Congestive heart failure with preserved EF pharmacotherapy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
Overview
Treatment of HFpEF is focused on treating underlying disease, such as hypertension, coronary artery disease and atrial fibrillation. Diuretics are the mainstay of pharmacotherapy. Other effective measures to control HFpEF include exercise, weight control and lipid control.
Heart failure mildly reduced ejection fraction (HPmrEF), EF (41-49%)
The diagnosis of heart failure with mildly reduced ejection fraction
- The diagnosis of HFmrEF requires the presence of symptoms and/or signs of HF, and a mildly reduced EF (41-49%) The presence of elevated NPs (BNP >_35 pg/mL or NT-proBNP >_125 pg/mL) and other evidence of structural heart disease including increased left atrial (LA) size, LVH or echocardiographic measures of LV filling.
Clinical characteristics
- Clinical characteristics, risk factors, patterns of cardiac remodelling are similar to other subgroups of HF.
- HFmrEF is more common in men, younger, and are more likely to have CAD (50-60%) and less likely to have AF and non-cardiac comorbidities. ambulatory
- HFmrEF have lower mortality rate than those with HFrEF.
Treatment
Angiotensin-converting enzyme inhibitors
- ACE-I may be considered in patients with HFmrEF and underlying CAD, hypertension, or post-MI LV systolic dysfunction.
Angiotensin receptor II type 1 receptor blockers
- Candesartan reduced the number of patients hospitalized for HF among those with HFmrEF.
- Treatment with ARBs may be considered in patients with HFmrEF patients with other cardiovascular indications.
Beta-blockers
- Treatment with beta-blockers may be considered in patients with HFmrEF and another cardiovascular indication, such as AF or angina.
Mineralocorticoid receptor antagonists
- In a retrospective analysis of the TOPCAT trial in patients with LVEF >_45%, spironolactone reduced hospitalizations for HF in patients with an LVEF <55%.
- Treatment with an MRA may be considered in patients with HFmrEF.
Angiotensin receptor-neprilysin inhibitor
- Analysis of the PARADIGM-HF and PARAGON-HF trials showed that sacubitril/valsartan, compared to other forms of RAAS blockade reduced hospitalizations in patients with HFmrEF.
Other drugs
- In the DIG trial, use of digoxin for patients with HFmrEF in sinus rhythm was associated with fewer hospitalizations but no reduction in mortality and a trend to increase of cardiovascular deaths.
- Therefore, there are insufficient data to recommend its use.
- There are insufficient data on ivabradine in HFmrEF.
Devices
Medications indicated in patients with New York Heart Association (NYHA class II–IV) HFmrEF (heart failure with mildly reduced ejection fraction) (LVEF41-49%)
| Recommedation for patients with NYHA class 2-4 heart failure with mildly reduced ejection fraction |
| Diuretics (Class I, Level of Evidence C): |
|
❑ Diuretics are recommended in patients with congestion and HFmrEF in order reduce symptoms and signs |
| ACEI (Class IIb, Level of Evidence C): |
|
❑ ACE-I may be considered for patients with HFmrEF to reduce the risk of HF hospitalization and death |
| The above table adopted from 2021 ESC Guideline |
|---|
Heart failure preserved ejection fraction (HFpEF)
Clinical characteristics
- HFpEF patients are older and more often female.
- AF, CKD, and non-cardiovascular comorbidities are more common in patients with HFpEF.
- It is important to exclude other conditions that might mimic the HFpEF syndrome including lung disease, anaemia, obesity, and deconditioning.
