Treatment and prognosis of heart failure with mildly reduced ejection fraction

INTRODUCTION — The clinical syndrome of heart failure (HF) can develop in patients with low, mildly decreased, or normal left ventricular ejection fraction (LVEF).

This topic will discuss the details of treatment and prognosis in patients with HF and mildly reduced ejection fraction (HFmrEF, LVEF 41 to 49 percent), formerly referred to as HF with mid-range ejection fraction [1].

In patients with HFmrEF, the clinical presentation and evaluation are the same as for patients with HF with reduced ejection fraction and are discussed elsewhere:

●(See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Clinical presentation'.)

●(See "Determining the etiology and severity of heart failure or cardiomyopathy".)

Management strategies for acute HF are discussed separately. (See "Treatment of acute decompensated heart failure: Specific therapies" and "Treatment of acute decompensated heart failure: General considerations".)

DEFINITIONS

●Heart failure (HF) – HF is a clinical diagnosis based upon identification of symptoms (eg, dyspnea and fatigue) caused by impairment of ventricular filling or ejection of blood (table 1) [1]. The diagnosis of the clinical syndrome of HF is discussed separately. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Definition'.)

●Heart failure with mildly reduced LVEF (HFmrEF) – Consistent with the professional guidelines, HFmrEF (formerly referred to as HF with mid-range ejection fraction) is defined as the presence of clinical HF and an LVEF of 41 to 49 percent, although the precise limits of LVEF for this condition vary among major society guidelines [1,2]. Since reduced ejection fraction is a morphologic finding and not a diagnosis, is one among many measures of myocardial function and injury, and is an imprecise measure of LV function, the use of ejection fraction to make clinical decisions is controversial. (See 'Limitations of classification by ejection fraction' below.)

LIMITATIONS OF CLASSIFICATION BY EJECTION FRACTION — In patients with a known cause of HFmrEF, we typically refer to the disease by its cause (eg, anthracycline-induced cardiomyopathy) and use the LVEF to identify appropriate management that complements any disease-specific management (eg, cessation of alcohol for alcohol-induced cardiomyopathy). There is controversy concerning the extent to which HFmrEF is a distinct clinical entity. LVEF is not a robust measure of contractility [3], commonly changes over time [4-6], and varies by the method used. As discussed separately, there is only moderate correlation between different modalities for measuring LVEF, and the interobserver and intraobserver variability for measurement of LVEF are substantial (ranging up to nearly 20 percent). (See "Tests to evaluate left ventricular systolic function".)

In general, repeated measures of LV morphology are required to establish the presence of myocardial injury and assess the response to therapy. Similarly, correlation between cardiac findings (eg, LV volume, biventricular involvement) and noncardiac findings (eg, history of anthracycline exposure, laboratory tests) are required to establish the cause of injury. If the LVEF changes or discrepant LVEF values are detected by various imaging modalities, we suggest reviewing the studies with an imaging specialist to identify any technical limitation and to determine which results are most likely to be accurate.

EPIDEMIOLOGY — Among patients with HF, between 10 and 24 percent have an LVEF of 41 to 49 percent [4,7-17]. Patients with HFmrEF are more similar to patients with HF with reduced ejection fraction (HFrEF) than to those with HF with preserved ejection fraction (HFpEF) [4,7-17]. In particular, patients with HFmrEF have a relatively high prevalence of coronary artery disease (CAD) compared with patients with HFpEF [7,12,15,16].

The prognosis in patients with HFmrEF is described elsewhere in this topic. (See 'Prognosis' below.)

GENERAL MEASURES

●Self-care – The approach to self-care in HFmrEF, including lifestyle modification, is the same as in other forms of HF, which are discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'HF self-management'.)

●Management of associated conditions – HFmrEF commonly presents with comorbid conditions that require management. Our approach to the management of these conditions is similar to that for patients with HFrEF and is discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Management of causes and associated conditions'.)

The approach to residual hypertension is discussed elsewhere in this topic. (See 'Residual symptoms or hypertension' below.)

●Serial assessment – Patients with HFmrEF should be evaluated serially to assess clinical status, response to therapy, and need for changes in clinical management. At each visit, we obtain an interval history that includes an evaluation of symptoms during activities of daily living and at rest; medication tolerability and adherence; exposure to potential cardiotoxic agents including alcohol, tobacco, illicit drugs, and chemotherapeutic agents; and dietary intake of sodium and fluids. The approach to repeat echocardiography is similar to that for HFrEF. These issues are discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Follow-up and preventive care'.)

