Cryptogenic stroke, defined as a stroke of unknown origin after extensive investigation, remains a clinical enigma, affecting a significant number of stroke patients worldwide. When it occurs alongside left atrial cardiomyopathy, an abnormality of the heart's atrial tissue linked to a higher risk of thromboembolism, the challenge of preventing stroke recurrence becomes even more complex [1]. Traditional antiplatelet therapy with aspirin has long been a cornerstone in stroke prevention, primarily due to its accessibility, low cost, and established efficacy in reducing the risk of cardiovascular events. However, despite its widespread use, aspirin may not offer sufficient protection for certain patient populations, particularly those with underlying cardiac conditions like left atrial cardiomyopathy [2].

Left atrial cardiomyopathy, though not a primary focus in many stroke prevention strategies, has gained attention as a potential contributor to stroke risk. It is characterized by structural and functional abnormalities in the left atrium, which can lead to atrial fibrillation (AF) and increased thrombogenesis, even in the absence of overt arrhythmias [3]. This creates a situation where standard stroke prevention therapies, such as aspirin, may not adequately address the underlying prothrombotic state. This has led researchers and clinicians to explore whether anticoagulants, traditionally reserved for patients with atrial fibrillation or other clear indications for anticoagulation, might be more effective in preventing recurrent strokes in this specific subset of patients [4].

Rivaroxaban, a direct oral anticoagulant (DOAC) that inhibits Factor Xa, has emerged as a potential alternative to aspirin in stroke prevention [5]. DOACs like rivaroxaban have transformed the management of thromboembolic diseases by offering similar or superior efficacy to traditional anticoagulants (such as warfarin) but with a more predictable pharmacokinetic profile, fewer dietary restrictions, and no need for routine blood monitoring. These advantages have made rivaroxaban an attractive option for patients with cardiovascular conditions that predispose them to stroke, including those with left atrial cardiomyopathy [6].

The potential superiority of rivaroxaban over aspirin in this population stems from its ability to target and inhibit thrombin generation more effectively. Whereas aspirin works by inhibiting platelet aggregation, it does not directly affect the coagulation cascade[7]. Rivaroxaban, on the other hand, interferes with the formation of fibrin clots by inhibiting Factor Xa, a key component in the coagulation pathway [8]. This broader mechanism of action may offer better protection against the types of clots that form in patients with left atrial cardiomyopathy, who may have a higher burden of thromboembolic risk due to atrial dysfunction. Several clinical trials have sought to investigate whether rivaroxaban could reduce stroke recurrence more effectively than aspirin in patients with cryptogenic stroke [9]. Notably, the NAVIGATE ESUS trial examined the efficacy of rivaroxaban in patients with embolic strokes of undetermined source (ESUS), a category that overlaps with cryptogenic stroke. Although the trial did not demonstrate a statistically significant benefit of rivaroxaban over aspirin in reducing overall stroke recurrence in the general ESUS population, questions remain about its efficacy in specific subgroups, such as those with left atrial cardiomyopathy [10]. This has prompted further research focused specifically on patients with this underlying condition, where rivaroxaban’s anticoagulant properties may have a more pronounced impact. Recent studies have highlighted the potential role of left atrial cardiomyopathy in promoting thromboembolic events, even in the absence of detectable atrial fibrillation [11]. As a result, experts have called for more tailored stroke prevention strategies that account for the structural and functional abnormalities in the atrium. Since rivaroxaban has demonstrated efficacy in preventing thromboembolism in patients with atrial fibrillation, it stands to reason that it could be equally effective in those with atrial cardiomyopathy, even in the absence of traditional arrhythmias [12]. The current investigation aims to determine whether this hypothesis holds true by comparing the rates of stroke recurrence between patients treated with rivaroxaban and those treated with aspirin. If rivaroxaban proves to be superior to aspirin in preventing stroke recurrence in this population, it could significantly alter clinical practice guidelines. Stroke prevention strategies could shift toward a more individualized approach, where anticoagulation is considered not only for patients with overt atrial fibrillation but also for those with left atrial cardiomyopathy. This would represent a significant paradigm shift in how clinicians approach stroke prevention in cryptogenic cases, focusing on the underlying cardiac abnormalities rather than just the observable arrhythmias [13].

OBJECTIVE:
To evaluate the effectiveness of rivaroxaban versus aspirin in reducing stroke recurrence in patients with a history of cryptogenic stroke and left atrial cardiomyopathy.

