Management of refractory heart failure with reduced ejection fraction

INTRODUCTION — Although the majority of patients with heart failure with reduced ejection fraction (HFrEF) respond to optimal medical therapy, some patients do not improve or experience rapid and repetitive recurrences of symptoms. These patients have symptoms at rest or on minimal exertion and often require repeated prolonged hospitalizations for intensive management. Patients with chronic HF with severe symptoms despite maximum guideline-directed medical therapy are classified by the American College of Cardiology Foundation/American Heart Association as having stage D HF [1].

Specialized strategies for patients with refractory HFrEF include intravenous vasodilator and inotropic therapy, ultrafiltration, mechanical circulatory support, surgery including cardiac transplantation, and palliative care.

An overview of therapies used to treat refractory HFrEF is presented here. General treatment strategies for HFrEF and treatment of HF with preserved ejection fraction (HFpEF) are discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Treatment and prognosis of heart failure with preserved ejection fraction".)

GENERAL MANAGEMENT — The general management of patients with refractory HFrEF includes optimizing all standard evidence-based drug and device therapy as well as volume management. Referral to a program with expertise in the management of refractory HF and advanced therapies is recommended. Monitoring is indicated to assess patient status as well as the effects of therapy. Palliative care has a role across the stages of HF and promotes careful discussion of goals of care and patient preferences to guide decision making in refractory HF.

Optimizing evidence-based therapy — The first step in managing suspected refractory HFrEF is to confirm that all conventional evidence-based strategies (including pharmacologic therapy and device therapy such as cardiac resynchronization therapy and implantable cardioverter-defibrillator) have been optimally employed and that contributing conditions have been recognized and treated. Recommendations for patients with other stages of HF are also appropriate for patients with end-stage (stage D) HF. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

Volume and sodium management — Intravenous loop diuretics are the cornerstone of diuretic therapy in patients hospitalized with acute decompensated (including refractory) HF. The approach to refractory volume overload is discussed below. (See "Use of diuretics in patients with heart failure" and 'Approach to refractory volume overload' below.)

As discussed separately, limited evidence is available on the impact of fluid and sodium restriction in patients with HFrEF.

●Consistent with the 2013 American College of Cardiology/American Heart Association (ACC/AHA) HF guidelines, we suggest restricting fluid intake to 2L/day in patients with HFrEF who are not diuretic resistant or significantly hyponatremic. In patients with HFrEF who are refractory to diuretic therapy or hyponatremic, we suggest fluid restriction to 1.5 to 2.0 L/day.

●Based upon clinical experience, we advise our patients with HF to restrict sodium intake to 2 to 3 g per day, although the optimum level of sodium intake has not been established. The 2013 ACC/AHA guidelines suggested some degree (eg, <3 g/day) of sodium restriction in patients with symptomatic HF.

For patients with HF with volume overload with persistent severe hyponatremia (ie, serum sodium ≤120 mEq/L) despite water restriction and maintenance of guideline-directed medical therapy, short-term use of a vasopressin receptor antagonist (either a V₂ receptor selective or nonselective vasopressin antagonist) is an option to improve serum sodium concentration [2]. While the use of vasopressin antagonists in patients hospitalized with HF may improve symptoms and increase serum sodium concentration, they have no effect on mortality or hospitalization risk [3,4]. Cautions include hepatotoxicity (with the United States Food and Drug Administration warning that tolvaptan should be not be used in any patient for longer than 30 days and should not be used at all in patients with liver disease due to risk of liver failure or death) and overly rapid correction of hyponatremia, which can lead to irreversible neurologic injury. These issues are further discussed separately. (See "Hyponatremia in patients with heart failure", section on 'Vasopressin receptor antagonists'.)

Appropriate referral — Referral of patients with refractory HFrEF to a program with expertise in the management of refractory HF and advanced treatment strategies is suggested. Hospitalization rates for patients with HF may be reduced by approximately 20 to 30 percent through the implementation of comprehensive outpatient and inpatient support programs. However, less intensive strategies have been found to be ineffective in improving patient outcomes. (See "Systems-based strategies to reduce hospitalizations in patients with heart failure".)