The diagnosis of heart failure preserved ejection fraction
- Echocardiographic criteria:
- LA size (LA volume index >32 mL/m2)
- Mitral E velocity <90 cm/s
- Septal e' velocity <9 cm/s
- E/e' ratio >9
- The diagnosis is made when there are the following:
(1) Symptoms and signs of HF
(2) An LVEF >_50%
(3) Objective evidence of cardiac structural and/or functional abnormalities consistent with the presence of LV diastolic dysfunction/ raised LV filling pressures, including raised NPs
- Of note, patients with a history of overtly reduced LVEF (<_40%),
who later present with LVEF >_50%, should be considered to have recovered HFrEF or ‘HF with improved LVEF’ (rather than HFpEF). Continued treatment for HFrEF is recommended in these patients.271 It is not known whether starting HF therapy in patients with recov�ered LVEF is beneficial. Patients with HFpEF tend to have stable tra�jectory of LVEF over time.272 However, in those who develop a clinical indication for a repeat echo during follow-up, around one third have a decline in LVEF.273 In the presence of AF, the threshold for LA volume index is >40 mL/m2 . Exercise stress thresholds include E/e0 ratio at peak stress >_15 or tricuspid regurgitation (TR) velocity at peak stress >3.4 m/s.275 LV global longitudinal strain <16% has a sensitivity of 62% and a specificity of 56% for the diagnosis of HFpEF by invasive testing.261 The approach to the diagnosis should involve additional confirma�tory tests in cases of diagnostic uncertainty, such as cardiopulmonary exercise testing (to confirm a reduction in exercise capacity and to help differentiate the cause of dyspnoea), exercise stress testing, and invasive haemodynamic testing.259 If resting echocardiographic and laboratory markers are equivocal, a diastolic stress test is recommended.259,274 The confirmatory test for the diagnosis of HFpEF is invasive haemodynamic exercise testing. An invasively measured pulmonary capillary wedge pressure (PCWP) of >_15 mmHg (at rest) or >_25 mmHg (with exercise) or LV end-diastolic pressure >_16 mmHg (at rest) is generally considered diagnostic.266 However, instead of an exercise PCWP cut-off, some have used an index of PCWP to cardiac output for the invasive diag�nosis of HFpEF260,276. Recognizing that invasive haemodynamic exer�cise testing is not available in many centres worldwide, and is associated with risks, its main use is limited to the research setting. In the absence of any disease-modifying treatments, the current guide�lines do not mandate gold standard testing in every patient to make the diagnosis, but emphasize that the greater the number of objective non-invasive markers of raised LV filling pressures (Table 9), the higher the probability of a diagnosis of HFpEF. 8.4 Treatment of heart failure with preserved ejection fraction To date, no treatment has been shown to convincingly reduce mortality and morbidity in patients with HFpEF, although improve�ments have been seen for some specific phenotypes of patients within the overall HFpEF umbrella. However, none of the large RCTs conducted in HFpEF have achieved their primary endpoints. These include PEP-CHF (perindopril),277 CHARM-Preserved (can�desartan),245 I-PRESERVE (irbesartan),278 TOPCAT (spironolac�tone),246 DIG-Preserved (digoxin),279 and PARAGON-HF (sacubitril/valsartan)13 (see Supplementary Table 12 for the details about these and additional trials). Hospitalizations for HF were reduced by candesartan and spironolactone and there was a trend towards reduction with sacubitril/valsartan, although as these trials were neutral for their primary endpoints, these are hypothesis�generating findings only. Although nebivolol significantly reduced the combined primary endpoint of all-cause mortality or CV hospi�tal admission in the SENIORS trial, this trial included only 15% with an LVEF >50%.119,249 Trials targeting the nitric oxide-cyclic guano�sine monophosphate pathway have also failed to improve exercise Table 9 Objective evidence of cardiac structural, functional and serological abnormalities ccapacity or QOL in HFpEF, e.g. NEAT-HFpEF,280 INDIE-HFpEF,281 VITALITY-HFpEF,282 and CAPACITY-HFpEF (praliciguat).283 Despite the lack of evidence for specific disease-modifying thera�pies in HFpEF, as the vast majority of HFpEF patients have underlying hypertension and/or CAD, many are already treated with ACE-I/ ARB, beta-blockers, or MRAs. In the PARAGON-HF study at base�line, more than 86% of patients were on ACE-I/ARBs, 80% were on beta-blockers, and more than 24% were on MRAs.13 The Task Force acknowledge that the treatment options for HFpEF are being revised as this guideline is being published. We note that the Food and Drug Administration (FDA) has endorsed the use of sacubitril/valsartan and spironolactone in those with an LVEF ‘less than normal’. These statements relate to patients within both the HFmrEF and HFpEF categories. For sacubitril/valsartan, this decision was based on the subgroup analysis from the PARAGON-HF study, which showed a reduction in HF hospitalizations in those with an LVEF <57%, and a meta-analysis of the PARADIGM-HF and PARAGON-HF studies, showing a reduction in CV death and HF hospitalization in those with an LVEF below the normal range.247 Regarding spironolactone, the subgroup of individuals in the TOPCAT study recruited in the Americas had a significant reduc�tion in the primary endpoint of CV death and HF hospitalization, and a subsequent post hoc analysis by EF showed a significant reduction in outcomes for those with an LVEF <55%.9,247 There are also ongoing trials with SGLT2 inhibitors. These developments may well accelerate a redefinition of HFpEF in the future and have thera�peutic implications. In the absence of recommendations regarding disease-modifying therapies, treatment should be aimed at reducing symptoms of con�gestion with diuretics. Loop diuretics are preferred, although thiazide diuretics may be useful for managing hypertension. Reducing body weight in obese patients and increasing exercise may further improve symptoms and exercise capacity and should therefore be considered in appropriate patients.284,285 It is important to identify and treat the underlying risk factors, aeti�ology, and coexisting comorbidities in HFpEF (e.g. hypertension in section 12.4, CAD in section 12.2, amyloidosis in section 14.6, AF in section 12.1.1, and valvular heart disease in section 12.3). Undoubtably, treatment of some of the underlying phenotypes of the the HFpEF syndrome leads to improVE OUTCOME
| Recommedation for treatment of patients with HFpEF (heart failure preserved ejection fraction) |
| (Class I, Level of Evidence C): |
|
❑ Screening, treatment, investigation about underlying etiologies, and
cardiovascular and non-cardiovascular comorbidities is recommended in patients with HFpEF |
| The above table adopted from 2021 ESC Guideline |
|---|
Medications
Aldosterone Antagonists
May lead to improvement in diastolic function and hypertrophy but not in clinical outcomes.[2][3] However, a subgroup analysis of patients in the TOPCAT trial with brain natriuretic peptide levels showed benefit[3].
