Complementary and Alternative Medicines in the Management of Heart Failure

Authors, Journal, Affiliations, Type, DOI

• Authors: Sheryl L. Chow (Chair), Biykem Bozkurt (Vice Chair), William L. Baker, Barry E. Bleske, Khadijah Breathett, Gregg C. Fonarow, Barry Greenberg, Prateeti Khazanie, Jacinthe Leclerc, Alanna A. Morris, Nosheen Reza, Clyde W. Yancy; on behalf of the AHA Clinical Pharmacology Committee and Heart Failure and Transplantation Committee
• Journal: Circulation
• Type: AHA Scientific Statement
• DOI: https://doi.org/10.1161/CIR.0000000000001110
• Published: January 10, 2023

Overview

This AHA Scientific Statement provides a comprehensive review of complementary and alternative medicine (CAM) efficacy and safety in heart failure management. More than 30% of HF patients use CAM, yet patients rarely disclose use and clinicians rarely inquire, creating clinically significant drug-interaction and toxicity risks. The statement reviews evidence for beneficial CAM agents (omega-3 PUFAs, CoQ10, L-Carnitine, yoga, tai chi) and harmful agents (licorice, high-dose vitamin E, high-dose alcohol, grapefruit juice, licorice, plant-based cardiac glycosides), catalogued against HF therapies. Omega-3 PUFAs are the only CAM agent with an AHA guideline recommendation (Class 2b) for HF; most other agents lack high-quality RCT evidence.

Keywords

AHA Scientific Statements · coenzyme Q10 · complementary therapies · dietary supplements · heart failure · tai chi · yoga

Key Takeaways

Global Utilization and Social Determinants of Health

• 30% of HF patients use CAM; 1 in 5 use herbal therapy annually; patients do not disclose CAM use to clinicians approximately 50% of the time

• CAM use is higher in White vs. Black individuals in the US; college graduates use CAM more than those with less education; receipt of care by a cardiologist is independently associated with higher CAM use
• Clinicians should inquire about CAM at every encounter and use a shared decision-making model to address benefits, interactions, and adverse effects

Oversight and Regulation

• The Dietary Supplement Health and Education Act (DSHEA, 1994) classifies most CAM products as dietary supplements regulated like foods — exempting manufacturers from pre-marketing FDA safety and efficacy testing
• Red yeast rice exemplifies regulatory ambiguity: 21% of brands contain monacolin K (lovastatin) at pharmacological levels; some brands also contain citrinin (nephrotoxin)
• St. John's wort is a potent CYP3A4 inducer — reduces plasma concentrations of warfarin, simvastatin, methadone, and calcineurin inhibitors
• Kava: associated with hepatotoxicity; banned in multiple countries

CAM with Potential Benefit in HF (Table 1)

Omega-3 Polyunsaturated Fatty Acids (PUFA) / Fish Oil

• GISSI-HF (1 g EPA/DHA daily, NYHA II–IV): modest reductions in CV hospitalizations (HR 0.92) and death (HR 0.91) vs. placebo
• VITAL-HF (1 g/day omega-3): no reduction in first HF hospitalisation, but significant reduction in recurrent HF hospitalisation (HR 0.86, P=0.048)
• Improvement in LVEF, LV dimensions, inflammation markers (hsCRP, ST2, TNF-α) in smaller RCTs
• Dose-dependent risk: at ≥4 g/day, AF incidence increases significantly (two large trials) — benefit-harm balance favours doses <4 g/day
• AHA 2022 Guideline (Class 2b, LOE B-R): Omega-3 PUFA supplementation recommended for NYHA II–IV HF as adjunctive therapy to reduce mortality and CV hospitalizations

Coenzyme Q10 (CoQ10)

• Q-SYMBIO trial (420 patients): significant improvement in NYHA class; 50% reduction in MACE at 2 years (HR 0.50, 95% CI 0.32–0.80, P=0.003); no change in 6MWD or NT-proBNP
• Meta-analysis data suggest reduction in all-cause mortality with supplementation
• Theoretically: statins may lower CoQ10 levels (additive interaction concern)
• Overall: uncertain evidence; larger RCTs needed; no definitive guideline recommendation

L-Carnitine

• Meta-analysis (Song et al., 2017): significant improvement in NYHA class, LVEF, LV dimensions, stroke volume, cardiac output, diastolic filling indices, BNP/NT-proBNP
• Significant improvement in mortality rate in RCT data
• Mechanism: involved in fatty acid transport into mitochondria; reduces oxidative stress
• No major adverse effects; no major HF therapy interactions

D-Ribose

• Small RCTs: improvement in LV structure and function, quality of life, NYHA class, 24-hour urinary GMP excretion (endothelium-dependent vasodilation marker)
• Mechanism: substrate for ATP regeneration

Thiamine (Vitamin B1)

• Severe deficiency causes wet beriberi (high-output HF); relative thiamine deficiency common in HF due to loop diuretics, dietary factors, age
• IV thiamine 200 mg/day for 7 days → LVEF improvement from 0.27 to 0.33 (P<0.01) in one RCT
• Meta-analysis: thiamine supplementation → net improvement in LVEF +3.28% (95% CI 0.64–5.93%) in systolic HF
• No benefit in patients without clinically significant thiamine deficiency: Oral thiamine supplementation in ambulatory HFrEF without deficiency showed no improvement in QoL, 6MWD, NT-proBNP, or LVEF
• Loop diuretics → thiamine depletion (interaction to monitor)

Hawthorn (Crataegus spp.)

• Multiple small RCTs: significant improvement in exercise workload, exercise tolerance, reduction in pressure×heart rate product, improvement in symptoms (dyspnoea, fatigue, palpitations)
• SPICE trial (>5000 patients, Crataegus extract WS 1442): Did NOT meet primary endpoint of reduced cardiac events or HF hospitalizations; adverse effects similar to placebo
• Potential HARM in LVEF ≤35%: Subanalysis data suggest potential progression of HF risk in patients >18 years with NYHA II–III and LVEF ≤40%, especially LVEF ≤35%, over 6 months
• Pharmacodynamic (not pharmacokinetic) interaction with digoxin — combination should be avoided

L-Arginine

• Small RCTs: improvement in LV structure/function, quality of life, NYHA class, endothelium-dependent vasodilation
• AVOID after acute MI: RCT demonstrated initiation post-infarction associated with increased mortality in older patients
• Potential risk of hypotension with vasodilators, nitrates, and PDE5 inhibitors

Vitamin D

• Supplementation associated with reduced inflammatory markers and improved LV function in some groups
• VITAL-HF and other RCTs: no significant reduction in first HF hospitalisation, no mortality benefit, no improvement in functional capacity
• Low 25(OH)D levels associated with worse NYHA class, worse LV function, higher SCD risk — but supplementation does not consistently reverse these associations
• Overall: insufficient evidence for routine supplementation

Yoga and Tai Chi

• Multiple RCTs: improvements in peak VO2, quality of life, exercise self-efficacy, 6MWD, reduction in BNP and serum inflammatory markers (IL-6, hsCRP)
• Yoga specifically: improvements in endurance, strength, balance; benefits demonstrated in African American patients with HF
• Tai chi in HFpEF: higher 6MWD increase vs. aerobic exercise; improvements in quality of life and mood in HFrEF
• Mechanism: increased parasympathetic and decreased sympathetic activity
• Safe and well-tolerated adjunctive therapies for patients with HF — recommended alongside GDMT

Acupuncture

• Significant improvement in 6MWD, quality of life, and reduced heart rate variability in small RCTs
• No significant improvement in LVEF or peak VO2

CAM Agents with Potential Harm or Interactions in HF (Table 2)

High-Dose Alcohol

• 10 drinks/week → increased new-onset AF risk in hypertension + LV hypertrophy patients (HR 1.60)

• 6–7 drinks/day → alcoholic cardiomyopathy (reversible with abstention if not long-standing)
• Mild-to-moderate consumption (observational data only): associated with 10–23% lower HF incidence — this association is confounded and does not support recommending alcohol

Licorice

• Glycyrrhetinic acid inhibits 11-β-hydroxysteroid dehydrogenase type 2 → cortisol acts on mineralocorticoid receptor → apparent mineralocorticoid excess
• Manifestations: sodium retention, hypertension, hypokalemia, cardiac arrest
• Potentiated by mineralocorticoid receptor antagonists
• Red licorice (flavoured by other means): no risk

