This systematic literature review reports incidence of adverse drug effects associated with guideline-directed medical therapy for patients with heart failure with reduced ejection fraction.
Objectives: To summarize published literature on the incidence of adverse drug effects (ADEs) associated with guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF).
Study Design: Systematic literature review.
Methods: A systematic literature review was conducted in PubMed, Ovid MEDLINE, and Clinical Key covering January 1990 to December 2018. Key search terms were ADEs for β-blockers (BBs), ACE inhibitors (ACEis), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and/or angiotensin receptor-neprilysin inhibitors (ARNis) in adult patients (≥ 18 years) with HFrEF.
Results: A total of 279 eligible articles were identified, of which 29 reported drug-related adverse effects and were included in this review. Of the 29 studies, 11 examined BBs; 9, MRAs; 6, ARNis; 2, ACEis; and 1, ARBs. The most common reported ADEs across these therapeutic classes included bradycardia, dizziness, hypotension, hyperkalemia, cough, and renal impairment. The incidence of BB-induced bradycardia was 1% to 52% based on 9 studies, and 6 studies described dizziness as a result of BBs and ARNis (15%-43%). Fourteen studies reported induced hypotension (1.4%-63%); 13 studies, hyperkalemia (0.6%-30.2%); 3 studies, cough (37%-50%); and 4 studies, renal impairment (0.6%-7.6%).
Conclusions: Findings show that drug-related adverse effects are commonly reported in clinical trials and highlight the sizable burden of ADEs with medical therapy across patients with HFrEF. Additional real-world evidence and studies aiming to improve the tolerability of GDMT for patients with HFrEF are warranted.
Am J Manag Care. 2022;28(3):e113-e120. https://doi.org/10.37765/ajmc.2022.88844
Heart failure (HF) is a major epidemic in the United States, with an estimated prevalence of 6.3 million adults (≥ 20 years) from 2013 to 2016.1,2 In the United States, the prevalence of HF is expected to increase by 46% from 2012 to 2030.3 HF with reduced ejection fraction (HFrEF) is a common type of HF defined as having an ejection fraction of 40% or less.4 Based on data from the Get With The Guidelines – Heart Failure initiative, linked with Medicare claims (2005-2009), the incidence of HFrEF in 39,982 US patients admitted for HF to 254 hospitals was 46%.5 The rates of rehospitalization for HF in the United States are high despite currently available therapies, with 30% of patients being readmitted 60 to 90 days post discharge.6
Per the 2017 update to the American College of Cardiology/American Heart Association guidelines, indicated medical treatment includes angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), β-blockers (BBs), and, most recently, angiotensin receptor-neprilysin inhibitors (ARNis) for all patients with HFrEF. The guidelines also highlight common cardiovascular adverse drug effects (ADEs), including bradycardia, dizziness, hypotension, hyperkalemia, cough, and renal impairment. Guideline-directed medical therapy (GDMT) has been shown to reduce all-cause mortality for patients with HFrEF through titration to maximum tolerated doses; however, not all patients achieve these high doses in clinical practice, in part because of ADEs.7,8 In fact, less than 50% of patients with HFrEF reach the target dose of most GDMTs, including at discharge or in the outpatient setting.7
A negative contributor to drug management is patient and physician perception of ADEs.9 Concerns about ADEs at higher doses may deter physicians from prescribing, which makes the recommended strategy problematic. Patients with HFrEF with comorbidities such as renal insufficiency and hyperkalemia are less likely to receive target doses of GDMT or may even receive none at all. Gaps in evidence include information on which ADEs have reliable evidence of induction by specific HF drugs. The ability to identify incidence of patients reporting a listed ADE that is genuinely drug related is critical, yet it is limited in the medical literature.9 Although individual HF trials have reported ADEs, only a limited number of studies have combined the available information and reported ADEs for multiple classes of HF drugs in a single review. Because of the limited data available on the ADEs arising from guideline-directed HF therapies, the objective of this study was to summarize existing published literature on the incidence of ADEs for patients with HFrEF.
This systematic literature review followed the Cochrane methodology and was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist.
