Across the different classes of heart failure (HF) drugs, beta-blockers stood out for their association with limb loss in patients with concomitant chronic limb-threatening ischemia (CLTI), according to an observational analysis.
From a large database of de-identified electronic health records as recent as late 2024, investigators found that patients with chronic HF and the most severe form of peripheral artery disease (PAD) had varying risks of major and minor amputations (above and below the ankle, respectively) depending on the drugs they used:
- Mineralocorticoid receptor antagonists: reduced risks of both major (HR 0.65, 95% CI 0.57-0.73) and minor amputations (HR 0.87, 95% CI 0.78-0.97)
- SGLT2 inhibitors: lower risk of major amputation (HR 0.59, 95% CI 0.50-0.70) and no relationship with minor amputation (HR 0.97, 95% CI 0.84-1.11)
- Angiotensin receptor blockers: lower risk of major amputation (HR 0.82, 95% CI 0.74-0.90) and no relationship with minor amputation (HR 0.97, 95% CI 0.89-1.06)
- Angiotensin receptor-neprilysin inhibitors: no significant relationship with major (HR 0.80, 95% CI 0.63-1.01) or minor amputations (HR 1.12, 95% CI 0.93-1.36)
- Angiotensin-converting enzyme inhibitors: no significant relationship with major (HR 0.97, 95% CI 0.88-1.08) or minor amputations (HR 0.99, 95% CI 0.90-1.09)
- Beta-blockers: increased risks of both major (HR 1.81, 95% CI 1.56-2.10) and minor amputations (HR 1.60, 95% CI 1.40-1.82)
Patrick Kwaah, MBChB, a resident at Yale School of Medicine in New Haven, Connecticut, cautioned that the beta-blocker findings conflicted with other research: some studies have shown no link to major amputation, and there was a Taiwanese group that reported reduced amputation among beta-blocker users with type 2 diabetes and PAD.
"We hypothesize that the beta-blockers' effect on peripheral vasoconstriction, especially in those without prior intervention, in CLTI may explain these [present] findings," Kwaah told the audience at the Society for Cardiovascular Angiography and Interventions annual meeting.
Kwaah noted that the amputation risks were estimated based on just over 2.5 years of follow-up on average in the TriNetX database. The analysis was conducted using propensity matching to create comparable cohorts of users and non-users of each medication class. "The results should be considered hypothesis-generating owing to the observational design," he said. "Prospective randomized trials are needed to confirm these findings."
In any case, the retrospective study gained points for analyzing a broader range of medications than before and for providing reassurance on SGLT2 inhibitors in particular, said session moderator Herb Aronow, MD, MPH, of Henry Ford Health in Detroit.
In 2020, the FDA removed the black box warning from canagliflozin (Invokana) that had described an increased risk of lower limb amputation with use of the drug. The risk of amputation, regulators found, was lower than previously described in CANVAS, especially when appropriately monitored and when considering the heart- and kidney-related benefits of canagliflozin shown in trials like CREDENCE.
Regarding the apparent protection from major amputations reported here, there is evidence that "dapagliflozin [Farxiga] enhances tissue oxygenation, particularly in PAD patients with diabetes, which may in part help reduce lower extremity amputation rates," Kwaah noted.
Aronow added that "the data have convinced me that if there's any risk [from SGLT2 inhibitors], it's minimal and outweighed by the benefits."
As for the observed link between beta-blockers and lower limb amputation, Aronow suggested confounding by indication and the possibility that beta-blockers helped people live longer so they had more time to accrue amputation events.
Disclosures
Kwaah and Aronow had no disclosures.
Primary Source
Society for Cardiovascular Angiography and Interventions
Source Reference: Kwaah PA, et al "Association of heart failure guideline-directed medical therapy agents and rates of amputation in patients with chronic heart failure and chronic limb-threatening ischemia" SCAI 2025.
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