Vitamin E ≥400 IU/day

• HOPE trial: 13% increased risk of incident HF; 21% increased risk of HF hospitalisation vs. placebo (n=9,541 patients without HF at baseline)
• GISSI-Prevenzione: 50% increased risk of symptomatic HF in patients with LVEF <50%
• Should be used with caution at high doses; moderate dietary consumption only

Grapefruit Juice

• Inhibits intestinal CYP-450 3A4 → increases bioavailability of drugs undergoing first-pass metabolism
• Clinically significant interactions with HF medications: amiodarone (↑bioavailability), carvedilol (+16%), losartan (↓efficacy), clopidogrel/ticagrelor (↓antiplatelet effect)
• Additive QT prolongation with amiodarone, dofetilide, sotalol, disopyramide, procainamide
• High-risk population: Older patients (>70 years) with multiple comorbid drug regimens; ≥200 mL juice/grapefruit within 4 hours of affected medication is clinically significant
• Repeated ingestion cumulative; 10-hour interval reduces but does not eliminate interaction

Caffeine

• 500 mg within 5 hours: not associated with arrhythmia risk in regular coffee drinkers (RCT, n=51 HF patients)
• Before cardiac perfusion imaging → false-positive results (adenosine antagonism)
• Moderate intake (<300–400 mg/day) generally safe; wide inter-individual variability; avoid in patients with tendency toward tachyarrhythmias

Gossypol

• Cotton plant polyphenol; depletes serum potassium → hypokalemia → increased cardiac glycoside toxicity
• Chronic use ≥20 mg/day for >1 year → circulatory problems

Bitter Orange

• Sympathomimetic + CYP3A4 inhibitor → increases BP and heart rate; may cause angina via coronary vasoconstriction
• May counteract antihypertensive drugs; increases blood glucose

Plant-Based Cardiac Glycosides (Lily of the Valley, Oleander, Strophanthus/Ouabain)

• All contain cardiac glycosides (potent Na⁺/K⁺-ATPase inhibitors); narrow therapeutic index
• Toxicity symptoms: arrhythmias, confusion, nausea, visual disturbances
• Effects potentiated by hypokalemia; avoid with loop diuretics and corticosteroids without potassium monitoring
• Historical use for mild HF and AF but not recommended given toxicity profile

Vitamin E Interaction Note

• Acts as anticoagulant/antiplatelet at high doses → interact with warfarin and antiplatelet agents

Multidisciplinary Approach

• Pharmacist involvement in community and hospital settings is key to identifying CAM–drug interactions and ensuring safe integration
• Team approach: cardiologist + nurse + pharmacist + advanced practice clinician for documentation, medication reconciliation, and interaction management
• Patients rarely voluntarily disclose CAM use; <15% of cardiac patients have discussed CAM with their clinician

Gaps in Research

• Urgent need for well-powered RCTs with CV outcomes for most CAM agents
• Pragmatic trial designs needed given diversity and complexity of CAM products
• Equity, diversity, and inclusion must be prioritized in trial enrollment

Limitations of the Document

• Literature search up to November 2021 — does not include post-2021 trial data (e.g., DELIVER for SGLT2i relevance context)
• Most efficacy evidence from small, underpowered trials; few large randomized controlled trials
• Absence of Federal regulation and poor product standardization means trial results may not translate to commercially available products
• Social and ethnic determinants of CAM use are understudied in HF populations specifically
• Traditional Chinese medicine (dozens of active ingredients per formulation) excluded from scope

Key Concepts Mentioned

• concepts/CAM-in-Heart-Failure — main subject of document; evidence synthesis for CAM in HF
• concepts/Heart-Healthy-Dietary-Patterns — context for fish oil vs. omega-3 PUFA distinction
• concepts/Drug-Induced-Arrhythmia — grapefruit juice interactions with QT-prolonging antiarrhythmics

Key Entities Mentioned

• entities/Heart-Failure — clinical context for all CAM evidence reviewed
• entities/Atrial-Fibrillation — AF risk from high-dose omega-3, hawthorn, licorice (hypokalemia), grapefruit juice + antiarrhythmic interactions

Wiki Pages Updated

• wiki/sources/alt-medicine-hf-aha-2023.md — this file (created)
• wiki/concepts/CAM-in-Heart-Failure.md — new concept page (created)
• wiki/entities/Heart-Failure.md — CAM section added
• wiki/sourceindex.md — source entry added
• wiki/wikiindex.md — concept entry added