Most HFrEF Patients Eligible for Quadruple Therapy, but Few Get It

Only a minority of patients are prescribed triple therapy and even fewer are prescribed quadruple therapy at the time of hospital discharge following a new diagnosis of heart failure with reduced ejection fraction (HFrEF), according to a new analysis of data from Get With The Guidelines—Heart Failure (GWTG-HF) registry.

While more than 80% of hospitalized patients were eligible for a renin-angiotensin-aldosterone system inhibitor, beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter 2 (SGLT2) inhibitor, just 15.3% were prescribed all four pillars of HFrEF guideline-directed medical therapy (GDMT).

Importantly, investigators showed that implementing quadruple therapy in eligible patients at the time of discharge can have a significant impact on all-cause mortality during the next 12 months. Compared with not receiving any GDMT, just four patients need to be treated with quadruple therapy to prevent one death.

“We're talking strikingly large benefits,” senior investigator Gregg Fonarow, MD (University of California, Los Angeles), told TCTMD. “Compared to almost anything else we do in cardiology, it's hard to find treatment effects this large affecting this number of individuals each year. The impact we could have with optimal implementation of these therapies is profound.”

Guidelines Support Quickly Starting Meds

Both the US and European guidelines for the management of HF recommend use of all four classes of medications to reduce morbidity and mortality, but adoption of full GDMT in HFrEF has been relatively poor, with studies showing that less than 10% of patients are prescribed the necessary treatments. As a way to boost prescribing, experts have pushed for a strategy of starting all four medications in the hospital at the time of diagnosis.

Data also support the rapid initiation of GDMT after acute HF. In STRONG-HF, for example, getting patients up to full doses of GDMT within 2 weeks of an acute HF hospitalization, including in those with newly diagnosed HFrEF, improved measures of congestion and clinical outcomes. Fonarow said there has been some concern about how patients would tolerate rapid titration of all four drug classes, as well the number of patients who’d be eligible for quadruple therapy in the real world.

The new study was led by Stephen Greene, MD (Duke Clinical Research Institute, Durham, NC), and published in JACC: Heart Failure ahead of the American College of Cardiology 2024 Scientific Session in Atlanta, GA, where it will be presented. It includes 33,036 patients (median age 66 years; 36.7% female) at 373 hospitals with newly diagnosed HFrEF between 2016 and 2023 in the GWTG-HF registry. Eligibility for quadruple therapy was based on regulatory labeling, guidelines, and expert consensus statements.

Overall, 82.2% of patients were eligible for quadruple therapy and 93% were eligible for 3 or more components of the four available drug classes. From 2021 to 2023, a period after SGLT2 inhibitors were approved for the treatment of HFrEF, just 15.3% of 14,303 hospitalized patients in the GWTG-HF registry were prescribed quadruple therapy and 41.5% were prescribed triple therapy, which was defined as an ACE inhibitor/ARB/angiotensin-receptor neprilysin inhibitor (ARNI), MRA, and beta-blocker.

“We're really talking the vast majority of patients being truly eligible by the guidelines, by FDA approved indications, for these therapies,” said Fonarow.

The impact we could have with optimal implementation of these therapies is profound. Gregg Fonarow

While cost might be a factor limiting uptake of quadruple therapy since SGLT2 inhibitors are not available as generic medications, triple therapy is still infrequently started at the time of discharge, said Fonarow. “With generic-based triple therapy, the cost is $120 a year,” he said. “Even with the recommendations and guidelines for triple therapy [that have been around] for over a decade, it’s still only used in 42% of patients.”

The proportion of patients eligible for quadruple therapy ranged from 21% to 100% across hospitals, with 160 hospitals having between 80% to 90% of patients eligible for all four drug classes. Hospital-level use of quadruple therapy ranged from zero to 100%, with roughly one-third of hospitals discharging no patients on all four drugs. These tended to be smaller, rural hospitals without teaching affiliations.

To TCTMD, Fonarow said that high-achieving hospitals show that starting quadruple therapy at the time of discharge can be done. While there are some differences between centers more likely to initiate all four drug classes, the variation is not explained by patient or structural demographics of the hospitals. 

“It really seems to be the culture of the institution where [they] translate clinical trial evidence and guidelines into routine practice,” said Fonarow. “We would suspect they have clinical-decision support, data feedback, and other quality-implementation systems in place.”

Similar Patients to RCTs

Finally, the researchers assessed clinical outcomes among 2,759 patients with newly diagnosed HFrEF by linking to Medicare claims data.

For patients eligible for quadruple therapy, the estimated natural history of all-cause mortality among those not treated with any GDMT was 36.3%. Based on the clinical trial data, all-cause mortality was estimated to be 21.8% in those treated with just an ACE inhibitor/ARB and beta-blocker, an absolute difference of 14.5% compared with no GDMT. For those discharged on quadruple therapy, the incidence of all-cause mortality was 11.5%, an absolute risk difference of 10.4% compared with those on ACE inhibitor/ARB and beta-blocker and 24.8% compared with no GDMT.

Fonarow pointed out that the researchers also looked at the characteristics of the GWTG-HF patients and those in key clinical trials, such as PARADIGM-HF and DAPA-HF. There’s been a common perception that results of the trials aren’t generalizable to real-world patients, but that doesn’t hold up, he said. “What is striking is how representative the real-world patients are once [the trials] are confined to those with heart failure with reduced ejection fraction,” said Fonarow. “For that group, the trials are pretty representative.”