Findings confirm DAPA-HF ’no fluke’

Adding empagliflozin to standard heart failure treatment reduced the risk of cardiovascular death or hospitalization for worsening heart failure by 25% (P <0.001) compared to placebo, a finding that should be practice-changing if physicians are willing to follow the evidence, said Milton Packer, MD, principal investigator of the 3,730-patient EMPEROR-Reduced trial on the opening day of the European Society of Cardiology Congress (ESC 2020).

Moreover, that finding is entirely concordant with the results of DAPA-HF, which reported a similar benefit with the SGLT2 inhibitor dapagliflozin just a year ago.

Packer presented the EMPEROR-Reduced findings, which were also published online by the New England Journal of Medicine and The Lancet, at a virtual Hot Line presentation and at an ESC press conference.

In an editorial published with the trial, NEJM Deputy Editor John A. Jarcho, MD, wrote that the results of EMPEROR-reduced confirm that the heart failure benefit reported in DAPA-HF was “no fluke and substantially strengthen the rationale for the use of SGLT2 inhibitors in patients with heart failure and a reduced ejection fraction. Guidelines committees will now need to contend with the evidence. The Canadian Cardiovascular Society and the Canadian Heart Failure Society have already done so: they have recommended the use of SGLT2 inhibitors in patients with mild or moderate heart failure who have an ejection fraction of 40% or less to improve symptoms and quality of life and to reduce the risk of hospitalization and cardiovascular mortality. The EMPEROR-Reduced data will provide further impetus for other groups to address this question.”

Patients enrolled in the trial had class II, III, or IV heart failure and ejection fractions of <40%. Empagliflozin is commonly used to treat type 2 diabetes (T2D), and the EMPEROR-Reduced trial recruited patients with and without T2D.

The researchers randomized 1,863 patients to empagliflozin (10 mg) and 1,867 to placebo. “Half the patients had a history of diabetes, 73% had a left ventricular ejection fraction of 30% or less, 79% had a NT-proBNP level of at least 1000 pg per milliliter, 48% had an estimated GFR of less than 60 ml per minute per 1.73 m2, and nearly 20% were receiving an angiotensin receptor–neprilysin inhibitor,” Packer and colleagues wrote.

The primary outcome measure was a composite of cardiovascular death or hospitalization for worsening heart failure, but secondary endpoints included first and recurrent heart failure hospitalizations and slope of decline in glomerular filtration rate (GFR) over time.

Packer said the benefit for those secondary endpoints was even more impressive: a 30% reduction in risk of first or recurrent hospitalization for worsening heart failure and a 50% reduction in renal events (as recorded by decline in GFR) (P <0.001 for each).

The outcomes were consistent for those with and those without diabetes.

In both EMPEROR-Reduced and DAPA-HF, the “benefit of the SGLT2 inhibitor on the primary composite outcome was driven mainly by a reduction in hospitalizations for heart failure. The risk of cardiovascular death was 8% lower with empagliflozin than with placebo in our trial (hazard ratio, 0.92; 95% CI, 0.75-1.12) and was 18% lower with dapagliflozin in the DAPA-HF trial (hazard ratio, 0.82; 95% CI, 0.69-0.98),” Packer said. “Of note, in large-scale trials involving patients with type 2 diabetes, the risk reductions in cardiovascular death among patients with similar cardiovascular histories (i.e., those with a prior myocardial infarction) were 41% for empagliflozin (hazard ratio, 0.59; 95% CI, 0.44-0.79) and 8% for dapagliflozin (hazard ratio, 0.92; 95% CI, 0.69-1.23). Therefore, as noted by other investigators, the effect of SGLT2 inhibitors on mortality appears to be heterogeneous, with no consistent evidence that one member of the drug class is superior to another with respect to the effects on survival.”

Packer noted that empagliflozin was extremely well-tolerated and “there is no need to adjust the dose. You give it as one 10 mg pill once a day.”

Of note, in EMPEROR-Reduced, 19% of patients were receiving ARNI therapy (sacubitril-valsartan), which was more than double the ARNI use in DAPA-HF. “And there is evidence that SGLT2 inhibition is additive,” Packer said. Yet, the fact that only 19% of the patients were taking sacubitril-valsartan during the recruitment period for the study (April 2017 to Nov. 2019) is itself troubling.

Packer was a principal investigator for the PARADIGM-HF trial, which was reported at ESC in 2014 and led to the FDA approval of sacubitril-valsartan in 2015 and its addition as a class I recommendation in heart failure guidelines.

But 6 years later, that drug, also called a game-changer, has not been widely accepted by treating physicians.

Asked about the impact of EMPEROR-Reduced and the possibility that it will be practice-changing, Packer said the results of PARADIGM-HF “were practice-changing and the combined results of EMPEROR-Reduced and DAPA-HF are also practice-changing. So, over the past 5 years we have the introduction of two very important classes of drugs for heart failure… physicians should really take notice for the benefit of our patients.”

During the panel discussion following his Hot Line presentation, Packer noted that SGLT2 inhibitors are the “fourth cornerstone of heart failure treatment. The other three are angiotensin/neprilysin inhibitors, beta blockers, and mineralocorticoid receptor agonists (MRA)”

When Rudolf de Boer, MD, of the University of Groningen in The Netherlands, asked Packer if there was a preferred order to use those drugs, Packer used himself as an example:

“The only way I can answer the question is to describe what I would like to happen to me if I was just given the diagnosis of heart failure with reduced ejection fraction. I would want my physicians to initiate therapy with all four classes above within the first four to six weeks after they have made my diagnosis. Now, that means I am recommending concomitant, nearly simultaneous initiation of therapy — not on the same day — but within a reasonably short period of time.”

But when pressed on the issue of how many heart failure patients will be likely to benefit from SGLT2 inhibitors, Packer said it depends “on whether physicians are paying attention… If we published the results of this trial simultaneously in the New England Journal of Medicine and in The Lancet. So, we have the great privilege of doing so, but if physicians don’t pay attention, and they don’t prescribe these drugs, then no patients will benefit.

“We have a real challenge in treating heart failure that many physicians who treat patients with heart failure, are treating them in a way which resembles the state of the art 15 years ago,” he continued. “So, I don’t know the determination as to how many patients will benefit. It would be thousands, hundreds of thousands, but it depends on whether physicians actually are paying attention and incorporate these drugs into clinical practice.”

  1. Be aware that findings from a double-blind, randomized trial of more than 3,700 heart failure patients found a benefit for the addition of SGLT2 inhibition to Guideline Directed Therapy.
  2. Findings from EMPEROR-Reduced are largely concordant with findings from DAPA-HF, suggesting a class effect for SGLT2 inhibition in treatment of HFrEF. The benefit — if any — for HFpEF is unknown.

The EMPEROR trial was funded by Boehringer Ingelheim and Eli Lilly.

Packer disclosed relationships with Abbvie, Actavis, Akcea, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Cardiomentis, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance.

Jarcho is employed by the New England Journal of Medicine as a deputy editor.


Peggy Peck, Editor-in-Chief, BreakingMED™

Cat ID: 204

Topic ID: 74,204,730,204,3,838,192,925,203