Frailty Does Not Hinder Dapagliflozin’s HFrEF Impact: DAPA-HF Analysis

Dapagliflozin’s protective effects in patients who have heart failure with reduced ejection fraction (HFrEF) are maintained irrespective of frailty, a post hoc analysis of the DAPA-HF trial suggests. In fact, the most-frail patients appear to derive the greatest benefit, not only when it comes to outcomes like worsening heart failure and cardiovascular death, but also with regard to symptoms and quality of life.

This is the latest in a series of positive developments for the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga; AstraZeneca), approved by the US Food and Drug Administration for use in HFrEF back in May 2020 based on the results of DAPA-HF. FDA approval for empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly), another SGLT2 inhibitor, followed in August 2021.

Jawad H. Butt, MD (University of Glasgow, Scotland, and Copenhagen University Hospital Rigshospitalet, Denmark), lead author of the analysis published recently in Annals of Internal Medicine, told TCTMD that going into the study, they’d anticipated dapagliflozin to perform similarly irrespective of frailty.

While what they found solidly supports that hypothesis, it was a pleasant surprise to see that the drug’s benefits seem to be enhanced among the most frail, Butt noted in an email. “These data are very important and reassuring considering the common reluctance of clinicians to introduce medications to patients that are perceived to be frail. We believe that these results certainly should motivate clinicians to prescribe SGLT2 inhibitors to their frailest patients.”

Frailty is an emerging global health burden, he pointed out, one that’s particularly common in heart failure patients and carries a worse prognosis. One explanation for why medical therapy continues to be underused in HFrEF “is that clinicians are reluctant to initiate new therapies in frail individuals due to doubts about the benefit of treatments in these patients or concerns about predisposing them to potential new adverse effects,” Butt said. “Since these doubts/concerns are not evidence-based, we wanted to provide actual data on the safety and efficacy of dapagliflozin in patients with HFrEF.”

Alexander T. Sandhu, MD (Stanford University School of Medicine, CA), who wasn’t involved in the current analysis, speculated that underuse of proven therapies reflects the “classic risk-treatment paradox,” where the most-vulnerable patients who are most likely to benefit are least likely to receive it. On the other hand, he told TCTMD, it’s possible that medical therapy is somehow less beneficial among these high-risk patients, either because of the nature of their disease or because of competing noncardiovascular risk factors.

For clinicians, “there’s a number of reasons to be concerned and speculate that lower rates of treatment among frail patients might not be entirely inappropriate, that there might be reasons for this. I think their study does a wonderful job addressing those concerns regarding lower benefit or higher risks for frail patients [taking] dapagliflozin,” Sandhu commented, noting that the data showed no increase in serious adverse events in comparison to placebo. “This should give us further support in applying these therapies to our population as quickly as possible to reduce the incredible morbidity of heart failure.”

For patients, the potential to improve quality of life could be enticing, he added. “I think it’s really motivating to say, ‘We’re giving you this medication not only because it might improve your outcomes, but also because it’s going to help you feel better.’”

Frailty in DAPA-HF

Butt and colleagues calculated a frailty index for all but two of the 4,744 patients who were randomized in DAPA-HF. Among them, half were considered “not frail” (class 1), 34% were “more frail” (class 2), and 16% were “most frail” (class 3).

Those with greater frailty tended to be older and white, and to have more comorbidities. They had higher blood pressure, heart rate, body mass index, and NT-proBNP levels on average, with worse renal function. Their heart failure was more likely to have an ischemic cause and be longer in duration. And while their LVEF tended to be higher, they also had more NYHA heart failure and worse quality-of-life measures on the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQoL-5 Domain (EQ-5D). Compared with the nonfrail patients, they were less apt to receive a renin-angiotensin-aldosterone-system or angiotensin receptor-neprilysin inhibitor but more likely to have a defibrillator.

This should give us further support in applying these therapies to our population as quickly as possible to reduce the incredible morbidity of heart failure. Alexander T. Sandhu

Over a median follow-up of 18.2 months, dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death in all of the frailty groups. The largest difference in the number of events per 100 person-years was seen among patients with class 3 frailty, which translated into the lowest number needed to treat (NNT) to prevent one event.

Outcomes With Dapagliflozin vs Placebo by Frailty Index

These patterns were consistent across individual endpoints related to HF hospitalization, CV death, and all-cause death, with the most-frail patients again tending to derive the most benefit from dapagliflozin. Additionally, among the patients with KCCQ scores available, the largest improvements in quality of life with dapagliflozin were seen in patients with greater frailty at baseline.

“Not surprisingly, we found that frail patients overall were more likely to discontinue study treatment (including placebo) and more frequently had serious adverse events, although neither was common. Importantly, study drug discontinuation and serious adverse events were not more frequently reported in the dapagliflozin group than in the placebo group in any of the frailty classes,” the investigators note.

Sandhu said these results should motivate clinicians to pursue optimal medical therapy regardless of their patients’ frailty status, with the caveat that extremely frail patients may not have been well represented in randomized controlled trials. This analysis, he added, offers robust evidence to ease concerns.

Future studies could look into whether there are any HF therapies that could slow progression of the frailty or, in the opposite direction, interventions aimed at frailty that could slow progression of heart failure, he suggested. One example is the REHAB-HF trial, said Sandhu. As reported by TCTMD, that study showed how a comprehensive, individually tailored cardiac rehabilitation program that starts in the hospital and escalates after discharge can greatly improve physical functioning for frail, elderly patients with decompensated HF.

More broadly, he suggested, it’s also important to keep in mind how strategies to optimize HF therapy will apply in the most-vulnerable populations, as denoted by frailty, by social determinants of health, or by income level.