The American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Failure Society of America (HFSA) jointly published an updated clinical practice guideline for the management of heart failure (HF) in April 2022.1 This guideline consolidates and replaces the 2013 American College of Cardiology Foundation (ACCF)/AHA guideline for HF management and its subsequent 2017 focused update, which was developed by the ACC/AHA/HFSA.1,2 As it emphasizes both the importance of applying clinical judgement and a shared decision-making approach, the 2022 guideline outlines management recommendations based upon up-to-date evidence.1
Focusing on HF prevention, management strategies, and implantable devices, the guideline addresses new recommendations for treatments (eg, for sodium-glucose cotransporter-2 [SGLT2] inhibitors, angiotensin receptor-neprilysin inhibitors [ARNIs]), atrial fibrillation (AF) management, management strategies specific to cardiac amyloidosis and cardio-oncology, and the use of left ventricular (LV) assist devices.1 This article reviews key takeaways from the 2022 guideline and summarizes the guideline’s recommendations for SGLT2 inhibitor therapy.
The 2022 HF guideline emphasizes the need for primary prevention, which may help mitigate the health and economic burden associated with HF, which is projected to spread to 2.97% of the US population by 2030.1,3 To address this need, guideline authors revised the stages of HF to emphasize those who are at risk, and highlighted the evolving role that structural cardiac changes and biomarkers play in identifying at-risk patients.1 These patients are potential candidates for preventive targeted treatment strategies.
The guideline describes persons with stage A disease as being “at risk for HF;” they lack HF symptoms, structural and/or functional heart disease, or abnormal cardiac biomarkers. Patients given a diagnosis of stage A HF may have such comorbidities as hypertension, cardiovascular disease (CVD), obesity, or diabetes; exposure to cardiotoxic agents; a genetic variant for cardiomyopathy; or a family history of cardiomyopathy. Stage B disease is described as “pre-HF;” although patients may not have symptoms or signs of the disease, they display evidence of 1 of the following: structural heart disease, increased filling pressures, or risk factors plus increased natriuretic peptide levels or persistently elevated cardiac troponin levels in the absence of competing diagnoses that could result in abnormal biomarkers. Stage C HF corresponds to symptomatic HF; this describes patients with structural heart disease and current or previous HF symptoms. Finally, stage D disease represents advanced HF; this includes individuals who have HF symptoms that interfere with their daily lives and who are admitted to the hospital recurrently despite attempts to optimize their guideline-directed medical therapy (GDMT).1
The classification of HF by LV ejection fraction (LVEF) has been modified.1 The guideline now defines HF with reduced ejection fraction (HFrEF) as involving an LVEF less than or equal to 40%. Patients who previously were in the HFrEF category and who have a follow-up measurement of LVEF greater than 40% are described as having HF with improved EF (HFimpEF). The use of the term “improved LVEF” for these patients is new in the 2022 guideline; the 2013 ACCF/AHA guideline had categorized these patients as having “HF with preserved EF-improved.”1,4 Authors of the updated guideline emphasized that this patient subgroup is more appropriately characterized by HFimpEF, since improvement in LVEF does not necessarily represent full myocardial recovery or normalization of LV function.1 The authors underscored the need for these patients to continue treatment—many patients with improvement in LVEF and biomarkers and resolution of symptoms relapse after 6 months following withdrawal of GDMT.1,5
Patients with an LVEF of between 41% and 49% and evidence of increased LV filling pressures (either spontaneous or provokable) are described as having HF with mildly reduced EF (HFmrEF). HF with preserved EF (HFpEF), the final category, describes patients with an LVEF greater than or equal to 50% and evidence of spontaneous or provokable increased LV filling pressures. According to the guideline authors, establishing the diagnosis of HFmrEF and HFpEF can be challenging, because HF signs and symptoms often are nonspecific, and they can overlap with other conditions. Additionally, whereas elevated natriuretic peptide levels support the diagnosis, the presence of normal values do not exclude it. To address these challenges and improve diagnostic specificity, the guideline authors added the need to obtain evidence of increased filling pressures for the diagnosis of HF in the setting of LVEF greater than 40%. As described in the guideline, natriuretic peptide levels, echocardiographic diastolic parameters, or results from invasive hemodynamic measurement at rest or exercise can be used to fulfill the diagnostic criteria.1
