Canagliflozin Improves Quality of Life in HF Patients

Treating heart failure (HF) patients with canagliflozin (Invokana; Janssen), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, significantly improves quality of life, with the marked benefit observed early and sustained through follow-up, according to the results of the CHIEF-HF trial.

In perhaps a sign of the times, the study, which was led by John Spertus, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO), launched the same week the COVID-19 pandemic shut down the United States and was conducted without a single face-to-face visit or laboratory assessment.

The novel trial, performed in an era of increased telemedicine visits, was not without its challenges, though. Investigators planned to randomize 1,900 patients, but the sponsor stopped the trial “because of shifting priorities” after just 476 patients were enrolled in the study.

Despite the setback, and the relatively short follow-up, canagliflozin significantly improved patients’ HF symptoms regardless of ejection fraction or diabetes status. “These effects were observed as early as 2 weeks and sustained out to 3 months,” said Spertus, who presented the results of the late-breaking clinical trial at the American Heart Association 2021 Scientific Sessions.

CHIEF-HF models a new approach to how clinical research can be conducted in the future, said Spertus, adding that he believes “decentralized” trials are highly possible, particularly with drugs or interventions that have a proven track record.  

“There are several features to think about when doing such a trial,” he said. “First of all, we benefited by a wealth of data about the safety of SGLT2 inhibitors. If there are real safety concerns, then I think it’s risky to not have in-person visits with patients. Secondly, the design of the trial focusing on quality of life was one of the key opportunities we had to be able to conduct this completely virtually.”

Decentralized Clinical Trial

At the time CHIEF-HF was launched, the benefits of SGLT2 inhibitors on quality of life in HF patients were not well understood, particularly in those with heart failure with preserved ejection fraction (HFpEF), Spertus told TCTMD. Since then, several large trials have been published, including DAPA-HF, EMPEROR-Preserved, EMPEROR-Reduced, DEFINE-HF, and PRESERVED-HF, a veritable onslaught of research into the use of SGLT2 inhibitors. Those trials have shown not only that the drugs reduce HF hospitalizations and mortality, but also that they improve quality of life.

Canagliflozin is currently approved for glycemic control in patients with type 2 diabetes. It is also approved for the treatment of diabetic kidney disease and to reduce the risk of HF hospitalizations in patients with type 2 diabetes on the basis of the CREDENCE study. After the CANVAS trial, canagliflozin gained an indication for the reduction of major adverse cardiovascular events in patients with type 2 diabetes and an increased risk of atherosclerotic cardiovascular disease. Unlike empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) and dapagliflozin (Farxiga; AstraZeneca), it does not have an indication for use in patients with HF.

“When thinking about approving a drug for heart failure, you either want the intervention to make patients live longer by minimizing progression of the disease or you want to make patients feel better by improving their symptoms, function, and quality of life,” said Spertus, explaining the rationale for their study.

In CHIEF-HF, the researchers utilized the Kansas City Cardiomyopathy Questionnaire (KCCQ) to assess the frequency and severity of symptoms after treatment with canagliflozin. Patients were screened using electronic health records to identify those with HF, and all eligible patients interested in participating downloaded the KCCQ app and provided informed consent electronically. Study medications were sent directly to the patient, as was a wearable device (Versa 2; Fitbit) to measure physical activity.

In total, 208 patients randomized to placebo and 209 randomized to canagliflozin 100 mg completed the study. Nearly 60% of patients had HFpEF, and 28% had diabetes.

At 12 weeks, there was a significant improvement in the KCCQ total symptom score favoring canagliflozin (mean difference 4.3 points; P = 0.016). Within 2 weeks, said Spertus, there were already signs of an improvement in quality of life compared with placebo. The benefit was seen in all subgroups, including in patients with HFpEF, those with HF with reduced ejection fraction (HFrEF), and those with and without diabetes.   

Eldrin Lewis, MD, MPH (Stanford University School of Medicine, CA), the discussant following the CHIEF-HF presentation, said the focus of treatment for patients with HF is both quantity and quality of life. Across the various clinical trials, improvements in KCCQ score with the different SGLT2 inhibitors range from 1.5 points with empagliflozin in EMPEROR-Preserved to 4.8 and 5.8 points with dapagliflozin in DEFINE-HF and PRESERVED-HF, respectively.

Lewis said one of the strengths of CHIEF-HF is the diversity of participants, noting that 14% of patients were Black and 45% were female. However, the follow-up is relatively short at 12 weeks and investigators were only able to randomize roughly 25% of their intended study population. Still, despite those limitations, “we clearly saw benefit with canagliflozin,” said Lewis.

Speaking with the media, Lewis emphasized the importance of patient-specific outcomes in clinical trials. Quality of life is really important to patients, and “as we have more-robust measures for some of these patient-reported outcomes, we need to incorporate them more in clinical trials,” said Lewis.