Clinical bottom line
Early initiation of dual pathway inhibition (DPI)—combining low-dose rivaroxaban with aspirin—represents a promising strategy to reduce major adverse cardiovascular events in patients with stable coronary artery disease (CAD). Evidence suggests that DPI may provide incremental ischemic protection beyond aspirin alone, particularly in patients at elevated ischemic risk without prohibitive bleeding risk. However, the balance between ischemic benefit and bleeding hazard remains a critical consideration, and patient selection is key. DPI is not yet universally adopted in stable CAD management but warrants consideration in appropriate candidates.
What the evidence shows
Stable CAD is characterized by a complex interplay of atherosclerotic plaque stability, thrombogenicity, and systemic inflammation (ESC Textbook of Cardiovascular Medicine, 2018). Antithrombotic therapy aims to mitigate thrombotic complications arising from plaque disruption or endothelial dysfunction.
Dual pathway inhibition, combining low-dose oral anticoagulation (rivaroxaban 2.5 mg twice daily) with aspirin, targets both platelet aggregation and thrombin generation pathways. The COMPASS trial and subsequent analyses (Romeo et al., 2024) demonstrated that DPI significantly reduced the composite of cardiovascular death, stroke, and myocardial infarction compared to aspirin monotherapy in patients with stable atherosclerotic disease, including CAD.
Switching from dual antiplatelet therapy (DAPT) to DPI after an initial period post-revascularization has also been explored, showing potential benefits in reducing ischemic events while maintaining an acceptable bleeding profile (Case Medical Research, 2019). This approach may be particularly relevant in patients with stable CAD who remain at high ischemic risk but are beyond the acute phase requiring DAPT.
Peripheral artery disease (PAD), a common comorbidity in stable CAD patients, further elevates ischemic risk. Meta-analyses indicate that patients with concomitant PAD may derive greater absolute benefit from DPI, given their higher baseline event rates (Case Medical Research, 2019; Özbakkaloğlu et al., 2026).
Caveats and uncertainty
While DPI offers ischemic risk reduction, it is associated with increased bleeding risk, including major and intracranial hemorrhage. Careful patient selection is essential to optimize the risk-benefit ratio. Current evidence primarily derives from randomized controlled trials with selected populations; real-world applicability may vary.
Long-term adherence and cost considerations may also impact DPI implementation in clinical practice. Furthermore, the optimal timing for initiation—immediate post-diagnosis versus after a period of DAPT or monotherapy—remains to be fully elucidated.
Data on DPI in specific subgroups, such as those undergoing complex coronary interventions (e.g., bifurcation stenting) or with concomitant comorbidities like chronic kidney disease, are limited (Abdel-Latif et al., 2015; Özbakkaloğlu et al., 2026). Additional studies are needed to clarify these nuances.
How this may change practice
Clinicians managing stable CAD patients should consider DPI as a potential therapeutic option for secondary prevention in individuals at high ischemic risk without contraindications to anticoagulation. This includes patients with prior myocardial infarction, multivessel disease, or concomitant PAD.
Incorporating DPI may shift practice away from aspirin monotherapy or prolonged DAPT in select stable CAD populations. Shared decision-making regarding bleeding risk, patient preferences, and adherence is critical.
Ongoing education about DPI’s benefits and risks will be important to optimize uptake. Future guidelines may increasingly endorse DPI based on accumulating evidence, particularly as further data emerge on long-term outcomes and subgroup effects.