Effects of Dual Antiplatelet Therapy on Secondary Stroke Prevention

Introduction  

Strokes occur when blood flow to a part of the brain is blocked or disrupted. There are two primary causes: ischemic, where blood flow is blocked by a clot, and hemorrhagic, where blood flow is disrupted due to a brain bleed. A common method of stroke prevention is the use of platelet anti-aggregation medications like aspirin, which help prevent ischemic strokes. Platelets are clotting factors in the blood, designed to stop blood loss whenever there is a wound, whether inside the body or external. In both cases, platelets gather at the site of the injury to form a clot that plugs the hole. However, platelets can sometimes form clots where they are not needed, blocking blood flow to vital areas of the body. 

Aspirin works by preventing platelets from aggregating, reducing the risk of clot formation. Unfortunately, in some cases, aspirin alone is insufficient. To improve outcomes in ischemic stroke prevention, dual antiplatelet therapy (DAPT) has been introduced. DAPT typically involves the combination of aspirin and clopidogrel, targeting different platelet aggregation pathways to enhance clot prevention. While DAPT has proven effective in reducing recurrent strokes, it is also associated with a higher risk of major bleeding events. 

This research paper explores the impact of DAPT on secondary stroke prevention, focusing on the balance between its benefits and risks. By examining existing literature and clinical trials, this study aims to provide a comprehensive understanding of the optimal use of DAPT in preventing recurrent strokes. It evaluates the efficacy and safety profiles of DAPT compared to single antiplatelet therapy (SAPT), aiming to inform future treatment guidelines and improve patient outcomes in secondary stroke prevention. 

Literature Review

Dual antiplatelet therapy, typically involving the combination of aspirin and clopidogrel, works by inhibiting two different pathways of platelet aggregation, thereby reducing the likelihood of thrombus formation, which is crucial in preventing secondary strokes. Aspirin inhibits cyclooxygenase-1 (COX-1), which reduces the synthesis of thromboxane A2, a potent promoter of platelet aggregation and vasoconstriction. Conversely, Clopidogrel is a P2Y12 adenosine diphosphate (ADP) receptor antagonist, further inhibiting platelet aggregation. By targeting these two pathways, DAPT provides a more comprehensive approach to preventing clot formation than single antiplatelet therapy. 

The efficacy of DAPT in preventing secondary strokes has been demonstrated in several major clinical trials. The CHANCE trial found that DAPT significantly reduced the risk of recurrent stroke compared to aspirin alone in patients with minor ischemic stroke or transient ischemic attack (TIA) within 90 days¹. Similarly, the POINT trial corroborated these findings, showing that DAPT was more effective than aspirin alone in reducing the risk of major vascular events, including stroke. However, it also noted an increased risk of significant bleeding². A meta-analysis of various studies, including the MATCH and CHARISMA trials, also concluded that DAPT was generally more effective in reducing stroke recurrence than SAPT, particularly in the early period following the initial event³. 

While dual antiplatelet therapy has demonstrated efficacy in reducing the risk of recurrent strokes, it also carries significant safety concerns, primarily related to an increased risk of bleeding. Major bleeding events are a well-documented risk associated with DAPT, as seen in the POINT trial, where patients receiving DAPT experienced a higher incidence of major hemorrhagic complications compared to those on aspirin alone². The MATCH trial similarly reported a higher risk of life-threatening bleeding events among patients on DAPT compared to those on clopidogrel alone³. 

Though less severe, minor bleeding events are also more common with DAPT. The CHANCE trial, while showing benefits in stroke reduction, noted an elevated risk of minor bleeding, which can still be clinically significant and impact patient compliance and quality of life¹. Furthermore, the SOCRATES and PRoFESS trials highlighted concerns about gastrointestinal bleeding, which is particularly relevant in older populations who are more likely to be on concurrent medications that increase bleeding risk, such as anticoagulants and nonsteroidal anti-inflammatory drugs (NSAIDs)²⁰. 

Although less frequent, the risk of intracranial hemorrhage is a serious concern with DAPT. Studies like the TARDIS trial have shown that while DAPT reduces ischemic events, it simultaneously increases the risk of intracranial bleeding, necessitating careful patient selection and monitoring²⁵. 

The clinical implications of using dual antiplatelet therapy for secondary stroke prevention are substantial. It offers a powerful tool for reducing the risk of recurrent ischemic events in high-risk populations. The early period following a minor stroke or TIA is critical for intervention, and DAPT is particularly effective during this phase. This makes DAPT an essential consideration in acute management strategies for secondary stroke prevention. 

