Dapagliflozin Benefits Consistent Across Risk Groups in Heart Failure

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Investigators examined the effect of dapagliflozin on patients with varying risk for heart failure-related mortality.

The relative risk reduction observed with dapagliflozin added to standard therapy was consistent among patients with varying baseline risk for heart failure (HF), researchers reported in JACC: Heart Failure.

In a previous study, The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial (ClinicalTrials.gov Identifier: NCT03036124), researchers found that dapagliflozin decreased the risk of worsening HF events and cardiovascular death in patients with HF and reduced ejection fraction (HFrEF). The randomized, double-blind, controlled trial compared dapagliflozin 10 mg once daily with placebo, added to standard care. For the current study, the investigators aimed to evaluate the effects of dapagliflozin across the risk spectrum in the participants.

The Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) and Prospective comparison of Angiotensin Receptor-neprilysin inhibitors with ACE inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) Risk of Events and Death in the Contemporary Treatment of Heart Failure (PREDICT-HF) risk models were used to classify patients based on risk score quintiles. The primary outcome was the composite of an episode of worsening HF or cardiovascular death, whichever occurred first.

The study population included 4744 patients (mean age, 66.3 years; 76.6% men)—67.5% of which were in the New York Heart Association (NYHA) functional class II, 31.6% in functional class III, and 0.9% in functional class IV.

MAGGIC risk scores were calculable in 4740 patients from DAPA-HF. The median score was 22 (IQR, 18-25; range, 3-43 points). Each 1-point score increase was associated with an 8.2% (95% CI, 6.9%-9.4%) higher relative risk for a worsening HF event or cardiovascular death (P<.001).

Regarding the unadjusted incidence of the primary outcome according to baseline risk category and randomized treatment, the incidence in the placebo group increased incrementally with increasing score. The relative risk reduction with dapagliflozin vs placebo was consistent throughout the range of risk scores when evaluated as a categorical variable. Thus, the absolute treatment effect was greater in patients who had higher risk scores.

When applying the overall proportional risk reduction of 26% with dapagliflozin to patients with a risk score of 28 to 43 points, about 7 fewer patients per 100 person-years of treatment would have the primary outcome, compared with about 2 in those with a score of 3 to 16 points.

Cardiovascular death and worsening HF event rates, individually, in the placebo group increased stepwise with increasing score. Each 1-point score increase was associated with an 8.8% (95% CI, 7.2-10.4) higher risk of cardiovascular death (P<.001). The effect of dapagliflozin vs placebo was generally consistent across risk groups.

Regarding PREDICT-HF, the median score in the 4744 patients was 57 (IQR, 53-62; range, 38-84). Each 1-point score increase was associated with an 11.5% (95% CI, 10.3%-12.7%) higher relative risk for the primary composite outcome (P<.001). Dapagliflozin’s effects were consistent in the range of risk scores assessed as a categorical variable.

Other findings with PREDICT-HF were similar to those with MAGGIC, although PREDICT-HF led to better risk discrimination. For all-cause death, the C-statistic for the MAGGIC and PREDICT-HF risk scores was 0.63 and 0.71, respectively.

The researchers noted that because of the absence of certain laboratory values in DAPA-HF, they imputed median values from PARADIGM-HF to allow calculation of the PREDICT-HF score, which may have limited the accuracy of the score in DAPA-HF patients.

“Although two-thirds of patients in DAPA-HF were in NYHA class II, many were at high risk of adverse outcomes and obtained a large absolute benefit from the addition of dapagliflozin to standard therapy for HFrEF over a relatively short period,” the investigators noted. “However, even patients at lower risk obtained a worthwhile benefit from dapagliflozin.”

Disclosure: DAPA-HF was funded by AstraZeneca. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Docherty KF, Simpson J, Jhund PS, et al. Effect of dapagliflozin, compared with placebo, according to baseline risk in DAPA-HF. J Am Coll Cardiol HF. Published online January 12, 2022. doi:10.1016/j.jchf.2021.09.002