Sources and selection criteria

We searched PubMed and the Cochrane Database of Systematic reviews for articles published between January 2015 and 7 July 2023 to identify new randomized controlled trials (RCTs) and large cohort studies of treatments and diagnostic strategies for heart failure. We also identified epidemiologic studies published from 2020 to 2023. We included older studies to provide context. We focused on studies not included in the recent European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) guidelines from 2021 and 2022.12 We prioritized RCTs over observational data when reviewing interventions. We did not consider case reports or case series in our review.

Epidemiology

The Global Burden of Disease Study estimated that 57 million people were living with heart failure in 2019.34 Although this number has been increasing in countries with aging populations, the age standardized rate has fallen from 7.7 per 1000 in 2010 to 7.1 per 1000 in 2019.34 The change over time in the age adjusted prevalence from 2009 to 2019 (an average 0.3% decline per year during this period) has not been linear, with rates initially falling but then increasing by 0.6% per year between 2016 and 2019.34 The reason for this change in prevalence is unclear and requires further investigation. An increase in hospital admissions for heart failure has been noted for young adults (age 18-45) in the US, with rates increasing from 1.8 per 10 000 in 2013 to 2.5 per 10 000 in 2018.5

Large differences in prevalence are noted across global regions for both men and women (fig 1).34 The region with the highest prevalence of heart failure includes the high income countries of North America, and the lowest prevalence was in central Asia. An estimated 3% of the US population will have heart failure by 2030.6 The largest declines in age adjusted rates were noted in high income countries of North America and Australasia regions.

Fig 1

Country specific, age adjusted prevalence of heart failure from 1990 to 2019 in men (top) and women (bottom). Estimates are from the Global Burden of Disease Study34

Survival

Survival following a diagnosis of heart failure is poor and is highly influenced by age. In the UK, survival approaches 80% at five years for people aged 45-64 but is closer to 20% at five years for those aged ≥85.7 Fortunately, survival rates have improved since 2000, particularly among younger patients.7

Although overall survival is an important outcome, it reflects the combined effects of all the patient’s conditions. The incremental impact of heart failure on survival is difficult to discern, as most patients with heart failure have multiple comorbidities. Years of life lost due to heart failure can be estimated by examining survival relative to actuarial estimates of life expectancy. Data from the UK have shown that heart failure is associated with a 2.4-fold greater loss of time alive than observed in the age and sex matched general population over 10 years.8 Length of life lost with heart failure varies from five months (women) to one year (men) for people with no comorbidities and from three years (women) to 4.5 years (men) for those with three or more comorbidities.8

The impact of covid-19 on the incidence of heart failure is uncertain but may be substantial. Studies from the US Veterans Affairs healthcare system have suggested that covid-19 is associated with an increased risk of cardiovascular events including death, myocardial infarction, and stroke.910

Prevention, screening, and identification of heart failure

Heart failure can be largely prevented or delayed with optimal control of risk factors.1112 Uncontrolled hypertension remains the most common risk factor for incident heart failure.1314 Optimal blood pressure control is associated with a 40% reduction in heart failure events,15 and multiple therapies for comorbid conditions reduce the risk of progression to heart failure including sodium-glucose cotransporter-2 (SGLT2) inhibitors, which reduce the risk of incident heart failure in patients with diabetes mellitus.161718 Among patients with chronic kidney disease, both SGLT2 inhibitors and finerenone (in those with diabetes) reduce the risk of incident heart failure.1920

Several clinical risk models can identify patients at high risk for progression to heart failure.21222324 Concentrations of natriuretic peptide (B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP)) are also elevated among patients at high risk of incident heart failure or asymptomatic systolic dysfunction.252627 In the STOP-HF (St Vincent’s Screening to Prevent Heart Failure) study, patients with a cardiovascular risk factor were screened using BNP. Patients with elevated concentrations had echocardiography and collaborative cardiology and primary care management. This led to a reduction in subsequent left ventricular systolic dysfunction and emergency hospital admissions for cardiovascular reasons.28 Similar results were confirmed in a trial among patients with diabetes mellitus.29 Since these trials, additional treatment options are now available to prevent incident heart failure among people at high risk.12 Expanding natriuretic peptide screening could lead to earlier diagnosis and treatment, substantially reducing the morbidity of heart failure.

Given that heart failure is a progressive condition with high early morbidity, prompt recognition is critical. In the UK, more than 80% of first diagnoses of heart failure are made in the hospital, and more than 40% of these patients have symptoms that should promote earlier assessment.30 Women were noted to take six times longer to receive a diagnosis of heart failure and were twice as likely to be misdiagnosed.31 Similar patterns of delayed diagnosis of heart failure have been noted in the US and Canada.323334 Minimizing the morbidity of heart failure requires increased awareness among patients and primary care clinicians, as well as additional strategies to facilitate disease recognition.

Diagnosis

The diagnosis of heart failure requires the presence of symptoms consistent with cardiac dysfunction along with evidence of either significantly reduced left ventricular systolic function (≤40%) or increased filling pressures. This is now incorporated into the recently published universal definition of heart failure.35 Heart failure is categorized into three groups based on the left ventricular ejection fraction (LVEF): heart failure with reduced ejection fraction (HFrEF) if the LVEF is ≤40%; heart failure with mildly reduced ejection fraction (HFmrEF) if the LVEF is 41-49%, and heart failure with preserved ejection fraction (HFpEF) if the LVEF is ≥50%. Patients with LVEF >40% require additional evidence of increased filling pressures (at rest or with exercise) to establish a diagnosis of heart failure.

Diagnosis of HFpEF

The diagnosis of HFpEF is particularly challenging, as determining increased filling pressure can be difficult. Most definitions of HFpEF exclude patients with heart failure symptoms due to valve disease, arrhythmia, pericardial constraint, or high cardiac output. Although invasive testing with cardiac catheterization is the gold standard for determining elevated left ventricular filling pressures, the diagnosis can be made non-invasively. Unfortunately, no single non-invasive test result has both a high sensitivity and a high specificity (fig 2).

Fig 2

Test characteristics for common non-invasive tests of increased left ventricular filling pressure. No single test threshold has both sensitivity and specificity above 70%.10 E/e’=early diastolic mitral inflow velocity to early diastolic mitral annulus velocity; GLS=global longitudinal strain; LA=left atrium; NT-proBNP=N-terminal pro B-type natriuretic peptide

Accordingly, clinical scores have been created using the results from multiple tests to diagnose HFpEF. These include H2FPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension (pulmonary artery systolic pressure >35 mm Hg), Elder age >60, elevated Filling pressures, E/e’ >9)36 and HFA-PEFF (Heart Failure Association—Pre-test assessment; Echocardiography and natriuretic peptide score; Functional testing; Final etiology).37 A recent evaluation found that these two scores have similar prognostic value, although 28% of patients had discordant findings (HFpEF diagnosed by only one of the algorithms).38

Perhaps as important as making the diagnosis of heart failure is determining whether the patient will benefit from therapy for HFpEF. Thus, clinicians can use the enrollment criteria from clinical trials showing benefit to make a diagnosis of HFpEF. The two clinical trials of SGLT2 inhibitors that showed benefit for patients with HFpEF used the following enrollment criteria: New York Heart Association (NYHA) II-IV symptoms, treatment with a diuretic, an NT-BNP >300 pg/mL if sinus rhythm (>600 or >900 pg/mL if atrial fibrillation), and evidence of structural heart disease (left atrial enlargement, left ventricular hypertrophy), in the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, or a recent hospital admission for heart failure.3940

Four medication pillars of HFrEF therapy

For patients with heart failure and a reduced left ventricular ejection fraction to ≤40% (HFrEF), four classes of drugs are now known to improve survival.12 These are renin-angiotensin system inhibitors including angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) or angiotensin receptor/neprilysin inhibitors (ARNI); β blockers; mineralocorticoid receptor antagonists (MRAs); and SGLT2 inhibitors (table 1; fig 3). Using the relative risk reduction from the clinical trials, it has been estimated that the combination of the four pillars of HFrEF therapy will lead to a 73% relative risk reduction in mortality and a number needed to treat of four to prevent a death compared with no treatment.42

Fig 3

Schematic of treatment for heart failure with reduced ejection fraction. ARNI=angiotensin receptor/neprilysin inhibitor therapy; BP=blood pressure; CRT=cardiac resynchronization therapy; EF=ejection fraction; HF=heart failure; ICD=implantable cardiac defibrillator; LBBB=left bundle branch block; MRA=mineralocorticoid receptor antagonist; NYHA=New York Heart Association; PA=pulmonary artery; SGLT2i=sodium glucose linked cotransporter 2 inhibitor; TEER=transcatheter edge-to-edge repair

Importance of rapid initiation of therapy

The importance of rapid initiation of life prolonging heart failure medication is now recognized owing to results from the Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies (STRONG-HF) trial.49 This multicenter study with 1078 patients from 87 hospitals in 14 countries examined rapid up-titration of guideline directed medication after an admission for acute heart failure. The intervention group had their medications up-titrated to 100% of recommended doses within two weeks of discharge. The primary endpoint of 180 day readmission to hospital due to heart failure or all cause death was reduced by an absolute percentage of 8.1% (95% confidence interval 2.9% to 13.2%) with rapid titration. We note that the STRONG-HF trial was conducted before SGLT2 inhibitors became standard of care for HFrEF therapy.

Further evidence of the benefit of rapid initiation comes from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial.50 Among 4744 patients in this trial, the time to clinical benefit was surprisingly fast with a significant reduction in cardiovascular death or worsening heart failure observed by 28 days after randomization to dapagliflozin compared with placebo (hazard ratio 0.51, 95% confidence interval 0.28 to 0.94).50 Similarly, in 1222 patients treated with sotagliflozin compared with placebo,47 the time to a sustained and significant reduction in the primary endpoint was 27 days (hazard ratio 9.62, 0.39 to 0.99). However, the time to benefit was twice as long for patients with heart failure and preserved ejection fraction.51

Although the goal is to initiate all four drug classes in a timely manner, the optimal order and timing of initiation remains controversial. Investigators have modeled the potential benefit of different strategies based on how quickly benefits were observed in clinical trials.52 They found that a strategy of starting with SGLT2 inhibitors and MRAs should lead to the greatest improvement in outcome. Other authors advocate for a more rapid approach, starting all four drugs at low doses together.53 Starting drugs rapidly in combination may be the quickest way to reach recommended doses, although it also may increase the risk of temporary side effects (for example, hypotension or elevated creatinine). Side effects may lead clinicians and patients to assume a permanent drug intolerance and reduce the chances that the patient is ultimately treated with all four recommended classes. The patient’s condition may indicate the appropriate drug to use first. For example, an SGLT2 inhibitor or MRA may be the appropriate first drug in those with borderline low blood pressure. Additional studies are needed to determine which initiation strategy leads to the optimal sustained use of recommended treatments. Strategies for implementation of guideline directed medical therapy have been recently reviewed.54

Diuretics

Although diuretics are a mainstay of treatment for patients with signs or symptoms of congestion, they have not been shown to improve mortality.255 The efficacies of two loop diuretics were compared in the TRANSFORM-HF trial of 2859 patients who were randomized to furosemide or torsemide.56 The primary outcome of all cause death was similar for the two loop diuretics (hazard ratio with torsemide treatment 1.02, 0.89 to 1.18).

Recently, the efficacy of intravenous acetazolamide in addition to intravenous loop diuretics was examined in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial.57 Among 519 patients with heart failure, greater decongestion was seen in the group randomized to acetazolamide (successful decongestion within three days: 42.2% v 30.5%; P<0.001). In the Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC) trial, 239 patients were randomized to a thiazide diuretic or placebo in addition to a loop diuretic.58 The addition of the thiazide significantly increased decongestion but with an increase in serum creatinine. Together, the ADVOR and CLOROTIC trials suggest that add-on diuretic therapy can improve decongestion compared with loop diuretics alone, although long term safety is uncertain.5758

Treatment of HFmrEF and HFpEF

As noted above, an LVEF of 41-49% is mildly reduced (HFmrEF) whereas patients with an LVEF ≥50% are considered to have preserved ejection fraction (HFpEF). These labels apply only to patients who have not previously had an LVEF ≤40% (these are referred to as heart failure with improved ejection fraction). SGLT2 inhibitors are recommended as the first line medication for patients with mildly reduced or preserved LVEF on the basis of the two trials that enrolled many patients with an LVEF >40%.3940

Of the other treatments for HFrEF, ARNI, ACE inhibitors, ARBs, and MRAs are second line therapies as the evidence for benefit is much weaker than for patients with HFrEF. Accordingly, MRAs and ACE inhibitors/ARBs/ARNI have a class 2B recommendation for HFmrEF and HFpEF in guidelines for patients with mildly reduced or preserved LVEF.2

Of note, β blockers are not recommended for patients with HFpEF (2B recommendation for HFmrEF).2 Lack of benefit for HFpEF was noted in a meta-analysis of randomized trials of β blockers, which reported a non-significant trend toward increased cardiovascular and all cause mortality in patients with preserved LVEF and sinus rhythm (hazard ratio 1.70, 0.78 to 4.10).61

