INTRODUCTION — The clinical syndrome of heart failure (HF) may develop in patients with any left ventricular ejection fraction (LVEF). Nearly half of patients with HF have an LVEF ≤40 percent (HF with reduced LVEF [HFrEF]), and similar numbers have an LVEF ≥50 percent (HF with preserved LVEF [HFpEF]) [1]. The remaining 10 to 24 percent of patients with HF present with an LVEF falling in the intermediate range (41 to 49 percent) [2-13].
This topic will discuss long-term treatment and prognosis of HF with mid-range ejection fraction (HFmrEF); the discussion here focuses on management of patients with HF who present with an LVEF of 41 to 49 percent or who previously presented with HFpEF and later developed an LVEF of 41 to 49 percent. (See 'Definitions' below.)
Patients with HFrEF with subsequent improvement in LVEF are treated according to recommendations for HFrEF, as discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)
Diagnosis and evaluation of HF is discussed separately. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Determining the etiology and severity of heart failure or cardiomyopathy".)
Management strategies for acute HF and HFpEF are discussed separately. (See "Treatment of acute decompensated heart failure: Specific therapies" and "Treatment of acute decompensated heart failure: General considerations" and "Treatment and prognosis of heart failure with preserved ejection fraction".)
DEFINITIONS — The following definitions are used in this topic review:
●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). As defined by the American College of Cardiology/American Heart Association (ACC/AHA), the clinical diagnosis of HF applies only to symptomatic or previously symptomatic patients; clinical HF corresponds to stage C (structural heart disease with prior or current symptoms of HF) and stage D (refractory HF requiring specialized interventions) HF [14]. Patients with the other stages of HF do not have clinical HF but are at risk for HF; stage A applies to patients at high risk for HF but without structural heart disease or symptoms of HF, and stage B applies to patients with structural heart disease without current or prior signs or symptoms of HF [14]. (See "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Stages in the development of HF'.)
●Heart failure with mid-range LVEF (HFmrEF) – Consistent with the 2013 ACC/AHA HF guidelines, HFmrEF is defined to include patients with clinical HF with an LVEF of 41 to 49 percent, although the precise limits of LVEF for this condition have varied slightly among major society guidelines [14,15]. Since prospective clinical trials focused on patients with HFmrEF are lacking, current understanding is derived largely from observational data and clinical trials studying patients with HFrEF or HFpEF that included some patients having LVEF in this intermediate range.
Patients may transition into and out of the phenotype of HFmrEF [10,16,17]; thus, this phenotype includes the following subcategories [10]:
●HFmrEF with no prior LVEF determination – For patients with no prior LVEF determination, it is not possible to apply the three definitions below. Patients with newly diagnosed mid-range LVEF require evaluation for the cause. (See "Determining the etiology and severity of heart failure or cardiomyopathy".)
●HFmrEF unchanged is a term to describe HF with an LVEF that has remained in the 41 to 49 percent range during repeated study.
●HFmrEF deteriorated is a term to describe HFmrEF with prior LVEF ≥50 percent (including prior HFpEF).
●HFmrEF improved is a term to describe HFmrEF with prior LVEF ≤40 percent (including prior HFrEF).
This topic discusses management of patients in the first three categories. Patients with a documented decline in LVEF require evaluation to determine the etiology for this change (eg, coronary artery disease). (See "Tests to evaluate left ventricular systolic function" and "Determining the etiology and severity of heart failure or cardiomyopathy".)
Patients with HFrEF with subsequent improvement in LVEF are treated according to recommendations for HFrEF, as discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)
LIMITATIONS — There is controversy concerning the extent to which HFmrEF is a distinct clinical entity. It is essential to recognize that the categorization of HF by LVEF is not based upon etiology or pathophysiology but rather by clinical convention given the widespread availability of methods to measure LVEF (chiefly echocardiography) and inclusion of LVEF thresholds as criteria in clinical HF trials. LVEF is not a robust measure of contractility [18], commonly changes over time [10,16,17], and varies by the method used. As discussed separately, limits of agreement between modalities for measuring LVEF are wide, and the interobserver and intraobserver variability for measurement of LVEF is substantial (ranging up to nearly 20 percent). (See "Tests to evaluate left ventricular systolic function".)