This randomized, controlled, open-label trial was conducted at PIMS Hospital Islamabad during June 2023 to June 2024. The study included a total of 220 patients with a history of cryptogenic stroke and evidence of left atrial cardiomyopathy, as confirmed by cardiac imaging (echocardiogram or MRI) and clinical evaluation. All patients were aged 40 to 80 years and had experienced a cryptogenic stroke within the past six months.

Inclusion criteria:

• A history of cryptogenic stroke with no identified source after standard diagnostic workup (including imaging, cardiac monitoring, and laboratory testing).
• Evidence of left atrial cardiomyopathy, such as left atrial enlargement, left atrial fibrosis, or abnormal atrial function.
• No history of atrial fibrillation or other documented arrhythmias.

Exclusion criteria:

• Presence of known contraindications to anticoagulant or antiplatelet therapy, recent major bleeding events, severe renal or hepatic impairment, and life expectancy of less than one year.

Data collection

Upon enrollment, patients were randomly assigned in a 1:1 ratio to receive either rivaroxaban (15 mg once daily) or aspirin (100 mg once daily). The randomization process was computer-generated to ensure equal distribution of patients between the two groups. The study was open-label, meaning both patients and healthcare providers were aware of the assigned treatment.  Participants in the rivaroxaban group received 15 mg of the drug orally once daily, while those in the aspirin group received 100 mg of aspirin once daily. Both treatments were administered for a duration of 12 months. Patients were regularly monitored for adherence to the treatment protocol and for any adverse events. Follow-up visits occurred at 1 month, 3 months, 6 months, and 12 months after the initiation of therapy, during which clinical evaluations and diagnostic tests were conducted to monitor for stroke recurrence or any other complications. The primary endpoint of the study was the recurrence of stroke, either ischemic or hemorrhagic, during the 12-month follow-up period. Stroke recurrence was confirmed through clinical assessment and neuroimaging. All relevant patient data were collected at each follow-up visit, including the occurrence of recurrent stroke, adverse events, and any changes in medication adherence.

Data Collection and Analysis

Data were analyzed using SPSS (29.0). Continuous variables were expressed as mean ± standard deviation, while categorical variables were presented as percentages. The primary analysis was conducted using an intention-to-treat approach.

The study enrolled 220 patients, with 110 patients randomized to the rivaroxaban group and 110 patients to the aspirin group. All patients completed the 12-month follow-up, and data from each group were analyzed for stroke recurrence, major adverse cardiovascular events (MACE), major bleeding events, and functional outcomes. The baseline characteristics of the two groups were comparable in terms of age, sex, and risk factors for stroke, such as hypertension, diabetes, and previous transient ischemic attacks (TIA). The mean age of patients was 66.4 ± 8.5 years, with 54% male participants. Around 70% of patients in both groups had hypertension, and 30% had diabetes. There was no significant difference between the two groups in terms of baseline characteristics (p > 0.05).

Table 1: Baseline Characteristics of the Study Population

At the end of the 12-month follow-up, stroke recurrence was observed in 16 patients (14.5%) in the aspirin group, compared to 7 patients (6.4%) in the rivaroxaban group. This difference was statistically significant (p = 0.03), indicating that rivaroxaban was associated with a lower rate of recurrent stroke compared to aspirin.

• Rivaroxaban group (n = 110): 7 patients (6.4%) experienced a recurrent stroke.
• 6 ischemic strokes
• 1 hemorrhagic stroke
• Aspirin group (n = 110): 16 patients (14.5%) experienced a recurrent stroke.
• 14 ischemic strokes
• 2 hemorrhagic strokes

The hazard ratio (HR) for recurrent stroke in the rivaroxaban group compared to the aspirin group was 0.41 (95% CI: 0.18–0.95, p = 0.03), demonstrating a significant reduction in stroke recurrence with rivaroxaban.

Table 2: Primary Endpoint - Stroke Recurrence

The incidence of major adverse cardiovascular events (including myocardial infarction, cardiovascular death, and hospitalization for cardiovascular causes) was lower in the rivaroxaban group compared to the aspirin group.

• Rivaroxaban group: 8 patients (7.3%) experienced a MACE.
• Aspirin group: 13 patients (11.8%) experienced a MACE.

However, this difference was not statistically significant (p = 0.23). The rate of major bleeding events was slightly higher in the rivaroxaban group compared to the aspirin group, but the difference was not statistically significant.

• Rivaroxaban group: 6 patients (5.5%) had a major bleeding event.
• Aspirin group: 3 patients (2.7%) had a major bleeding event.

The bleeding events in both groups were primarily gastrointestinal (GI) in origin, with no fatal bleeding incidents reported in either group. Functional outcomes were assessed using the modified Rankin Scale (mRS) at the end of the 12-month follow-up. A score of 0–2 indicated good functional recovery, while a score of 3–6 indicated worse outcomes.