The 2022 HF guideline authors modified treatment recommendations across the spectrum of HF, and the addition of SGLT2 inhibitors is a key update. The SGLT2 inhibitors are now part of the 4 medication classes recommended as GDMT for HFrEF; the others are β-blockers, mineralocorticoid receptor antagonists (MRAs), and renin-angiotensin system inhibitors that include ARNIs, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs). For the treatment of HFmrEF, SGLT2 inhibitors have a class 2a recommendation; the weaker class 2b recommendation is given to ARNIs, ACEIs, ARBs, MRAs, and β-blockers in this setting. New recommendations for the treatment of HFpEF include the use of SGLT2 inhibitors (class 2a recommendation) or MRAs or ARNIs (class 2b recommendation for both). Several prior recommendations for HFpEF have been renewed, including those for the treatment of hypertension and AF and the use of ARBs.1
Other key updates include the addition of value statements, recommendations for amyloid heart disease, and the need for referral to HF specialty teams. Recognizing the importance of cost-value considerations, the authors developed and added value statements for select guideline recommendations related to published, high-quality cost-effectiveness studies. Among new recommendations for the treatment of amyloid heart disease are a diagnostic and therapeutic approach for cardiac amyloidosis that includes screening for monoclonal light chains and use of bone scintigraphy, genetic sequencing, anticoagulation therapy, and tetramer stabilizer therapy. Finally, guideline authors emphasized the importance of referring patients with advanced HF who wish to prolong survival to a HF specialty team, who would review the management of HF and assess patient suitability for advanced HF therapies. Additionally, the specialty team would use palliative care interventions including palliative inotropes according to the goals of the patient.1
After initially demonstrating an improved rate of HF hospitalizations among patients with type 2 diabetes (T2D) who were at risk for HF, data on SGLT2 inhibitors also revealed benefits in patients with HF, irrespective of the presence of T2D.6-10 The updated HF guideline incorporates accumulating evidence on the beneficial CV effects of SGLT2 inhibitors.1 These agents are now recommended across the spectrum of HF (Table).1
In patients with T2D who have or are at high risk for CVD, SGLT2 inhibitors have a class 1 recommendation to prevent HF-related hospitalizations.1 Such patients are at risk for HF (stage A). The recommendation is based on results from the randomized CANVAS program, DECLARE-TIMI 58, and EMPA-REG OUTCOME clinical trials, which examined the impact of SGLT2 inhibitor therapy on HF-related hospitalizations in this patient population.6-8
The CANVAS program evaluated the impact of canagliflozin on CV, renal, and safety outcomes.6 This program consisted of 2 trials with identical inclusion criteria and enrolled patients with T2D who either were aged 30 years or older and had a history of symptomatic CVD or were aged 50 years or older and had 2 or more specific risk factors for CVD. After a mean follow-up of 188.2 weeks, treatment with canagliflozin was associated with a significantly reduced rate of hospitalization for HF compared with placebo (hazard ratio [HR], 0.67; 95% CI, 0.52-0.87). The DECLARE-TIMI 58 trial evaluated the impact of dapagliflozin on atherosclerotic CV and renal outcomes among patients aged 40 years or older with T2D and established CVD or multiple risk factors for CVD.7 The median follow-up was 4.2 years. The rate of HF hospitalization was significantly reduced in patients treated with dapagliflozin compared with those treated with placebo (HR, 0.73; 95% CI, 0.61-0.88). The EMPA-REG OUTCOME trial evaluated the impact of empagliflozin on CV morbidity and mortality in patients with T2D and established CVD.8 The median treatment duration was 2.6 years, and the median follow-up was 3.1 years. Compared with those given placebo, the empagliflozin group was associated with a significantly reduced HF hospitalization rate (HR, 0.65; 95% CI, 0.50-0.85; P = .002).
The 2022 HF guideline notes that HF was present at baseline in approximately only 10% to 14% of participants in these trials.1,6-8 Thus, prevention of primary HF symptoms accounted for most of the reduction of HF-related hospitalizations following SGLT2 inhibitor therapy.1 The recommendation for the use of SGLT2 inhibitors in patients at risk for HF due to T2D and established or high risk of CVD also applies to patients with pre-HF, as management strategies instituted in stage A should be continued through stage B (pre-HF).
SGLT2 inhibitors carry a class 1 recommendation for reducing HF hospitalization and CV mortality in patients with symptomatic chronic HFrEF, regardless of the presence of T2D.1 Prior data suggested that use of SGLT2 inhibitors offered these benefits in patients without T2D.11 Results of the DEFINE-HF trial found that a greater proportion of patients with symptomatic HFrEF who were treated with dapagliflozin experienced clinically meaningful improvements in HF-related symptoms, functional status, and quality of life than did those given placebo. The observed benefits were consistent, regardless of T2D.