Diuretics
Diuretics are useful to control volume overload and decrease the preload.[4]
Angiotensin receptor neprilysin inhibitors
They may improve symptoms and quality of life in HFpEF patients but clinical trials to evaluate their effectiveness are ongoing.[5][6][7]
ACE inhibitors
ACE inhibitors do not have direct effect on mortality and morbidity in HFpEF but they have great role on hypertension, renal function, CAD and diabetes as underlying disease.[8][9]
Angiotensin II receptor blockers
There is no evidence that they improve morbidity or mortality in HFpEF patients.[9]
β-blockers
β-blockers have not shown benefits in HFpEF.[10][11]
References
- ↑ 1.0 1.1 McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland J, Coats A, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam C, Lyon AR, McMurray J, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano G, Ruschitzka F, Kathrine Skibelund A (September 2021). "2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure". Eur Heart J. 42 (36): 3599–3726. doi:10.1093/eurheartj/ehab368. PMID 34447992 Check
|pmid=value (help). Vancouver style error: initials (help) - ↑ Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, Duvinage A, Stahrenberg R, Durstewitz K, Löffler M, Düngen HD, Tschöpe C, Herrmann-Lingen C, Halle M, Hasenfuss G, Gelbrich G, Pieske B (2013). "Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial". JAMA. 309 (8): 781–91. doi:10.1001/jama.2013.905. PMID 23443441.
- ↑ 3.0 3.1 Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM (2014). "Spironolactone for heart failure with preserved ejection fraction". N. Engl. J. Med. 370 (15): 1383–92. doi:10.1056/NEJMoa1313731. PMID 24716680.
- ↑ Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, Shah SJ, Ahmed A, Bonow RO, Cleland JG, Cody RJ, Chioncel O, Collins SP, Dunnmon P, Filippatos G, Lefkowitz MP, Marti CN, McMurray JJ, Misselwitz F, Nodari S, O'Connor C, Pfeffer MA, Pieske B, Pitt B, Rosano G, Sabbah HN, Senni M, Solomon SD, Stockbridge N, Teerlink JR, Georgiopoulou VV, Gheorghiade M (2014). "Developing therapies for heart failure with preserved ejection fraction: current state and future directions". JACC Heart Fail. 2 (2): 97–112. doi:10.1016/j.jchf.2013.10.006. PMC 4028447. PMID 24720916.
- ↑ Macdonald PS (2015). "Combined angiotensin receptor/neprilysin inhibitors: a review of the new paradigm in the management of chronic heart failure". Clin Ther. 37 (10): 2199–205. doi:10.1016/j.clinthera.2015.08.013. PMID 26386501.
- ↑ Hubers SA, Brown NJ (2016). "Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition". Circulation. 133 (11): 1115–24. doi:10.1161/CIRCULATIONAHA.115.018622. PMID 26976916.
- ↑ Prenner SB, Shah SJ, Yancy CW (2016). "Role of Angiotensin Receptor-Neprilysin Inhibition in Heart Failure". Curr Atheroscler Rep. 18 (8): 48. doi:10.1007/s11883-016-0603-4. PMID 27324636.
- ↑ Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, Yip T, Lau ST, Lau CP, Tang MO, Yu CM, Sanderson JE (2008). "The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction". Heart. 94 (5): 573–80. doi:10.1136/hrt.2007.117978. PMID 18208835.
- ↑ 9.0 9.1 Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J (2003). "Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial". Lancet. 362 (9386): 777–81. doi:10.1016/S0140-6736(03)14285-7. PMID 13678871.
- ↑ Yamamoto K, Origasa H, Hori M (2013). "Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF)". Eur. J. Heart Fail. 15 (1): 110–8. doi:10.1093/eurjhf/hfs141. PMID 22983988.
- ↑ Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J, Vardas PE, Böhm M, Dei Cas L (2012). "Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study". Eur. J. Heart Fail. 14 (2): 219–25. doi:10.1093/eurjhf/hfr161. PMID 22147202.