While HF may be categorized based on LVEF, the pathogenesis of the reduction in LVEF must be addressed to appropriately treat the patient with HF. It is important to identify and treat coronary artery disease and other treatable causes in these patients. Patients with the same LVEF may display marked and important differences in underlying pathophysiology and prognosis, and these differences may not be apparent from a single time point assessment of LVEF. Despite these limitations, depressed LVEF is an adverse prognostic indicator in HF patients, with increasing morbidity and mortality as LVEF falls below 40 to 50 percent [19-21]. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and 'Coronary artery disease' below and "Predictors of survival in heart failure with reduced ejection fraction", section on 'Left ventricular ejection fraction' and "Prognosis of heart failure", section on 'Factors affecting mortality rates'.)
EPIDEMIOLOGY — Between 10 and 24 percent of patients with HF have an LVEF of 41 to 49 percent [2-13]. Across the spectrum of HF, patients with HFrEF are younger, more often male, and have more coronary artery disease, whereas patients with HFpEF are more often older, female, obese, and hypertensive, with a greater burden of atrial fibrillation [19,22]. As might be predicted, patients with HFmrEF display an intermediate clinical phenotype that falls in between these two clinical phenotypes [2-13]. However, patients with HFmrEF are more similar to patients with HFrEF in some respects, including a high prevalence of coronary artery disease [2,7,11,12].
GENERAL MEASURES
Overview — General management measures for HFmrEF are similar to those in patients with HFrEF and HFpEF. These include lifestyle modification, management of associated conditions, and serial routine assessment with additional follow-up as needed to evaluate and manage changes in symptoms or signs of HF.
Lifestyle modification — These include:
●Regular exercise and weight loss to achieve ideal body weight should be encouraged.
●Moderation of alcohol consumption should be recommended, and patients should be advised to avoid tobacco.
●Vaccinations should be kept up to date, including pneumococcal vaccine and annual influenza vaccination.
●As for patients with HFrEF and HFpEF, we advise patients with HFmrEF to restrict sodium intake to 3 g/day, as more restrictive sodium intake may be associated with harm. (See "Heart failure self-management", section on 'Sodium restriction'.)
Management of associated conditions — Like HFpEF and HFrEF, HFmrEF commonly presents with comorbid conditions which require management.
Hypertension — Longstanding hypertension leads to HF, including HFmrEF. Even in patients with mild systolic dysfunction (as with HFmrEF), there may be impairment in ventricular ejection as cardiac afterload increases that can worsen congestion and impair forward output [23]. Therefore, we recommend treatment of hypertension to a goal systolic blood pressure of 130 mmHg or less in patients with HF, in agreement with the 2017 ACC/AHA heart failure guideline update [24]. (See "Goal blood pressure in adults with hypertension".)
●First-line therapy to control arterial pressure for patients with HFmrEF is stepwise combination therapy includes (see 'First-line agents' below):
•A diuretic as needed for volume control.
•A renin-angiotensin system (RAS) antagonist (specifically an angiotensin converting enzyme [ACE] inhibitor, a single-agent angiotensin II receptor blocker [ARB], or an angiotensin receptor-neprilysin inhibitor [ARNI]).
•A beta blocker. (See 'Beta blocker' below.)
●Second-line therapy is indicated for patients who have not reached goal blood pressure despite optimized titration of first-line therapy.
•Mineralocorticoid receptor antagonist (MRA) therapy for patients who can be closely monitored for hyperkalemia; MRA therapy is also indicated for persistent symptoms of HF. (See 'Mineralocorticoid receptor antagonist' below.)
•The other preferred second-line agents are:
-Hydralazine plus nitrate. (See 'Hydralazine plus nitrate' below.)
OR
-A second-generation calcium channel blocker (amlodipine or felodipine). (See 'Second-generation calcium channel blockers' below.)
Coronary artery disease — Coronary atherosclerosis is a major cause of and contributor to HFmrEF [2,7,11,12]. All patients with documented coronary disease should be treated medically for symptom relief and secondary prevention. (See "Chronic coronary syndrome: Overview of care" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)
There are few data on the effects of revascularization in HFmrEF. The available evidence suggests that percutaneous or surgical revascularization may improve symptoms, ventricular function, and prognosis in patients with coronary disease and HFrEF [25,26] as well as in patients with coronary disease and HFpEF [27]. Thus, patients with HFmrEF with an indication for coronary revascularization are likely to benefit from such intervention. Indications for revascularization are discussed separately. (See "Chronic coronary syndrome: Indications for revascularization" and "Treatment of ischemic cardiomyopathy" and "Revascularization in patients with stable coronary artery disease: Coronary artery bypass graft surgery versus percutaneous coronary intervention" and "Non-ST-elevation acute coronary syndromes: Revascularization".)
