What does this research mean for the field?

Patients with heart failure with reduced ejection fraction (HFrEF) on triple or quadruple guideline-directed medical therapy (GDMT) have a 48%-46% lower risk of all-cause mortality compared to those on a single GDMT class. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

To evaluate hospitalization and mortality risks in patients with heart failure with reduced ejection fraction not experiencing worsening heart failure while on guideline-directed medical therapy.

February 8, 2026

Residual risk of hospitalization & all-cause mortality among patients with heart failure with reduced ejection fraction without worsening heart failure who received guideline-directed medical therapy

Key Result

In HFrEF patients without recent WHF, use of more GDMT classes significantly lowered all-cause mortality risk (HR 0.52 to 0.72; p<0.001) with no HF hospitalization difference.

Key Points

To evaluate hospitalization and mortality risks in patients with heart failure with reduced ejection fraction not experiencing worsening heart failure while on guideline-directed medical therapy.
Used Optum’s Clinformatics Data Mart Database to identify patients with HFrEF prescribed GDMT.
Defined recent worsening heart failure based on hospitalization or diuretic use in the prior year.
Assessed clinical outcomes (hospitalization and mortality) over a year using Kaplan-Meier analysis.
Overall, 10% of patients experienced heart failure-related hospitalization and 11% experienced all-cause mortality.
Higher numbers of GDMT classes were associated with significantly lower mortality risk.
93% of patients were on single or double GDMT classes despite availability of more effective therapies.

Structured PICO

Does receiving multiple GDMT classes reduce HF-related hospitalizations and all-cause mortality in patients with HFrEF without recent worsening HF compared to a single GDMT class?

Population

53,195 patients with HFrEF without recent worsening HF (no HF hospitalization or IV diuretics in the 12 months prior to index), prescribed ≥1 GDMT class. Mean age 73.8 years, 38% female, 65% White.

Intervention

Multiple guideline-directed medical therapy (GDMT) classes (2, 3, or 4 classes among ACEi/ARB/ARNi, BB, MRA, and SGLT2i)

Comparator

Single GDMT class (1 class)

Outcome

HF-related hospitalizations (HFH) and all-cause mortality (ACM) over a 1-year follow-up periodhard clinical

In patients with HFrEF without recent worsening heart failure, receiving more GDMT classes is associated with a significantly lower risk of all-cause mortality, highlighting the need to increase GDMT utilization.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Abstract Background Patients with heart failure (HF) with reduced ejection fraction (HFrEF) and worsening HF (WHF) have high clinical and economic burden. However, the residual risk and disease burden in patients without WHF on guideline-directed medical therapy (GDMT) is less well known. Quantifying the clinical burden in this population will help inform GDMT implementation efforts. Purpose To evaluate the residual risk for HF-related hospitalizations (HFH) and all-cause mortality (ACM) among patients with HFrEF without recent history of WHF on GDMT. Methods Optum’s deidentified Clinformatics® Data Mart Database was used to identify patients diagnosed with HFrEF, who were prescribed ≥1 GDMT class (ACEi or ARB or ARNi, BB, MRA, and/or SGLT2i) and did not have a recent WHF event (defined as having a HFH or receiving intravenous diuretics in the 12 months prior to index) between January 1, 2021, to September 30, 2022. The study index was defined as the first GDMT fill during the identification period. Baseline characteristics were assessed, stratified by the number of GDMT classes prescribed during the 90 days post-index. Clinical outcomes, specifically HFH and ACM, were evaluated over a 1-year follow-up period and the Kaplan-Meier (KM) method used to evaluate the risk of these events. Results The study sample included a total of 53,195 patients (mean age SD = 73.8 10.7 years), 38% female, 65% White, mean Charlson Comorbidity Index score (SD = 4.1 2.7). The most common GDMT classes prescribed were ACEi/ARB/ARNi (75%) and BB (43%). Approximately 56% of patients were on ACE/ARB, 25% were on MRA, 19% were on ARNi, and 6% were on SGLT2i; 93% of patients were on single (60%) or double (33%) GDMT classes, 7% were on triple, and 1% were on quadruple GDMT classes. Overall, the frequencies of HFH and ACM across GDMT classes were 10% and 11%, respectively. Among patients with single, double, triple, and quadruple GDMT classes, 12%, 9%, 7%, and 6%, respectively, experienced ACM during follow-up. The descriptive KM analysis showed that patients receiving more GDMT classes had a significantly lower risk of ACM (4, 3, and 2 vs. 1 GDMT: HR=0.52; (95% CI:0.32-0.84), HR=0.54; (95% CI:0.47-0.61), HR=0.72; (95% CI:0.68-0.76), p0.001, respectively). There was no difference in the time to HFH by the number of GDMT classes received. Conclusions In a real-life cohort, most patients with HFrEF (93%) without recent WHF were on single or double GDMT classes despite the proven efficacy of triple or quadruple GDMTs. Irrespective of GDMT use, patients had residual risk for HFH and ACM. However, patients receiving more GDMT classes had a lower risk for ACM. These findings underscore the clinical burden of HFrEF in patients without recent WHF and highlight the need for novel therapies to increase GDMT utilization and improve outcomes.

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