Patients with refractory HF who may be candidates for heart transplant and/or mechanical circulatory support should undergo evaluation at a program offering these therapies. Limited data suggest that patient outcomes may be better at programs with higher annual heart transplant [5,6] and left ventricular assist device volumes [7]. (See "Heart transplantation in adults: Indications and contraindications".)

Monitoring

General monitoring — Monitoring in hospitalized patients with refractory HF generally includes frequent assessment of arterial blood pressure and pulse, pulse oximetry, and cardiac telemetry. Refractory HF not responsive to diuretic therapy is an indication for pulmonary artery catheterization, particularly when accompanied by hypotension or worsening renal function or when considering inotrope therapy, Response to diuretic therapy can be assessed by monitoring of fluid intake and output and daily measurement of patient weight.

Use of pulmonary artery catheter — Based upon the available evidence (including the ESCAPE trial described below), the routine use of pulmonary artery catheter monitoring in HF patients is not recommended. However, the management of a subset of advanced HF patients may still be improved by invasive monitoring and tailored therapy.

Flow-directed pulmonary artery catheters (Swan-Ganz catheters) can be used for determination of central venous, pulmonary artery, and pulmonary capillary wedge pressure, as well as for measurement of mixed venous oxygen saturation, cardiac output, and systemic and pulmonary vascular resistance. All of these measures may be helpful in the management of patients with HF, particularly those with refractory HF and repeated hospital admissions. Although small uncontrolled studies have suggested that hemodynamic guidance may be of benefit [8,9], these findings were not supported in a randomized trial. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults".)

The ESCAPE trial included 433 patients with decompensated HF at 26 sites who were randomly assigned to receive therapy guided by clinical assessment and invasive monitoring or by clinical assessment alone [10]. After six months of follow-up, there was no difference between the two groups in the primary end point of days alive out of the hospital. There was also no significant difference in mortality. Patients in both groups improved with therapy to reduce volume overload.

Concern has risen regarding a possible increase in mortality in patients who undergo pulmonary artery catheterization. An observational study evaluated the effect of this technique within the first 24 hours of admission to the intensive care unit on patient survival [11]. A statistical tool, called a propensity score, was used to adjust for treatment selection bias. Patients who underwent right heart catheterization had increased 30-day mortality (odds ratio 1.24) compared with those who did not undergo the procedure. However, the ESCAPE trial did not support the concern that pulmonary artery catheterization, per se, leads to an increase in mortality. Due to the limitations of observational data and the challenges inherent in randomized trials of critically ill patients, the interpretation of these results has been debated and remains controversial [12].

We concur with the recommendation in the 2013 American College of Cardiology Foundation/American Heart Association HF guideline that pulmonary artery catheter placement should be performed in patients with respiratory distress or impaired systemic perfusion when clinical assessment is inadequate [13].

Role of palliative care — A careful discussion of goals of care and patient preference is important to guide decision making in refractory HF, especially when considering cardiac transplantation and mechanical circulatory support interventions. Palliative care is a multidisciplinary approach to care that focuses on communication, shared decision making, and advance care planning; it prioritizes relief from pain and other distressing symptoms; it integrates psychological and spiritual aspects of care; and it offers a support system to help caregivers cope during illness and bereavement. Palliative care has a role across the stages of HF, starting early in the course of illness, intensifying in end-stage disease, and extending into caregiver bereavement. Palliative care for patients with HF is discussed separately. (See "Palliative care for patients with advanced heart failure: Indications and systems of care".)

APPROACHES TO SPECIFIC REFRACTORY HEART FAILURE PRESENTATIONS — The approach to treatment of refractory HFrEF is individualized according to the patient’s clinical condition (eg, refractory volume overload or low cardiac output) and response to therapy.

Approach to refractory volume overload — We suggest the following approach to refractory volume overload in patients with HF. The general approach to patients with refractory edema is discussed in detail separately. (See "Causes and treatment of refractory edema in adults".)

