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Association of Guideline-Directed Medical Therapy for Heart Failure and Major Amputation Rates in Patients With

Patrick A Kwaah1, Samuel A Mensah2, Clara Nkongho Tabot-Ntoung2

  • 1Division of Cardiology, Howard University, Washington, District of Columbia.

The American Journal of Cardiology
|June 9, 2026
PubMed

Insights

Heart failure (HF) significantly increases amputation risk in chronic limb-threatening ischemia (CLTI). Mineralocorticoid receptor antagonists (MRAs) and SGLT2 inhibitors (SGLT2i) reduce this risk, while beta-blockers (BBs) may increase it.

Area of Science:

  • Cardiology
  • Vascular Surgery
  • Pharmacology

Background:

  • Chronic limb-threatening ischemia (CLTI) is a severe form of peripheral artery disease (PAD) associated with high mortality and amputation rates.
  • Concomitant heart failure (HF) exacerbates the poor prognosis in CLTI patients, but the specific impact of HF guideline-directed medical therapy (GDMT) on limb outcomes is not well understood.

Purpose of the Study:

  • To investigate the association between different classes of HF GDMT and the risk of major lower-extremity amputation (MLEA) in patients with CLTI and chronic HF.
  • To analyze these associations overall and stratified by HF phenotype (heart failure with reduced ejection fraction [HFrEF] and heart failure with preserved ejection fraction [HFpEF]).

Main Methods:

  • A large cohort of adult patients with CLTI and chronic HF was identified using ICD-10 codes from the TriNetX Analytics Network (2014-2024).
  • Propensity-score matching (1:1 ratio) was employed to create comparable cohorts.
  • The primary outcome was the time to MLEA, analyzed using Cox proportional hazards models, with subgroup analyses based on HF phenotype.

Main Results:

  • Patients with CLTI and chronic HF had a significantly higher risk of MLEA compared to those with CLTI alone (2-year HR 1.41).
  • In the CLTI + chronic HF cohort, mineralocorticoid receptor antagonists (MRAs) and SGLT2 inhibitors (SGLT2i) were associated with a reduced risk of MLEA (HR 0.74 and 0.65, respectively).
  • Beta-blocker (BB) use was linked to an increased MLEA risk (HR 1.88), particularly in HFpEF, while ACE inhibitors, ARBs, and ARNI showed neutral effects, except for ARNI in HFrEF (HR 0.57).

Conclusions:

  • Chronic HF significantly increases the risk of limb loss in patients with CLTI.
  • MRAs and SGLT2i demonstrate a protective effect on limb outcomes in this high-risk population.
  • BBs may be associated with an increased risk of amputation, especially in HFpEF, highlighting the need for tailored HF GDMT strategies in advanced PAD.

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