Atrial fibrillation — Atrial fibrillation is very common in HFmrEF and is associated with adverse outcomes [28]. Standard recommendations for anticoagulation and control of rhythm or heart rate apply to patients with HFmrEF. (See "Arrhythmia-induced cardiomyopathy" and "The management of atrial fibrillation in patients with heart failure".)
Valvular disease — Valvular heart disease commonly causes and/or coexists with HF, including HFmrEF, and should be treated according to current recommendations, as discussed in separate topic reviews for specific valve lesions.
Other associated conditions — Management of each of the following associated conditions is discussed separately:
●Diabetes mellitus (see "Overview of general medical care in nonpregnant adults with diabetes mellitus")
Pharmacologic management of type 2 diabetes mellitus (including the role of sodium-glucose co-transporter 2 [SGLT2] inhibitor therapy as a secondary agent) is discussed in detail separately. The benefits (including reduction in hospitalization for HF) and risks of SGLT2 therapy are discussed separately. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus".)
●Thromboembolism (see "Antithrombotic therapy in patients with heart failure")
●Anemia (see "Evaluation and management of anemia and iron deficiency in adults with heart failure")
●Sleep-disordered breathing (see "Sleep-disordered breathing in heart failure")
Serial assessment — Patients with HFmrEF should be evaluated serially to assess clinical status, response to therapy, and need for changes in clinical management. Each visit should include interval history with evaluation of symptoms during activities of daily living; medication tolerability and adherence; and exposure to potential cardiotoxic agents including alcohol, tobacco, illicit drugs, and chemotherapeutic agents. Dietary evaluation including sodium use should be assessed. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Follow-up and preventive care'.)
It is not uncommon for LVEF to change over time in patients with HF. For example, many patients with HFrEF experience improvement in LVEF with guideline-directed medical therapy such that they eventually fall into the range of HFmrEF or even HFpEF [9,10,29]. Conversely, patients with HFpEF may deteriorate to HFmrEF or even HFrEF [16]. This is most common in patients with coronary artery disease, which should be considered as a potential cause when a significant clinical change (eg, worsening HF) has been noted [27]. These LVEF changes have prognostic implications, but it is also important to consider the impact of variability in the measurement of LVEF. Thus, when a change in LVEF is detected or if 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. (See 'Prognosis' below and 'Definitions' above and "Tests to evaluate left ventricular systolic function", section on 'Management of discrepant results'.)
In patients with a significant clinical change based on either history or examination findings, a follow-up echocardiogram is recommended to assess for changes in cardiac function, remodeling, and valve appearance and function.
The role of serial natriuretic peptide measurement as a guide to therapy of chronic HF is discussed separately. (See "Natriuretic peptide measurement in heart failure", section on 'Chronic HF'.)
SPECIFIC MEASURES
Approach to pharmacologic therapy — In contrast with HFrEF and HFpEF, there are no clinical trials devoted specifically to patients with HFmrEF. However, patients with LVEF 41 to 49 percent were included in clinical trials studying patients with HFrEF and HFpEF, allowing for insight into potential efficacy of pharmacologic treatments. In general, the available evidence suggests that patients with HFmrEF respond to medical therapy in a manner more similar to HFrEF than to HFpEF. (See 'First-line agents' below and 'Second-line agents' below.)
Given the limited available evidence, starting and target doses for these initial agents are the same as those for HFrEF (table 2).
Thus, our approach to management of HFmrEF includes the following agents:
●First-line therapy for HFmrEF involves stepwise combination of the following three agents:
•Diuretic therapy is required to control volume overload. This is generally the first agent that is initiated. This therapy is continued as needed to treat and prevent volume overload or for the management of hypertension. (See 'Diuretic' below.)
