Dual pathway inhibition versus antiplatelet therapy for "symptomatic" lower-extremities peripheral artery disease in diabetes mellitus: a systematic review and a meta-analysis of randomized controlled trials for the development of the Italian guidelines for the treatment of diabetic foot syndrome.

Background and aims: Dual pathway inhibition (DPI) with aspirin and low-dose rivaroxaban (LDR) has shown benefits in reducing major adverse cardiovascular (MACEs) and limb (MALEs) events in patients with lower extremity peripheral artery disease (LE-PAD). This study aimed to determine whether DPI is preferable to anti-platelet therapy alone in reducing adverse outcomes in diabetic patients with "symptomatic" LE-PAD and to assess the safety of DPI, specifically bleeding risks. The findings aim to support development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome.

Methods: A Medline and Embase search was conducted through October 31, 2024, to identify RCTs comparing DPI with anti-platelet therapy in diabetic patients with symptomatic LE-PAD. Key efficacy outcomes included MALEs, MACE, and a composite of cardiovascular death, myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation. Safety outcomes primarily focused on major bleeding and fatal/critical organ bleeding. Mantel-Haenzel odds ratios and 95% confidence intervals (MH-OR, 95%CI) were calculated.

Results: From a total 153 items retrieved, 4 studies were assessed for eligibility; however only one study met the inclusion criteria for efficacy and safety outcomes component of the review. Due to lack of disaggregated data, efficacy and safety outcomes were estimated indirectly through proportional calculations. DPI demonstrated a reduced risk of MALEs [MH-OR 0.52; (95% CI 0.26-1.06)], MACE or MALE [MH-OR 0.67; (95% CI 0.45-1.00)], and the overall composite (MH-OR 0.70 [95% CI, 0.46-1.05]) compared to aspirin alone. A similar pattern was observed for MACE [MH-OR 0.70; (95% CI 0.44-1.11)]. While DPI did not significantly increase the risk of major or fatal/critical organ bleeding, a trend towards lower major bleeding rate in favor of aspirin was found. The net clinical benefit favored DPI (MH-OR 0.55 [95%CI, 0.36-0.84]).

Conclusions: In diabetic patients with symptomatic LE-PAD, LDR plus aspirin is preferable to aspirin alone in reducing cardiovascular and limb outcomes, with acceptable bleeding risk.