Fewer sudden cardiac deaths in HF with SGLT2i therapy

SGLT2 inhibitors reduce sudden cardiac death risk in heart failure: Meta-analysis of randomized clinical trials

Literature - Oates CP, Santos-Gallego CG, Smith A, et al. - J Cardiovasc Electrophysiol. 2023 Mar 23 [Online ahead of print]. doi: 10.1111/jce.15894

Introduction and methods

Background

While SGLT2i therapy has been shown to reduce the incidence of CV death or HF hospitalization across the spectrum of LVEF in patients with HF [1-5], its clinical antiarrhythmic effects in this population are uncertain.

Aim of the study

The study aim was to characterize the impact of SGLT2i therapy on arrhythmic outcomes including sudden cardiac death (SCD) in patients with HF.

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Methods

This was a systematic review and meta-analysis of RCTs published in PubMed, Google Scholar, and clinicaltrials.gov before August 28, 2022. Trials had to meet the following criteria: (1) patients were diagnosed with clinical HF; (2) an SGLT2i and placebo were compared; (3) all patients received conventional medical therapy in addition to the randomized treatment; and (4) outcomes of interest were reported. A total of 22,084 patients with HF from 11 RCTs were included. Median study follow‐up time ranged from 2 to 28 months.

Outcomes

The primary endpoint was SCD. Secondary endpoints were sustained ventricular arrhythmias—defined as episodes of ventricular tachycardia, ventricular fibrillation, and torsades de pointes that did not result in SCD—and sustained atrial arrhythmias including episodes of AF and atrial flutter.

Main results

Primary endpoint

  • The occurrence of SCD was reported in 7/11 RCTs (n=10,796 in both SGLT2i and placebo cohorts). In the entire HF population, SGLT2i therapy was associated with a reduction in the risk of SCD compared with placebo (RR: 0.68; 95%CI: 0.48–0.95; P=0.03; number need to treat: 415). Statistical heterogeneity between these trials was low (I²=0%).
  • A prespecified subgroup analysis showed that SGLT2i therapy was not associated with SCD risk reduction in patients with HFrEF (defined as LVEF <40%; 4/7 trials; n=7670 in the SGLT2i cohort and n=7669 in the placebo cohort), with an RR of 0.70 (95%CI: 0.43−1.13; P=0.14; I²=0%).

Secondary endpoints

  • In an analysis of 8 RCTs that reported on the secondary endpoints, there was no difference in the risk of sustained ventricular arrhythmias not related to SCD between the SGLT2i (n=4420) and placebo (n=4415) groups (RR: 1.03; 95%CI: 0.83–1.29; P=0.77; I²=0%).
  • A similar result was observed for the risk of sustained atrial arrhythmias (n=10,836 in the SGLT2i cohort and n=10,835 in the placebo cohort; RR: 0.91; 95%CI: 0.77–1.09; P=0.31; I²=29%).

Conclusion

In this meta-analysis of 11 RCTs, SGLT2i therapy was associated with a lower risk of SCD in HF patients receiving contemporary medical therapy compared with placebo, although this effect did not carry over to patients with HFrEF. There was no difference in the risk of sustained ventricular or atrial arrhythmias between the treatment groups. The authors remark that the included trials showed a lack of dedicated rhythm monitoring, which could have led to an underrepresentation of asymptomatic arrhythmic events.

Furthermore, they hypothesize that the reduction in SCD they observed was “driven by a reduction in the incidence of nonshockable rhythms [...] that would not be helped by implantable cardiac defibrillators. This provocative hypothesis emphasizes the need for improved characterization of malignant arrhythmias and SCD [in patients] receiving modern medical treatment of HF to improve risk stratification for SCD before the implantation of defibrillators.”

References

1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995‐2008.

2. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413‐1424.

3. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451‐1461.

4. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387:1089‐1098.

5. Butler J, Packer M, Filippatos G, et al. Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction. Eur Heart J. 2022;43(5):416‐424

Find this article online at J Cardiovasc Electrophysiol.

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