•Renin-angiotensin system (RAS) antagonist (specifically an angiotensin converting enzyme [ACE] inhibitor, a single-agent angiotensin II receptor blocker [ARB], or an angiotensin receptor-neprilysin inhibitor [ARNI]); this is generally started soon after initiation of diuresis. The RAS antagonist is titrated to a low or moderate dose while diuretic therapy is continued until there is minimal residual fluid retention.
AND
•One of the following beta blockers: carvedilol, metoprolol succinate, or bisoprolol is initiated when there is minimal residual fluid retention. (See 'Beta blocker' below.)
We generally start beta-blocker therapy after initiation of an RAS antagonist, although the order of initiation of these drugs varies. After initiation of beta-blocker therapy, the RAS antagonist and the beta blocker are titrated to target doses. As for patients with HFrEF, only one agent is generally initiated or titrated at a time. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Approach'.)
●Second-line therapy is indicated for patients with HFmrEF with persistent symptoms or who have not attained goal blood pressure despite optimally titrated first-line therapy. Given the limited available evidence, starting and target doses for these secondary agents are the same as those for HFrEF, but ivabradine is not used for HFmrEF (table 3).
•For patients with persistent HF symptoms despite optimal titration of first-line therapy:
-For patients who are at acceptably low risk for hyperkalemia or worsening kidney function (serum potassium <5 mEq/L and estimated glomerular filtration rate >30 mL/min per 1.73 m2) and who can be safely monitored, we suggest a mineralocorticoid receptor antagonist (MRA). (See 'Mineralocorticoid receptor antagonist' below.)
-For patients with persistent HF symptoms despite optimal titration of first-line therapy plus MRA (when appropriate), we suggest addition of digoxin therapy. (See 'Digoxin' below.)
•For patients with HFmrEF who have not attained goal blood pressure despite optimal titration of first-line therapy (plus MRA therapy when appropriate), options include:
-Hydralazine plus nitrate. (See 'Hydralazine plus nitrate' below.)
OR
-A second-generation calcium channel blocker (amlodipine or felodipine). (See 'Second-generation calcium channel blockers' below.)
First-line agents — First-line therapy includes diuretic therapy to treat volume overload and an RAS antagonist.
Diuretic — Patients with HFmrEF and volume overload require diuretic therapy.
Limited evidence is available on the efficacy of diuretic therapy in HFmrEF, as well as in HF generally. A meta-analysis of diuretic treatment in chronic HF (LVEF not specified for most studies) demonstrated a beneficial effect on clinical outcomes including mortality and hospitalization for HF, although total numbers of events were limited, as discussed separately [30]. (See "Use of diuretics in patients with heart failure", section on 'Efficacy and safety'.)
A subgroup analysis of the CHAMPION trial of wireless pulmonary artery hemodynamic monitoring [31] limited to patients with LVEF ≥40 percent found that the hospitalization rate was reduced by 50 percent over an average follow-up of 17.6 months (incidence rate ratio 0.50, 95% CI 0.35-0.70) [32]. While this was not a trial of diuretics per se, most of the medication changes made to respond to pulmonary pressures in this trial involved diuretic use [32], providing indirect evidence supporting the importance of reducing vascular congestion with diuretics in this population, similar to patients with HFrEF. (See "Use of diuretics in patients with heart failure", section on 'Efficacy and safety'.)
Renin-angiotensin system antagonist — For patients with HFmrEF, we recommend treatment with an RAS antagonist (specifically an ACE inhibitor, single-agent ARB, or ARNI). The choice among these agents is based largely on patient access (including cost) and safety profile, given similar efficacy. RAS antagonist therapy is generally started soon after initiation of diuretic therapy for volume overload. The RAS antagonist therapy should be started at a low dose, with titration to target doses and evaluation for intolerance as in patients with HFrEF. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Approach'.)
ACE inhibitor or ARB — Since there is limited direct evidence in patients with HFmrEF, use of ACE inhibitor or ARB therapy in this setting is based in part upon indirect evidence from studies in patients with HFrEF. As discussed separately, randomized trials in patients with HFrEF have shown significant reduction in mortality with ACE inhibitor therapy compared with placebo; one trial in patients with enlarged heart size by chest radiograph did not specify LVEF [33]. One study showing a mortality benefit of ACE inhibitor compared with hydralazine plus nitrate included patients with HFmrEF [34]. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'ACE inhibitor'.)