Information Sources, Search Strategy, and Study Selection
A systematic literature review of studies of patients with HFrEF comparing standard-of-care HF drugs with placebo or alternative HF drugs was performed. We queried PubMed, Ovid MEDLINE, and Clinical Key and applied the following key search terms: heart failure with reduced ejection fraction, reduced ejection fraction, HFrEF, adults, English, pharmacy, therapeutics, and pharmacology. Filters were applied to identify studies that were published in English from January 1990 to December 2018 to include a broad range of clinical evidence available for ADEs. Additionally, filters were used to identify studies of adult patients (≥ 18 years). We included randomized controlled trials, open-label trials, and prospective and retrospective cohort studies. Included studies presented outcomes of ADEs for BBs, ACEis, ARBs, ARNis, and/or MRAs in adult patients with HFrEF. The main ADEs are defined as those most commonly reported in the literature. We excluded editorials, conference reports, systematic literature reviews, manuscript reviews, meta-analyses, and unpublished studies and abstracts. Also excluded were studies including other HF drug classes, articles with low quality ratings based on Cochrane criteria, and those missing information for extraction.
The PRISMA data extraction form was used to extract articles and remove duplicate records. Two authors (M.B. and P.S.) screened studies for relevance based on title and abstract and reviewed the full text of relevant articles for study inclusion. Discrepancies on whether to include specific studies were resolved through formal discussion and consensus between the same 2 authors. The PRISMA checklist was used to validate and assess the quality of all the articles meeting criteria for inclusion in this review. Additionally, we examined the reference lists of all included articles for other relevant references. Articles were excluded from the systematic literature review owing to wrong disease type, wrong drug class, and wrong outcomes. Figure 1, the PRISMA flow chart, outlines the data extraction methods. The following information was extracted from each article: author, trial name, year, study design, drug class, sample size, patient population, treatment group, control group, dose, follow-up time, and risk and ranges of ADEs. The articles were grouped according to HF drug class into the following categories: BB, ACEi, ARB, ARNi, and MRA.
A total of 279 articles were identified in the initial search, 29 of which reported ADEs and were included after full text review.10-38 Of these, 22 studies (75.9%) included in the review were randomized controlled trials (Table 110-38). The majority of the studies evaluated ADEs of BBs (n = 11), with only 1 study evaluating ARBs. Table 2 [part A and part B]10-38 summarizes the characteristics of studies included in the review. The sample sizes across these studies ranged from 30 to 8399 patients, with a mean follow-up range of 0.7 to 41.4 months. The most commonly reported ADEs across these HF drug classes included bradycardia, dizziness, hypotension, hyperkalemia, cough, and renal impairment (Figure 2).
Table 3 [part A and part B]10-38 outlines the distribution of ADEs in the included studies and their percentage incidence. Nine studies reported bradycardia risk of 1% to 52%, caused by BB usage. Also attributable to BB usage was dizziness risk of 15% to 43%, reported in 6 studies. One other study reported an ARNi (omapatrilat)–induced dizziness risk of 19.4%; however, the clinical development of omapatrilat was discontinued and it is not a marketed drug. Fourteen studies described a high incidence of induced hypotension (1.4%-63%), resulting from treatment with a BB (9 studies), ARNi (4 studies), or ARB (1 study). Hyperkalemia was reported in 13 studies (9 with an MRA, 3 with an ARNi, 1 with an ARB) with a risk of 0.6% to 30.2%. Three studies reported cough risk of 37% to 50%, caused by ACEi (2 studies) or ARB (1 study) usage. Four studies described a high incidence of induced renal impairment (0.6%-7.6%), 3 resulting from ARNi treatment and 1 following treatment with an ARB.
As a consequence of the limited data available on the ADEs arising from guideline-directed HF therapies, the objective of this study was to summarize existing published literature on the incidence of ADEs for patients with HFrEF. This systematic literature review examines a multitude of studies reporting ADEs of guideline-directed HF therapies and is one of the few reports to summarize the incidences of common ADEs associated with GDMT for HFrEF. The results show that ADEs from clinical trials for GDMT are very common. This review highlights the sizable burden of ADEs across patients with HFrEF in the United States.
These ADEs, compared with traditional clinical outcomes for HF such as mortality and hospitalization, have been primarily studied in clinical trials and are underrepresented in the literature and, possibly, real-world practice. For example, sacubitril/valsartan was approved by the FDA in 2015 and, since approval, there has been minimal reporting on ADEs of sacubitril/valsartan in longitudinal, real-world studies for patients with HFrEF. Based on the incidence of common ADEs from randomized controlled trials in this review, these results may suggest that in real-world populations ADEs are similarly common and may result in patients discontinuing their GDMT. However, because of a lack of registry-based studies in published medical literature, risks of real-world GDMT ADEs are not well established. Owing to clinical significance, it is critical that we continue to examine the causality of ADEs related to GDMT in real-world populations. This review supports the need for future retrospective and prospective registry-based and other real-world evidence studies to evaluate ADEs across patients with HFrEF in the United States.
