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]]
8 Heart failure with preserved ejection fraction 8.1 The background to heart failure with preserved ejection fraction This guideline acknowledges the historical changes in nomenclature and the lack of consensus on the optimal LVEF cut-off to define the group of patients with HF without overtly reduced EF. The term ‘pre�served’ was originally proposed in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Programme to refer to patients with an EF (>40%) that was not clearly ‘reduced’ or completely ‘normal’.252 While the current guide�lines have designated patients with an LVEF 41�49% as HFmrEF, we recognize that there will be debate about what constitutes ‘mildly reduced’ EF, what these EF cut-offs should be, and whether they should be different for men and women.14,253 The EACVI defines sys�tolic dysfunction as being <52% for males and <54% for females.16 Whether patients with higher EFs and HF should be named HF with ‘normal’ EF has also been considered.14,254 However, given the known variability of echocardiographic measurements of LVEF, the difficulties in interpreting LVEF measured using different imaging modalities, and remaining controversies regarding the precise LVEF cut-off to define ‘normal’ , which may vary not only with sex but also with other factors such as age and ethnicity,255 this guideline has kept the nomenclature of HFpEF using an EF cut-off of 50%. Importantly, clinicians should be aware that LVEF is a continuous variable with a normal distribution in the general population, and the EF cut-offs used in definitions are therefore arbitrary. Moreover, while the LVEF cut-off to define ‘normal’ will likely be higher than 50%, the presence of a very high EF (e.g. above 65�70%) should also prompt a search for pathology, such as cardiac amyloidosis (CA) or hypertrophic car�diomyopathy (HCM), where a ‘supra-normal’ EF may result from shrinkage of the LV end-diastolic volume (denominator of EF).256,257 8.2 Clinical characteristics of patients with heart failure with preserved ejection fraction HFpEF differs from HFrEF and HFmrEF in that HFpEF patients are older and more often female. AF, CKD, and non-CV comorbidities are more common in patients with HFpEF than in those with HFrEF.258 There are numerous potential causes of HFpEF (Table 5). The pathophysiology of various HFpEF syndromes differs, and thus they require distinct therapies. Red flags for the potential presence of CA include low normal BP in patients with a history of hypertension, intolerance to beta-blockers or ACE-I, history of bilateral carpal tun�nel syndrome, low voltage on ECG and echocardiographic features such as thickening of the septum, posterior wall, or RV wall, enlarged atria, a small pericardial effusion, or valve thickening [for more details see the section on CMP (section 14.2)]. Furthermore, it is important to exclude other conditions that might mimic the HFpEF syndrome (e.g. lung disease, anaemia, obesity, and deconditioning). For a more comprehensive overview on HFpEF, see the ESC/HFA position statement.259 8.3 The diagnosis of heart failure with preserved ejection fraction The diagnosis of HFpEF remains challenging. Several diagnostic criteria have been proposed by societies and in clinical trials.260 These criteria vary widely in their sensitivities and specificities for diagnosing HFpEF. More recently, two score-based algorithms (H2FPEF and HFA-PEFF) have been proposed to aid the diagnosis.259,261 While the generaliz�ability of the scores has been tested in various trial and observational cohorts, their diagnostic performance has varied.262�269 Both scores assign a substantial proportion of suspected HFpEF patients as intermediate likelihood, wherein additional diagnostics are proposed. Thus, depending on which score is used, different patients will be referred for additional testing or allocated as having HFpEF. Furthermore, physicians may not have access to all the specialized tests recommended by the specific diagnostic algorithms. This limits the broad clinical applicability of the scores and demonstrates the ongoing diagnostic uncertainty in HFpEF.267 To facilitate broad clinical application, this guideline recom�mends a simplified pragmatic approach that distils the common major elements in prior diagnostic criteria and emphasizes the most frequently used variables widely available to clinicians. Some of these variables, in particular, LA size (LA volume index >32 mL/m2 ), mitral E velocity <90 cm/s, septal e0 velocity <9 cm/ s, E/e0 ratio >9 have been shown to be pivot points beyond which the risk of CV mortality is increased, underscoring their value.270 This recommendation is therefore consistent with the consensus document of the HFA, and does not represent a new algorithm or diagnostic score but rather a simplified approach. Physicians with access to expertise may refer to the full diagnostic approach recommended by the HFA.2This simplified diagnostic approach starts with assessment of pre�test probability (see clinical characteristics above). The diagnosis should include the following: (1) Symptoms and signs of HF. (2) An LVEF >_50%.* (3) Objective evidence of cardiac structural and/or functional abnor�malities consistent with the presence of LV diastolic dysfunction/ raised LV filling pressures, including raised NPs (Table 9).
