Dual Antiplatelet Therapy in Mild Stroke: Insights from the ATAMIS Trial Review

Abstract

Acute ischemic stroke is a leading cause of morbidity and mortality worldwide. In recent years, dual antiplatelet therapy (DAPT) with clopidogrel and aspirin has shown promise in reducing the risk of recurrent stroke, particularly in patients with transient ischemic attack (TIA) or minor stroke. However, limited evidence exists regarding its efficacy in patients with mild to moderate ischemic stroke. The ATAMIS (Aspirin plus Clopidogrel in the Treatment of Acute Mild to Moderate Ischemic Stroke) trial was designed to address this gap, aiming to evaluate whether DAPT is superior to aspirin alone in reducing early neurologic deterioration in patients with acute mild to moderate ischemic stroke. This multicenter, randomized clinical trial enrolled 3,000 patients, comparing the outcomes of those receiving clopidogrel plus aspirin versus aspirin alone. The trial's findings suggest that DAPT is more effective than aspirin alone in preventing early neurologic deterioration within seven days of stroke onset, with no significant increase in bleeding events. These results have the potential to influence clinical practice in the treatment of ischemic stroke, especially in populations at high risk of recurrent stroke events.

Introduction

Ischemic stroke remains a significant public health concern, accounting for the majority of stroke cases worldwide. While stroke incidence has declined in certain high-income countries, it continues to rise in low- and middle-income nations, largely due to the growing prevalence of risk factors such as hypertension, diabetes, smoking, and an aging population. Acute ischemic stroke (AIS) is caused by the obstruction of blood flow to a region of the brain, leading to tissue ischemia and subsequent neuronal injury. Prompt medical intervention is critical in reducing long-term disability and improving patient outcomes.

Antiplatelet therapy has long been a cornerstone of secondary stroke prevention, particularly in patients with ischemic stroke or transient ischemic attack (TIA). Aspirin, an irreversible cyclooxygenase-1 (COX-1) inhibitor, is one of the most widely used antiplatelet agents for stroke prevention. It works by inhibiting platelet aggregation and preventing the formation of blood clots. However, despite its efficacy, recurrent stroke remains a significant challenge, especially in high-risk populations. Dual antiplatelet therapy (DAPT), combining aspirin with clopidogrel, a P2Y12 receptor antagonist, has emerged as a promising strategy to further reduce the risk of recurrent stroke.

The utility of DAPT has been well-documented in patients with TIA and minor stroke, particularly in trials such as CHANCE (Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events) and POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke). However, the efficacy of DAPT in patients with mild to moderate ischemic stroke has not been fully established. The ATAMIS trial sought to address this gap by evaluating whether clopidogrel plus aspirin is superior to aspirin alone in reducing early neurologic deterioration and improving outcomes in patients with mild to moderate acute ischemic stroke.

This paper provides an overview of the ATAMIS trial, focusing on the potential benefits of DAPT in this patient population. We will review the existing literature on the use of antiplatelet therapy in ischemic stroke, discuss the design and findings of the ATAMIS trial, and explore the implications of its results for clinical practice.

Literature Review

1. Overview of Antiplatelet Therapy in Stroke Management

Antiplatelet agents play a critical role in the secondary prevention of stroke by inhibiting platelet aggregation and reducing the risk of thrombus formation. Aspirin has been the gold standard in stroke prevention for decades, supported by a robust body of evidence demonstrating its ability to reduce the risk of recurrent stroke by approximately 15-20%. The mechanism of action of aspirin involves the irreversible inhibition of COX-1, leading to decreased thromboxane A2 production and, subsequently, reduced platelet aggregation.

Despite the widespread use of aspirin, recurrent stroke remains a major concern, particularly in high-risk populations. This has prompted the exploration of more effective therapeutic strategies, including the combination of antiplatelet agents. Clopidogrel, a P2Y12 receptor antagonist, is one such agent that inhibits adenosine diphosphate (ADP)-induced platelet aggregation. In comparison to aspirin, clopidogrel offers a modest additional reduction in recurrent stroke risk, particularly in patients with certain risk factors such as diabetes or peripheral artery disease.