Medical management

●If response to initial intravenous loop diuretic therapy is inadequate, the first step is to optimize loop diuretic dosing (eg doubling the diuretic dose until diuresis ensues or the maximum recommended dose is reached. (See "Loop diuretics: Dosing and major side effects", section on 'Maximum effective doses'.)

●Once the intravenous loop diuretic has been optimized, if diuretic response is still suboptimal, a second diuretic is added to potentiate the effects of the loop diuretic. Reasonable choices for a second diuretic are intravenous chlorothiazide or oral metolazone or a mineralocorticoid receptor antagonist (eg, spironolactone or eplerenone).

Although it has been suggested that metolazone is the thiazide of choice in refractory patients with advanced renal failure (glomerular filtration rate below 20 mL/min), there is at present no convincing evidence that metolazone has unique efficacy among the thiazides when comparable doses are given. (See "Causes and treatment of refractory edema in adults", section on 'Enhanced tubular sodium reabsorption'.)

Addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone) is recommended in selected patients with HF with reduced ejection fraction to improve survival. In addition, the associated reduction in collecting tubule sodium reabsorption and potassium secretion can both enhance the diuresis and minimize the degree of potassium wasting. Thus, if not already being given, it is reasonable to initiate mineralocorticoid receptor antagonist therapy prior to the addition of a thiazide diuretic in patients with a low or low-normal serum potassium and estimated glomerular filtration rate ≥30 mL/min per 1.73 m² on loop diuretic therapy alone. Mineralocorticoid receptor antagonist therapy should be continued following hospital discharge if tolerated with close outpatient monitoring for hyperkalemia. (See "Causes and treatment of refractory edema in adults", section on 'Enhanced tubular sodium reabsorption' and "Treatment of acute decompensated heart failure: Specific therapies", section on 'Approach to long-term therapy in hospitalized patients' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.)

●Based upon clinical experience, we advise our patients with HF to restrict sodium intake to 2 to 3 g per day, although the optimum level of sodium intake has not been established. (See 'Volume and sodium management' above and "Heart failure self-management".)

●For patients with refractory volume overload without symptomatic hypotension, intravenous vasodilator therapy can be used as a temporizing measure to relieve congestion. Vasodilator agents and doses are discussed separately. (See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Vasodilator therapy'.)

Selected patients with hypotension may also benefit from vasodilator therapy guided by invasive monitoring with a pulmonary artery catheter. If the systolic blood pressure is <85 mmHg and there is evidence of cardiogenic shock or hypoperfusion, addition of a continuous intravenous inotrope should be considered. (See 'Approach to low cardiac output' below.)

Ultrafiltration — For patients who fail to respond to adequately to an aggressive diuretic regimen, extracorporeal ultrafiltration or hemodialysis can be used to remove intravascular fluid. Studies have not found a clinical benefit from ultrafiltration over diuretic therapy and ultrafiltration does not preserve renal function [14]. (See "Causes and treatment of refractory edema in adults".)

Consultation with a kidney specialist may be appropriate prior to opting for a mechanical strategy of fluid removal. (See "Continuous kidney replacement therapy in acute kidney injury", section on 'Slow continuous ultrafiltration (SCUF)'.)

Most studies have used a peripherally inserted ultrafiltration device that does not require central access, specialized nursing, or intensive care unit admission [15].

The efficacy of ultrafiltration in patients with ADHF has been evaluated in several randomized trials [14,16-18]:

In the UNLOAD trial, 200 patients hospitalized for ADHF were randomly assigned to ultrafiltration or to standard care, including intravenous diuretics during the admission [17]. Renal dysfunction and/or anticipated diuretic resistance were not entry criteria. The following findings were noted:

●At 48 hours, patients assigned to ultrafiltration had a significantly greater fluid loss (4.6 versus 3.3 liters with standard care). This difference may in part reflect the relatively modest level of diuretic therapy used in the standard care arm.

●At 90 days, patients assigned to ultrafiltration had significantly fewer HF rehospitalizations than patients assigned to standard care (0.22 versus 0.46 admissions per patient) and fewer unscheduled clinic visits (21 versus 44 percent with standard care).