However, the balance between efficacy and safety remains a key concern. Clinicians must weigh the benefits of reduced ischemic events against the heightened risk of bleeding. This necessitates personalized treatment plans that consider individual patient risk factors, such as age, comorbid conditions, and history of bleeding. The American Heart Association/American Stroke Association guidelines recommend a limited duration of DAPT, typically around 21 to 90 days, followed by a transition to single antiplatelet therapy to mitigate bleeding risks¹⁹. 

Further research is needed to optimize DAPT protocols and identify patient subgroups that may benefit most from extended or tailored therapy. For instance, exploring genetic markers that predict response to antiplatelet therapy or developing new agents with a better safety profile could enhance treatment outcomes. Additionally, more studies are required to understand the long-term impacts of DAPT beyond the initial high-risk period and to develop strategies to monitor and manage bleeding risks effectively². 

Methods 

A comprehensive literature search initially yielded 97,500 articles. To refine this vast number, a systematic search strategy was employed using specific terms such as “dual antiplatelet therapy,” “secondary stroke prevention,” “aspirin and clopidogrel,” “stroke recurrence,” and “major bleeding events.” Databases searched included PubMed, Cochrane Library, and Embase, covering publications from 2000 to 2023. The search was further narrowed by applying inclusion criteria for human studies that examined either dual antiplatelet therapy or single antiplatelet therapy in patients with a minor stroke or transient ischemic attack. Animal studies, non-human research, and studies not focused on secondary stroke prevention were excluded. 

From the initial results, 25 primary studies were selected, comprising 10 randomized controlled trials, eight cohort studies, and seven meta-analyses. This selection process assessed relevance, clarity, and quality. Studies were reviewed to align with the research objectives, and duplicates were removed. The final selection focused on research that addressed primary outcomes such as stroke recurrence, major bleeding events, and mortality, with secondary outcomes including minor bleeding events, medication adherence, and quality of life. Data extraction involved collecting information on study design, location, participant demographics, and therapy details. Meta-analysis techniques were then used to pool data and assess heterogeneity, with subgroup and sensitivity analyses performed to ensure robustness and identify patterns across studies. 

The study included human patients of all ages, genders, and ethnicities who had experienced a minor stroke or transient ischemic attack and were undergoing either dual antiplatelet therapy or single antiplatelet therapy. Animal studies, non-human participants, and any research not focused on secondary stroke prevention were excluded from the study. The primary outcomes measured were stroke recurrence, major bleeding events, and mortality, while secondary outcomes included minor bleeding events, medication adherence, and quality of life. 

Data extraction involved gathering information on the author and publication year, type of study and study design, study location, and the number of participants. Additional data were collected on the age group, gender, and demographics of the patients, as well as the type of antiplatelet therapy, dosage, and duration. The study outcomes focused on stroke recurrence, bleeding events, and mortality, with all data extracted from peer-reviewed studies. 

Meta-analysis techniques were employed to pool data on both primary and secondary outcomes for data analysis. Heterogeneity among the studies was assessed using the I² statistic. Subgroup analyses were conducted based on demographic factors and clinical characteristics, and sensitivity analyses were performed to test the robustness of the results. Comparisons were made among similar studies by grouping those with analogous objectives and methodologies, allowing for the identification of congruent findings or factors contributing to differing outcomes. 

Results 

A total of 25 primary studies (10 randomized controlled trials, eight cohort studies, and seven meta-analyses) were included in the systematic review. Across the included studies, DAPT was associated with a 25-30% reduction in stroke recurrence within the first 90 days post-initial stroke². However, this benefit came with a notable increase in major bleeding events, highlighting the need for careful patient selection and monitoring¹. Subgroup analyses indicated that the efficacy of DAPT was particularly pronounced in patients with minor strokes or high-risk transient ischemic attacks (TIAs), while the bleeding risks were elevated in older adults and those with comorbidities³.

Figure 1: PRISMA Flow Diagram showing how studies were selected to be included for review 

The 25-30% reduction in stroke recurrence and the associated increase in major bleeding events are based on critical clinical trials and meta-analyses that have extensively examined the efficacy and safety of dual antiplatelet therapy compared to single antiplatelet therapy in secondary stroke prevention. Specifically, the CHANCE and POINT trials were instrumental in establishing the 25-30% reduction in stroke recurrence. The CHANCE trial, which involved Chinese patients with minor ischemic stroke or transient ischemic attack, demonstrated a significant reduction in stroke recurrence with DAPT, showing a relative risk reduction of about 32% within the first 90 days post-event. Similarly, the POINT trial, conducted in the USA and Canada with patients experiencing minor ischemic stroke or high-risk TIA, reported a 25% relative risk reduction with DAPT. Together, these trials indicate that DAPT can effectively reduce stroke recurrence by approximately 25-30% within the first 90 days following an initial event. 

