Even With Optimized GDMT, HFrEF Prognosis Remains Dire

Patients who have heart failure with reduced ejection fraction (HFrEF) are rarely prescribed all four pillars of guideline-directed medical therapy (GDMT) upon hospital discharge, and even among those who do receive these medications, clinical outcomes remain poor at 1 year, registry data show.

Among 20,651 patients with HFrEF who were eligible for all drugs—angiotensin receptor-neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonist (MRA), sodium-glucose cotransporter 2 (SGLT2) inhibitor, and beta-blocker—just 7.2% were prescribed the medications.

“As startling as that [rate] is, we’ve seen very low rates of GDMT use in real-world practice, including quadruple medical therapy,” lead investigator Stephen Greene, MD (Duke Clinical Research Institute/Duke University School of Medicine, Durham, NC), told TCTMD. “That’s been, somewhat unfortunately, well established, and this is really a huge problem for the heart failure community.”

Heart failure has a prognosis comparable to some cancers, Greene said, adding that it would be egregious if just 7% of patients with cancer were treated with chemotherapy. “Oncology would never tolerate that, and yet that’s unfortunately what’s happened in patients with heart failure with reduced ejection fraction,” he said.

The new analysis, which was published this week in JAMA Cardiology, includes Medicare beneficiaries hospitalized with HFrEF between July 2021 and December 2023 at 532 US sites participating in the Get With The Guidelines-Heart Failure registry.

Just 11.8% were prescribed quadruple therapy when the definition was expanded to include ACE inhibitors, ARBs, or ARNIs. The rates of quadruple therapy varied across hospitals, suggesting this might come down to a quality-of-care issue, said Greene. One-quarter of hospitals discharged zero patients on quadruple therapy, for example, and 2.8% discharged 25% or more of HFrEF patients on all four medications. 

Over 12 months of follow-up, roughly one in five patients (19.3%) who were prescribed quadruple therapy that included the ARNI had died and 26.0% were rehospitalized. The rate of all-cause mortality or HF hospitalization was 37.1% and hospitalization for all causes was 54.5%. Rates were similar when the definition of quadruple therapy was expanded to include use of an ACE inhibitor, ARB, or ARNI. Comparing the first and second time periods of the study, there were no significant differences in 30-day or 12-month mortality or hospitalizations in those prescribed quadruple therapy.

The median healthcare cost for a patient prescribed all four medications was $27,956, with a mean per-patient cost of $51,337, over the 12 months.

There’s essentially no such thing as a low-risk HFrEF patient population. So, I think we just need to have humility for what we’re dealing with here. Stephen Greene

Greene said that while quadruple therapy lowers the relative risk of clinical outcomes, it doesn’t result in a low absolute risk.

“Quadruple therapy is a tremendous advance,” said Greene. “It substantially lowers the risk of dying and substantially lowers the risk of going to the hospital for heart failure. It is essential for patients, but I will argue that although it is essential, it is not enough to make HFrEF a low-risk population. There’s essentially no such thing as a low-risk HFrEF patient population. So, I think we just need to have humility for what we’re dealing with here.”

While physicians need to do more to get patients on all four medications, researchers need to continue searching for other therapies to lower the residual risk patients face even when they’re on quadruple therapy, said Greene.

Last year, DIGIT-HF showed that adding digitoxin to GDMT reduced the risk of all-cause mortality and hospitalization for worsening HF when compared with placebo plus GDMT. In the VICTOR trial, which missed its primary endpoint, there was a signal that vericiguat (Verquvo; Merck Sharp & Dohme/Bayer) might lower the risk of cardiovascular mortality.  

Those trials hinted that the treatment of HFrEF might evolve beyond the four pillars.

“Needless to say, there’s always this tension with polypharmacy,” said Greene. “A lot of people view polypharmacy in a negative light, and for good reason, and I wish we could make this a low-risk condition with one or two medicines. But that’s not the scientific reality. To the people worried about polypharmacy, I would argue we clearly need more tools to combat heart failure risk. . . . This is such an extreme-risk condition that we need all the help we can get.”