- 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 |
|---|
Treatment for HFpEF is based on underlying associated conditions. These measure are mainly focused on:
- Hypertension Control[2]
- It is recommended to maintain BP less than 150/90 mm Hg in persons who are 60 years of age or older in the general population and of less than 140/90 mm Hg in persons with kidney disease (estimated GFR<60 ml per minute per 1.73 m2 of body-surface area or >30 mg of albumin per gram of creatinine,regardless of diabetic status) and for persons with diabetes, regardless of age.[3]
- Diuretics must be used to relief symptoms of volume overload according to patients' weight, symptoms and electrolyte status. Also, sodium restriction may be helpful in patients who are prone to volume overload.[6]
- Atrial fibrillation treatment[7]
- Patients with Atrial fibrillation (AF) must be treated according to last guideline for rate control and anti coagulation but if the symptoms remained consider rhythm control.[8]
- Appropriate diet and exercise[9][10]
- Weight control[9]
- Control of co-morbid conditions, such as diabetes, anemia, hyperlipidemia, sleep apnea and COPD.[11]
- Patients with coronary artery diseases (CAD) should be treated based on the guidelines recommendations.
Medications
Aldosterone Antagonists
May lead to improvement in diastolic function and hypertrophy but not in clinical outcomes.[12][13] However, a subgroup analysis of patients in the TOPCAT trial with brain natriuretic peptide levels showed benefit[13].
Diuretics
Diuretics are useful to control volume overload and decrease the preload.[14]
Angiotensin receptor neprilysin inhibitors
They may improve symptoms and quality of life in HFpEF patients but clinical trials to evaluate their effectiveness are ongoing.[15][16][17]
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.[18][19]
Angiotensin II receptor blockers
There is no evidence that they improve morbidity or mortality in HFpEF patients.[19]
β-blockers
β-blockers have not shown benefits in HFpEF.[20][21]
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) - ↑ Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ (2008). "Treatment of hypertension in patients 80 years of age or older". N. Engl. J. Med. 358 (18): 1887–98. doi:10.1056/NEJMoa0801369. PMID 18378519.
- ↑ Reisin E, Harris RC, Rahman M (2014). "Commentary on the 2014 BP guidelines from the panel appointed to the Eighth Joint National Committee (JNC 8)". J. Am. Soc. Nephrol. 25 (11): 2419–24. doi:10.1681/ASN.2014040371. PMC 4214539. PMID 25114277.
- ↑ Takei M, Kohsaka S, Shiraishi Y, Goda A, Izumi Y, Yagawa M, Mizuno A, Sawano M, Inohara T, Kohno T, Fukuda K, Yoshikawa T (2015). "Effect of estimated plasma volume reduction on renal function for acute heart failure differs between patients with preserved and reduced ejection fraction". Circ Heart Fail. 8 (3): 527–32. doi:10.1161/CIRCHEARTFAILURE.114.001734. PMID 25737498.
- ↑ Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM (2011). "Diuretic strategies in patients with acute decompensated heart failure". N. Engl. J. Med. 364 (9): 797–805. doi:10.1056/NEJMoa1005419. PMC 3412356. PMID 21366472.
- ↑ Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P (2016). "2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC". Eur. Heart J. 37 (27): 2129–200. doi:10.1093/eurheartj/ehw128. PMID 27206819.
- ↑ Zakeri R, Chamberlain AM, Roger VL, Redfield MM (2013). "Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction: a community-based study". Circulation. 128 (10): 1085–93. doi:10.1161/CIRCULATIONAHA.113.001475. PMC 3910441. PMID 23908348.
- ↑ January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW (2014). "2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society". Circulation. 130 (23): 2071–104. doi:10.1161/CIR.0000000000000040. PMID 24682348.
- ↑ 9.0 9.1 Haass M, Kitzman DW, Anand IS, Miller A, Zile MR, Massie BM, Carson PE (2011). "Body mass index and adverse cardiovascular outcomes in heart failure patients with preserved ejection fraction: results from the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial". Circ Heart Fail. 4 (3): 324–31. doi:10.1161/CIRCHEARTFAILURE.110.959890. PMC 3100162. PMID 21350053.
- ↑ Smart NA, Haluska B, Jeffriess L, Leung D (2012). "Exercise training in heart failure with preserved systolic function: a randomized controlled trial of the effects on cardiac function and functional capacity". Congest Heart Fail. 18 (6): 295–301. doi:10.1111/j.1751-7133.2012.00295.x. PMID 22536983.
- ↑ Alehagen U, Benson L, Edner M, Dahlström U, Lund LH (2015). "Association Between Use of Statins and Mortality in Patients With Heart Failure and Ejection Fraction of ≥50". Circ Heart Fail. 8 (5): 862–70. doi:10.1161/CIRCHEARTFAILURE.115.002143. PMID 26243795.
- ↑ 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.
- ↑ 13.0 13.1 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.
- ↑ 19.0 19.1 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.