Dapagliflozin Benefits in HF No matter Diuretics: DAPA-HF

The DAPA-HF trial has already changed cardiology in opening up a brand unique class of remedy to sufferers with heart failure (HF), whether or not they’ve diabetes. Now the trial is yielding clues as to how it advantages them. For now, or not it is doing so by capability of elimination.

A unique diagnosis suggests that dapagliflozin (Farxiga, AstraZeneca) didn’t need assist from loop diuretics to carve the risk for scientific events in sufferers with HF with diminished ejection fraction (HFrEF), a assist considered all the way via the spectrum of glycosylated hemoglobin stages and without compromising renal purpose, advise DAPA-HF investigators.

Also, use of dapagliflozin and its scientific effects weren’t associated with adjustments in loop diuretic dosage.

These findings and others indicate the drug helps in HFrEF on the least partly by some different mechanism than its maintain diuretic form, the researchers advise.

Such insights is continually most essential to case-by-case decisions on whether to use the drug, a sodium-glucose cotransporter 2 (SGLT2) inhibitor as soon as reserved for sufferers with diabetes, given the lately broader panorama of HF therapy alternatives.

As previously reported from DAPA-HF, with more than 4700 sufferers, other folks that obtained dapagliflozin confirmed most necessary reductions in the significant end level, a composite of cardiovascular (CV) death, HF hospitalization, and urgent HF scurry to requiring IV therapy over about 18 months. The 45% of sufferers with and 55% without kind 2 diabetes enjoyed about equal assist in the placebo-controlled trial for that end level, as effectively as for all-cause mortality.

SGLT2 inhibitors work in diabetes by promoting urinary glucose excretion. That had led some to speculate that its assist in HFrEF comes primarily from a diuretic form; the sizzling findings largely build that question to leisure.

“Our findings impress that therapy with dapagliflozin was efficient despite diuretic use or diuretic dose. They also impress that dapagliflozin did not consequence in an expand in renal negative events or discontinuation of therapy in sufferers treated with a diuretic,” trialist Alice M. Jackson, MB, ChB, urged theheart.org | Medscape Cardiology.

“If truth be told, renal negative events had been fundamentally less long-established in sufferers treated with dapagliflozin, all the way via the diuretic lessons,” acknowledged Jackson, from the University of Glasgow, United Kingdom.

Jackson presented the unique diagnosis June 5 at a Unhurried-Breaking Science Session at some level of HFA Discoveries, the procure exchange for the annual scientific meeting of the Heart Failure Association (HFA) of the European Society of Cardiology. The HFA lessons had been conducted almost this year due to the COVID-19 pandemic.

At baseline, 84% of sufferers had been on outmoded diuretics. The put up hoc diagnosis broke out all sufferers by loop-diuretic dosage stage: none; not up to 40 mg furosemide equivalents (FE); 40 mg FE; or more than 40 mg FE. Medical outcomes had been an identical all the way via the four groups.

Clinicians in the trial “weren’t given explicit advice about adjusting diuretic doses, however had been impressed to assess quantity situation and form adjustments to clinical therapy in accordance with this, if most necessary,” Jackson acknowledged.

“This implies that, for many sufferers, starting dapagliflozin is not going to necessitate a commerce in diuretic dose.”

With the caveat that the event rate was low in the rather few sufferers not prescribed loop diuretics, she acknowledged, “the magnitude of the have the assist of dapagliflozin perceived to be greater in sufferers not treated with a diuretic.”

There was no recommendation of a diuretic dose–response form or statistical interplay between diuretic use and scientific outcomes on dapagliflozin, Jackson observed in the interview.

Of screen in the diagnosis, hematocrit stages shot up soon after sufferers started bright therapy, however they didn’t rise mighty in the placebo community. The sustained hematocrit elevation on dapagliflozin, considered at all diuretic dosage stages, persisted even after dosage reductions at 6 months, she acknowledged.

“Dapagliflozin is efficient in HFrEF without reference to background diuretic therapy; therefore, it is almost completely not purely acting as a diuretic,” Andrew J. Coats, MD, DSc, MBA, urged theheart.org | Medscape Cardiology.

The findings also “reduce the downside that dapagliflozin’s valuable effects are handiest considered in sufferers without efficient diuretic dosing,” acknowledged Coats, from University of Warwick, Coventry, United Kingdom.

“Altogether, these data give additional reassurance that dapagliflozin can safely be outmoded in heart failure, and has a valuable form fair of the utilization of diuretic capsules,” invited discussant Wolfram Doehner, MD, PhD, Charité-Universitätsmedizin Berlin, acknowledged after Jackson’s presentation of the diagnosis.