●The rates of adverse events were similar in the two groups, although there was a higher incidence of bleeding in the standard care arm. There was no difference in serum creatinine, as was also found in a smaller trial with detailed assessment of renal hemodynamics [18].

In CARRESS-HF, 188 patients with ADHF, worsened renal function (defined as an increase in the serum creatinine level of at least 0.3 mg/dL [26.5 micromol/L]), and persistent congestion were randomly assigned to either stepped pharmacology therapy or ultrafiltration [14]. The stepped pharmacologic care algorithm included bolus plus high doses of continuous infusion loop diuretic, the addition of metolazone, and selective use of inotrope or vasodilator therapy. The primary end point was the bivariate change in the serum creatinine level and body weight from baseline to 96 hours after enrollment. Ultrafiltration was inferior to pharmacologic therapy with respect to the primary end point due to increase in serum creatinine in the ultrafiltration group in contrast to a fall in mean serum creatinine in the pharmacologic therapy group (+0.23±0.70 mg/dL [+20.3±61.0 micromol/L] versus -0.04±0.53 mg/dL [-3.5±46.9 micromol/L]). There was no significant difference in weight loss at 96 hours between the ultrafiltration and pharmacologic therapy groups (5.7±3.9 kg [12.6±8.5 lb] and 5.5±5.1 kg [12.1±11.3] lb]). A higher percentage of patients in the ultrafiltration group had serious adverse events (eg, HF, renal failure, anemia or thrombocytopenia, electrolyte disorder, hemorrhage, pneumonia, sepsis; 72 versus 57 percent).

Thus, while ultrafiltration was an effective method for fluid volume removal, providing similar amounts of weight loss to stepped pharmacologic therapy, it was inferior to stepped pharmacologic therapy for preservation of renal function at 96 hours and was associated with a higher rate of adverse events.

Approach to low cardiac output — For patients with refractory HFrEF and evidence of low cardiac output with hypoperfusion (eg, cool extremities, narrow pulse pressure, low urine output, confusion), therapy includes vasodilators and inotropes. Patients with refractory HFrEF despite optimum pharmacologic and device therapy, including cardiac resynchronization therapy, should be evaluated for candidacy for mechanical circulatory support (eg, left ventricular assist device) as a bridge to cardiac transplantation or as destination (or permanent) therapy for patients who are not candidates for cardiac transplantation. (See "Heart transplantation in adults: Indications and contraindications" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

COMPONENTS OF THERAPY — Refractory HFrEF is managed by a combination of strategies including pharmacologic and device therapy, surgical approaches, mechanical circulatory support, and cardiac transplantation.

Pharmacologic therapy — As noted above, the first step in managing suspected refractory HFrEF is to optimize all pharmacologic and device evidence-based strategies. Additional pharmacologic agents that may be helpful are discussed below.

Intravenous vasodilator therapy

Indications — Intravenous vasodilator therapy is suggested in patients with refractory HF who require reduction in afterload, preload or both. The use of these agents should be reserved for patients in whom improved hemodynamic function is likely to lead to clinically useful improvements in oxygenation and/or organ perfusion, and may be most effective when their use is guided by hemodynamic monitoring. However, routine use of intravenous vasodilators does not improve acute HF outcomes, and thus their routine use should be avoided.

Indications for intravenous vasodilator therapy in the setting of acute HF include the following:

●For patients without adequate response to diuretics who continue to have evidence of elevated left heart filling pressures, vasodilators with venodilator action (eg, nitroglycerin, nitroprusside) are an option as an adjunct to diuretic therapy. (See 'Approach to refractory volume overload' above.)

●For patients with refractory HF and low cardiac output, a vasodilator with arterial dilator action (eg, nitroprusside) is an option to decrease left ventricular afterload. (See 'Approach to low cardiac output' above.)

●Vasodilator therapy is also used in patients with urgent need for afterload reduction (ie, to treat severe hypertension, which is more commonly associated with HF with preserved ejection fraction). (See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Vasodilator therapy'.)

