Newly diagnosed heart failure with reduced ejection fraction: timing, sequencing, and titration of guideline-recommended medical therapy

Abstract

Background and aims: Despite guidelines recommending rapid initiation and up-titration of Guideline-recommended medical therapy (GRMT) for heart failure (HF) with reduced ejection fraction (HFrEF), its feasibility in daily practice remains unclear. TITRATE-HF studies the feasibility of rapid GRMT implementation in de novo HFrEF patients, investigating titration patterns and identifying barriers to effective treatment.

Methods: This analysis focuses on the de novo HFrEF patients included in the TITRATE-HF study, an ongoing prospective HF registry conducted in 48 Dutch hospitals. A detailed logbook for each GRMT drug class was recorded, from diagnosis to six months, including initiations, dose adjustments, discontinuations, and reasons for changes.

Results: The study included 1508 de novo HFrEF patients (median age: 70 years [inter-quartile ranges, IQR 62-77]; 31% women; median left ventricular ejection fraction: 30% [IQR 25-35]). At 6 weeks, 46% of patients were using quadruple therapy. Within 6 weeks post-HFrEF diagnosis, 50% of patients were prescribed quadruple therapy at some point, with 84% remaining on it after 180 days. At 6 months, 66.3% of patients were prescribed quadruple therapy, but only 1.3% achieved target doses for all four drug classes. While side effects accounted for 20%-37% of cases where target doses were not reached, a large proportion was attributed to physicians accepting suboptimal doses. Drug titrations occurred frequently in the first 60 days after diagnosis, fading afterwards. Discontinuation rates for angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blocker, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors were 13%, 11%, 9%, 9%, 11%, and 9%, respectively, primarily due to side effects or intolerances. Rechallenging these drug classes was successful in over 83% of patients.

Conclusions: The TITRATE-HF study demonstrates that rapid initiation of GRMT for HFrEF is feasible in real-world clinical practice. Nonetheless, our results highlight the urgency for a proactive approach and ongoing dose titration of pharmacological therapy beyond the initial first months to fully optimize treatment.

Keywords: Guidelines; Implementation; Pharmacotherapy; Registry; Sequencing; Titration.

Structured Graphical Abstract

Figure 1

GRMT sequencing order in de novo HFrEF patients who were naïve to GRMT prior to HF diagnosis. GRMT, guideline-recommended medical therapy; HFrEF, heart failure with reduced ejection fraction; HF, heart failure; RAS, renin–angiotensin system; MRA, mineralocorticoid receptor antagonist; SGLT2, sodium–glucose cotransporter −2

Figure 2

GRMT prescription rates from diagnosis until 6-month follow-up. GRMT, guideline-recommended medical therapy; RAS, renin–angiotensin system; MRA, mineralocorticoid receptor antagonist; SGLT2, sodium–glucose cotransporter 2; HF, heart failure

Figure 3

Dose titration across GRMT drug classes in patients initiating therapy within 6 weeks after HF diagnosis. GRMT, guideline-recommended medical therapy; HF, heart failure; ARNI, angiotensin receptor–neprilysin inhibitor; BB, beta-blocker; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor; TD, target dose

Figure 4

Number of down-titrations per reason and drug class. The percentages indicate the proportion of the reported down-titrations caused by each side-effect within each drug class. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitors; BB, beta-blocker; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor

Figure 5

Number of discontinuations per reason and drug class. The percentages indicate the proportion of the reported discontinuations caused by each side-effect within each drug class. LVEF, left ventricular ejection fraction; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; BB, beta-blocker; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor