Beyond Guideline-Directed Medical Therapy

Onyedika J. Ilonze, MD, MPH, Daniel E. Forman, MD, Lisa LeMond, MD, Jonathan Myers, PHD, Scott Hummel, MD, Amanda R. Vest, MBBS MPH, Ersilia M. DeFilippis, MD, Eiad Habib, MBBS, Sarah J. Goodlin, MD

Disclosures

JACC Heart Fail. 2025;13(2):185-199.

Abstract

Heart failure (HF) is a leading cause of cardiovascular morbidity, mortality, and health care expenditure. Guideline- directed medical therapy and device-based therapy in HF are well established. However, the role of nonpharmacologic modalities to improve HF care remains underappreciated, is underused, and requires multimodal approaches to care. Diet, exercise and cardiac rehabilitation, sleep-disordered breathing, mood disorders, and substance use disorders are potential targets to reduce morbidity and improve function of patients with HF. Addressing these factors may improve symptoms and quality of life, reduce hospitalizations, and improve mortality in heart failure. This state-of-the-art review discusses dietary interventions, exercise programs, and the management of sleep-disordered breathing, mood disorders, and substance use in individuals with heart failure. The authors review the latest data and provide optimal lifestyle recommendations and recommended prescriptions for nonpharmacologic therapies.

Introduction

Heart failure (HF) poses major clinical challenges with signiﬁcant morbidity and mortality. While pharmacologic and device advancements for HF have improved the survival and quality of life of patients living with HF, nonpharmacologic treatments are important but often underutilized. Nonpharmacologic therapies may reduce symptom burden, improve quality of life, and even improve survival when added to background guideline-directed therapy for HF. Of note, most of the evidence for these treatments pertains to chronic stable HF. This state-of-the-art review discusses lifestyle recommendations for patients living with HF including diet, exercise and movement, sleep, mood, and substance use.

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Cite this: Beyond Guideline-Directed Medical Therapy - Medscape - Mar 20, 2025.

Abstract and Introduction
Diet and Nutrition for Patients With HF
Exercise and Movement
Challenges of Initiating Exercise and Activity Among HF Patients
Sleep-Disordered Breathing
Mood Disorders: Depression and Anxiety
Substance Use Disorders
Conclusions
References