In terms of safety, the associated increase in major bleeding events with DAPT is well-documented, particularly in the POINT trial, which reported a significant rise in major hemorrhagic complications among patients on DAPT compared to those on SAPT. This finding is further supported by the MATCH and CHARISMA trials, which explored the long-term effects of DAPT in patients with cardiovascular risks. While these trials did not find a significant difference in stroke prevention between DAPT and SAPT, they did observe a higher incidence of major bleeding events in the DAPT groups, highlighting the safety concerns related to dual antiplatelet therapy. 

Subgroup analyses within these trials and across various studies included in systematic reviews and meta-analyses provided additional insights into specific populations where DAPT was particularly effective or risky. These analyses typically focused on demographic factors such as age, gender, and ethnicity, as well as clinical characteristics like comorbidities, including hypertension, diabetes, and previous cardiovascular events. The data revealed that DAPT was especially effective in reducing stroke recurrence in younger patients with minor strokes or TIAs. However, the analyses also indicated that older adults and those with multiple comorbidities faced increased risks of bleeding, underlining the importance of individualized therapy.  

Figure 2: Table summarizing information and results from the 25 trials that were included in this study 

Figure 3: Bar graph comparing percentage of stroke reduction vs percentage of increased bleeding in the patients for the 25 trials included in this study 

The CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events) trial and the POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial are pivotal studies that have demonstrated the efficacy of dual antiplatelet therapy, particularly the combination of aspirin and clopidogrel, in significantly reducing the risk of recurrent strokes within the first 90 days following an initial stroke or transient ischemic attack¹. The CHANCE trial, conducted in China with 5,170 participants, showed a 32% reduction in stroke recurrence when patients were administered 75 mg aspirin combined with clopidogrel 75 mg for 21 days, followed by clopidogrel alone for up to 90 days². Similarly, the POINT trial, conducted across the USA and Canada with 4,881 participants, reported a comparable reduction in ischemic events using a broader range of aspirin dosages (50-325 mg) combined with clopidogrel 75 mg for 90 days²⁰. These studies underscore the efficacy of DAPT in the acute phase post-stroke, highlighting a crucial period where the risk of recurrence is highest³. 

Supporting evidence from other trials further corroborates these findings. For instance, the FASTER trial, a Canadian study with 392 participants, demonstrated reduced embolization with DAPT (aspirin 81-325 mg + clopidogrel 300 mg loading dose, then 75 mg daily for 90 days). However, it did not show significant differences in clinical outcomes regarding stroke recurrence¹⁹. Additionally, the DEFUSE 3 trial, conducted in the USA with 182 participants, showed improved outcomes when combining endovascular therapy with DAPT (aspirin 81-325 mg + clopidogrel 75 mg for 90 days), thereby supporting the use of DAPT in acute stroke management². The consistent findings across these multiple trials reinforce the conclusion that DAPT significantly reduces the risk of early recurrent strokes²⁵. 

However, the efficacy of DAPT is accompanied by a heightened risk of major bleeding, which is a significant consideration for its clinical application. Several trials have highlighted these safety concerns³. The MATCH trial, a multinational study involving 7,599 participants, found no significant difference in stroke prevention between DAPT (75 mg aspirin + 75 mg clopidogrel for 18 months) and aspirin alone but noted a substantial increase in major bleeding events²⁰. Similarly, the CHARISMA trial, which involved 15,603 high-risk cardiovascular patients, reported no significant difference in efficacy but observed increased major bleeding with DAPT (aspirin 75-162 mg + clopidogrel 75 mg for 28 months)¹. The TARDIS trial, conducted in the UK with 3,096 participants, tested a more complex regimen (aspirin 75 mg + clopidogrel 75 mg + dipyridamole 200 mg for 30 days) and found no significant efficacy improvement but a substantial increase in bleeding risks². The increased bleeding risk, particularly gastrointestinal and intracranial hemorrhages, is a critical factor that limits the widespread use of DAPT. These findings suggest that while DAPT is effective in reducing stroke recurrence, the associated bleeding risks necessitate careful patient selection and monitoring¹⁹. 

Comparative studies on different antiplatelet regimens have provided further insights into their relative efficacy and safety. The PRoFESS trial, a multinational study with 20,332 participants, compared aspirin + dipyridamole (25 mg + 200 mg twice daily) to clopidogrel (75 mg) over 2.5 years and found no significant difference in stroke recurrence rates. However, there was an increased incidence of bleeding with the aspirin-dipyridamole combination²⁵. The SOCRATES trial, involving 13,199 participants, compared ticagrelor (90 mg twice daily) to aspirin (100 mg) over 90 days and found no significant difference in stroke recurrence; however, the ticagrelor group experienced higher bleeding rates³. These studies highlight that while different antiplatelet regimens can provide similar efficacy in preventing recurrent strokes, their safety profiles vary. Aspirin and clopidogrel remain the most studied and utilized combination, with a well-established efficacy and safety profile²⁰. 