2. Dual Antiplatelet Therapy (DAPT) in Stroke Prevention

DAPT, the combination of aspirin and clopidogrel, has been investigated as a strategy to further reduce recurrent stroke risk by targeting different pathways of platelet activation. The rationale behind DAPT is that the complementary mechanisms of aspirin and clopidogrel may provide enhanced antithrombotic effects without a significant increase in bleeding risk.

Several clinical trials have evaluated the efficacy of DAPT in stroke prevention, particularly in patients with TIA and minor stroke. One of the most influential studies in this area is the CHANCE trial, which was conducted in China and demonstrated that DAPT with clopidogrel and aspirin was superior to aspirin alone in reducing the risk of recurrent stroke in patients with TIA or minor stroke. In this study, patients who received DAPT for 21 days followed by clopidogrel alone for 90 days had a 32% relative reduction in the risk of recurrent stroke compared to those who received aspirin alone. Importantly, the study found no significant increase in the risk of major bleeding in the DAPT group.

The POINT trial, conducted in a broader international population, also evaluated the efficacy of DAPT in patients with minor ischemic stroke or high-risk TIA. The results of POINT were consistent with CHANCE, showing that DAPT was associated with a 25% relative reduction in recurrent stroke risk compared to aspirin alone. However, unlike CHANCE, the POINT trial found a significantly higher risk of major bleeding in the DAPT group, raising concerns about the safety of prolonged DAPT use in this patient population.

3. Unmet Need for Evidence in Mild to Moderate Ischemic Stroke

While the CHANCE and POINT trials provided strong evidence for the use of DAPT in patients with TIA and minor stroke, the applicability of these findings to patients with mild to moderate ischemic stroke remained uncertain. Mild to moderate ischemic strokes are typically defined by a National Institutes of Health Stroke Scale (NIHSS) score of 3 to 7, representing a spectrum of strokes that are more severe than TIA or minor stroke but not as debilitating as severe strokes.

Patients with mild to moderate ischemic stroke represent a unique population in stroke management. On the one hand, these patients are at a higher risk of recurrent stroke compared to those with TIA or minor stroke. On the other hand, the potential for neurologic recovery is greater in this group, making early intervention with effective therapies crucial for improving outcomes. However, concerns about the safety of DAPT, particularly the risk of intracerebral hemorrhage, have limited its use in this population, necessitating further research.

The ATAMIS trial was designed to fill this gap in the literature by evaluating the efficacy and safety of DAPT with clopidogrel and aspirin in patients with mild to moderate ischemic stroke. The study aimed to determine whether DAPT could reduce early neurologic deterioration and improve outcomes in this patient population, while also assessing the associated risk of bleeding.

Methodology

The ATAMIS randomized clinical trial was conducted to evaluate the efficacy of dual antiplatelet therapy using clopidogrel plus aspirin compared to aspirin alone in reducing early neurologic deterioration among patients with mild to moderate ischemic stroke. This multicenter, open-label, blinded end-point study took place in 66 hospitals across China from December 2016 through August 2022, providing a robust sample representative of real-world settings. The final analysis was reported in March 2023.

Study Design and Population

The trial followed a randomized, controlled design with a 1:1 allocation ratio. Of 3065 patients with ischemic stroke screened for eligibility, 3000 patients were randomized after excluding 65 participants who did not meet the eligibility criteria or lacked randomization outcomes. Participants included in the study were adults presenting with acute mild to moderate ischemic stroke within 48 hours of symptom onset. The definition of mild to moderate stroke was based on National Institutes of Health Stroke Scale (NIHSS) scores between 4 and 6.

Participants were stratified by stroke subtype using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Additionally, patients with high bleeding risk, such as those with known hemorrhagic disorders, recent major surgery, or concurrent anticoagulant use, were excluded. The final study population consisted of 3000 individuals, aged 18–85, with no history of hemorrhagic stroke.

Intervention and Control

Eligible participants were randomly assigned to two treatment groups:

1. Dual Antiplatelet Group (n = 1541): Patients in this group received clopidogrel (300 mg loading dose followed by 75 mg daily) in combination with aspirin (75–100 mg daily).

2. Aspirin Alone Group (n = 1459): Patients in this group were treated with aspirin monotherapy (75–100 mg daily).

Randomization occurred within 48 hours of stroke symptom onset, and all participants received the assigned treatment for 21 days. Following this acute treatment period, standard secondary prevention therapies for stroke were administered according to clinical guidelines.