The new guideline recommendation is based on results of the DAPA-HF and EMPEROR-Reduced trials, which evaluated the efficacy of SGLT2 inhibitors (dapagliflozin and empagliflozin, respectively) in patients with symptomatic HFrEF irrespective of the presence of T2D.1,9,10 In the DAPA-HF trial, the primary composite outcome of worsening HF or CV death was 26% lower in patients treated with dapagliflozin compared with those treated with placebo (HR, 0.74; 95% CI, 0.65-0.85; P < .001), and consistent benefits were observed in patients without diabetes.9 In the EMPEROR-Reduced trial, empagliflozin therapy was associated with a 25% reduction in the primary composite outcome of CV death or HF hospitalization compared with placebo (HR, 0.75; 95% CI, 0.65-0.86; P < .001), with a consistent effect observed in patients with and without diabetes.10 The results of a meta-analysis of both trials found that SGLT2 inhibitor therapy was associated with a 13% reduction in all-cause mortality, a 14% reduction in CV death, and a 31% reduction in the risk of first HF hospitalization compared with use of placebo.12 Additionally, treatment with an SGLT2 inhibitor was associated with a significantly reduced risk of a composite renal end point (50% or higher sustained declines in estimated glomerular filtration rate, end-stage renal disease, or renal death) compared with placebo.
A key addition to the updated guideline is the incorporation of value statements for select recommendations.1 The guideline includes a value statement for its class 1a recommendation for the use of SGLT2 inhibitors in patients with symptomatic chronic HFrEF that is based upon the results of 2 model-based economic evaluations of the use of dapagliflozin.13,14 Recognizing the wide range of costs currently associated with dapagliflozin, guideline authors indicate that treatment with SLGT2 inhibitors in this patient population provides “intermediate economic value.”1
The guideline authors emphasize the need to initiate GDMT for HFrEF at low-starting doses and to titrate up at specified intervals to achieve and maintain clinical trial–defined target doses, as tolerated by the patient.1 Initiation and titration of GDMT should be individualized and optimized as frequently as every 1 to 2 weeks based on patient-specific factors (eg, symptoms, vital signs, laboratory findings). For patients with HFrEF, decisions regarding simultaneous initiation or sequencing of GDMT usually are individualized, and they do not necessarily need to follow the sequence of trial publications. Based on a decision analytical model evaluating the impact of adding SGLT2 inhibitor therapy to GDMT, implementing quadruple therapy (ARNI, β-blocker, aldosterone antagonist, and SGLT2 inhibitor therapy) would, at the population level in patients with HFrEF eligible for SGLT2 inhibitor treatment, lead to an estimated relative risk reduction in all-cause mortality of 73%.15
The guideline also includes a recommendation to use SGLT2 inhibitors in patients within the HFpEF and HFmrEF categories.1 In patients with HFpEF, SGLT2 inhibitors carry a class 2a recommendation as a potentially beneficial treatment for reducing HF hospitalizations and CV mortality. This recommendation is based on results of the EMPEROR-Preserved trial, which evaluated empagliflozin in patients with chronic symptomatic HF, a LVEF greater than 40%, and elevated N-terminal pro-B-type natriuretic peptide levels.16 After a median follow-up of 26.2 months, treatment with empagliflozin was associated with a 21% lower risk of the primary composite outcome of HF hospitalization or CV death when compared with treatment with placebo (HR, 0.79; 95% CI, 0.69-0.90; P < .001). Study investigators stated that this benefit was mostly driven by a 29% reduction in HF hospitalization with empagliflozin treatment. Of note, these outcomes associated with empagliflozin therapy were similar, regardless of the presence of diabetes.
The guideline gives SGLT2 inhibitors a class 2a recommendation for the treatment of patients with HFmrEF, noting that use of these agents can be beneficial in reducing HF hospitalizations and CV mortality in this setting.1 The recommendation is based on data from the subgroup of patients enrolled in the EMPEROR-Preserved trial who had an LVEF of 40% to 50% at baseline.16 In this patient subgroup, empagliflozin therapy was associated with a reduced risk of the primary composite outcome of CV death or HF hospitalization by 29% compared with treatment with placebo (HR, 0.71; 95% CI, 0.57-0.88). The guideline notes the lack of prospective, randomized clinical trials designed specifically for patients within the HFmrEF category.1 Study results indicate that patients with an LVEF closer to 41% have shown a similar response to medical therapies to that of patients with HFrEF. Therefore, as indicated in the guideline, it may be reasonable to treat patients on the lower end of the HFmrEF spectrum with the GDMT used to treat patients with HFrEF.