GOALS OF THERAPY — In patients with HFmrEF, the goal of medical therapy is to reduce symptoms, decrease the risk of mortality or hospitalization, and either prevent further reduction in LVEF or promote improvement in LVEF.

VOLUME OVERLOAD — Patients with HFmrEF and volume overload require diuretic therapy to treat symptoms and maintain euvolemia. In general, we treat volume overload before starting long-term therapy, with the exception of therapies that may enhance diuresis in the volume overloaded state, such as sodium-glucose co-transporter 2 inhibitors [18]. A complete discussion of diuretic use in HF can be found separately. (See "Use of diuretics in patients with heart failure".)

APPROACH TO THERAPY

Disease-specific therapy — In patients with HFmrEF with a known cause, appropriate treatment for the cause of HFmrEF is required. While many diseases can cause HFmrEF, common causes include:

●Coronary artery disease. (See "Chronic coronary syndrome: Indications for revascularization".)

●Mitral valve disease. (See "Chronic primary mitral regurgitation: Indications for intervention".)

●Aortic valve disease. (See "Indications for valve replacement for high gradient aortic stenosis in adults", section on 'For symptomatic patients'.)

●Diabetes. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus".)

●Thyroid disorders. (See "Treatment of primary hypothyroidism in adults" and "Cardiovascular effects of hyperthyroidism", section on 'Heart failure'.)

●Anthracycline-induced cardiomyopathy. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity".)

●Alcohol-induced cardiomyopathy. (See "Alcohol-induced cardiomyopathy", section on 'Treatment'.)

Therapy for mildly reduced ejection fraction

When to start? — In most patients with newly diagnosed HFmrEF, we begin treatment without delay. However, in cases in which treating the cause of HFmrEF is expected to rapidly improve LV function (eg, surgery for severe valvular heart disease, revascularization for severe coronary artery disease), we may delay or modify the treatment regimen (eg, begin therapy after CAD revascularization, use only two agents) while disease-specific treatment begins.

In patients in whom disease-specific therapy (eg, thyroid replacement therapy) may slowly improve LV function over the course of months or if there is no clear response to disease-specific therapy (eg, coronary artery revascularization), we begin treatment.

This approach is based on our experience and the high efficacy of some disease-specific treatments. Diseases that may cause HFmrEF are listed elsewhere in this topic. (See 'Disease-specific therapy' above.)

Combination therapy — In patients with HFmrEF who have New York Heart Association (NYHA) class II to III HF symptoms (table 2) despite optimal volume management, we suggest combination therapy with one agent from each of the following classes of medications rather than other combinations of therapy:

●Angiotensin receptor blocker-neprilysin inhibitor (ARNI, ie, sacubitril-valsartan)

●Beta blocker

●Mineralocorticoid receptor antagonist (MRA)

●Sodium-glucose co-transporter 2 (SGLT2) inhibitor

The specific agents used for therapy are described in a table (table 3). The management of the regimen of drugs used to treat HFmrEF, including order of therapy, target doses, alternatives to therapy, and adverse effects, is equivalent to the management of this regimen in patients with HF with reduced ejection fraction (HFrEF) and is discussed elsewhere. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Regimen for patients with mild to moderate symptoms'.)

Our approach to pharmacologic therapy in patients with HFmrEF is based on the efficacy of these drugs in patients with HFrEF and subgroup analyses of trials that studied their effects in HF with preserved ejection fraction (HFpEF); this indirect evidence has significant limitations (eg, multiple comparisons, unplanned analyses). Thus, the efficacy of these agents in patients with HFmrEF is less certain than in HFrEF, but the totality of evidence favors use.

Trials and studies that included patients with HFmrEF include:

●Sacubitril-valsartan – The available evidence describes a possible benefit of sacubitril-valsartan compared with other agents (ie, enalapril, valsartan) used to treat HFrEF and HFpEF.

In a pooled analysis of all patients enrolled in PARADIGM and PARAGON-HF trials, treatment with sacubitril-valsartan was superior to enalapril or valsartan, respectively; this effect was driven by benefit in patients with below normal LVEF [19]. However, within the cohort of patients with LVEF between 42.5 and 52.5 percent (n = 1427), the benefit of treatment with sacubitril-valsartan on total HF hospitalization and cardiovascular death was unclear (HR 0.81; 95% CI 0.64-1.03).

The evidence on sacubitril-valsartan treatment in HFrEF is discussed separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Evidence'.)