As discussed separately, the strength of evidence for ARB therapy in patients with HFrEF is weaker than that for ACE inhibitor therapy; randomized trials have shown a borderline statistically significant reduction in mortality therapy compared with placebo in patients with HFrEF. In an analysis from the CHARM Programme focused on 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) [21]. Candesartan also reduced recurrent HF hospitalizations by 52 percent in patients with HFmrEF, a magnitude of effect that was not different from the effect observed in HFrEF. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Angiotensin II receptor blocker'.)
In a large, community-based, propensity-score-matched analysis from Sweden, treatment with ACE inhibitor or ARB (74 percent taking an ACE inhibitor) was associated with reduced mortality in patients with HF and LVEF ≥40 percent, and this effect was driven largely by the subpopulation with HFmrEF (HR 0.85, 95% CI 0.76-0.95), who tended to respond more favorably than those with HFpEF [35].
Angiotensin receptor-neprilysin inhibitor — The available evidence suggests that an ARNI provides benefits similar to an ACE inhibitor or single-agent ARB in patients with HFmrEF. In the PARADIGM trial in patients with HFrEF (LVEF ≤40 percent), treatment with the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan was superior to the ACE inhibitor enalapril in reducing the risk of death and hospitalization for HF [36]. In the PARAGON-HF trial in patients with HF with LVEF ≥45 percent, there was a nominally but not significantly reduced frequency of the primary composite outcome of total hospitalizations for HF and death from cardiovascular causes and there was a small, almost significantly reduced rate of total hospitalization for HF with sacubitril-valsartan compared with the ARB valsartan [37]. In both trials, the risk of hypotension was higher and the risk of hyperkalemia was lower with sacubitril-valsartan than with enalapril or valsartan. These trials are discussed in detail separately. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Angiotensin receptor-neprilysin inhibitor'.)
In a subsequent analysis pooling patient data from the PARADIGM and PARAGON-HF trials, treatment with ARNI was overall superior to the comparator (enalapril or valsartan), driven by benefit in patients with below normal LVEF [38]. Within the cohort of patients with LVEF between 42.5 and 52.5 percent (n = 1427), treatment with ARNI nominally but not significantly reduced the frequency of total HF hospitalization and cardiovascular death (HR 0.81; 95% CI 0.64-1.03) as well as total HF hospitalization (HR 0.77; 95% CI 0.58-1.02). A benefit from ARNI was observed up to a higher LVEF in women compared with men. These data suggest that sacubitril-valsartan is a reasonable alternative to ACE inhibitor or ARB, but patient access to this drug may be limited given greater cost, particularly since this medication is approved for use only for HFrEF.
Beta blocker — For patients with HFmrEF, we recommend treatment with one of the beta blockers that have been shown to reduce mortality and hospitalizations for HF in patients with HFrEF (carvedilol, metoprolol succinate, or bisoprolol). When initiating beta-blocker therapy in a patient with HFmrEF, we recommend starting at a low dose when clinical euvolemia is present and gradually titrating up to achieve doses used in the clinical trials, as in patients with HFrEF. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults".)
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 [39]. For patients with HFmrEF and sinus rhythm, there was a 4.7 percent absolute reduction in cardiovascular mortality (7.3 versus 11.1 percent) over 1.3 median years.
Second-line agents
Mineralocorticoid receptor antagonist — We suggest the addition of an MRA for patients with HFmrEF with persistent symptoms despite optimized titration of first-line agents who are at acceptably low risk for hyperkalemia or worsening kidney function (serum potassium <5 mEq/L and estimated glomerular filtration rate >30 mL/min per 1.73 m2) and who can be safely monitored. Treatment with MRAs improves morbidity and mortality in patients with HF and LVEF ≤35 percent [40,41]. The TOPCAT trial, enrolling patients with HF and LVEF ≥45 percent, showed a neutral effect of spironolactone overall [42], but in patients with more robust evidence for clinical HF, there was evidence of benefit [43]. In an ancillary analysis from this trial, there was an estimated benefit from spironolactone in patients with HF and LVEF between 45 and 55 percent, whereas there was no such benefit at higher levels of LVEF, suggesting that patients at the lower end of the LVEF range (as in HFmrEF) may respond in a fashion more similar to HFrEF [44]. We recommend starting MRA at a low dose with close monitoring of renal function and potassium, as in patients with HFrEF. (See "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'Mineralocorticoid receptor antagonist'.)