Recommendations provided in the guideline are based on available evidence. However, though data and treatment strategies for patients with HF continue to evolve, significant evidence gaps remain. Providing clinicians with current, evidence-based recommendations would facilitate shared decision-making with patients and optimize outcomes.1 Many patients who would benefit from GDMT for HF remain undertreated in real-world settings.17 According to findings from the CHAMP-HF registry, only 22.1% of patients with HFrEF who were eligible for all drug classes were prescribed some dose of an ACEI/ARB/ARNI, a β-blocker, and an MRA simultaneously, and just 1.1% of patients were prescribed target doses of medications in all 3 drug classes simultaneously. Other studies also highlighted the suboptimal implementation of GDMT for HF in routine practice, with many eligible patients failing to receive recommended treatments.18,19
Authors of the guideline call for future research, providing a list of selected issues that should be addressed. For instance, real-world evidence is needed to characterize the generalization of therapies in patient populations that may have been underrepresented in HF trials. Data are also needed on the impact of therapies in patient-reported outcomes and on optimal strategies for sequencing and titration of GDMT.1
The need for additional data on treatment strategies for patients with HFpEF or HFmrEF, including additional efficacy and safety data concerning the use of SGLT2 inhibitor therapies in these populations, is also highlighted by the guideline.1 Recent clinical trial data have provided further understanding about the use of SGLT2 inhibitor therapy in this setting.20
The EMPULSE trial compared the clinical benefit of empagliflozin treatment with placebo among patients hospitalized with acute HF. At baseline, 28.7% of patients in the empagliflozin group and 35.1% of those in the placebo group had an LVEF greater than 40%. The primary outcome was clinical benefit, defined as a hierarchical composite of the time to all-cause death, the number of HF events, the time to first HF event, and a difference of 5 points or greater in the change from baseline on the Kansas City Cardiomyopathy Questionnaire Total Symptom Score. After 90 days, the results favored empagliflozin, with clinical benefit achieved by 53.9% of patients in the empagliflozin group compared with 39.7% of patients in the placebo group (stratified win ratio, 1.36; 95% CI, 1.09-1.68; P = .0054).
The DELIVER trial is evaluating the efficacy and safety of dapagliflozin therapy compared with placebo in patients with HFmrEF, HFpEF, or improved LVEF.21 A total of 6263 patients fulfilled inclusion criteria; they have been randomly assigned to dapagliflozin treatment or placebo. The primary end point is CV death or either a hospitalization or an urgent visit for HF.
Trial data will further the understanding of SGLT2 inhibitor use in patients with HF and LVEF greater than 40% and will address some evidence gaps highlighted by the 2022 HF guideline.1,21
1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 ACC/AHA/HFSA guideline for the management of heart failure. J Card Fail. 2022;28(5):e1-e167. doi:10.1016/j.cardfail.2022.02.010
2. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161. doi:10.1161/CIR.0000000000000509
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. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05.019
5. Halliday BP, Wassall R, Lota AS, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet. 2019;393(10166):61-73. doi:10.1016/S0140-6736(18)32484-X
6. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925
7. Wiviott SD, Raz I, Bonaca MP, et al; DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389
8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes; EMPA-REG OUTCOME Investigators. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
9. 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
10. Packer M, Anker SD, Butler J, et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190
11. Nassif ME, Windsor SL, Tang F, et al. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial. Circulation. 2019;140(18):1463-1476. doi:10.1161/CIRCULATIONAHA.119.042929
12. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819-829. doi:10.1016/S0140-6736(20)31824-9
13. Parizo JT, Goldhaber-Fiebert JD, Salomon JA, et al. Cost-effectiveness of dapagliflozin for treatment of patients with heart failure with reduced ejection fraction. JAMA Cardiol. 2021;6(8):926-935. doi:10.1001/jamacardio.2021.1437
14. Isaza N, Calvachi P, Raber I, et al. Cost-effectiveness of dapagliflozin for the treatment of heart failure with reduced ejection fraction. JAMA Netw Open. 2021;4(7):e2114501. doi:10.1001/jamanetworkopen.2021.14501
15. Bassi NS, Ziaeian B, Yancy CW, Fonarow GC. Association of optimal implementation of sodium-glucose cotransporter 2 inhibitor therapy with outcome for patients with heart failure. JAMA Cardiol. 2020;5(8):948-951. doi:10.1001/jamacardio.2020.0898
16. Anker SD, Butler J, Filippatos G, et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038
17. 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
18. Luo N, Lippmann SJ, Mentz RJ, et al. Relationship between hospital characteristics and early adoption of angiotensin-receptor/neprilysin inhibitor among eligible patients hospitalized for heart failure. J Am Heart Assoc. 2019;8(3):e010484. doi:10.1161/JAHA.118.010484
19. Luo N, Ballew NG, O'Brien EC, et al. Early impact of guideline publication on angiotensin-receptor neprilysin inhibitor use among patients hospitalized for heart failure. Am Heart J. 2018;200:134-140. doi:10.1016/j.ahj.2018.01.009
20. Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568-574. doi:10.1038/s41591-021-01659-1
21. Solomon SD, Vaduganathan M, Claggett BL, et al. Baseline characteristics of patients with HF with mildly reduced and preserved ejection fraction: DELIVER Trial. JACC Heart Fail. 2022;10(3):184-197. doi:10.1016/j.jchf.2021.11.006
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