Table 1. Selected Trials of Nonpharmacologic Interventions in HF
Study, Year (NCT#)	Subjects, Mean, Follow-Up	Study Design	Study Findings
Diet and cachexia
SODIUM-HF (Study of Dietary Intervention under 100 mmol in Heart Failure), 2022 (NCT02012179)¹	N = 806; outpatients with HF, unspecified EF; 12 mo	Randomized controlled trial of patients on optimal GDMT to dietitian-guided, culturally tailored sodium restriction (<1,500 mg/d) vs usual care	No difference in all-cause death: 6% of the low sodium and 4% of the usual care group (HR: 1.38; P = 0.32) Cardiovascular-related hospitalization: 10% of the low-sodium group and 12% of the usual care group (HR: 0.82; P = 0.36)
HART (Heart Failure Adherence and Retention Trial), 2016 (NCT00018005)²	N = 902; HFrEF or HFpEF; over 36 mo	Randomized controlled trial; usual care vs self-management skills training self-monitoring of sodium intake, assessed by questionnaire; propensity matching of 17% of cohort achieving sodium restriction (<2,500 mg/d)	Sodium restriction was associated with a higher risk of death and/or HF hospitalization (42% vs 26%; HR: 1.85 [95% CI: 1.21-2.84]; P = 0.004) Self-reported physical inactivity was associated with a greater risk of all-cause death (HR: 2.01 [95%CI: 1.47-3.00]; P < 0.001) and cardiac death (HR: 2.01 [95% CI: 1.28-3.17]; P = 0.002) but no significant difference in HF hospitalization (P = 0.548) Modest exercise (1-89 min/wk) was associated with a significant reduction in the rate of death (P = 0.003) and cardiac death (P = 0.050)
EFFORT (Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial), 2021 (NCT02517476)	N = 645; hospitalized patients with HF (unspecified EF) and malnutrition (36% of patients had ADHF and 64% had HF but hospitalized with another diagnosis)	Randomized to individualized nutrition with high-dose protein and micronutrients vs usual diet	Mortality increased with the severity of malnutrition Intervention reduced mortality (OR: 0.44 [95% CI: 0.26-0.75]; P = 0.002) and cardiovascular events (OR: 0.50 [95% CI: 0.34-0.75]; P = 0.001)
FRESH-UP (Fluid REStriction in Heart Failure vs Liberal Fluid Uptake), Ongoing (NCT04551729)	N = 506; ongoing; outpatients with HF, unspecified EF	Randomized controlled trial; liberalized fluid intake vs guidance for 1,500 mL/d restriction	Primary outcome: aims to assess the effect of fluid restriction over 3 months on the KCCQ Overall Summary Score Secondary outcome: thirst distress, safety Exploratory outcome: safety, mortality, or HF hospitalization Safety is both a secondary and exploratory outcome The composite endpoint is the secondary outcome, each component is assessed as exploratory
PICNIC (Nutritional Randomized Controlled Trial of Intervention Program in Malnourished Patients Admitted for Heart Failure), 2016 (NCT01472237)³	N = 120; hospitalized patients with HFpEF and malnutrition; 12 mo (stopped early due to beneficial effect of nutritional intervention found in the interim analysis)	Randomized controlled trial of 6 mo; dietician-directed customized diet including calories, protein, and micronutrients vs usual care	Beneficial effect on mortality or rehospitalization for HF over 24 mo in 27.1% of patients in the intervention group vs 60.7% of patients in the control group (HR: 0.45 [95% CI: 0.19-0.62]; P = 0.0004)
Health of the Food Environment Is Associated With Heart Failure Mortality⁴	N = 4,032; admitted with HF and followed postdischarge	Observational cohort study; receipt of 1-4 shipments of home-delivered meals after hospital discharge vs no receipt	Posthospitalization home-delivered meals were associated with lower 30-d rehospitalization and mortality; 2021/2022 cohort (OR: 0.55 [95% CI: 0.43-0.71]; P < 0.001)
KP NOURISH (Kaiser Permanente Evaluation of Medically Tailored Meals in Adults With Chronic Medical Conditions at High Readmission Risk), 2022 (NCT05166525)⁵	N = 1,977; 10 wks; hospitalized patients enrolled at discharge (HF all EF, n = 641)	Randomized hospitalized patients with diabetes mellitus, chronic kidney disease, and/or HF usual care vs once daily MTM 2,000-3,000 mg/d of sodium, DASH diet pattern	MTM did not reduce all-cause rehospitalization at 90 d; however, both all-cause mortality (HR: 0.65 [95% CI: 0.43-0.98]) and HF readmissions (HR: 0.53 [95% CI: 0.33-0.88]) decreased over this period
GOURMET-VA (Geriatric OUt-ofhospital Randomized MEal Trial in heart failure: Veterans Affairs), Ongoing (NCT05996328)	Ongoing; outpatients with chronic HF (unspecified EF)	Randomized parallel assignment trial of home delivered low sodium meals for 6 wks and dietary counseling vs usual care	Aims to assess the impact of MTMs on clinical events and QoL in older postdischarge patients with HF
