Boston—The risk of cardiovascular death or worsening heart failure (HF) declined quickly when dapagliflozin was initiated in patients with heart failure with reduced ejection fraction (HFrEF), according to a new analysis that points out how patients with more recent HF hospitalization had even greater risk reductions.

The report in JAMA Cardiology addressed the questions of how quickly the clinical benefit of dapagliflozin appears in HFrEF patients and how prior hospitalization for the condition affects the level of improvement.

The TIMI Study Group at Brigham and Women’s Hospital in Boston led the research, noting that, while the clear benefits of dapagliflozin have been demonstrated in these patients, “However, clinical inertia often underlies deferred initiation of effective therapies.”

An accompanying editor’s note argues for almost immediate incorporation of the new information into clinical practice.

The secondary analysis was of a completed multinational effort, the Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure trial. From February 2017 to August 2018, the double-blind, placebo-controlled, randomized clinical trial of dapagliflozin enrolled 4,744 patients with chronic HFrEF.

Participants, who were mostly men and had a mean age of 66.3 years, were in New York Heart Association classes II through IV and with left ventricular ejection fraction of 40% or less. After median follow-up time of more than 18 months, researchers calculated hazard ratios (HR) for the primary efficacy outcome with dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), versus placebo by time following randomization. In addition, efficacy and safety of dapagliflozin were assessed according to the timing of the most recent HF hospitalization prior to trial enrollment.

Results indicate that the reduction in the primary outcome with dapagliflozin was rapidly apparent, with a sustained, statistically significant benefit by 28 days after randomization (HR at 28 days, 0.51; [95% CI, 0.28-0.94]; P = .03). Nearly half, 47.4%, of the patients had been previously hospitalized for HF, and more than a fourth, 27.4%, spent time in the hospital within the year prior to enrollment.

Among patients treated with placebo, researchers point to a stepwise gradient of risk for the primary outcome according to timing of most recent HF hospitalization, with 2-year Kaplan-Meier rates of 21.1%, 25.3%, and 33.8% (adjusted P = .003) for patients with a prior HF hospitalization never, more than 12 months ago, and 12 or fewer months ago, respectively.

Across these subgroups, they report that dapagliflozin reduced the relative risk of the primary outcome by 16% (HR, 0.84; 95% CI, 0.69-1.01), 27% (HR, 0.73; 95% CI, 0.54-0.99), and 36% (HR, 0.64; 95% CI, 0.51-0.80), respectively (P = .07 for trend).

“Accordingly, patients with a more recent HF hospitalization tended to experience greater absolute risk reductions with dapagliflozin at 2 years: 2.1% (95% CI, −1.9%-6.1%); 4.1% (95% CI,-3.6%-11.7%), and 9.9% (95% CI, 3.3%-16.5%), respectively (P = .05 for trend),” the authors of the analysis add.

In an editor’s note, JAMA Cardiology’s associate editor Gregg C. Fonarow, MD, of David Geffen School of Medicine at UCLA, and deputy editor Clyde W. Yancey, MD, MSc, of Northwestern University Feinberg School of Medicine made a strong case for rapidly incorporating the new evidence into practice.

“The patient-level clinical benefits of the use of comprehensive disease-modifying medical therapy (e.g., sacubitril/valsartan, β-blockers, mineralocorticoid receptor antagonist, and SGLT2i) for HFrEF is estimated to extend median survival by more than 6 years,” they write, adding, “Delays in the initiation of multidrug evidence-based therapies for HFrEF are unwarranted. A sense of urgency must now emerge for optimal implementation.”

Their commentary suggests that treating HFrEF with SGTL2i therapy could save as many as 34 000 additional lives per year in the United States alone.

“Nevertheless, the challenges of access, costs, clinical inertia, and health equity are real and should not be underestimated. Implementation science may address how best to overcome clinical inertia, and clinical practice guideline endorsement will help, Dr. Fonarow and Dr. Yancey conclude. “However, the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes.”

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