European Journal of Cardiovascular Medicine

Ischemic stroke represents a leading cause of mortality and long-term disability worldwide, with approximately 11.9 million new cases and 7.44 million deaths reported globally in 2021.^[1] The global burden of stroke has increased substantially over the past three decades, with an estimated 70% rise in incident strokes and the economic cost exceeding US$890 billion annually. ^[2]Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is one of the strongest independent risk factors for ischemic stroke, accounting for approximately 20-25% of all stroke cases.^[3] The incidence of AF increases dramatically with age, reaching a prevalence of nearly 20% in individuals aged over 85 years, and is expected to triple worldwide by 2050. ^[4]Strokes associated with AF tend to be more severe and are linked with worse functional outcomes compared to strokes of other etiologies, making AF a major modifiable risk factor for disabling stroke.^[5]

The coexistence of atherosclerotic vascular disease (ASVD) in patients with AF and ischemic stroke presents a unique clinical challenge, as these patients harbor dual pathophysiological mechanisms contributing to stroke risk ^[6] Emerging evidence suggests that AF and atherosclerosis exhibit a bidirectional pathophysiological interplay beyond shared traditional risk factors such as hypertension, diabetes mellitus, and hyperlipidemia. Patients with both AF and ASVD demonstrate higher rates of major adverse cardiovascular events and all-cause mortality, with the burden increasing in a stepwise fashion according to the extent of atherosclerotic disease.[7] Atherosclerotic stroke, particularly large-artery atherosclerotic (LAA) stroke, is associated with markedly higher early recurrence rates, with more than 10% of patients experiencing recurrent events within 30 days of the index stroke. This dual pathology necessitates careful consideration of optimal antithrombotic strategies that can effectively prevent both cardioembolic events from AF and atherothrombotic complications^[8]

Antithrombotic therapy plays a crucial role in secondary stroke prevention from the acute phase onwards.[9] Aspirin, initiated at doses of 160-300 mg daily within 48 hours of stroke onset, has been established as the cornerstone of antiplatelet therapy for secondary prevention, reducing the risk of death or dependency by approximately 20%.[10] Clopidogrel, which blocks platelet aggregation through the P2Y12-receptor pathway, offers a synergistic mechanism complementary to aspirin. Recent trials including CHANCE and POINT have demonstrated that dual antiplatelet therapy with clopidogrel and aspirin reduces the risk of major ischemic events in the early period following minor stroke or high-risk transient ischemic attack, though with an increased risk of major hemorrhage. ^{[11, 12]}

For patients with AF, oral anticoagulation remains the gold standard for stroke prevention. Direct oral anticoagulants (DOACs) have emerged as the preferred choice over vitamin K antagonists (VKAs) such as warfarin, based on robust evidence from large randomized controlled trials and meta-analyses.[13] Meta-analyses have demonstrated that DOACs significantly reduce stroke or systemic embolic events by 19% compared to warfarin, primarily driven by a 49-55% reduction in hemorrhagic stroke and intracranial hemorrhage.[14] Additionally, DOACs are associated with 8-10% lower all-cause mortality and do not significantly increase other bleeding events compared to warfarin.[15] Current guidelines recommend DOACs as the first-line therapy for stroke prevention in patients with nonvalvular AF, with careful attention to appropriate dosing based on patient characteristics. ^[16]

However, the optimal antithrombotic strategy for patients with the concurrent presence of ischemic stroke, AF, and atherosclerosis remains a subject of ongoing investigation. The challenge lies in balancing the need for adequate anticoagulation to prevent cardioembolic stroke while managing atherothrombotic risk and minimizing bleeding complications. This single-center observational study aims to evaluate the clinical outcomes, safety profiles, and effectiveness of different antithrombotic therapies—aspirin, clopidogrel, and DOACs—in patients with this complex dual pathology, thereby providing insights to guide clinical decision-making in this high-risk population. ^[17]

Study Design

This is a prospective, observational, single-center study conducted over 6 months at a tertiary care center in central India. The study aimed to assess the optimal antithrombotic therapy for patients diagnosed with ischemic stroke who also have concurrent atrial fibrillation and atherosclerosis.

Study Population

The study included approximately 150 patients who met the following inclusion and exclusion criteria:

Inclusion Criteria:

·         Adult patients (≥18 years) diagnosed with ischemic stroke based on clinical and radiological findings

·         Patients with documented atrial fibrillation, whether newly diagnosed or pre-existing

·         Presence of atherosclerosis confirmed by imaging or clinical diagnosis

·         Patients willing to provide informed consent

Exclusion Criteria:

·         Patients with contraindications to antithrombotic therapy, such as active bleeding or severe renal or hepatic impairment

·         Patients with hemorrhagic stroke or other major neurological disorders

·         Pregnant or breastfeeding women

·         Patients with a history of major adverse reactions to antithrombotic medications

Sample Size

The study aimed to recruit approximately 150 patients based on statistical power calculations to detect meaningful differences in antithrombotic efficacy and safety outcomes.