SICA-HF (Studies Investigating Comorbidities Aggravating HF), 2018 (NCT01872299)⁶	N = 1,462; subjects with chronic stable HFrEF and HFpEF	Prospective multicenter observational study to evaluate cachexia, sarcopenia, and weight loss	Sarcopenia (skeletal muscle wasting) in 17.5% was an independent predictor of death
STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With HF and Obesity), 2023 (NCT04788511) and STEP-HFpEF-DM, 2024 (NCT04916470)⁷	N = 1,145: pooled analysis of outpatients with HFpEF and body mass index ≥30 kg/m2and HFpEF and T2DM with: 1) elevated filling pressures; 2) elevated natriuretic peptide + echocardiographic abnormalities; or 3) HF hospitalization within 12 mo + ongoing diuretic treatment or echocardiographic abnormalities	Randomized trial of semaglutide 2.4 mg subcutaneous or placebo weekly for 52 wks	Semaglutide improved KCCQ Clinical Summary Score, reduced body weight, improved 6-minute walk distance, reduced C-reactive protein and NTproBNP, and reduced HF events Semaglutide led to a 20% reduction in and frequent stopping and less initiation of loop diuretics; the largest KCCQ improvements were seen in the most congested patients (which may be a proxy for disease severity and worse outcomes)
SDB
CANPAP (Continuous positive airway pressure for central sleep apnea and heart failure), 2005¹³	N = 258; HFrEF and CSA	Randomized controlled trial assigned to receive or no CPAP	CPAP did not affect survival Improved CSA: reductions in the frequency of episodes of AHI (-21 ± 16 per hour vs -2 ± 18 per hour; P<< 0.001)
ADVENT-HF (Adaptive servoventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction), 2024 (NCT01128816)¹⁴	N = 731; 3.6 y; HFrEF and SDB (CSA and OSA)	Randomized controlled trial assigned to standard optimal treatment or with the addition of peak flow–triggered ASV	ASV did not affect the primary composite outcome (180 events control group vs 166 in the ASV group; HR: 0.95 [95% CI: 0.77-1.18]; P = 0.67) or the secondary endpoint of all-cause mortality (88 deaths control group vs 76 ASV group; HR: 0.89 [95% CI: 0.66-1.21]; P = 0.47)
SERVE-HF (Adaptive Servo- Ventilation for Central Sleep Apnea in Systolic Heart Failure), 2015 (NCT00733343)	N = 1,325; HFrEF patients with CSA	Randomized controlled trial of ASV; intention-to-treat analysis	No significant difference in composite endpoint (cardiovascular event or hospitalization and all-cause death), but significantly higher all-cause and cardiovascular mortality in the ASV group 29% noncompliance with ASV in the treatment group
LOFT-HF (The Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Admissions and Mortality in Patients With Heart Failure and Central Sleep Apnea), Ongoing (NCT03745898)	Ongoing	Randomized clinical trial	Assess the impact of low-flow nocturnal oxygen on hospital admissions and mortality in HF and CSA
Exercise and CR
HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), 2009 (NCT00047437)⁸	N = 2,331; subjects with HFrEF; outpatient, 30 mo (median)	Randomized controlled trial	All-cause and cardiovascular survival benefit of an exercise training protocol for adults with HFrEF
HF-ACTION, 2012 subanalysis (NCT00047437)⁹	N = 959; subjects with HFrEF, outpatient; 28.2 mo	Randomized controlled trial; subanalysis	Moderate exercise volumes of 3 to <5 MET h/wk and 5 to <7 MET h/wk were associated with reductions in all-cause and cardiovascular risk >30%
REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients), 2021 (NCT05525663)¹⁰	N = 349; patients ≥60 y with HFrEF or HFpEF hospitalized with ADHF; 6 mo	Randomized controlled trial, 1-on-1 multidomain physical rehabilitation starting during hospital admission and continuing as outpatient 3x/week for 12 weeks	Intervention group: improved physical function, QoL, depression and frailty scores at 3 mo; no differences in hospitalization at 6 mo HFpEF patients had worse baseline scores and nominally greater improvement in function and QoL than HFrEF patients
REHAB-HF, 2023 subanalysis (NCT05525663)¹¹	N = 337; HFpEF and HFrEF hospitalized with ADHF; 6 mo	Prespecified subanalysis stratified by frailty status; intervention as above	Patients with worse baseline frailty and function had more significant improvement with intervention than those who were prefrail
OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure), 2021 (NCT02078947)⁵⁶	N = 180; chronic stable HFpEF	Randomized trial of 1) moderate continuous training 2) high-intensity interval training 3) control group: counseled but not offered supervised exercise sessions	No statistically significant difference in change in peak VO_{2 at 3 mo between high-intensity interval vs moderate continuous training Change in peak VO₂ over 3 mo for high-intensity interval training vs guideline control was 1.1 vs -0.6 mL/kg/min (difference: 1.5 [95% CI: 0.4-2.7]); for moderate continuous training vs guideline control, 1.6 vs-0.6 mL/kg/min (difference: 2.0 [95% CI: 0.9-3.1]); and for high-intensity}