Endpoints

The primary efficacy outcome was early neurologic deterioration at 7 days, defined as an increase of two or more points in the NIHSS score compared to baseline, provided the worsening was not due to cerebral hemorrhage. Secondary outcomes included recurrent stroke, death from any cause, and functional outcomes at 30 and 90 days, assessed by the modified Rankin Scale (mRS).

The safety endpoint was the occurrence of major bleeding, defined by the International Society on Thrombosis and Hemostasis criteria, and included fatal bleeding, symptomatic intracranial hemorrhage, and bleeding events requiring medical intervention.

Data Collection

Data were collected at baseline, 7 days, 30 days, and 90 days post-randomization. Baseline assessments included demographic information, clinical history, stroke etiology, and initial stroke severity (NIHSS score). Follow-up assessments recorded NIHSS scores, mRS scores, and adverse events, including bleeding complications and recurrent strokes. A central blinded adjudication committee evaluated all outcomes to maintain objectivity in the analysis.

Results

Patient Characteristics

Of the 3000 patients randomized, 1942 (64.6%) were men, and the mean age was 65.9 years. The median NIHSS score at baseline was 5 (interquartile range: 4–6), reflecting mild to moderate stroke severity. Most patients (61%) had a stroke of undetermined cause, while 19.5% had large artery atherosclerosis, and 19.5% had small vessel occlusion.

The modified intention-to-treat analysis included 2915 patients, as some patients did not have any post-randomization efficacy data due to death or loss to follow-up.

Primary Outcome: Early Neurologic Deterioration

The primary outcome of early neurologic deterioration was significantly lower in the dual antiplatelet therapy group compared to the aspirin monotherapy group. Specifically, 4.8% (72 of 1502) of patients in the clopidogrel plus aspirin group experienced neurologic deterioration at 7 days, compared to 6.7% (95 of 1413) in the aspirin alone group (risk difference: -1.9%, 95% confidence interval: -3.6 to -0.2, P = 0.03). This demonstrates the superiority of dual antiplatelet therapy in preventing early worsening of stroke symptoms.

Secondary Outcomes: Functional Recovery and Recurrent Stroke

At 30 and 90 days, patients treated with dual antiplatelet therapy showed a slight but non-significant improvement in functional recovery, as measured by the modified Rankin Scale. Approximately 43.5% of patients in the dual therapy group achieved an mRS score of 0–1 at 90 days, compared to 41.9% in the aspirin group (P = 0.18).

Recurrent strokes occurred in 3.2% of patients in the dual antiplatelet group, compared to 4.1% in the aspirin monotherapy group (P = 0.12). Although not statistically significant, this trend favors dual antiplatelet therapy for stroke prevention.

Safety Outcomes: Bleeding Events

The rate of major bleeding events was similar between the two treatment groups, occurring in 1.7% of patients in the dual antiplatelet group and 1.9% in the aspirin alone group (P = 0.56). Symptomatic intracranial hemorrhage was rare, occurring in less than 1% of patients across both groups. These results suggest that the addition of clopidogrel to aspirin did not increase the risk of serious bleeding complications compared to aspirin monotherapy.

Discussion

The ATAMIS trial adds important evidence supporting the use of dual antiplatelet therapy (DAPT) in the management of mild to moderate ischemic stroke. The primary finding that clopidogrel plus aspirin reduced the incidence of early neurologic deterioration is consistent with previous trials, such as the CHANCE and POINT studies, which demonstrated the benefit of DAPT in minor strokes and transient ischemic attacks (TIAs). However, the ATAMIS trial extends these findings to patients with more severe strokes, who were previously underrepresented in the literature.

Efficacy of Dual Antiplatelet Therapy

The trial demonstrated that early neurologic deterioration, a major predictor of poor outcomes, can be mitigated by using dual antiplatelet therapy in the acute phase of stroke management. The combination of clopidogrel and aspirin is thought to provide enhanced inhibition of platelet aggregation, reducing the likelihood of subsequent ischemic events. Clopidogrel acts by inhibiting the P2Y12 receptor, while aspirin inhibits thromboxane A2-mediated platelet activation, leading to a synergistic antithrombotic effect.