Additionally, ADEs have been noted to influence perceptions of HF therapies.9 Providers have genuine concern around certain HF drug classes, dose titration schedules, or combinations thereof for the likelihood that an ADE may affect the patient’s ability to tolerate continued treatment. Hyperkalemia, as noted in this review, is a very prevalent ADE of using MRAs and can be expected to only increase with additional renin-angiotensin-aldosterone system inhibitors such as ACEis, ARBs, or ARNis. Given the overwhelming burden of ADEs reported in this review, new pharmacotherapies with fewer off-target effects and more modest adverse effect profiles are needed to treat patients with HFrEF. Several pharmacologic therapies are on the horizon or recently approved for the treatment of patients with HFrEF, including sodium-glucose co-transporter 2 inhibitors (SGLT2is),39 soluble guanylate cyclase (sGC) stimulators,40 and a cardiac myosin activator, omecamtiv mecarbil.41
Dapagliflozin, an SGLT2i originally approved for the treatment of type 2 diabetes (T2D), was recently approved by the FDA for the treatment of patients with HFrEF with or without T2D. Vericiguat, a novel sGC stimulator, reduced the risk of HF hospitalization or cardiovascular death in a phase 3 clinical trial of patients with HFrEF.42 Omecamtiv mecarbil, a selective cardiac myosin activator, was generally safe and well tolerated in a phase 2 clinical trial, with cardiac serious adverse events occurring at a similar incidence risk across treatment groups.43 A phase 3 clinical trial of patients with HFrEF receiving omecamtiv mecarbil recently reported a lower incidence of an HF event or cardiovascular death vs placebo.41 These new treatments may influence the profile of ADEs associated with the pharmacologic treatment of HFrEF. It remains a major evidence gap and priority to improve patients’ quality of life by reducing the incidence of drug-induced adverse effects from HFrEF GDMT.
There are several limitations to this systematic literature review. First, the study population included only adult patients with HFrEF. The reported incidence ranges of ADEs are limited to HFrEF and are not applicable to other HF populations, such as HF with preserved or mid-range ejection fraction. Second, although this review highlights the ADEs of BBs, ACEis, ARBs, ARNis, and MRAs that have been most commonly reported in the literature, it does not cover all potential ADEs included in the medication label and, therefore, does not provide a complete list. Third, the diversity of methods of articles included did not allow for meta-analysis, nor risk or rate of ADEs. However, risks of ADEs were transparently reported and directly extracted from published articles. The risks were not combined or altered using standard meta-analysis or statistical techniques. Fourth, the quality of this review is contingent on the quality of the included studies, in which ADEs were not a prespecified outcome. The risk of bias was limited by inclusion of studies with a range of quality ratings and range of clear reporting of bias. Finally, it is possible that there are additional relevant studies that were not included in the review. Further real-world evidence studies are needed to examine and report ADEs for long-term drug use outside of controlled settings like clinical trials.
This systematic literature review reported that ADEs from clinical trials for GDMT occur very commonly, and it highlights the sizable burden of these effects across patients with HFrEF in the United States. This review reports association and is not a direct assessment of ADE causality; however, pharmacologically, these ADEs have been well characterized. The decision to examine the most common ADEs translates to health outcomes in real-world practice and emphasizes the importance for practitioners and stakeholders to be mindful of the common cardiovascular ADEs vs all possible ADEs included in the medication label. Future retrospective and prospective registry-based and other real-world evidence studies to evaluate adverse drug effects across patients with HFrEF in the United States, as well as studies aiming to analyze and improve medical therapy tolerability for patients with HFrEF, are warranted.
The authors acknowledge Ciara Duffy, PhD (Evidence Scientific Solutions, Horsham, UK); Richard Fay, PhD, CMPP (Envision Pharma Group, Philadelphia, PA); and Charlene Rivera, PhD (Envision Pharma Group, Fairfield, CT), for limited editorial assistance, which was funded by Cytokinetics, Inc.
Author Affiliations: Health Economics and Outcomes Research, Cytokinetics, Inc (MB, PS), South San Francisco, CA; Department of Public Health Sciences, Pennsylvania State University (MB), Hershey, PA; Clinical and Translational Research Accelerator, Yale School of Medicine (RJR), New Haven, CT; Center for Outcomes Research and Evaluation, Yale New Haven Hospital (NRD), New Haven, CT; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine (NRD), New Haven, CT.
