- The all-virtual CHIEF-HF randomized trial evaluated whether 12 weeks of canagliflozin, compared with placebo, would improve the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ TSS)
- The mean difference between study arms in the change in score at 12 weeks was 4.3 points (95% CI, 0.8–7.8; P=0.016) in favor of canagliflozin; a change of five points in the KCCQ TSS is considered small but clinically important
- Changes in scores began to separate between the groups after two weeks of therapy
- The benefit of canagliflozin was noted across the range of ejection fractions and in patients with and without type 2 diabetes
- This novel approach to conducting a trial raises the possibility of lowering the cost and increasing the speed of generating evidence, at least for drugs established to be safe and whose effects don't need to be monitored via in-clinic testing or imaging
The expenses borne by clinical trial centers when collecting data represent up to 50% of trial costs and nearly quadrupled between 1990 and 2010. At the same time, there have been calls to make clinical trials more pragmatic.
Subscribe to the latest updates from Cardiovascular Advances in Motion
James L. Januzzi, MD, director of the Dennis and Marilyn Barry Fellowship in Cardiology Research at the Corrigan Minehan Heart Center at Massachusetts General Hospital, John A. Spertus, MD, of Saint Luke's Mid America Heart Institute, and colleagues have completed the first all-virtual randomized, controlled trial to be conducted on a large scale. It was logistically feasible and demonstrated that canagliflozin was significantly superior to placebo in improving heart failure patients' symptoms.
The Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure (CHIEF-HF) trial was conducted at 18 health systems. CHIEF-HF was planned without regard to COVID-19, but recruitment started on March 26, 2020.
Eligible patients provided electronic informed consent via a smartphone app after reviewing the form by phone with the site principal investigator. Once consented, they completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) on the app, and those with an overall summary score ≤80 were enrolled.
448 patients with HF were centrally randomized 1:1 to use canagliflozin 100 mg daily or a matching placebo for 12 weeks. 60% had HF with preserved ejection fraction (≥40%), and 28% had type 2 diabetes. Given the well-established safety of sodium–glucose co-transporter 2 inhibitors, the study drug was delivered to patients' homes. Patients also received a Fitbit and transmitted data on their daily steps, and they completed electronic diaries of medication use. Participants completed the KCCQ again at two, four, six, and 12 weeks after randomization.
The primary outcome was the change in the KCCQ total symptom score (TSS), which quantifies symptom frequency and severity over the past two weeks. Scores are transformed from 0 points (the worst) to 100 points.
At 12 weeks, both groups showed improvement in their scores:
- Placebo group—From 58.0 at baseline to 63.2 at 12 weeks
- Canagliflozin group—From 57.4 to 67.1
Changes in scores began to separate between the groups at two weeks.
The mean difference between groups in the change in score at 12 weeks was 4.3 points (95% CI, 0.8–7.8; P=0.016) in favor of canagliflozin. A change of five points on the KCCQ TSS is considered small but clinically important.
The effects of canagliflozin on the change in KCCQ TSS at 12 weeks were consistent whether patients had preserved EF (4.5 points) or reduced EF (4.0 points; P for interaction, 0.35), and whether or not they had diabetes.
A Feasible New Approach to Clinical Trials
Improving symptom burden is a critical goal for HF management, especially now that the FDA has increased the priority of patient-reported outcomes in approving new medications. Although canagliflozin doesn't have an HF indication, this study provides important evidence about its benefits in improving HF symptoms as early as two weeks after initiation.
It's also notable that symptoms improved in patients treated with placebo. That result might be considered a placebo effect, but participants' adherence to other HF medications may have improved while they were receiving weekly reminders to report their medication use.
The CHIEF-HF trial also demonstrates that an SGLT2 inhibitor can be safely initiated without requiring in-person visits, and patients can be monitored remotely to assess the drug's effect. This novel approach raises the possibility of lowering the cost and increasing the speed of generating clinical trial evidence.
Learn more about the Corrigan Minehan Heart Center
Refer a patient to the Corrigan Minehan Heart Center