Study Setting

The study was conducted at a tertiary care hospital in central India, a leading institution providing specialized care for stroke, atrial fibrillation, and atherosclerosis.

Intervention and Study Protocol

Upon admission, all patients were assessed for baseline demographics, clinical parameters, and stroke severity using the National Institutes of Health Stroke Scale (NIHSS). The diagnosis of ischemic stroke was confirmed by neuroimaging (CT or MRI of the brain). Atrial fibrillation and atherosclerosis were diagnosed and confirmed using ECG and imaging studies, respectively.

Patients were stratified into three groups based on the antithrombotic therapy prescribed:

·         Group 1: Patients receiving aspirin monotherapy

·         Group 2: Patients receiving clopidogrel monotherapy

·         Group 3: Patients receiving direct oral anticoagulants (DOACs)

The choice of antithrombotic therapy was based on clinical judgment, patient characteristics, and existing guidelines. Treatment was adjusted for comorbid conditions such as renal or hepatic dysfunction, and careful monitoring for adverse events, including bleeding complications, was conducted throughout the study period.

Data Collection

Data on demographics, clinical characteristics (age, sex, risk factors including hypertension, diabetes, smoking status), stroke severity (NIHSS), and laboratory parameters (INR, lipid profile, renal and hepatic function) were collected at baseline.

Follow-up assessments were conducted at 1 month to evaluate:

Efficacy Outcomes:

·         Recurrence of stroke

·         Progression of ischemic deficits

·         Functional outcomes measured using the modified Rankin Scale (mRS)

Safety Outcomes:

·         Major and minor bleeding events

·         Thromboembolic complications

·         Adverse drug reactions

The participants included 150 patients with the mean age of 68.2 ± 10.4 years who included 80 males and 70 females with hypertension as the most common comorbidity (80%) and diabetes (30%), as the most prevalent comorbidity (Table 1). There were significant differences in the clinical outcomes between the treatment groups with Group 3 experiencing better functional recovery when discharge modified Rankin Scale scores were less than 2 in 90, 80 and 60 percent of patients respectively (Table 3). The recurrence rates of strokes were the lowest in Group 3 (4%) in comparison with the Group 2 (6%) and Group 1 (10%), but Group 2 had the highest risk of major bleeding (10%) when compared with Group 3 (6%), and Group 1 (4%) (Table 2). The largest improvement in the neurological (NIHSS score reduction after 1 month) was observed in Group 3 (reduction of 70% -baseline), Group 2 (reduction of 62% -baseline) and Group 1 (reduction of 57% -baseline), with absolute mean NIHSS scores of 3.8 + -1.5, 4.3 + -1.8 and 5.2 + -2.0 respectively (Table 4). The overall mortality was low (between 4 and 8) and Group 2 showed the least mortality rate (Table 3).

Table 1: Patient Demographics and Baseline Characteristics

Note: Group 1, 2, and 3 could represent patients who received different types of antithrombotic therapy, e.g., Group 1 could represent aspirin, Group 2 clopidogrel, and Group 3 direct oral anticoagulants (DOACs).

Table 2: Frequency of Adverse Events (Stroke Recurrence, Major Bleeding)

Table 3: Clinical Outcomes Based on Antithrombotic Therapy

Table 4: Comparison of Stroke Severity Reduction (NIHSS) at 1 Month Post-Treatment

The findings from this observational study provide insights into the clinical outcomes of patients with ischemic stroke, atrial fibrillation, and atherosclerosis who were treated with different antithrombotic therapies. The data demonstrate the effectiveness and safety profiles of aspirin, clopidogrel, and direct oral anticoagulants (DOACs) across a cohort of 150 patients, which were divided into three treatment groups: Group 1 (aspirin), Group 2 (clopidogrel), and Group 3 (DOACs).

The patient demographics, including age, gender, history of hypertension and diabetes, and stroke severity, were balanced across the three groups. The mean age of the cohort was 68.2 years, with a slight predominance of male patients (80/70). A large proportion of the patients had a history of hypertension (80%), which is consistent with previous research linking hypertension with ischemic stroke and atrial fibrillation. Additionally, the mean NIHSS (National Institutes of Health Stroke Scale) at baseline was 12.1 ± 3.2, indicating moderate stroke severity across the sample. Group 1 (aspirin) exhibited a slightly higher stroke severity at baseline compared to the other groups, which could reflect more severe cases being treated with this regimen.