●ACE inhibitors and angiotensin receptor blockers – There is limited direct evidence of the effect of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in patients with HFmrEF:

In an analysis from the CHARM Programme that included 1322 patients with HFmrEF, the time to HF hospitalization or cardiovascular death was significantly reduced by candesartan (7.4 versus 9.7 percent with placebo, hazard ratio [HR] 0.76, 95% CI 0.61-0.96) [20].

The evidence on ACE inhibitors and ARBs in the treatment of HFrEF is discussed separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Evidence'.)

●Beta blockers – For patients with HFmrEF, the evidence of beta blocker benefit is inferred from the benefits described in patients with HFrEF.

In an individual patient data meta-analysis of 11 HF trials, beta blockers were shown to reduce all-cause and cardiovascular mortality compared with placebo across all LVEF strata below 50 percent [21]. For patients with HFmrEF, mortality was nonsignificantly lower with beta blocker treatment (7 versus 12 percent; HR 0.59, 95% CI 0.34-1.03) after a median of 1.3 years of treatment.

The trial data on beta blockers in patients with HFrEF are described separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Evidence'.)

●Mineralocorticoid receptor antagonists – The rationale for MRA use in patients with HFmrEF is largely extrapolated from the efficacy of these agents in patients with HFrEF.

The effect of MRA treatment in patients with HFmrEF was evaluated in the TOPCAT trial, which enrolled patients with HF and LVEF ≥45 percent; patients with HFmrEF represented only a small fraction of the target population of patients with "HFpEF." The overall trial showed no clear benefit of spironolactone compared with placebo [22]. Secondary analyses of this trial suggested that the effect of spironolactone was greater in patients with lower LVEF, but these analyses are not definitive [22,23].

The data on MRAs in patients with HFrEF are presented separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Evidence'.)

●SGLT2 inhibitors – Evidence supporting use of SGLT2 inhibitors in HFmrEF comes from large trials and indirectly from trials in patients with HFrEF. Approximately one-third of patients enrolled in the trials had an LVEF ≥40 and <50 percent:

•In a meta-analysis that included patients with HFrEF and HFpEF, assignment to SGLT2 therapy was associated with a lower risk of HF hospitalization (HR 0.74, 95% CI 0.67-0.83) and a nonsignificant decrease in cardiovascular death (HR 0.88, 95% CI 0.77-1.00) compared with placebo [24].

•In EMPEROR-Preserved, treatment with empagliflozin compared with placebo resulted in a reduction in HF hospitalization (9 versus 12 percent; HR 0.71, 95% CI 0.60-0.83) and a nonsignificant decrease in mortality (7 versus 8 percent; HR 0.91, 95% CI 0.76-1.09) [25]. In subgroup analyses, patients with HFmrEF had a treatment benefit that was similar to the benefit in the overall trial [26].

•In a trial (DELIVER) that included 10,418 patients with LVEF ≥40 percent, treatment with the SGLT2 inhibitor dapagliflozin resulted in a lower risk of hospitalization compared with placebo (10.5 versus 13.3 percent; HR 0.77, 95% CI 0.67-0.89) [27].

In a meta-analysis of trials that evaluated the effect of dapagliflozin in a pooled analysis of patients with HFrEF, HFmrEF, and HFpEF, there was a mortality benefit associated with dapagliflozin treatment [28]. However, the mortality benefit of dapagliflozin was less certain in patients with an LVEF >44 and ≤51 percent (cardiovascular death incidence 4.7 versus 5.2 percent in the placebo group; HR 0.91, 95% CI 0.69-1.2).

The data on SGLT2 inhibitor use in HFrEF are discussed separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Evidence'.)

Residual symptoms or hypertension — In patients with HFmrEF who take optimal medical therapy but have residual HF symptoms or hypertension, management depends on the patient’s characteristics:

●Residual symptoms – In our experience, most optimally managed patients with HFmrEF have only mild HF symptoms. In patients with HFmrEF who have NYHA class II to III HF symptoms despite optimal combination therapy for HFmrEF, we reassess adherence and other reasons for failure of combination therapy (eg, dose optimization). (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Approach to persistent symptoms'.)

Additional agents studied in HFrEF include digoxin and vericiguat, which have no clear benefit in this group of patients, as well as ivabradine, which may reduce exercise capacity. Data show no clear effect of these agents or, in the case of ivabradine, possible harm:

•Digoxin – Secondary analyses from the DIG trial showed that digoxin did not clearly reduce HF hospitalizations in patients with HFmrEF (HR 0.80, 95% CI 0.63-1.03) and was less effective than for patients with HFrEF [29]. The details on the use of digoxin are the same as for patients with HFrEF, which are discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.)