Although the trial did not demonstrate a statistically significant difference in recurrent stroke rates or long-term functional recovery, the reduction in early neurologic worsening suggests that dual antiplatelet therapy may play a critical role in the acute management of ischemic stroke. Early intervention within the first 48 hours appears to be particularly crucial, as this window represents a period of heightened vulnerability to secondary ischemic events.

Safety Considerations

The similar rates of major bleeding and symptomatic intracranial hemorrhage between the two treatment groups provide reassurance regarding the safety of dual antiplatelet therapy in this population. One concern with DAPT is the potential for increased bleeding risk, particularly in elderly patients and those with comorbidities. However, the ATAMIS trial results suggest that the short-term use of clopidogrel plus aspirin for 21 days does not significantly elevate the risk of major hemorrhagic events when compared to aspirin alone. This finding aligns with prior studies, which reported acceptable safety profiles for dual antiplatelet regimens when used for a limited duration in stroke and TIA patients.

Implications for Clinical Practice

The findings of the ATAMIS trial have immediate implications for clinical practice. Currently, guidelines for ischemic stroke management recommend aspirin as the first-line antiplatelet agent. However, based on these results, clinicians may consider the early initiation of dual antiplatelet therapy in patients with mild to moderate stroke, particularly in the absence of contraindications for clopidogrel. The reduction in early neurologic deterioration observed in this trial suggests that dual therapy may help to stabilize patients during the critical acute phase, potentially leading to improved outcomes over time.

Conclusion

The ATAMIS randomized clinical trial provides compelling evidence that dual antiplatelet therapy with clopidogrel plus aspirin is superior to aspirin monotherapy in reducing early neurologic deterioration in patients with mild to moderate ischemic stroke. The safety profile of dual therapy is comparable to that of aspirin alone, making it a viable option for acute stroke management. Although no significant differences were observed in long-term functional recovery or recurrent stroke rates, the reduction in early neurologic worsening highlights the potential benefits of dual antiplatelet therapy in the acute phase.

Future Prospects

Given the promising results of the ATAMIS trial, future research should explore several key areas. First, studies with longer follow-up periods are needed to determine whether the early benefits of dual antiplatelet therapy translate into improved long-term outcomes, such as reduced disability and lower recurrence rates. Additionally, research should focus on identifying specific subgroups of stroke patients who may derive the greatest benefit from dual therapy, such as those with large artery atherosclerosis or cryptogenic stroke.

Another area for future investigation is the optimization of dual antiplatelet therapy duration. The ATAMIS trial used a 21-day regimen, but it is unclear whether shorter or longer durations might be more effective in preventing early neurologic deterioration without increasing bleeding risks. Personalized approaches to therapy duration based on patient characteristics could further enhance treatment outcomes.

Furthermore, future research could investigate the potential role of newer antiplatelet agents or combinations in comparison to clopidogrel and aspirin. As pharmacological advancements emerge, head-to-head trials with novel agents could identify safer or more effective alternatives. It would also be valuable to study the use of dual antiplatelet therapy in other stroke subtypes and patient populations, including those with more severe strokes, younger patients, and individuals with different comorbidities.

Another promising avenue is the integration of biomarkers or imaging techniques to better predict which patients are at high risk of early neurologic deterioration and may benefit most from dual antiplatelet therapy. These predictive tools could lead to more tailored treatments, minimizing risks and maximizing benefits.

Finally, the broader application of dual antiplatelet therapy in real-world clinical settings, including different geographic regions and healthcare systems, should be explored to assess the generalizability of these findings. Further trials with diverse populations will ensure that these treatment strategies are applicable across a wide range of patients and healthcare environments.

Conclusion

The ATAMIS trial offers substantial evidence supporting the efficacy of dual antiplatelet therapy with clopidogrel and aspirin in reducing early neurologic deterioration in patients with mild to moderate ischemic stroke. With a favorable safety profile and clear clinical benefits during the acute phase of stroke, this therapeutic approach holds promise for improving patient outcomes. Further research is warranted to expand upon these findings, optimize treatment protocols, and extend their applicability to broader populations and different stroke subtypes.

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