Heart Failure with Preserved Ejection Fraction - Managing Comorbidities

Heart failure (HF) is a complex condition characterized by signs of volume overload or symptoms such as dyspnea, exercise intolerance, and fatigue. Being a syndrome, HF is not explained by one unifying pathophysiologic cause.  Rather, various mechanisms lead to the deficit between the amount of blood delivered and the amount of blood that needs to be delivered through the body to maintain homeostasis.  HF is defined as the previously mentioned signs or symptoms being caused by structural or functional cardiac abnormalities plus either 1) elevated natriuretic peptides (e.g., BNP) or 2) objective evidence of cardiogenic pulmonary or systemic congestion (e.g., left ventricular filling pressures).  (Heidenreich)

HFpEF Classification

HF has been categorized by NYHA functional class, ACC/AHA staging, ejection fraction, or systolic/diastolic dysfunction. While there is overlap among these categorization methods, they are distinct ways of describing heart failure (e.g., diastolic dysfunction may be present in HF with preserved ejection fraction but it is not a synonymous term).  The ejection fraction classification is useful because modern trials generally evaluate patients based on such categories:

• HFpEF: Clinical HF with preserved ejection fraction is HF specifically with a left ventricular ejection fraction ≥50%. It can be from a cardiac or non-cardiac cause (e.g., infiltrative disease, valvular disease, hypertrophic cardiomyopathy, or kidney/liver disease, respectively). (Kittleson)
• HFmrEF: Clinical HF with mildly reduced ejection fraction features an ejection fraction of 41-49%. 
• HFrEF: Clinical HF with reduced ejection fraction has a left ventricular ejection fraction ≤40%.
• HFimpEF: Clinical HF with improved ejection fraction is the designation when the ejection fraction was previously reduced <40% but later was ≥40%. It is a distinct entity from HFpEF and treatment is not necessarily the same.

The various pathophysiologic mechanisms that contribute to HFpEF include hypertension, cardiometabolic dysfunction, inflammation, oxidative stress, and others. These cause myocardial fibrosis, hypertrophy of the left ventricle, increased fibroblast and macrophage activity, microvascular inflammation, endothelial dysfunction, pulmonary vascular disease, and mitochondrial dysfunction.  

 

With such a heterogenous list of causes, the treatment of HFpEF has generally focused on the management of comorbid conditions and removing excess fluid (when necessary).  Guideline-directed medical therapy (GDMT) benefits are much less robust when compared to HFrEF, though some agents do have clinical benefits.  That discussion is left for another post.  What follows is an abbreviated version of how to tackle comorbidities commonly associated with HFpEF.

 

Comorbidities

Atrial fibrillation

• Goal: 1) rate-control vs. rhythm-control plus 2) anticoagulation (if necessary)
• If rate-control approach
• Goal: heart rate 81-110 bpm (reduces HF hospitalizations compared to higher rates)
• ꞵ-blockers - first line therapy
• Nondihydropyridine CCBs can be alternative to ꞵ-blockers (yes, they're "not recommended" in HFrEF but can be used in HFpEF) (Kittleson)
• Digoxin - can be alternative to prior two classes or can be add-on
• If rhythm-control approach, assess comorbidities to narrow options
• Avoid antiarrhythmics class III and Ic if post-MI or with structural heart disease (including left ventricular hypertrophy)
• Avoid dronedarone if recent decompensated HF NYHA class II/III with symptoms
• Avoid certain antiarrhythmics with prolonged QTc and with renal dysfunction 
• Anticoagulate as per usual with CHADS-VASc (3 in females or 2 in males warrants full anticoagulation)

Chronic Coronary Disease / Coronary Artery Disease

•  Correcting ischemia helps reduce progression from HFpEF to HFrEF
• Revascularization improves survival
• Treat with antiplatelets and antihyperlipidemics as per guidelines to reduce major adverse cardiovascular events
• Use ꞵ-blockers as first line for angina or following myocardial infarction
• Then consider CCBs or long-acting nitrates for angina 
• Nondihydropyridine CCBs (e.g., diltiazem, verapamil) can be used for angina

 

Chronic Kidney Disease

• Careful not to overdiurese - can precipitate acute kidney injury
• SGLT2 inhibitors improve renal outcomes in CKD studies but here is some HF-specific info 
• Dapagliflozin (DELIVER trial - large RCT in HF with ejection fraction >40%)
• Prevented worsening HF 
• Excluded patients if eGFR <25 mL/min/1.73 m2 by CKD-EPI equation 
• Empagliflozin (EMPEROR-Preserved trial - large RCT in HF with ejection fraction >40%) 
• Prevented hospitalizations for HF
• Excluded patients if eGFR <20 mL/min/1.73 m2 by CKD-EPI equation
• ARNI improves renal outcomes in HFpEF with eGFR >30 mL/min/1.73 m2 (PARAGON-HF)
• If HTN, proteinuria, and/or diabetes mellitus:
• ACEI and ARBs also slow CKD progression (ARBs preferred over ACEI)
• Do not give concomitantly with ARNI - 36 hour washout needed for ACEI 

 

Hypertension

• Goal: blood pressure <130/80 mm Hg
• ARBs, ARNIs, MRAs preferred over ACEI (more evidence for the former)
• Chlorthalidone reduced new HF compared to lisinopril, amlodipine, or doxazosin (ALLHAT trial)
• Avoid ꞵ-blockers unless a compelling indication exists 

Obesity

• Refer those with BMI ≥35 kg/m2 to multidisciplinary weight loss team 
• Perform aerobic physical activity ≥150 minutes/week (this is consistent with guidelines for primary prevention of cardiovascular disease).  
• Adding resistance training is also beneficial to improve leg muscle strength.(Kittleson)
• Incretin analogs and similar medications (e.g., tirzepatide, liraglutide, semaglutide) can aid substantially with weight loss and improve quality of life and cardiac function
• Diet and lifestyle changes must also take place to be effective
• Substantial weight is typically regained after medication is discontinued
• Patients also may lose lean muscle mass so overall risk:benefit in HF population is uncertain but studies are pending 
• Avoid phentermine/topiramate and naltrexone/bupropion due to adverse cardiac effects (tachycardia, hypertension, arrhythmias) which are likely to be detrimental to cardiac comorbidities 

 

Type 2 Diabetes Mellitus

• Metformin - first line therapy (reduces mortality)
• SGLT2 inhibitors 
• Empagliflozin, dapagliflozin - first line therapy regardless of metformin
• Sotagliflozin - indicated for HF but SOLOIST-WHF trial (finding reduced hospitalizations and urgent HF visits) only had 21% HFpEF patients so data are less confident compared to empagliflozin and dapagliflozin
• GLP1 agonists - give if atherosclerotic disease present or there is high risk
• Avoid - thiazolidinediones (e.g., rosiglitazone, pioglitazone - worsen fluid retention) and saxagliptin/alogliptin (increase HF hospitalizations) 

 

Select References:

Kittleson, M, Panjrath, G, Amancherla, K. et al. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. JACC. 2023 May, 81 (18) 1835–1878.
https://doi.org/10.1016/j.jacc.2023.03.393

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022 May 3;79(17):e263-e421. doi: 10.1016/j.jacc.2021.12.012. Epub 2022 Apr 1. Erratum in: J Am Coll Cardiol. 2023 Apr 18;81(15):1551. doi: 10.1016/j.jacc.2023.03.002. PMID: 35379503.

Solomon SD, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Lindholm D, Wilderäng U, Öhrn F, Claggett B, Langkilde AM, Petersson M, McMurray JJV. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail. 2021 Jul;23(7):1217-1225. doi: 10.1002/ejhf.2249. Epub 2021 Jun 9. PMID: 34051124; PMCID: PMC8361994.

Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE, Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B, Nicholls SJ, Perrone SV, Piña IL, Ponikowski P, Senni M, Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S, Vinereanu D, Zhang J, Carson P, Lam CSP, Marx N, Zeller C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27. PMID: 34449189.

 

Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B; SOLOIST-WHF Trial Investigators. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021 Jan 14;384(2):117-128. doi: 10.1056/NEJMoa2030183. Epub 2020 Nov 16. PMID: 33200892.

 

Kittleson MM, Panjrath GS, Amancherla K, Davis LL, Deswal A, Dixon DL, Januzzi JL Jr, Yancy CW. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023 May 9;81(18):1835-1878. doi: 10.1016/j.jacc.2023.03.393. Epub 2023 Apr 19. PMID: 37137593.

 

 image: “Hearts” by Robbie Sproule, CC BY 2.0 (no changes were made)