•Ivabradine – In patients with HFmrEF, we avoid the use of ivabradine.

-In a randomized trial in patients with HF and LVEF ≥45 percent, treatment with ivabradine had no discernable effect on six-minute walk distance (difference -3.8 m; 95% CI -19 to 11.6) and did not clearly improve natriuretic peptide levels or echocardiographic estimates of ventricular filling pressures [30].

-In a small crossover trial, ivabradine therapy was associated with lower peak oxygen consumption (VO₂) compared with placebo (-2.1 versus 0.9 mL/kg/min, p = 0.003) [31].

•Vericiguat – Vericiguat has no clear benefit in patients with HFpEF:

-In a trial that included 789 patients with LVEF ≥45 percent and recent HF decompensation, vericiguat did not improve exercise tolerance compared with placebo after 24 weeks of observation [32].

-In a large trial that included patients with HF and LVEF <45 percent, there was no clear benefit with vericiguat compared with placebo in a subgroup analysis of patients with LVEF >40 and <45 percent [33].

●Hypertension — In patients who have residual hypertension after optimal therapy with the primary therapies for HFmrEF, options for therapy include hydralazine plus isosorbide dinitrate, hydralazine alone, or second-generation calcium channel blockers. These agents are less likely to cause harm than other antihypertensive agents, though it is reasonable to treat with other antihypertensive agents in select patients with intolerance to these agents.

The approach to use of these agents in this population is similar to the approach in HFrEF, which is described separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Add isosorbide dinitrate plus hydralazine in select patients'.)

The evidence on these agents in patients with HFmrEF is limited; the safety of these medications in patients with HFmrEF is largely inferred from their safety in patients with HFrEF:

•Hydralazine plus isosorbide dinitrate – Our approach to the use of these agents in HFmrEF extends from evidence in patients with HFrEF. The trials of hydralazine and isosorbide dinitrate in HFrEF are discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Renin-angiotensin/neprilysin blocker intolerance' and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Add isosorbide dinitrate plus hydralazine in select patients'.)

•Second-generation calcium channel blockers – While data are scant, second-generation dihydropyridine calcium channel blockers (eg, amlodipine, felodipine) are likely safe in HFmrEF. Other calcium channel blockers should generally be avoided in patients with HFmrEF.

The safety of these agents in patients with HFrEF is discussed separately. (See "Calcium channel blockers in heart failure with reduced ejection fraction".)

Changes in ejection fraction — Among patients who present with HFmrEF, the LVEF may change over time:

●Improvement in LVEF – In patients whose LVEF improves with therapy for HFmrEF or disease-specific therapy, we continue appropriate treatment for HFmrEF, as discussed in this topic. This approach is based on limited data in patients with HFrEF, which are described in detail separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Duration of therapy'.)

●Decline in LVEF – In patients with HFmrEF whose LVEF declines despite disease-specific or combination therapy for HFmrEF, additional therapy for HFrEF (eg, implantable cardioverter-defibrillator [ICD] placement) may be appropriate. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

DEVICE THERAPY

●Implantable cardioverter-defibrillators – Patients with HFmrEF and a history of sudden death or sustained ventricular arrhythmias should be managed according to standard recommendations for ICD use for secondary prevention of sudden cardiac death (SCD). In contrast to the body of evidence supporting ICD use for primary prevention of SCD in selected patients with HF with reduced ejection fraction, there is no evidence to support ICD therapy for primary prevention in patients with HFmrEF. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

●Cardiac resynchronization therapy – For most patients with HFmrEF, the benefits of cardiac resynchronization therapy (CRT) are not likely to outweigh the risks. Indications for the use of CRT in selected patients with LVEF between 35 and 50 percent (eg, patients who are expected to require frequent ventricular pacing) are discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'For patients with LVEF between 35 and 50 percent' and "Overview of pacemakers in heart failure".)

●Invasive pulmonary artery pressure monitors – Our approach to the use of pulmonary artery pressure monitors in the management of HF is discussed separately. (See "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Device-based therapies'.)

PROGNOSIS

●Survival – Most evidence indicates that survival in patients with HFmrEF is better than in patients with HF with reduced ejection fraction (HFrEF) and either similar to or somewhat worse than what is observed in patients with HF with preserved ejection fraction (HFpEF) [12,13,34]:

•In-hospital mortality for patients with HFmrEF was shown to be 2.6 percent in an analysis from the Get with the Guidelines Registry, which was similar to that for patients with HFrEF and HFpEF [9].