• Rivaroxaban group: 85 patients (77%) had good functional outcomes (mRS 0–2).
• Aspirin group: 76 patients (69%) had good functional outcomes (mRS 0–2).

Though more patients in the rivaroxaban group had favorable outcomes, the difference was not statistically significant (p = 0.12). Quality of life, measured by the Stroke Impact Scale (SIS), showed a slight improvement in the rivaroxaban group compared to the aspirin group, but the difference was not substantial.

Table 3: Secondary Endpoints - Major Adverse Cardiovascular Events (MACE), Major Bleeding Events, and Functional Outcomes (mRS)

Table 4: Stroke Recurrence by Type (Ischemic vs. Hemorrhagic)

The findings from this study provide valuable insights into the effectiveness of rivaroxaban compared to aspirin in preventing stroke recurrence among patients with cryptogenic stroke and left atrial cardiomyopathy. The results suggest that rivaroxaban, a direct oral anticoagulant (DOAC), significantly reduces the risk of recurrent strokes compared to aspirin, particularly in preventing ischemic strokes [14]. The primary endpoint—stroke recurrence—was notably lower in the rivaroxaban group (6.4%) compared to the aspirin group (14.5%), with a statistically significant p-value of 0.03. This suggests that rivaroxaban offers superior protection against recurrent stroke in this patient population, likely due to its ability to inhibit thrombin formation via Factor Xa, a key player in the coagulation cascade. In contrast, aspirin, which primarily works by inhibiting platelet aggregation, may not sufficiently address the thromboembolic risks associated with left atrial cardiomyopathy [15]. This supports the hypothesis that patients with underlying left atrial cardiomyopathy might benefit more from anticoagulation rather than antiplatelet therapy. The majority of recurrent strokes in both groups were ischemic. Importantly, rivaroxaban was associated with a significantly lower rate of ischemic strokes (5.5%) compared to aspirin (12.7%), with a p-value of 0.04. Hemorrhagic strokes were rare in both groups, with no significant difference in their occurrence (0.9% vs. 1.8%, p = 0.56). These findings underscore rivaroxaban’s ability to reduce the formation of ischemic clots while maintaining a relatively low risk of hemorrhagic complications. While rivaroxaban showed a trend towards lower rates of major adverse cardiovascular events (7.3% vs. 11.8%), this difference was not statistically significant (p = 0.23) [16]. Nonetheless, the data suggests that anticoagulation with rivaroxaban may provide some benefit beyond stroke prevention, reducing the risk of cardiovascular events associated with the underlying cardiomyopathy. A potential concern with anticoagulants like rivaroxaban is the risk of bleeding. In this study, there was a slightly higher incidence of major bleeding events in the rivaroxaban group (5.5%) compared to the aspirin group (2.7%), although the difference was not statistically significant (p = 0.31). Most of the bleeding events were non-fatal gastrointestinal bleeds. This highlights the need for careful patient selection and monitoring, particularly in those with a higher bleeding risk. However, the overall benefits in stroke prevention appear to outweigh the bleeding risks for most patients in this population. The functional outcomes, as measured by the modified Rankin Scale (mRS), favored the rivaroxaban group, with a higher proportion of patients achieving good functional recovery (77.3% vs. 69.1%). Although this difference was not statistically significant (p = 0.12), it suggests that better stroke prevention may lead to improved post-stroke recovery [17]. Similarly, the quality of life, measured by the Stroke Impact Scale (SIS), was slightly higher in the rivaroxaban group, indicating that patients who avoided recurrent strokes experienced a better overall quality of life. The results of this study suggest that anticoagulation with rivaroxaban could become a more widely adopted strategy for stroke prevention in patients with cryptogenic stroke and left atrial cardiomyopathy. While aspirin has traditionally been used as first-line therapy, this study’s findings support a shift toward DOACs like rivaroxaban for patients with evidence of left atrial cardiomyopathy, even in the absence of atrial fibrillation. Rivaroxaban’s ability to address thromboembolic risks more comprehensively may offer these patients better long-term protection against stroke recurrence. However, it is important to note the bleeding risk associated with anticoagulation. Clinicians must weigh the benefits of reduced stroke recurrence against the potential for increased bleeding, particularly in older patients or those with a history of bleeding disorders. Personalized treatment plans should be considered, considering each patient’s risk factors and comorbidities.

It is concluded that rivaroxaban is more effective than aspirin in reducing stroke recurrence, particularly ischemic strokes, among patients with cryptogenic stroke and left atrial cardiomyopathy. While there is a slightly higher risk of bleeding with rivaroxaban, its benefits in preventing recurrent strokes outweigh this risk for most patients.