Use — Nitrates reduce left ventricular filling pressure primarily via venodilation and, at higher doses, lower systemic vascular resistance and left ventricular afterload. Nitroprusside provides balanced arterial and venous dilation. Vasodilator use, including agents and doses for treatment of acute decompensated HF (including refractory HF), is discussed separately. (See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Vasodilator therapy'.)

Reliable blood pressure monitoring is required, and careful patient assessment is needed in determining the best vasodilator for the situation. If symptomatic hypotension develops, these agents should be reduced or discontinued and invasive monitoring should be used to assess hemodynamics.

Evidence — Use of intravenous vasodilator therapy in patients with refractory HF is largely based upon hemodynamic response and clinical experience [2,19], since other evidence on efficacy and safety of vasodilatory therapy in this setting is limited [20,21].

Intravenous inotropes

Indications — Use of intravenous inotropes can be helpful in patients hospitalized with acute decompensated HF with low cardiac output and evidence of end-organ hypoperfusion or hypotension. Given lack of evidence of a survival benefit and concerns about risk of increased mortality and side effects with their use, intravenous inotropes should not be used in the routine inpatient management of acute decompensated HF in the absence of hypotension or organ hypoperfusion. (See "Treatment of acute decompensated heart failure: General considerations" and "Inotropic agents in heart failure with reduced ejection fraction".)

Similarly, in the absence of a specific indication, continuous inotropic agent infusion should not be used in the outpatient setting due to the risk of harm. Selected patients who cannot be weaned from intravenous therapy in the hospital may be candidates for chronic outpatient inotrope infusion. This requires placement of an indwelling line to permit the continuous infusion of vasoactive and/or inotropic drugs. This is a commonly used short-term strategy in patients who are awaiting cardiac transplantation or mechanical circulatory support. In patients with refractory end-stage HF who are ineligible for advanced HF therapies, continuous outpatient intravenous inotropic agent infusion may be considered to palliate symptoms. (See "Palliative care for patients with advanced heart failure: Indications and systems of care".)

These recommendations are consistent with those in the 2013 American College of Cardiology Foundation/American Heart Association guideline on HF [13].

Agents — Inotropic drugs, such as dobutamine and milrinone, can acutely improve hemodynamics and relieve symptoms in patients hospitalized with decompensated HF and signs of low cardiac output and end-organ hypoperfusion (see "Inotropic agents in heart failure with reduced ejection fraction" and "Treatment of acute decompensated heart failure: Specific therapies" and "Treatment of acute decompensated heart failure: Specific therapies", section on 'Vasodilator therapy'). The most commonly used intravenous inotropes are dobutamine, milrinone, and dopamine (table 1).

At present, there are no orally active inotropic agents, other than digoxin, that are approved for the therapy of HF. (See "Inotropic agents in heart failure with reduced ejection fraction".)

Dobutamine — We prefer use of dobutamine, rather than milrinone, in patients with baseline hypotension or chronic renal insufficiency. Dobutamine is a beta receptor agonist. As such, the inotropic response to dobutamine may be reduced in patients treated with a beta blocker. In general, beta blockers should be discontinued with dobutamine use. In settings in which continuation of beta blockers is preferred, we recommend use of milrinone rather than dobutamine. Most patients will experience an increase in heart rate and blood pressure with use of dobutamine, though response can vary [22]. Dobutamine can worsen existing arrythmias and increases the risk of both atrial and ventricular arrythmias.

One approach is to start dobutamine at an initial dose of 2 to 5 mcg/kg/min based on the severity of HF. The dose can be increased or decreased by 2 mcg/kg/min every two hours (or more frequently with close monitoring) until an optimal clinical and hemodynamic response is achieved. The half-life of dobutamine is two minutes, and a steady-state is quickly reached after dose adjustments. The usual maintenance dose of dobutamine is 2 to 10 mcg/kg/min (maximum 20 mcg/kg/min).