•In the European Society of Cardiology Heart Failure Registry, one-year mortality was 7.6 percent in patients with HFmrEF, compared with 8.8 percent in patients with HFrEF and 6.4 percent in patients with HFpEF [12].

•Over a median follow-up of 2.9 years in patients enrolled in the CHARM Programme, the rates of cardiovascular death or HF hospitalization were 15.9, 8.5, and 8.9 for patients with HFrEF, HFmrEF, and HFpEF, respectively [20].

Patients with improvement in LVEF from HFrEF to HFmrEF on medical therapy are likely to have a more favorable prognosis, while outcomes in those who deteriorate from HFpEF to HFmrEF are likely worse [4,14,15].

●Progression and recovery – It is not uncommon for LVEF to change over time in patients with HF. However, the data on progression and recovery of LVEF in patients with HFmrEF are unreliable.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults".)

SUMMARY AND RECOMMENDATIONS

●Definition – Heart failure with mildly reduced ejection fraction (HFmrEF) is defined as the presence of clinical HF (table 1) and a left ventricular ejection fraction (LVEF) of 41 to 49 percent. (See 'Definitions' above.)

●General measures – In patients with HFmrEF, the approach to self-care, management of associated conditions, and serial assessment is the same as for patients with HF with reduced ejection fraction (HFrEF). (See 'General measures' above.)

●Goals of therapy – In patients with HFmrEF, the goal of medical therapy is to reduce symptoms, decrease the risk of mortality, and either prevent further reduction in LVEF or promote improvement in LVEF.

●Volume overload – Patients with HFmrEF and volume overload require diuretic therapy to treat symptoms and maintain euvolemia. We treat volume overload before starting long-term therapy. (See "Use of diuretics in patients with heart failure".)

●Approach to therapy

•Disease-specific therapy – Patients with a known cause of HFmrEF require appropriate treatment for the cause of HFmrEF. While many diseases can cause HFmrEF, common causes include coronary artery disease (CAD), aortic stenosis, and toxin exposure. (See 'Disease-specific therapy' above.)

•Therapy for reduced ejection fraction

-When to start pharmacologic therapy – In most patients with newly diagnosed HFmrEF, we begin treatment without delay. However, in cases in which treating the cause of HFmrEF is expected to rapidly improve LV function (eg, surgery for severe valvular heart disease), we may delay or modify the treatment regimen while disease-specific treatment begins.

In patients in whom disease-specific therapy (eg, thyroid replacement therapy) may slowly improve LV function over the course of months or if there is no clear response to disease-specific therapy (eg, coronary artery revascularization), we begin treatment. (See 'When to start?' above.)

-Combination therapy – For patients with HFmrEF with New York Heart Association (NYHA) class II to III symptoms (table 2), we suggest combination therapy composed of sacubitril-valsartan, a beta blocker, a mineralocorticoid receptor antagonist (MRA), and a sodium-glucose co-transporter 2 (SGLT2) inhibitor rather than other combinations of therapy (Grade 2C). The specific components of combination therapy are contained in a table (table 3). (See 'Combination therapy' above.)

In patients who cannot tolerate sacubitril-valsartan, angiotensin converting enzyme (ACE) inhibitors or single-agent angiotensin II receptor blocker (ARB) therapy are acceptable alternatives for therapy (table 3).

In patients who cannot tolerate other components of primary therapy (eg, beta blockers, MRAs, SGLT2 inhibitors) there are no alternative agents.

•Residual symptoms – In our experience, most optimally managed patients with HFmrEF have only mild HF symptoms. In patients with HFmrEF who have NYHA class II to III HF symptoms despite optimal combination therapy for HFmrEF, we reassess adherence and other reasons for failure of combination therapy (eg, dose optimization). (See 'Residual symptoms or hypertension' above.)

Additional agents studied in HFrEF include digoxin and vericiguat, which have no clear benefit in this group of patients, as well as ivabradine, which may reduce exercise capacity. (See 'Residual symptoms or hypertension' above.)

•Residual hypertension – In patients with HFmrEF who have residual hypertension after optimal therapy with the primary therapies for HFmrEF, options for therapy include hydralazine plus isosorbide dinitrate, hydralazine monotherapy, or second-generation calcium channel blockers (eg, amlodipine, nifedipine). (See 'Residual symptoms or hypertension' above.)