Association of Guideline-Directed Medical Therapy for Heart Failure and Major Amputation Rates in Patients With Chronic Limb-Threatening Ischemia and Concomitant Heart Failure.

Chronic limb-threatening ischemia (CLTI) represents end-stage peripheral artery disease (PAD) with high mortality and amputation risk. Concomitant heart failure (HF) further worsens prognosis, yet the limb impact of HF guideline-directed medical therapy (GDMT) on limb outcomes remains uncertain. To evaluate the association between individual HF GDMT classes and major lower-extremity amputation (MLEA) among patients with CLTI and chronic HF, overall and by HF phenotype. Using the TriNetX Analytics Network (2014 to 2024), adults with CLTI ± chronic HF were identified by ICD-10 codes. Propensity-score matching was applied in a 1:1 ratio across cohorts. The primary outcome was time to MLEA (above ankle) at 2 and 5 years, estimated using Cox models. Subgroup analyses were stratified by HF phenotype (HFrEF, HFpEF) based on ICD codes and ejection fraction. A total of 495,943 patients had CLTI only, and 78,349 had concomitant chronic HF; 65,458 pairs were successfully matched. CLTI with chronic HF was associated with a higher risk of MLEA compared with CLTI alone (2-year HR 1.41; 95% CI 1.33 to 1.50; p < 0.01). In CLTI + chronic HF, use of MRAs (HR 0.74; 95% CI 0.65 to 0.84) and SGLT2i (HR 0.65; 95% CI 0.55 to 0.76) was associated with a reduced risk of MLEA, whereas BB use increased the risk (HR 1.88; 95% CI 1.63 to 2.17; p < 0.001). The BB effect was observed in HFpEF (HR 1.47; 95% CI 1.10 to 1.96) but not HFrEF. ACEi, ARBs, and ARNI were neutral except for ARNI in HFrEF, associated with reduced MLEA risk (HR 0.57; 95% CI 0.42 to 0.78). Chronic HF markedly amplifies limb-loss risk in CLTI. MRAs and SGLT2i therapies showed protective limb effects, whereas BBs, particularly in HFpEF, were linked to higher amputation risk. These results underscore the need for phenotype-specific, perfusion-conscious tailoring of HF GDMT in advanced PAD.