LVEF and benefit of medical therapy

LVEF can be difficult to quantify with echocardiography, but it has been routinely used to determine eligibility for clinical trials in heart failure. Given the growing evidence for treatment benefit in patients with higher LVEF levels, some authors have questioned the continued use of the LVEF to classify patients with heart failure. Multiple drug therapies have been tested across the ejection fraction spectrum: β blockers, ACE inhibitors/ARBs, ARNI, MRAs, and SGLT2 inhibitors. Traditionally, trials have stratified patients on the basis of LVEF ≤40% or >40%. However, most therapies have shown a benefit at higher thresholds than the traditional cutoff of reduced LVEF at 40%. For β blockers, a reduction in cardiovascular mortality was observed with LVEF <50%.61 For MRA therapy, a larger treatment benefit is more likely for patients with LVEF 41-49% than with LVEF ≥50%.62 The treatment benefit of sacubitril/valsartan was observed with LVEF <60%.63 For SGLT2 inhibitor therapy, the relative treatment effect was similar across the LVEF spectrum.64 Overall, these results suggest that the LVEF thresholds for systolic dysfunction used in treatment trials may benefit from reclassification but that LVEF will remain important for determining optimal management.

The association of LVEF with the benefit of early initiation and titration was evaluated in a sub-study of the STRONG-HF trial.65 This study showed the consistency of the rapid implementation of guideline based medical therapy across the entire spectrum of LVEF after an admission for heart failure.

Other drug treatments

Several additional medications can be used to improve outcomes among patients with HFrEF. This section discusses several of these therapies: hydralazine/isosorbide dinitrate therapy, ivabradine, vericiguat, intravenous iron, and glucagon-like peptide-1 receptor agonists. We discuss their evidence and contemporary role.

Hydralazine/isosorbide dinitrate therapy

The combination of hydralazine and isosorbide dinitrate is a guideline recommended therapy for self-identified Black patients with HFrEF with NYHA class III or IV heart failure despite treatment with optimal medical therapy as described above.12 The combination therapy causes both arterial and venous vasodilation in addition to nitrous oxide augmentation that may have remodeling benefits.66 A-HeFT (African-American Heart Failure Trial) randomized 1050 self-identified Black patients to hydralazine/isosorbide dinitrate therapy versus placebo. Patients receiving hydralazine/isosorbide dinitrate therapy had a 43% relative reduction in death over a mean follow-up of 10 months (10.2% v 6.2%; P=0.02).67 However, rates of treatment and adherence to hydralazine/isosorbide dinitrate therapy are low.6869 This may be due to multiple factors, including the difficulty of adhering to a three times daily medication and concerns about a race based indication. Additionally, the effectiveness of combined hydralazine and isosorbide nitrate therapy among non-Black patients remains unclear.65 Although hydralazine/isosorbide dinitrate therapy remains an important tool for reducing morbidity among Black patients with HFrEF, we believe that it should remain a second line therapy for patients with persistent HFrEF after optimization of the four pillars described above (fig 4).

Fig 4

Updates in heart failure since the 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America and 2021 European Society of Cardiology heart failure guidelines.12 Of note, angiotensin receptor/neprilysin inhibitor (ARNI) may not be beneficial in patients with a left ventricular ejection fraction >60%.63 CV=cardiovascular; HF=heart failure; HFmrEF=heart failure with mildly reduced ejection fraction; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction; HRQOL=health related quality of life; PA=pulmonary artery; SGLT2=sodium-glucose cotransporter-2

Devices and invasive therapies

Treatment of advanced heart failure

Heart failure can be a progressive condition despite optimal therapy, and appropriate timing of referral to heart failure specialists is important.111 The I-NEED-HELP acronym provides potential triggers for that referral.112

Clinical outcomes with left ventricular assist device (LVAD) therapy have continued to improve over time. An improvement in post-implantation survival to more than 50% at five years has been seen, in addition to a reduction in rates of stroke and gastrointestinal bleeding.113 After recall of the Heartware LVAD, the HeartMate 3 centrifugal flow left ventricular assist device is the only available durable LVAD. In the MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial, the HeartMate 3 had lower rates of reoperation, pump thrombosis, stroke, and gastrointestinal bleeding than the HeartMate 2 axial flow pump.114

Heart transplant remains the cornerstone of therapy for patients with stage D heart failure. The median survival after heart transplant now exceeds 12 years.115 The ability to effectively transplant hearts from hepatitis C positive donors and following circulatory arrest has increased the potential donor pool.116117 Improvements in donor preservation have also allowed sharing of potential donors across greater distances.118

Non-drug, non-device therapies

Measuring patient reported outcomes in heart failure

Without treatment, heart failure not only substantially increases the risk of mortality but also impairs quality of life.125 Improving health related quality of life is an important goal of heart failure treatment. Multiple therapies have been shown to significantly improve quality of life on the basis of patient reported health status (table 2).87134140141142143144145 The two most commonly used measures of patient reported health status in treatment trials have been the KCCQ and the Minnesota Living with Heart Failure Questionnaire.146147