ADHF = acute decompensated heart failure; AHI = apnea-hypopnea index; ASV =adaptive servo-ventilation; CPAP = continuous positive airway pressure; CR = cardiac rehabilitation; CSA = central sleep apnea; DASH = Dietary Approaches to Stop Hypertension; EF = ejection fraction; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; KCCQ = Kansas City Cardiomyopathy Questionnaire; MET = metabolic equivalent of task; MTM = medically tailored meal; OSA = obstructive sleep apnea; NT-proBNP = N-terminal pro–B-type natriuretic peptide; QoL = quality of life; SDB = sleep-disordered breathing; T2DM = type 2 diabetes mellitus; VO₂ = oxygen consumption.

Table 2. Benefits of Exercise Training in Chronic HF
Improved peak VO₂
Improved skeletal muscle metabolism
Improved muscle strength and mass
Higher peak cardiac output (in some studies)
Reduced ventilatory response to exercise
Improved endothelial function
Improved autonomic function
Improved QoL (ability to perform daily activities, return to work)
Reduced rehospitalization rates
Improved survival

Abbreviations as in Table 1.

Table 3. Outcomes and Prevalence of Substance Abuse in Patients With HF
Substance	Prevalence in HF	Mechanism	Outcome
Alcohol	23%-47% of patients with dilated cardiomyopathy¹⁵ 4.5% of hospitalized patients	Generation of reactive oxygen species by ethanol and metabolites, activation of the renin-angiotensin-aldosterone system, altered mitochondrial function¹⁵	At median follow-up 59 mo, 15% experienced CV death, 15% underwent transplantation, 37% had recovery of function, 33% were stable¹⁶ Reduced alcohol intake (20-60 g) and complete abstinence associated with improvement in ejection fraction compared with those who continued to consume >80 g/d¹⁷
Cocaine	0.6% of hospitalized patients	Increased sympathetic tone, vasospasm, and vasoconstriction; platelet aggregation can lead to MI but risk of cardiomyopathy also independent of CAD	Cessation of cocaine can lead to recovery of systolic function¹⁸
Cannabis	2.2% of hospitalized patients	Dose-dependent decrease in contractility, platelet activation, proarrhythmogenic	THC associated with increased risk of incident HF, independent of MI risk Limited data about cannabis in patients with pre-existing HF
Methamphetamine	5% of hospitalized patients	Sympathetic activation; direct myocardial toxicity with production of reactive oxygen species and stimulation of apoptosis; vasospasm¹⁹	Continued use associated with worse HF symptoms, higher HF readmissions, increased all-cause mortality, longer length of stay
Opioids	8% of hospitalized patients	Acutely associated with decreases in blood pressure and heart rate	Withdrawal can be associated with worsening of existing HF or the development of stress cardiomyopathy
Tobacco	16% of patients with HF²⁰	Sympathetic activation, increased cardiac output, vasoconstriction, atrial fibrosis	Increased mortality and readmission rates among those with HF Up to 75% increased risk of HF for active smokers²¹

CAD = coronary artery disease; CV = cardiovascular; HF = heart failure; MI = myocardial infarction.

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Beyond Guideline-Directed Medical Therapy

Abstract

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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