Source of Funding: The study was conducted by Cytokinetics, Inc, South San Francisco, CA.
Author Disclosures: Mr Butzner is employed by Cytokinetics, Inc. Dr Riello has received consultancy payments and honoraria from AstraZeneca. Dr Sarocco was employed by Cytokinetics at the time this research was conducted and owns company stock as a former employee. Dr Desai has received consultancy payments from Amgen, Boehringer Ingelheim, Cytokinetics, Novartis, Relypsa, and SC Pharma and has received grants from Amgen, AstraZeneca, Boehringer Ingelheim, and Cytokinetics.
Authorship Information: Concept and design (MB, RJR, PS, NRD); acquisition of data (MB, PS); analysis and interpretation of data (MB, RJR, PS, NRD); drafting of the manuscript (MB, RJR, NRD); critical revision of the manuscript for important intellectual content (MB, RJR, PS, NRD); statistical analysis (MB); obtaining funding (PS); administrative, technical, or logistic support (MB); and supervision (MB, NRD).
Address Correspondence to: Michael Butzner, MPH, Cytokinetics, Inc, 350 Oyster Point Blvd, South San Francisco, CA 94080. Email: firstname.lastname@example.org.
1. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Fail. 2014;1(1):4-25. doi:10.1002/ehf2.12005
2. Benjamin EJ, Muntner P, Alonso A, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56-e528. doi:10.1161/CIR.0000000000000659
3. Heidenreich PA, Albert NM, Allen LA, et al; American Heart Association Advocacy Coordinating Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Stroke Council. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6(3):606-619. doi:10.1161/HHF.0b013e318291329a
4. Greene SJ, Butler J, Albert NM, et al. Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry. J Am Coll Cardiol. 2018;72(4):351-366. doi:10.1016/j.jacc.2018.04.070
5. Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol. 2017;70(20):2476-2486. doi:10.1016/j.jacc.2017.08.074
6. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol. 2013;61(4):391-403. doi:10.1016/j.jacc.2012.09.038
7. Komajda M, Anker SD, Cowie MR, et al; QUALIFY Investigators. Physicians’ adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey. Eur J Heart Fail. 2016;18(5):514-522. doi:10.1002/ejhf.510
8. Komajda M, Cowie MR, Tavazzi L, et al; QUALIFY Investigators. Physicians’ guideline adherence is associated with better prognosis in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry. Eur J Heart Fail. 2017;19(11):1414-1423. doi:10.1002/ejhf.887
9. Barron AJ, Zaman N, Cole GD, Wensel R, Okonko DO, Francis DP. Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information. Int J Cardiol. 2013;168(4):3572-3579. doi:10.1016/j.ijcard.2013.05.068
10. Woo KS, Nicholls MG. High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese. Br J Clin Pharmacol. 1995;40(2):141-144.
11. Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN; SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325(5):293-302. doi:10.1056/NEJM199108013250501
12. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349(9054):747-752. doi:10.1016/s0140-6736(97)01187-2
13. Eichhorn EJ, Domanski MJ, Krause-Steinrauf H, Bristow MR, Lavori PW; Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344(22):1659-1667. doi:10.1056/NEJM200105313442202
14. Packer M, Fowler MB, Roecker EB, et al; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106(17):2194-2199. doi:10.1161/01.cir.0000035653.72855.bf
15. Packer M, Colucci WS, Sackner-Bernstein JD, et al; PRECISE Study Group. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE Trial. Circulation. 1996;94(11):2793-2799. doi:10.1161/01.cir.94.11.2793
16. Colucci WS, Packer M, Bristow MR, et al; US Carvedilol Heart Failure Study Group. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation. 1996;94(11):2800-2806. doi:10.1161/01.cir.94.11.2800
17. Krum H, Sackner-Bernstein JD, Goldsmith RL, et al. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation. 1995;92(6):1499-1506. doi:10.1161/01.cir.92.6.1499
18. Flather MD, Shibata MC, Coats AJS, et al; SENIORS Investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26(3):215-225. doi:10.1093/eurheartj/ehi115
19. Bristow MR, Gilbert EM, Abraham WT, et al; MOCHA Investigators. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996;94(11):2807-2816. doi:10.1161/01.cir.94.11.2807
