Dapagliflozin Shows Event-Free, Survival Gains Over Lifetime of Patient with HFrEF

John J. V. McMurray, MD

In patients with heart failure and reduced ejection fraction (HFrEF), there has been a recent focus on the restricted mean survival time (RMST) in both patients and clinicians to describe the benefit of sodium glucose cotransporter 2 inhibitors (SGLT2i).

A recent analysis of the Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure (DAPA-HF) estimated the long-term treatment effects of dapagliflozin in comparison with placebo, over the course of a patient lifetime.

Investigators, led by John J. V. McMurray, MD, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, found dapagliflozin delivered clinically meaningful improvement in event-free and overall survival through the lifetime of patients with HFrEF.

Study

The DAPA-HF was a phase 3 prospective, randomized, double-blind trial in patients with HFrEF that evaluated safety and efficacy of once-daily, 10mg dapagliflozin in comparison to placebo.

Eligible patients included those ≥18 years, New York Heart Association functional classification II to IV symptoms, left-ventricular EF ≥40%, and elevated levels of plasma N-terminal pro-B-type natriuretic peptide.

Further, exclusions of patients included systolic blood pressure level >95 mm Hg, an estimated glomerular filtration rate >30 mL/min/1.73 m2, and type 1 diabetes or condition likely to prevent patient participation.

Patients were enrolled between February 2017 - August 2018, with final follow-up in June 2019.

The primary outcomes incorporated a composite of time to first worsening heart failure (HF) event or cardiovascular death. In addition, secondary outcomes include both individual components of the primary end point or death from any cause.

The team noted that the RMST is an estimate of mean event-free survival time from time 0 to a specified point.

They used age at randomization and at the time of events to calculate age-specific event rates for each treatment group.

In assessment of treatment over time, investigators performed a sensitivity analysis testing for a time-varying treatment effect in DAPA-HF through a Cox proportional hazards regression model.

Results

According to the data, a total of 4744 patients were randomized in DAPA-HF, with a mean age of 66.3 years, 76.6% men (n = 3635) and 23.4% women (n = 1109).

Data show dapagliflozin, in comparison with placebo, reduced risk of the primary endpoint by 26% (hazard ratio HR, 0.74; 95% CI, 0.65 - 0.85) and death from any cause by 17% (HR 0.83; 95% CI, 0.71 - 0.97).

They noted a sensitivity analysis showed no evidence of a time-varying treatment effect with dapagliflozin for the primary endpoint (P = .26) or death from any cause (P = .95).

In a patient aged 65 years, the extrapolated mean event-free survival time was 6.2 years for placebo and 8.3 years for dapagliflozin, representing a gain of 2.1 years (95% CI, 0.8 - 3.3, P = .002).

In addition, in patients aged 55 years, the numbers showed 6.0 years for placebo and 8.9 years for dapagliflozin at a gain of 3.0 years (95% CI, 1.2 - 4.7, P = .001).

Death from any cause showed a mean extrapolated life expectancy for an individual aged 65 years at 9.1 years for placebo, compared to 10.8 years for dapagliflozin. This showed a 1.7 year survival gain with dapagliflozin (95% CI, 0.1 - 3.3, P = .03).

Investigators noted the mean extrapolated life expectancy was greater with dapagliflozin across all age ranges, compared with placebo.

Conclusion

“The findings of this trial suggest that, when the results of DAPA-HF are extrapolated over a patient’s lifetime, dapagliflozin is estimated to provide clinically meaningful gains in event-free and overall survival,” investigators wrote. “These results may be helpful in communicating the benefits of this treatment to patients with HFrEF.”

The study, “Extrapolating Long-term Event-Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction,” was published online in JAMA Cardiology.