Post-Hoc Analysis of DAPA-HF: Dapagliflozin Use Is Associated With Rapid Reduction of Cardiovascular Death Among Patients With Heart Failure With Reduced Ejection Fraction

Sahar Memar Montazerin, MD
By Sahar Memar Montazerin, MD on

A recent study by Dr. David D. Berg, published in JAMA Cardiology, found that the use of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was associated with reducing the risk of cardiovascular death and heart failure hospitalization, emerging very early after randomization. Of note, patients with a recent history of hospitalization due to heart failure worsening tend to benefit more and experienced greater relative and absolute risk reductions when treated with dapagliflozin.

Previous analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes
in Heart Failure) trial revealed that the addition of dapagliflozin to guideline-directed medical therapy for heart failure with reduced ejection fraction (HFrEF) was associated with a reduction in risk of worsening heart failure (HF) events and cardiovascular death. Given that hospitalization for HF worsening is a prognostic factor of disease progression and predicts further requirement of advanced therapies, it seems reasonable to examine the timing and extent of clinical benefit of treatment with dapagliflozin and prevent the deferral of this potentially beneficial medical therapy in patients with HFrEF.

Dr. Berg and his colleagues conducted a multinational, double-blind, placebo-controlled randomized trial in patients with New York Heart Association (NYHA) functional classes II through IV and left ventricular ejection fraction (LVEF) of 40% or less who received optimal pharmacological and or device therapy for based on local guidelines for HFrEF. Patients were also required to have an elevated serum level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration (NT-proBNP ≥ 600pg/mL, or NT-proBNP 400pg/mL with a history of hospitalization for HF within the previous 12 months, or NT-proBNP ≥ 900 pg/mL in patients with atrial fibrillation or atrial flutter, regardless of prior history of HF hospitalization). Patients were classified into subcategories based on the timing of their recent HF worsening which required hospitalization in relation to the trial enrollment. The efficacy endpoints measured in the study were the individual components of worsening HF episode (a hospitalization for HF or urgent HF visit) and cardiovascular death. The safety outcomes assessed in the analysis included adverse events associated with the discontinuation of dapagliflozin or placebo treatment, adverse events of interest associated with volume depletion and renal adverse events, and serious adverse events.

Among 4,744 patients included in the study, a total of 2,251 (47.4%) had a previous history of
hospitalization for HF proximate to their enrollment, and 1,301 (27.4%) had been hospitalized within the past 12 months. Dapagliflozin use was associated with a promptly evident decrease in risk of cardiovascular death or worsening HF emerging as early as 28 days of randomization (worsening heart failure: hazard ratio (HR) at 28 days: 0.48 [95% CI: 0.23-0.94], cardiovascular death: HR at 28 days: 0.87 [95% CI: 0.31-2.41]). This reduction sustained statistically significant till the end of the trial (worsening heart failure: HR at end of the study: 0.70 [95% CI: 0.59-0.83]); (cardiovascular death: HR at end of the study: 0.82 [95% CI: 0.69-0.98]). Dapagliflozin use was also associated with a reduction in the relative risk of the primary efficacy outcome by 16% in patients with no prior history of HF worsening, and 36%  in those with an HF worsening within 12 months of trial enrollment (P = .07). These findings support the benefits of the early addition of dapagliflozin to the treatment regimen of patients with chronic, symptomatic HFrEF, in particular, those with a recent history of hospitalization due to worsening heart failure.

 It is important to consider the study limitations. Namely, in the DAPA-HF trial, patients with a history of hospitalization within the past 4 weeks of the enrollment or those in the midst of HF worsening were excluded from the study, therefore this analysis does not provide evidence for dapagliflozin use during the hospitalization period when patients may experience more treatment-associated complications. In addition, the study is a post-hoc analysis and the inclusion criteria should be taken into account while interpreting the data. 

According to this post-hoc analysis, in patients with chronic HFrEF, treatment with SGLT2 inhibitors can reduce the risk of cardiovascular death or worsening heart failure.

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