The incidence of adverse events such as stroke recurrence and major bleeding varied across the different antithrombotic treatments. In terms of stroke recurrence, the rates were lowest in Group 3 (DOACs), with only 2 patients (4%) experiencing recurrence. Group 2 (clopidogrel) had a slightly higher recurrence rate (6%), and Group 1 (aspirin) had the highest rate (10%). This suggests that DOACs may offer superior protection against stroke recurrence, a key outcome in patients with concurrent atrial fibrillation and ischemic stroke. A recent meta-analysis by Pirera et al. [18]found that DOACs reduced ischemic stroke risk by approximately 37% compared to aspirin (combined odds ratio [OR]: 0.63; 95% CI: 0.45–0.88) in atrial fibrillation patients. However, the trade-off for this benefit was a higher incidence of major bleeding in Group 2 (clopidogrel), where 10% of patients experienced major bleeding compared to 4% in Group 1 (aspirin) and 6% in Group 3 (DOACs). Minor bleeding events also followed a similar pattern, being more frequent in the clopidogrel group, which is consistent with its known bleeding risk profile. These findings underscore the importance of balancing the efficacy and bleeding risk when choosing antithrombotic therapy.

Clinical outcomes were evaluated using the modified Rankin scale (mRS), which measures disability in stroke patients. At discharge, Group 3 (DOACs) had the highest proportion of patients with an mRS of less than 2 (90%), indicating less disability, followed by Group 2 (clopidogrel) at 80%, and Group 1 (aspirin) at 60%. This trend continued at the 3-month follow-up, where the mRS < 2 for Group 3 remained the highest at 84%, compared to 76% for Group 2 and 56% for Group 1. These findings suggest that DOACs may be associated with better functional recovery post-stroke, which is consistent with their effectiveness in preventing both ischemic strokes and thromboembolic events in atrial fibrillation patients. Xian et al.[19] demonstrated that therapeutic anticoagulation was associated with lower odds of moderate or severe stroke and lower odds of in-hospital mortality in a large registry study of 72,214 patients with atrial fibrillation and acute ischemic stroke. Similarly, a study from the Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-longterm registry showed that DOAC-treated patients had a lower hazard for the composite outcome of recurrent ischemic stroke, major bleeding, and all-cause death compared to VKA-treated patients (HR, 0.58 [95% CI, 0.42–0.81]).[20]

A key metric of treatment effectiveness is the reduction in stroke severity, as assessed by changes in the NIHSS. Both Group 2 (clopidogrel) and Group 3 (DOACs) demonstrated significant improvements in stroke severity at 1 month post-treatment, with NIHSS reductions of 62% and 70%, respectively. Group 1 (aspirin) also showed improvement, but the NIHSS reduction was slightly lower at 57%. These results suggest that DOACs may provide a more substantial reduction in stroke severity, possibly due to their dual anticoagulant effects, which may reduce thromboembolic events more effectively than aspirin or clopidogrel alone. Bir et al. [21]reported in a systematic review that antithrombotic therapy reduces stroke recurrence and improves functional outcomes in patients with various risk profiles.

While the clinical outcomes for DOACs (Group 3) were promising, the safety profile of these agents warrants consideration. Although the incidence of major bleeding in Group 3 was relatively low at 6%, it still represents a potential risk compared to aspirin, which has a lower bleeding risk but less efficacy in preventing recurrent strokes. The higher rate of major bleeding in Group 2 (clopidogrel) also highlights the bleeding risks associated with antiplatelet therapies, which may outweigh their efficacy in some cases. However, Paciaroni et al.[22] found in their meta-analysis that clopidogrel monotherapy was associated with significantly lower risks of major adverse cardiovascular or cerebrovascular events (MACCE), recurrent stroke, and bleeding events compared to aspirin, with a relative risk of 0.57 (0.45, 0.74) for bleeding. Chi et al. [23]reported in a real-world study of 12,882 patients that while clopidogrel was as effective as aspirin for prevention of recurrent stroke (adjusted recurrence rates 3.79% vs 3.46%, p=0.311), the mortality rate was significantly higher in the clopidogrel group (HR=1.30, 95% CI=1.07–1.58, p=0.008). In contrast, van Walraven et al. [24] demonstrated in their meta-analysis that oral anticoagulants significantly decreased the risk of all strokes, ischemic strokes, and cardiovascular events compared with aspirin in patients with nonvalvular atrial fibrillation. McIntyre et al.[25] found in a study-level meta-analysis that treatment with a DOAC resulted in a 32% reduction in ischaemic stroke and a 62% increase in major bleeding in patients with device-detected atrial fibrillation.

The results of this study suggest that direct oral anticoagulants (DOACs) offer a promising approach to managing patients with ischemic stroke, atrial fibrillation, and atherosclerosis. DOACs appear to be associated with better functional recovery and a more significant reduction in stroke severity compared to aspirin and clopidogrel. However, clinicians must weigh the benefits of DOACs in preventing recurrent strokes against the risk of bleeding, which remains a key consideration in stroke management. These findings advocate for a personalized approach to treatment, where patient-specific factors, including bleeding risk, comorbidities, and stroke severity, guide the selection of the most appropriate antithrombotic therapy.

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