Digoxin — For patients with HFmrEF and severe HF symptoms despite optimized doses of diuretic, beta blocker, RAS antagonist, and an MRA, we suggest digoxin. Ancillary analyses from the DIG trial showed that digoxin tended to reduce HF hospitalizations in patients with HFmrEF, although this did not reach statistical significance (HR 0.80, 95% CI 0.63-1.03) and was a less dramatic benefit as compared with patients with HFrEF [45]. We recommend monitoring serum digoxin levels and maintaining the serum digoxin concentration between 0.5 and 0.8 ng/mL, as done in patients with HFrEF. (See "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'Digoxin'.)
Hydralazine plus nitrate — For patients with HFmrEF who have not reached blood pressure control targets despite treatment with optimal titration of first-line agents (plus MRA therapy as appropriate), hydralazine plus nitrate therapy is a reasonable option. Hydralazine plus nitrate use in this setting is based upon indirect evidence from the A-HEFT trial [46] and the observed increased afterload sensitivity of the left ventricle when LVEF is <50 percent [23], particularly in Black patients who may respond more favorably to this therapy [46]. Patients with HFmrEF were excluded from the A-HEFT trial which demonstrated a benefit from hydralazine plus nitrate therapy in patients with HFrEF [46].
Of note, this recommendation for patients with HFmrEF contrasts with the recommendation to avoid nitrate therapy in patients with HFpEF given evidence that organic nitrate therapy reduces physical activity levels in patients with HFpEF [47].
Second-generation calcium channel blockers — While data are scant, second-generation dihydropyridine calcium channel blockers such as amlodipine and felodipine are likely safe in HFmrEF, similar to HFrEF. Thus, for patients with HFmrEF who have not attained target blood pressure despite optimum titration of first-line therapies, treatment with amlodipine or felodipine is a reasonable option. Other calcium channel blockers should generally be avoided in patients with HFmrEF given studies in patients with HFrEF showing lack of clinical benefit and evidence that some first-generation agents may cause harm. (See "Calcium channel blockers in heart failure with reduced ejection fraction".)
Not used for HFmrEF
Ivabradine — We do not use ivabradine in patients with HFmrEF. In a randomized trial in patients with HF and LVEF ≥45 percent, no improvement in six-minute walk test distance, natriuretic peptide levels, or echocardiography Doppler estimates of ventricular filling pressure were observed [48]. This contrasts with the results of a randomized trial in patients with HFrEF (LVEF ≤35 percent), sinus rhythm, and resting heart rate ≥70 bpm despite maximal tolerated beta-blocker doses, in which ivabradine improved the composite of HF hospitalization or cardiovascular death [49]. Ivabradine may worsen exercise capacity in patients with HFpEF by exacerbating chronotropic incompetence [50].
Device therapy — Patients with HFmrEF should be managed according to standard recommendations for implantable cardioverter-defibrillator (ICD) use for secondary prevention of sudden cardiac death (SCD). (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)
In contrast to the body of evidence supporting ICD use for primary prevention of SCD in selected patients with HFrEF, there is currently no evidence to support ICD therapy for primary prevention in patients with HFmrEF.
For most patients with HFmrEF, the benefits of cardiac resynchronization therapy (CRT) are not likely to outweigh the risks. Indications for 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".)
Exercise training — We suggest exercise training and cardiac rehabilitation for patients with HFmrEF. In the United States, the Centers for Medicare and Medicaid Services provide coverage for cardiac rehabilitation services for patients with symptomatic HF and LVEF ≤35 percent despite treatment with optimal HF therapy for ≥6 weeks. While fewer data (and in the United States, less insurance coverage) are available for HFpEF and HFmrEF, there is evidence from randomized controlled trials that patients in both of these groups also derive benefit from cardiac rehabilitation, with improvements in aerobic capacity and quality of life. (See "Cardiac rehabilitation in patients with heart failure".)
PROGNOSIS — Most of the available evidence indicates that survival in patients with HFmrEF is better than in patients with HFrEF and either similar to or somewhat worse than what is observed in patients with HFpEF [7,8,19]. In-hospital mortality for HFmrEF was shown to be 2.6 percent in an analysis from the Get with the Guidelines Registry, which was similar to HFrEF and HFpEF [4]. In the European Society of Cardiology Heart Failure Registry, one-year mortality was 7.6 percent in HFmrEF as compared with 8.8 percent in HFrEF and 6.4 percent in HFpEF [7]. 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 HFrEF, HFmrEF, and HFpEF, respectively [21].