20. Packer M, Bristow MR, Cohn JN, et al; U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334(21):1349-1355. doi:10.1056/NEJM199605233342101
21. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet. 1997;349(9049):375-380. doi:10.1016/S0140-6736(97)80008-6
22. RESOLVD Investigators. Effects of metoprolol CR in patients with ischemic and dilated cardiomyopathy:
the Randomized Evaluation of Strategies for Left Ventricular Dysfunction pilot study. Circulation. 2000;101(4):378-384. doi:10.1161/01.cir.101.4.378
23. Owens RE, Twilla JD, Self TH, et al. β-blockade in heart failure with reduced ejection fraction: does heart rate control influence readmissions? J Pharm Pract. 2018;31(1):40-45. doi:10.1177/0897190017696951
24. McMurray JJV, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077
25. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106(8):920-926. doi:10.1161/01.cir.0000029801.86489.50
26. Antol DD, Casebeer AW, DeClue RW, Stemkowski S, Russo PA. An early view of real-world patient response to sacubitril/valsartan: a retrospective study of patients with heart failure with reduced ejection fraction. Adv Ther. 2018;35(6):785-795. doi:10.1007/s12325-018-0710-4
27. Senni M, McMurray JJV, Wachter R, et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016;18(9):1193-1202. doi:10.1002/ejhf.548
28. Jhund PS, Fu M, Bayram E, et al; PARADIGM-HF Investigators and Committees. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J. 2015;36(38):2576-2584. doi:10.1093/eurheartj/ehv330
29. Kobalava Z, Kotovskaya Y, Averkov O, et al. Pharmacodynamic and pharmacokinetic profiles of sacubitril/valsartan (LCZ696) in patients with heart failure and reduced ejection fraction. Cardiovasc Ther. 2016;34(4):191-198. doi:10.1111/1755-5922.12183
30. Pitt B, Zannad F, Remme WJ, et al; Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709-717. doi:10.1056/NEJM199909023411001
31. Pitt B, Remme W, Zannad F, et al; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321. doi:10.1056/NEJMoa030207
32. Zannad F, McMurray JJV, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21. doi:10.1056/NEJMoa1009492
33. Eschalier R, McMurray JJV, Swedberg K, et al; EMPHASIS-HF Investigators. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol. 2013;62(17):1585-1593. doi:10.1016/j.jacc.2013.04.086
34. Vardeny O, Wu DH, Desai A, et al; RALES Investigators. Influence of baseline and worsening renal function on efficacy of spironolactone in patients with severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). J Am Coll Cardiol. 2012;60(20):2082-2089. doi:10.1016/j.jacc.2012.07.048
35. Pitt B, Gheorghiade M, Zannad F, et al; EPHESES Investigators. Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction ≤30%. Eur J Heart Fail. 2006;8(3):295-301. doi:10.1016/j.ejheart.2005.11.008
36. Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013;34(31):2453-2463. doi:10.1093/eurheartj/eht187
37. Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J. 2016;37(27):2105-2114. doi:10.1093/eurheartj/ehw132
38. Sato N, Ajioka M, Yamada T, et al; ARTS-HF Japan Study Group. A randomized controlled study of finerenone vs. eplerenone in Japanese patients with worsening chronic heart failure and diabetes and/or chronic kidney disease. Circ J. 2016;80(5):1113-1122. doi:10.1253/circj.CJ-16-0122
39. McMurray JJV, Solomon SD, Inzucchi SE, et al; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303
40. Armstrong PW, Roessig L, Patel MJ, et al. A multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator: the VICTORIA trial. JACC Heart Fail. 2018;6(2):96-104. doi:10.1016/j.jchf.2017.08.013
41. Teerlink JR, Diaz R, Felker GM, et al; GALACTIC-HF Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2021;384(2):105-116. doi:10.1056/NEJMoa2025797
42. Investigational drug vericiguat significantly reduced the risk of the composite endpoint of heart failure hospitalization or cardiovascular death, compared to placebo, when given in combination with available heart failure therapies. News release. Merck; March 28, 2020. Accessed June 23, 2020. https://www.businesswire.com/news/home/20200328005001/en/Investigational-Drug-Vericiguat-Significantly-Reduced-Risk-Composite
43. Teerlink JR, Felker GM, McMurray JJV, et al; COSMIC-HF Investigators. Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet. 2016;388(10062):2895-2903. doi:10.1016/S0140-6736(16)32049-9