Discussion 

The findings from this systematic review and meta-analysis offer significant insights into the role of dual antiplatelet therapy (DAPT) in secondary stroke prevention, reinforcing and extending the current understanding of its efficacy and safety. By consolidating evidence from major trials like CHANCE¹ and POINT², this analysis confirms that DAPT, particularly with aspirin and clopidogrel, effectively reduces stroke recurrence rates by approximately 25-30% compared to single antiplatelet therapy (SAPT). This reduction is especially notable during the critical early period following a stroke or transient ischemic attack (TIA), where the risk of recurrence is highest. The consistency of these findings with the broader literature emphasizes DAPT's importance in the acute phase of stroke management. 

However, this review also sheds light on the dual nature of DAPT's effects. While the efficacy in preventing stroke recurrence is well-documented, the increased incidence of major bleeding events, as observed in trials such as MATCH³ and CHARISMA⁷, presents a significant risk. This highlights a critical need for a balanced approach in clinical practice, where the protective effects of DAPT must be carefully weighed against the potential for hemorrhagic complications. The subgroup analyses within this review further refine our understanding by identifying specific populations where DAPT’s benefits are most pronounced—such as patients with minor strokes or high-risk TIAs—while also pointing to increased bleeding risks in older adults and those with multiple comorbidities. These insights underscore the necessity for personalized therapy in secondary stroke prevention. 

In terms of broader implications, these findings contribute to the ongoing discourse on DAPT by providing a nuanced understanding of its role in secondary stroke prevention. They suggest that while short-term DAPT (up to 90 days) is effective, extending the duration beyond this period may not yield additional benefits and could increase the risk of adverse effects. This underscores the need for further research to optimize the duration of DAPT and explore newer antiplatelet agents that might offer better safety profiles. Additionally, the review highlights a gap in defining a clear dosage threshold at which DAPT becomes ineffective. Although current evidence supports the efficacy of commonly used dosages, higher dosages and prolonged use are associated with increased bleeding risks, reinforcing the need for individualized patient therapy. 

One limitation of this review is the variability in study design and patient populations across the included trials, which may affect the generalizability of the findings. Additionally, the reliance on published studies may introduce publication bias, as studies with positive results are more likely to be published. The review also primarily focuses on short-term outcomes, and the long-term effects of DAPT beyond 90 days require further investigation. 

The review’s findings are significant in that they highlight both the benefits and risks of DAPT, providing a comprehensive view of its efficacy and safety. This balanced perspective is crucial for clinicians to make informed decisions about stroke prevention strategies. By identifying specific patient populations that benefit most from DAPT and those at higher risk for bleeding, the review offers valuable guidance for personalized treatment approaches. 

Future research should focus on optimizing the duration of DAPT and exploring alternative antiplatelet agents with potentially better safety profiles. Long-term studies are needed to assess the efficacy and safety of DAPT beyond 90 days. Additionally, research should address the lack of a clear dosage threshold for DAPT efficacy and investigate the potential benefits of personalized dosing strategies. Collaboration among international research efforts could further refine guidelines and improve secondary stroke prevention practices. 

In summary, this review supports the continued use of DAPT in high-risk groups but advocates for a more tailored approach based on individual patient risk factors. By integrating these findings with the broader literature, the discussion underscores the need for ongoing research to refine DAPT strategies, optimize therapy, and balance efficacy with safety in secondary stroke prevention. 

Conclusion and Future Direction 

The evidence strongly supports that dual antiplatelet therapy significantly enhances secondary stroke prevention, reducing the risk of recurrent strokes, as demonstrated by trials such as CHANCE, POINT, and MATCH. Nonetheless, the challenge lies in balancing these benefits with the potential for bleeding complications. To optimize DAPT strategies and improve patient outcomes, future research should focus on identifying biomarkers for personalized therapy, conducting large-scale longitudinal studies, integrating advanced technologies for monitoring, and continually updating clinical guidelines. Addressing these areas will be crucial for refining stroke management and enhancing the quality of life for stroke survivors. If we can fix these shortcomings and tailor each DAPT treatment strategy to the individual patient, we can decrease stroke recurrence and bleeding for people around the world.  

Acknowledgements 

This research paper was completed within BeMo Academic Consulting’s Pre-Med Research Program framework. BeMo's contribution played a crucial role in enhancing the quality of this work, and I extend my gratitude for their invaluable guidance and support. 

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