Initiation, Adherence, and Persistence to Guideline-Directed Medical Therapy After Heart Failure Hospitalization: Bridging the Gap Between Prescription and Sustained Use

Highlights

• Despite increased prescription of guideline-directed medical therapy (GDMT) at discharge, primary nonadherence rates remain high across β-blockers, RAS inhibitors, MRAs, and SGLT2 inhibitors.
• Early initiation and persistent use of quadruple therapy in heart failure with reduced ejection fraction (HFrEF) patients correlates with improved left ventricular ejection fraction and reduced adverse events.
• Real-world data reveal suboptimal dose titration and frequent discontinuations, highlighting the need for interventions beyond initial discharge prescriptions.
• Frailty and other patient factors influence GDMT use, underscoring the necessity for personalized approaches to optimize therapy adherence and persistence.

Background

Heart failure (HF) is a chronic progressive syndrome affecting millions worldwide, characterized by high morbidity, frequent hospitalizations, and mortality. Guideline-directed medical therapy (GDMT) encompassing β-blockers, renin-angiotensin system inhibitors (RASis), mineralocorticoid receptor antagonists (MRAs), and more recently sodium-glucose co-transporter 2 inhibitors (SGLT2is) has demonstrated significant improvement in HF outcomes, especially in heart failure with reduced ejection fraction (HFrEF). The transition period following HF hospitalization represents a critical window for initiating and optimizing these therapies to improve prognosis. However, whether discharge prescriptions translate into initiation and sustained use remains inadequately described, limiting effective secondary prevention efforts.

Key Content

Real-World Evidence of Initiation and Primary Nonadherence Post-HF Hospitalization

The recent cohort study by Bessette et al. (JAMA Intern Med, 2026) involving 6111 patients in a US health system revealed striking patterns of medication use following hospitalization for HF. Although discharge prescriptions increased treatment rates across key HF drug classes, substantial primary nonadherence was observed—51% for β-blockers, 48% for RASis, 39% for MRAs, and 35% for SGLT2is accounting for new prescriptions that were never filled. Only 54% of new prescriptions were initiated within 7 days postdischarge, with an addition of 20% initiating between 7 and 90 days. At six months, medication persistence ranged from 55% to 70% depending on drug class, culminating in only 42% adherence and 51% persistence across all HF medications initiated at discharge. This evidence underscores a major implementation gap from prescribing to sustained pharmacotherapy adherence.

Guideline-Directed Medical Therapy Implementation Across HF Subtypes

The TITRATE-HF study (Eur J Heart Fail, 2025) prospectively evaluated GDMT in 4288 patients with HFrEF across different stages (de novo, chronic, worsening) in the Netherlands, illustrating dynamic prescription patterns over 12 months. Quadruple therapy uptake increased substantially within 6 weeks and was associated with significant improvements in left ventricular ejection fraction (LVEF). Early initiation and higher dosing correlated with superior clinical outcomes, emphasizing the necessity of timely, intensive implementation.

Similarly, the Swedish Heart Failure Registry study (Eur J Heart Fail, 2025) analyzing 55,581 individuals showed high early use of RASI and β-blockers, but limited uptake of ARNI, MRA, and SGLT2i irrespective of HF duration, pointing to persistent suboptimal GDMT adoption challenges.

Dose Titration, Discontinuation, and Clinical Event Risk

Comprehensive multinational registry data from the US, UK, and Sweden (Eur J Heart Fail, 2021) highlighted patterns of low dose titration and substantial discontinuations of ACE inhibitors, ARBs, β-blockers, MRAs, and ARNI in HF patients, despite the high risk of HF hospitalization (HHF) and mortality. Target dose attainment was low (10-30%), with discontinuation rates varying from 24% to 55% within a year post-initiation. These findings reveal the limited translation of evidence-based dose optimization into practice and the need for improved clinical decision support and patient management strategies.

The CHAMP-HF registry (Am Heart J, 2017) further characterized medication use and titration in US outpatients with chronic HFrEF, documenting limited dose escalation and modification over 12 months and describing multifactorial reasons—including medical, patient preference, and system-based barriers—for suboptimal therapy adjustments.

Influence of Patient Frailty and Comorbidities on Therapy Use

Frailty status, a marker of vulnerability in HF patients, significantly influences GDMT initiation and continuity. Danish register-based research (Eur J Heart Fail, 2024) demonstrated that frailer HF patients were less likely to receive ACE inhibitors/ARBs, β-blockers, and MRAs and had worse clinical outcomes including death and non-HF hospitalization. These real-world insights stress the importance of tailored interventions addressing patient complexity to optimize therapy use.

National Programs and Implementation Strategies

Large-scale quality improvement initiatives, such as China’s National Heart Failure Center Accreditation Program (HF-CAP) (Eur J Heart Fail, 2025), show promising results. Over 400,000 patients treated in accredited centers exhibited improved GDMT utilization post-discharge with concomitant reductions in HF readmission and cardiovascular mortality. Notably, face-to-face follow-up visits were more effective than phone calls in improving patient outcomes.

Expert Commentary

The consistent evidence across multiple registries and cohort studies illustrates a pronounced gap between guideline recommendations and clinical practice in GDMT initiation and maintenance after HF hospitalization. Primary nonadherence and early discontinuation severely undermine the potential survival and morbidity benefits. Barriers include system-level factors, patient frailty, medication side effects, complexity of polypharmacy, and imperfect clinical follow-up.

Mechanistically, optimal medical therapy improves cardiac remodeling, neurohormonal modulation, and fluid balance; disruption due to poor adherence compromises these benefits. Early and intensive therapy, including rapid quadruple drug initiation, is critical but must be balanced against patient tolerability. The disparity between prescription and use suggests that discharge time-point prescribing is necessary but insufficient. Post-discharge support, updated education, medication access facilitation, and frequent monitoring are pivotal.

Guidelines (e.g., ESC, AHA/ACC/HFSA) recommend initiation of core GDMT classes rapidly in post-HF hospitalization settings, with subsequent titration to target doses. However, real-world use patterns reveal slow or absent uptitration and high discontinuation rates, emphasizing the need for pragmatic, multifaceted approaches encompassing multidisciplinary teams, patient engagement, and technology-enabled adherence monitoring.

Future research should explore personalized interventions addressing frailty and comorbidities, as well as system innovations such as heart failure clinics, remote monitoring, and health policy reforms to reduce cost barriers. The role of wearable devices for risk stratification and dynamic therapy adjustment, as highlighted by the SCD-PROTECT study for sudden cardiac death prevention, complements pharmacotherapy by enhancing patient safety during vulnerable periods.

Conclusion

The initiation, adherence, and persistence of guideline-directed medical therapy after heart failure hospitalization remain suboptimal despite well-established clinical benefits. Real-world evidence reveals high rates of primary nonadherence and early discontinuation, highlighting a critical need for interventions beyond discharge prescriptions. Early initiation, dose titration, and sustained persistence across drug classes are associated with better cardiac function and reduced adverse events. Addressing patient-related factors like frailty, implementing national quality programs, and enhancing longitudinal care models are essential steps toward bridging this knowledge-to-practice gap and improving HF patient outcomes.

References

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• Fitzgerald AA et al. Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden). Eur J Heart Fail. 2021 Sep;23(9):1499-1511. PMID: 34132001.
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• Leiner T et al. Sudden cardiac death in newly diagnosed non-ischaemic or ischaemic cardiomyopathy assessed with a wearable cardioverter-defibrillator: the SCD-PROTECT study. Eur Heart J. 2025 Nov 14;46(43):4597-4606. PMID: 40879135.
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