Dapagliflozin might doubtless lower the risk for ventricular arrhythmias and surprising loss of life in sufferers with coronary heart failure and reduced ejection portion (HFrEF), a put up hoc diagnosis of the DAPA-HF trial suggests.
The addition of dapagliflozin to customary therapy reduced the relative risk for the predominant composite endpoint of any extreme ventricular arrhythmia, resuscitated cardiac arrest, or surprising loss of life by 21%, when in contrast with placebo (hazard ratio [HR], 0.79; 95% CI, 0.63 – 0.99). Absolutely the risk reduction became 1.5% (5.9% vs 7.4%).
The profit became fixed in a competing-dangers diagnosis that incorporated all-motive mortality (HR, 0.80; P = .043) and across the particular individual ingredients of the composite outcome, James Curtain, MD, Cardiovascular Be taught Centre of Glasgow, United Kingdom, said at the digital European Society of Cardiology Congress 2021.
As previously reported from the predominant trial, remedy with the sodium-glucose cotransporter 2 (SGLT2) inhibitor slash the predominant endpoint of cardiovascular loss of life or worsening coronary heart failure by 26% amongst 4744 sufferers with HFrEF and in Unusual York Coronary heart Affiliation life like class 2 to 4.
Cochair of the leisurely-breaking science session, Lars Lund, MD, Karolinska Institute, Stockholm, pointed out that dapagliflozin reduced surprising cardiac deaths and connected events to an extent such as that seen for cardiovascular deaths, total mortality, and the predominant trial’s predominant endpoint.
“So does that point out it has any yell enact on arrhythmic events or does it point out, equivalent to a beta-blocker, to illustrate, [it] reduces calcium transience and improves facing of calcium, or does it like an enact merely by improving coronary heart failure?” he asked.
Curtain spoke back they are silent making an attempt to own the effects of this novel class of drug but that stories like shown dapagliflozin and other SGLT2 inhibitors like favorable effects on adversarial cardiac reworking, which contributes to surprising loss of life and ventricular arrhythmia. They’ve also been shown to lower cardiac chamber size, left ventricular hypertrophy, and N-terminal pro-B-kind natriuretic peptide (NT-proBNP) phases over time, in holding with a reduction in in myocardial wall stress. “So it might perhaps doubtless certainly be no doubt one of several mechanisms in which they would maybe exert a in actual fact helpful cardiac enact.”
Talking 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 became after 9 months, suggestive of a selected action on adversarial cardiac reworking over time.
“This would attend the sufferers’ coronary heart failure enviornment, but additionally thick ventricles are a key risk factor for the occurrence of peculiar loss of life and ventricular arrhythmias,” he said. “The consequences on adversarial cardiac reworking, given its plausibility via our Kaplan-Meier curves, are one [mechanism] that I would perceive to within the first instance but I’m particular there are bigger than one actions at play.”
In holding with the novel diagnosis, the predominant outcome took place in 315 (6.6%) sufferers; there were 203 adjudicated surprising deaths (64%), 104 investigator-reported ventricular arrhythmias (33%), and eight resuscitated cardiac arrests (3%).
| Formula of the Composite Result within the Two Groups | |||
| Result | 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 loss of life | 93 (3.9) | 113 (4.8) | 0.81 (0.62–1.07) |
Self reliant predictors of the predominant outcome were increased NT-proBNP phases (odds ratio [OR], 1.54), old ventricular arrhythmia (OR, 1.93), old myocardial infarction (OR, 1.42), male sex (OR, 1.53), and increased physique mass index (OR, 1.03).
The enact of dapagliflozin on the predominant outcome became fixed in several sensitivity analyses and “mainly fixed” across key subgroups, Curtain said.
Sooner or later of a discussion of the outcomes, session cochair Mitja Lainscak, MD, General Health center Murska Sobota, Slovenia, known as out two exceptions. “In regards to sufferers with implanted ICDs, the enact became neutral, and within the sufferers without diabetes, the profit became not up to in diabetic sufferers. Any explanations for that?”
Curtain responded that “it be well-known to masks that within the subgroup analyses, the point estimates were all on the side favoring dapagliflozin and the interplay check became not vital in that subgroup. The numbers of sufferers who were within the defibrillator personnel were modest and there became a slightly smaller likelihood of events, so it might perhaps maybe be tougher to masks profit in that personnel.”
In the dapagliflozin and placebo groups, the match charges per 100 individual-years were 3.9 and 5.8, respectively, in sufferers with diabetes, and 4.1 and 4.7, respectively, in these without diabetes (P for interplay = .273).
Tournament charges per 100 individual-years were 5.8 and 5.9, respectively, in sufferers with a defibrillator at baseline, and 3.5 and 4.9, respectively, in these without a defibrillator (P for interplay = .174).
Requested to observation on the hunt for, which became concurrently revealed within the European Coronary heart Journal, Milton Packer, MD, Baylor University Medical Center, Dallas, said he had “diminutive or no confidence” within the findings.
“This became fully put up hoc and the investigators mixed events — with markedly varied phases of scientific importance — in describe to total a P worth not up to 0.05,” he told theheart.org | Medscape Cardiology. “If one takes asymptomatic ventricular arrhythmias out of the diagnosis, the enact is rarely any longer statistically vital. Furthermore, half of peculiar deaths in sufferers with coronary heart failure will not be connected to a ventricular arrhythmia.”
The authors masks of their sage that the diagnosis became not prespecified and the findings might doubtless like to silent be regarded as “hypothesis generating and require affirmation,” but additionally masks that a fresh meta-diagnosis confirmed that SGLT2 inhibitor use became connected with a lower risk for ventricular tachycardia. Other limitations to the put up hoc diagnosis are that adversarial-match reporting doubtless underestimated the accurate occurrence of ventricular arrhythmias, and that these events weren’t adjudicated.
DAPA-HF became funded by AstraZeneca. Curtain stories no relevant financial relationships. Disclosures for the coauthors are listed within the paper.
Eur Coronary heart J. Published online August 27, 2021. Corpulent text
European Society of Cardiology (ESC) Congress 2021. Presented August 27, 2021.
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