1. Sanna, Tommaso, et al. "Cryptogenic Stroke and Underlying Atrial Fibrillation." New England Journal of Medicine, vol. 370, no. 26, 2014, pp. 2478-2486. doi: 10.1056/NEJMoa1313600.
2. Gladstone, David J., et al. "Atrial Fibrillation in Patients with Cryptogenic Stroke." New England Journal of Medicine, vol. 370, no. 26, 2014, pp. 2467-2477. doi: 10.1056/NEJMoa1311376.
3. Hart, Robert G., L. Andrew Pearce, and Michael I. Aguilar. "Meta-Analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation." Annals of Internal Medicine, vol. 146, no. 12, 2007, pp. 857-867. doi: 10.7326/0003-4819-146-12-200706190-00007.
4. Ruff, C. Anthony, et al. "Comparison of the Efficacy and Safety of New Oral Anticoagulants with Warfarin in Patients with Atrial Fibrillation: A Meta-Analysis of Randomised Trials." The Lancet, vol. 383, no. 9921, 2014, pp. 955-962. doi: 10.1016/S0140-6736(13)62343-0.
5. Kasner, Scott E., et al. "Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial." Journal of Stroke and Cerebrovascular Diseases, vol. 27, no. 6, 2018, pp. 1673-1682. doi: 10.1016/j.jstrokecerebrovasdis.2018.01.027.
6. Kwong, C., et al. "A Clinical Score for Predicting Atrial Fibrillation in Patients with Cryptogenic Stroke or Transient Ischemic Attack." Cardiology, vol. 138, no. 3, 2017, pp. 133-140. doi: 10.1159/000476030.
7. Gladstone, David J., et al. "Atrial Premature Beats Predict Atrial Fibrillation in Cryptogenic Stroke: Results from the EMBRACE Trial." Stroke, vol. 46, no. 4, 2015, pp. 936-941. doi: 10.1161/STROKEAHA.115.008714.
8. Healey, J. Steven, et al. "Subclinical Atrial Fibrillation in Older Patients." Circulation, vol. 136, no. 14, 2017, pp. 1276-1283. doi: 10.1161/CIRCULATIONAHA.117.028845.
9. Perera, K.S., et al. "Global Survey of the Frequency of Atrial Fibrillation-Associated Stroke: Embolic Stroke of Undetermined Source Global Registry." Stroke, vol. 47, no. 9, 2016, pp. 2197-2202. doi: 10.1161/STROKEAHA.116.013378.
10. Larsen, B. S., et al. "Excessive Atrial Ectopy and Short Atrial Runs Increase the Risk of Stroke Beyond Incident Atrial Fibrillation." Journal of the American College of Cardiology, vol. 66, no. 3, 2015, pp. 232-241. doi: 10.1016/j.jacc.2015.05.018.
11. Mounier-Vehier, F., et al. "Silent Infarcts in Patients with Ischemic Stroke Are Related to Age and Size of the Left Atrium." Stroke, vol. 24, no. 9, 1993, pp. 1347-1351. doi: 10.1161/01.STR.24.9.1347.
12. Di Tullio, M. R., et al. "Left Atrial Size and the Risk of Ischemic Stroke in an Ethnically Mixed Population." Stroke, vol. 30, no. 10, 1999, pp. 2019-2024. doi: 10.1161/01.STR.30.10.2019.
13. Uphaus, Thomas, et al. "Development and Validation of a Score to Detect Paroxysmal Atrial Fibrillation After Stroke." Neurology, vol. 92, no. 2, 2019, pp. e115-e124. doi: 10.1212/WNL.0000000000006727.
14. Tsang, Timothy S., et al. "Silent Atrial Fibrillation in Olmsted County: A Community-Based Study." Canadian Journal of Cardiology, vol. 27, suppl. 122, 2011. doi: 10.1016/j.cjca.2011.07.121.
15. Yaghi, S., et al. "Left Atrial Enlargement and Stroke Recurrence: The Northern Manhattan Stroke Study." Stroke, vol. 46, no. 6, 2015, pp. 1488-1493. doi: 10.1161/STROKEAHA.115.008711.
16. Lang, R. M., et al. "Recommendations for Chamber Quantification." European Journal of Echocardiography, vol. 7, no. 2, 2006, pp. 79-108. doi: 10.1016/j.euje.2005.12.014.
17. Healey, J. Steven, et al. "Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial." JAMA Neurology, vol. 76, no. 7, 2019, pp. 764-773. doi: 10.1001/jamaneurol.2019.0617.