Milrinone — We prefer use of milrinone, rather than dobutamine, in patients with elevated pulmonary vascular resistance awaiting cardiac transplantation and in those without hypotension.

Milrinone is a phosphodiesterase inhibitor. Unlike dobutamine, it does not require use of the beta receptor to exert its effect. In addition to its inotropic properties, it is also a vasodilator for both the systemic and pulmonary circulation. As such, the most common side effect limiting its use is hypotension. Like all inotropes, milrinone can be arrhythmogenic.

One approach is to start at an initial dose of 0.125 mcg/kg/min, titrating by 0.125 mcg/kg/min every 6 to 12 hours until an optimal clinical and hemodynamic response is achieved. As the half-life of milrinone (2.3 hours) is much longer than dobutamine, it takes longer to reach a steady state after dosing changes, and titration should occur more slowly. The usual maintenance dose is 0.125 mcg/kg/min to 0.5 mcg/kg/min (maximum 0.75 mcg/kg/min). Doses >0.25 mcg/kg/min are not recommended in patients with significant renal impairment.

Dopamine — Although some have administered low-dose dopamine (ie, 2 to 3 mcg/kg/min) in an attempt to augment renal blood flow and diuresis in patients with refractory HF, we generally recommend against this approach since clinical trial data have shown no effect on urine volume, renal function, or outcomes compared with placebo [23]. Dopamine has inotropic effects at higher doses, but we favor use of dobutamine or milrinone when an inotrope is indicated.

Evidence — Use of intravenous inotropic therapy has been studied in patients either as outpatient therapy in an attempt to decrease repeat hospitalizations or as adjunctive therapy in hospitalized patients [24,25]. However, there is no evidence for a survival benefit when used in either setting, and there has been concern that there may be adverse effects on survival. A systematic review found that ambulatory inotrope infusions improve NYHA functional class (based on data from five trials) but there was no significant overall difference in mortality risk with inotrope therapy compared to controls (based on data from nine trials with a high level of imprecision) [26]. Similarly, the routine use of milrinone in patients hospitalized with decompensated HF has not been shown to be beneficial, and on the contrary, may increase the occurrence of adverse events including sustained hypotension requiring intervention [25]. The efficacy and safety of intravenous inotrope is discussed further separately. (See "Inotropic agents in heart failure with reduced ejection fraction".)

Surgery — Surgical approaches to end-stage HF are under active investigation.

The role of coronary artery bypass surgery in treating patients with ischemic cardiomyopathy is discussed separately. (See "Treatment of ischemic cardiomyopathy", section on 'Approach to revascularization'.)

The role of other approaches, such as reconstructive cardiac surgery, cardiomyoplasty, and mitral valve repair, remain to be established. (See "Left ventricular aneurysm and pseudoaneurysm following acute myocardial infarction" and "Chronic secondary mitral regurgitation: Intervention", section on 'Indications for mitral valve intervention'.)

Mechanical circulatory support — Mechanical circulatory support devices were initially designed to support patients in hemodynamic collapse. They are now used for a wide range of clinical conditions, including refractory HFrEF.

There are two major categories of devices:

●Short-term mechanical circulatory support devices including intra-aortic balloon pump (IABP), percutaneous circulatory assist devices (eg, Tandem Heart, Impella), and Extracorporeal Membrane Oxygenation (ECMO). (See "Short-term mechanical circulatory assist devices".)

●Long-term mechanical circulatory support devices such as left ventricular assist devices (LVAD) and biventricular support (eg, total artificial heart). (See "Treatment of advanced heart failure with a durable mechanical circulatory support device" and "Management of long-term mechanical circulatory support devices".)

The IABP is the most commonly used mechanical support device. It is inserted easily and rapidly, is the least expensive of all the devices, and does not require constant monitoring by technical support personnel. However, it is limited in that it is capable of generating only modest hemodynamic support. As such, the IABP is best suited for short-term use (eg, when rapid improvement in the underlying pathology is expected), and evidence for the use of IABP to treat refractory HF is scant. IABPs are often utilized for preoperative optimization for one to three days prior to durable LVAD placement. (See "Intraaortic balloon pump counterpulsation".)