Patients with improvement in LVEF from HFrEF to HFmrEF on medical therapy appear to have a more favorable prognosis, while outcomes in those who deteriorate from HFpEF to HFmrEF are poorer [9-11].
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
●Heart failure with mid-range ejection fraction (HFmrEF) is defined to include patients with a left ventricular ejection fraction (LVEF) between 41 and 49 percent and is relatively common, observed in approximately 10 to 24 percent of patients with HF. (See 'Definitions' above and 'Epidemiology' above.)
●Clinical characteristics, pathophysiology, and comorbidity burden are generally intermediate between patients with HF with reduced LVEF (HFrEF; LVEF <40 percent) and patients with HF with preserved LVEF (HFpEF; LVEF ≥50 percent), except for the high prevalence of coronary disease, which is more similar to HFrEF. (See 'Epidemiology' above.)
●Patients with HFmrEF commonly present with comorbid conditions requiring management including hypertension, coronary artery disease, atrial fibrillation, valvular disease, and diabetes mellitus. (See 'Management of associated conditions' above.)
●Patients with HFmrEF require careful serial assessment, similar to patients with HFrEF and HFpEF. Echocardiography should be performed when clinically significant changes in status or examination findings occur. (See 'Serial assessment' above.)
●Our approach to management of HFmrEF includes the following agents (see 'Approach to pharmacologic therapy' above):
•First-line therapy for HFmrEF involves stepwise combination of the following three agents:
-Diuretic therapy is required to control volume overload. This is generally the first agent that is initiated. (See 'Diuretic' above.)
-For patients with HFmrEF, we recommend a renin-angiotensin system (RAS) antagonist (specifically, an angiotensin converting enzyme [ACE] inhibitor, angiotensin II receptor blocker [ARB], or an angiotensin receptor-neprilysin inhibitor [ARNI]). (Grade 1B). The choice among these agents is based largely on patient access and safety profile, given similar efficacy. RAS antagonist therapy is generally started soon after initiation of diuretic therapy. (See 'Renin-angiotensin system antagonist' above.)
AND
-For patients with HFmrEF, we recommend beta-blocker therapy (Grade 1B). In this setting, we use one of the beta blockers (carvedilol, metoprolol succinate, or bisoprolol) proven to improve survival in patients with HFrEF. Beta-blocker therapy is initiated when there is minimal residual fluid retention. (See 'Beta blocker' above.)
We generally start beta-blocker therapy after initiation of an RAS antagonist, although the order of initiation of these drugs varies, as for HFrEF. After initiation of beta-blocker therapy, the RAS antagonist and the beta blocker are titrated to target doses (table 2). (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Approach'.)
●Second-line therapy is indicated for patients with HFmrEF with persistent symptoms or who have not attained goal blood pressure despite optimally titrated first-line therapy.
•For patients with persistent HF symptoms despite optimal titration of first-line therapy:
-For patients who are at acceptably low risk for hyperkalemia or worsening kidney function (serum potassium <5 mEq/L and estimated glomerular filtration rate >30 mL/min per 1.73 m2) and who can be safely monitored, we suggest a mineralocorticoid receptor antagonist (MRA) (Grade 2C). (See 'Mineralocorticoid receptor antagonist' above.)
-For patients with persistent HF symptoms despite optimal titration of first-line therapy plus MRA (when appropriate), we suggest addition of digoxin therapy (Grade 2C). (See 'Digoxin' above.)
•For patients with HFmrEF who have not attained goal blood pressure despite optimal titration of first-line therapy (plus MRA therapy when appropriate), options include:
-Hydralazine plus nitrate. (See 'Hydralazine plus nitrate' above.)
OR
-A second-generation calcium channel blocker (amlodipine or felodipine). (See 'Second-generation calcium channel blockers' above.)
●Morbidity and mortality rates in HFmrEF are generally intermediate between those for HFrEF (associated with higher rates) and HFpEF (associated with rates similar to or lower than those for HFmrEF). (See 'Prognosis' above.)
