Guideline Implementation and Dose Titration Reduces Heart Failure Outcomes

Primary results of the TITRATE-HF study have shown the importance of early and intensive implementation of guideline-recommended medical therapy (GRMT) and emphasize the need for continuous dose titration to improve heart failure (HF) outcomes.

Guidelines for HF currently recommend 4 separate medication classes in patients with reduced ejection fraction. This represents a distinct challenge, particularly in adequately implementing this GRMT, including the timely sequencing of drugs and reaching the target dose. There is currently limited knowledge regarding how the shift from a serial to a parallel approach for drug therapy, specifically the early application of these drug classes, will occur in a clinical setting. To that end, the TITRATE-HF trial was conducted.2

“By better understanding real-world adherence to GRMT prescription and dosages, as well as the trends in LVEF and clinical outcomes, TITRATE-HF seeks to bridge the gap between clinical guidelines and everyday practice,” wrote Jishnu Malgie, PhD candidate, department of cardiology, Erasmus MC University Medical Center, and colleagues.1

An ongoing observational cohort study conducted across 48 hospitals in the Netherlands from 2022-2024, TITRATE-HF examined guideline adherence and identified barriers to GRMT implementation among patients with HF. Included patients had a confirmed diagnosis with an left ventricular ejection fraction (LVEF) <50%; key exclusion criteria were a life expectancy of <1 year, a major cardiovascular event such as myocardial infarction or stroke within 2 months before consent, or advanced HF with planned left ventricular assist device implantation or heart transplantation within 6 months post-enrollment.1

Investigators highlighted 3 separate stages of HF, based on existing definitions: de novo HF, chronic HF, and worsening HF. Worsening HF was described as patients with chronic HF who experienced a related hospitalization or an urgent visit within 6 months prior to enrollment. The study investigated the composite endpoint of all-cause death and HF hospitalization.1

GRMT was defined as the use of renin-angiotensin system inhibitors (RASi), beta-blockers (BB), mineralocorticoid receptor agonists (MRA), and sodium-glucose co-transporter 2 inhibitors (SGLT2i). Quadruple therapy was defined as the simultaneous use of all 4 drug classes, regardless of dose. A GRMT log was maintained for each patient, beginning at the time of diagnosis for de novo HF or of study inclusion for chronic and worsening HF, as well as a 6-month follow-up.1

A collective 3367 patients were enrolled and stratified into the 3 HF categories. 1508 exhibited de novo HF, 1603 had chronic HF, and 256 were categorized as worsening HF. Median ages were 70 (interquartile range [IQR] 62-77), 72 (IQR 63-78), and 74 years (IQR 67-79), respectively. A total of 64%, 50%, and 45% of patients had non-ischemic cardiomyopathy (CMP), respectively.1

Quadruple therapy was prescribed to 47.2% of the de novo group at 6 weeks, 64.7% at 3 months, 69.5% at 6 months, and 64.4% at 12 months. It was prescribed to 44.6% of the chronic and worsening groups at baseline, 53.7% at 6 months, and 54.6% at 12 months. These increases were largely driven by greater SGLT2i uptake.1

Patients with de novo HF who were given serial echocardiograms (n = 752), median LVEF improved by 10% in ischemic versus 15% in non-ischemic cardiomyopathy (P <.001). Early quadruple GRMT initiation within 6 weeks and higher 6-month doses were associated with greater LVEF improvement.1

At 12 months, the composite endpoint had occurred in 13.3%, 13.3%, and 43.8% of the de novo, chronic, and worsening groups, respectively. An unadjusted Cox regression analysis showed a substantially higher risk of reaching the endpoint after discontinuation or down-titration (hazard ratio [HR] 1.88; 95% CI, 1.5-2.35; P <.001). The association remained significant after adjustment for potential cofounders (HR 1.54; 95% CI, 1.22-1.95; P <.001).1

“Although GRMT prescription rates in TITRATE-HF were relatively high compared to previous HF registries, substantial room for improvement remains,” Malgie and colleagues wrote. “Each patient contact should be approached with a sense of urgency for continuous GRMT up-titration and as an opportunity to improve guideline adherence.”1

References

1. Malgie J, Wilde M, Koudstaal S, et al. Real-life implementation of guideline-recommended medical therapy in heart failure with reduced ejection fraction: Effects on prognosis and left ventricular ejection fraction. Primary results of TITRATE-HF. (2025) Eur J Heart Fail. https://doi.org/10.1002/ejhf.70006

2. Clephas PRD, Malgie J, Schaap J, et al. Guideline implementation, drug sequencing, and quality of care in heart failure: design and rationale of TITRATE-HF. ESC Heart Fail. 2024;11(1):550-559. doi:10.1002/ehf2.14604