Although patient reported health status has been commonly measured in clinical trials, it is rarely used in clinical practice. However, multiple studies have shown that not only is patient reported health status often discordant with the clinician’s assessment but it also has a higher concordance with objective functional testing than does the NYHA classification.148149 Patient reported health status is also a strong predictor of hospital admission and death.150151152153154155 Therefore, the call to incorporate routine measurement of patient reported health status into clinical care is increasing.2156157 Theoretically, this could improve clinicians’ understanding of patients’ health status and guide improved shared decision making. Limited data support the potential utility and acceptability of routine assessment of patient reported health status in clinical care,158159160 but no data are available on the clinical impact of such a strategy. Additionally, the challenges of effectively implementing data collection within the electronic health record remain.161

Equity

Inequitable outcomes for health conditions among different groups often exist within societies, and heart failure is no exception. Data from the US suggest race/ethnicity differences in the incidence of and survival with heart failure.162163 The cause of disparities in outcome is multifactorial, and these are often driven as much or more by social determinants of health than by differences in patient management.163164 A recent analysis from the US found similar use of drug treatments known to prolong survival for patients with heart failure across race and ethnicity groups.165 Inequitable treatment rates have been observed for device therapies, such as CRT, and therapies for advanced heart failure; these may reflect not only bias but also the critical role of access to care in promoting improved equity.166167168 A focus beyond treatment differences is needed if overall health is to be improved. Improving representation in clinical trials is important to improve our ability to provide appropriate customized care to all patients with heart failure.169

Guidelines

Several clinical guidelines have been published recently including the ESC (2021) and ACC/AHA/HFSA (2022) guidelines.12 Important differences in guideline recommendations are rare and largely due to differences in the published evidence that occurred between publication. For example, the 2022 ACC/AHA/HFSA guideline includes a 2A recommendation for SGLT2 inhibitors for patients with HFmrEF and HFpEF following the publication of a large clinical trial showing outcome benefit.240 Important studies that were published after these guidelines include a second randomized trial showing benefit of SGLT2 inhibitors in patients with an LVEF >40%,39 the STRONG-HF trial showing benefit of rapid initiation and titration of medications for those with HFrEF,49 and a trial showing that pulmonary pressure monitoring using the CardioMEMS device improved outcome.89 Future guidelines will likely incorporate the trial results into revised recommendations. Figure 4 shows a summary of new evidence published since the 2022 ACC/AHA/HFSA and 2021 ESC heart failure guidelines.12 An update to the 2021 ESC guideline was recently published,170 and this incorporates new clinical trials of SGLT2 inhibitors, finerenone, and intravenous iron therapy.

Emerging treatments

Continued progress in treatment remains critical given the residual morbidity for patients with heart failure. Omecamtiv mecarbil is a cardiac myosin activator that improves cardiac contractility. In the GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure) trial, 8258 patients with HFrEF who received omecamtiv mecarbil showed an 8% relative reduction (0.92, 0.86 to 0.99) in the risk of cardiovascular death or heart failure event (hospital admission or urgent visit).171 The benefit was driven by the difference in heart failure events. Multiple secondary analyses have illustrated larger therapeutic benefit among patients with more severe heart failure based on LVEF, systolic blood pressure, NYHA class, or natriuretic peptides.172173174175 Omecamtiv mecarbil is not available as it was denied approval by the US Food and Drug Administration and is still pursuing approval in Europe.

Several trials will help to clarify the role of existing heart failure therapies. The VICTOR trial is evaluating the efficacy of vericiguat among patients with heart failure who have not had a recent worsening heart failure event (clinicaltrials.gov: NCT05093933). The DECISION trial is testing the efficacy and safety of digoxin at low serum concentrations (NCT03783429). Given the controversy of the TOPCAT trial findings, two ongoing trials are evaluating the efficacy of spironolactone among patients with heart failure with LVEF ≥40% (NCT04727073; NCT02901184).

Many novel therapies for heart failure are under evaluation in clinical trials. These include multiple trials of finerenone among patients with heart failure across the ejection fraction spectrum (NCT04435626; NCT06033950; NCT06024746). The SUMMIT trial will evaluate the effect of tirzepatide, another GLP1RA, among patients with HFpEF and obesity (NCT04847557). Other ongoing studies are testing anti-inflammatory therapies among patients with HFmrEF/HFpEF (NCT05636176; NCT04986202).

Non-drug care of patients with heart failure also continues to evolve. The CABA-HFPEF trial is testing catheter ablation among patients with heart failure with LVEF ≥40% and atrial fibrillation (NCT05508256). Multiple ongoing trials are evaluating tricuspid valve interventions among patients with severe tricuspid regurgitation.