Dapagliflozin in HFrEF May Cut Arrhythmias, Sudden Death: DAPA-HF

Patrice Wendling

August 27, 2021

Dapagliflozin might reduce the risk for ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF), a post hoc analysis of the DAPA-HF trial suggests.

The addition of dapagliflozin to standard therapy reduced the relative risk for the primary composite endpoint of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death by 21%, compared with placebo (hazard ratio [HR], 0.79; 95% CI, 0.63 - 0.99). The absolute risk reduction was 1.5% (5.9% vs 7.4%).

The benefit was consistent in a competing-risks analysis that included all-cause mortality (HR, 0.80; = .043) and across the individual components of the composite outcome, James Curtain, MD, Cardiovascular Research Centre of Glasgow, United Kingdom, said at the digital European Society of Cardiology Congress 2021.

As previously reported from the main trial, treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor cut the primary endpoint of cardiovascular death or worsening heart failure by 26% among 4744 patients with HFrEF and in New York Heart Association functional class 2 to 4.

Cochair of the late-breaking science session, Lars Lund, MD, Karolinska Institute, Stockholm, pointed out that dapagliflozin reduced sudden cardiac deaths and related events to an extent similar to that observed for cardiovascular deaths, total mortality, and the main trial's primary endpoint.

"So does that mean it has any particular effect on arrhythmic events or does it mean, such as a beta-blocker, for example, [it] reduces calcium transience and improves handling of calcium, or does it have an effect simply by improving heart failure?" he asked.

Curtain replied they are still trying to understand the effects of this new class of drug but that studies have shown dapagliflozin and other SGLT2 inhibitors have favorable effects on adverse cardiac remodeling, which contributes to sudden death and ventricular arrhythmia. They've also been shown to reduce cardiac chamber size, left ventricular hypertrophy, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels over time, consistent with a reduction in in myocardial wall stress. "So it could indeed be one of several mechanisms by which they may exert a beneficial cardiac effect."

Speaking with theheart.org | Medscape Cardiology, Curtain pointed out that the Kaplan-Meier curves for the composite outcome began to separate early on, but that the clearest separation was after 9 months, suggestive of a positive action on adverse cardiac remodeling over time.

"This would improve the patients' heart failure situation, but also thick ventricles are a key risk factor for the occurrence of sudden death and ventricular arrhythmias," he said. "The effects on adverse cardiac remodeling, given its plausibility in terms of our Kaplan-Meier curves, are one [mechanism] that I'd look to in the first instance but I’m sure there are more than one actions at play."

According to the new analysis, the primary outcome occurred in 315 (6.6%) patients; there were 203 adjudicated sudden deaths (64%), 104 investigator-reported ventricular arrhythmias (33%), and eight resuscitated cardiac arrests (3%).

Components of the Composite Outcome in the Two Groups
Outcome Dapagliflozin, n (%) Placebo, n (%) Hazard Ratio (95% CI)
Ventricular arrhythmia 50 (2.1) 65 (2.7) 0.76 (0.53–1.10)
Resuscitated cardiac arrest 5 (0.2) 3 (0.1) n/a
Sudden death 93 (3.9) 113 (4.8) 0.81 (0.62–1.07)

Independent predictors of the primary outcome were higher NT-proBNP levels (odds ratio [OR], 1.54), previous ventricular arrhythmia (OR, 1.93), previous myocardial infarction (OR, 1.42), male sex (OR, 1.53), and higher body mass index (OR, 1.03).

The effect of dapagliflozin on the primary outcome was consistent in several sensitivity analyses and "generally consistent" across key subgroups, Curtain said.

During a discussion of the results, session cochair Mitja Lainscak, MD, General Hospital Murska Sobota, Slovenia, called out two exceptions. "With regard to patients with implanted ICDs, the effect was neutral, and in the patients without diabetes, the benefit was less than in diabetic patients. Any explanations for that?"

Curtain responded that "it's important to note that in the subgroup analyses, the point estimates were all on the side favoring dapagliflozin and the interaction test was not significant in that subgroup. The numbers of patients who were in the defibrillator group were modest and there was a relatively smaller number of events, so it may be harder to show benefit in that group."

In the dapagliflozin and placebo groups, the event rates per 100 person-years were 3.9 and 5.8, respectively, in patients with diabetes, and 4.1 and 4.7, respectively, in those without diabetes (P for interaction = .273).

Event rates per 100 person-years were 5.8 and 5.9, respectively, in patients with a defibrillator at baseline, and 3.5 and 4.9, respectively, in those without a defibrillator (P for interaction = .174).

Asked to comment on the study, which was simultaneously published in the European Heart Journal, Milton Packer, MD, Baylor University Medical Center, Dallas, said he had "very little confidence" in the findings.

"This was entirely post hoc and the investigators combined events — with markedly different levels of clinical importance — in order to achieve a P value less than 0.05," he told theheart.org | Medscape Cardiology. "If one takes asymptomatic ventricular arrhythmias out of the analysis, the effect is no longer statistically significant. Furthermore, half of sudden deaths in patients with heart failure are not related to a ventricular arrhythmia."

The authors note in their report that the analysis was not prespecified and the findings should be regarded as "hypothesis generating and require confirmation," but also point out that a recent meta-analysis showed that SGLT2 inhibitor use was associated with a lower risk for ventricular tachycardia. Other limitations to the post hoc analysis are that adverse-event reporting likely underestimated the true prevalence of ventricular arrhythmias, and that these events were not adjudicated.

DAPA-HF was funded by AstraZeneca. Curtain reports no relevant financial relationships. Disclosures for the coauthors are listed in the paper.

Eur Heart J. Published online August 27, 2021. Full text

European Society of Cardiology (ESC) Congress 2021. Presented August 27, 2021.

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