A., M.W., and S.-I.S. contributed to writing, reviewing and editing of the manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.