He made particular level out of the sustained hematocrit elevation on dapagliflozin. “Whereas this form also can fair likely listing to the peaceful carve rate in plasma quantity secondary to dapagliflozin therapy, it is effectively-known that the expand in hematocrit was fair of any commerce of the diuretic dose,” Doehner acknowledged.

“If extra mechanisms have a purpose for this observed expand in hematocrit, it could presumably also very effectively be of pastime in additional investigations.”

Jackson pointed to various observations that indicate the hematocrit finding is just not for all time defined by hemoconcentration from diminished plasma quantity, on the least not utterly.

Shall we embrace, hematocrit stages rose “without any recommendation of a relationship between diuretic dose and stage of hematocrit elevation with dapagliflozin,” she urged theheart.org | Medscape Cardiology.

The elevations persisted even with diuretic dose reductions at 6 and 12 months, “which must have led to a decrease in hemoconcentration if it was brought about by quantity contraction.”

Also, she acknowledged, “amongst sufferers not taking a diuretic, quantity depletion took place less continually in the dapagliflozin community than in the placebo community, however there was light a an identical rise in hematocrit with dapagliflozin.”

Both Jackson and Coats acknowledged the sustained elevation in hematocrit on the drug is unlikely to pose a most necessary hazard.

Theoretically, Coats acknowledged, “increased hematocrit may per chance presumably perchance decrease peripheral vessel blood scurry along with the stride, making ischemia and thrombosis more likely. However the size of the shape is itsy-bitsy and unlikely to be clinically most necessary.”

A diuretic dose may per chance presumably perchance not be sure for 128 of the trial’s 4744 randomized sufferers with HFrEF, so the put up hoc diagnosis was restricted to the ideal 4616. Of these, 746 weren’t on diuretics at baseline; 1311 had been on loop diuretics at not up to 40 mg FE or on nonloop-diuretics handiest; 1365 had been taking 40 mg FE; and 1204 had been on increased doses of loop diuretics.

The mean baseline dosage was 60 mg FE, which rose a dinky bit at some level of the trial. However the baseline dosage and the increases had been every an identical in the placebo and dapagliflozin groups. Jackson acknowledged 84% and 83% of sufferers on dapagliflozin and placebo, respectively, maintained their baseline dose at every 6 months, and about 77% in every groups at 12 months.

The overall trial’s most necessary most most necessary end-level carve rate for dapagliflozin vs placebo utilized in an identical vogue to sufferers not on a diuretics and these on any dose of diuretic, with an interplay P cost of .23 for the shape of diuretic use. The hazard ratios (HR) had been:

• 0.57 (0.36–0.92) for sufferers not on diuretics

• 0.78 (0.68–0.90) for sufferers on any diuretic dosage

• 0.74 (0.65–0.85) total

Sufferers on diuretics, Jackson acknowledged at some level of her formal online presentation, confirmed a “tendency in opposition to a dinky bit more quantity depletion in these on dapagliflozin than in these on placebo, however the extra was itsy-bitsy and not increased than approximately 3% in these taking 40 mg furosemide an identical diuretic. And luckily, this did not consequence in an expand in frequency in renal negative events nor of discontinuation of stare drug.”

Renal negative events had been in an identical vogue prevalent in the 2 therapy groups, as had been such events ensuing in therapy discontinuation. But serious renal events had been less long-established in the dapagliflozin community (1.6% vs 2.7%; P = .009), as was investigator-reported serious acute kidney destroy (1.0% vs 1.9%; P = .007).

“General, renal events had been infrequent,” Jackson acknowledged, and “due to of the itsy-bitsy choice of events, it is very sophisticated to way conclusions regarding the impact of dapagliflozin on renal purpose per diuretic-dose subgroups.”

Restful, she acknowledged, worsening renal purpose was less long-established on dapagliflozin in three of the four groups by diuretic dosage; the exception was the not up to 40 mg FE community, “however the absolute difference on this community was handiest two events.”

There appear to be dapagliflozin mechanisms “beneath the ground that must be unraveled,” Doehner acknowledged as discussant, processes that are favorable for the therapy of HFrEF in which “diuretics play no huge purpose.”

Jackson has no disclosures. Coats has disclosed receiving personal payments from Actimed, AstraZeneca, Faraday, WL Gore, Menarini, Novartis, Nutricia, Respicardia, Servier, Stealth Peptides, Verona, and Vifor. Doener has lately disclosed receiving grants and personal payments from Vifor, Pfizer, Boehringer Ingelheim, Sphingotec, ZS Pharma, Bayer, and Medtronic. 

HFA Discoveries 2020 from the Heart Failure Association (HFA) of the European Society of Cardiology. Supplied June 5, 2020.

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