Percutaneous circulatory assist devices (eg, Tandem Heart, Impella) are continuous flow pumps that can provide greater hemodynamic support than an IABP. They can be placed by an experienced operator in a cardiac catheterization laboratory. The Impella is an axial flow pump that is placed across the aortic valve and pumps blood from the left ventricle to the aorta. The Tandem Heart is a percutaneous left atrial to aorta assist device with a venous catheter inserted into the left atrium by transseptal puncture and an arterial cannula inserted into the iliofemoral arterial system. Both types of percutaneous assist devices can be used in patients with cardiogenic shock as a bridge to surgery (such as LVAD or heart transplantation) or recovery and in patients undergoing high-risk percutaneous coronary intervention, though very little outcome evidence exists for their use. (See "Short-term mechanical circulatory assist devices", section on 'Non-IABP percutaneous circulatory devices'.)

Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is a cardiopulmonary support system that, in addition to helping move blood forward, removes carbon dioxide from and adds oxygen to venous blood using an artificial membrane lung. ECMO systems can be placed via percutaneous (in the cardiac catheterization laboratory) or central (in the operating room) cannulation. In percutaneous (peripheral) cannulation, most often a cannula is inserted into the right atrium via the femoral vein (drainage), with an arterial cannula in the femoral artery (infusion). Central VA ECMO is usually deployed via a median sternotomy with the venous cannula in the right atrium and the arterial cannula in the ascending aorta. Alternate cannulation sites that allow patients to be ambulatory are used in rare circumstances. VA ECMO is most often utilized in patients who require both cardiac and pulmonary support in the setting of cardiogenic shock. (See "Short-term mechanical circulatory assist devices", section on 'Extracorporeal membrane oxygenation'.)

Long-term mechanical circulatory support devices can be utilized in patients awaiting cardiac transplantation (bridge to transplantation) or as permanent mechanical assistance (destination therapy) in selected patients who are not eligible for cardiac transplantation. Indications and guidelines for use of these devices are discussed separately. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device".)

The vast majority of long-term mechanical circulatory support devices implanted are LVADs. In rare settings, biventricular support with either biventricular assist devices or a total artificial heart can be utilized in patients who are awaiting cardiac transplantation. Durable LVADs are implanted in patients who have failed all other pharmacologic therapies for severe HF. An important consideration is that the device be implanted before there is irreversible end-organ damage. Among patients with refractory HF who are not eligible for transplantation, a long-term LVAD can improve survival compared with optimal medical therapy. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device".)

Cardiac transplantation — Referral for cardiac transplantation is recommended for selected patients with refractory end-stage HF. Indications and contraindications for cardiac transplantation are discussed separately. Observational data suggest that cardiac transplantation can improve both survival and quality of life in selected patients with severe HF. (See "Heart transplantation in adults: Prognosis" and "Heart transplantation in adults: Indications and contraindications".)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Heart failure (Beyond the Basics)" and "Patient education: Low-sodium diet (Beyond the Basics)" and "Patient education: Heart transplantation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General management – The approach to management of refractory heart failure with reduced ejection fraction (HFrEF) includes general measures (including optimizing evidence-based therapy, volume and sodium management, monitoring, and appropriate referral). (See 'General management' above.)

●Use of a pulmonary artery catheter – For patients with refractory HF, we recommend against routine pulmonary artery catheter monitoring. However, pulmonary artery catheter placement may be useful to guide therapy in selected patients with refractory HF when clinical assessment is inadequate to guide hemodynamic management. (See 'Use of pulmonary artery catheter' above.)

●Approach to volume overload – Patients with refractory volume overload are treated with intensified medical management, including optimized loop diuretic dosing with possible addition of a thiazide-type diuretic or a mineralocorticoid receptor antagonist (eg, spironolactone or eplerenone) or intravenous vasodilator therapy as an adjunct to diuretic therapy. For patients who fail to respond to intensified medical management, extracorporeal ultrafiltration or hemodialysis is an option to remove intravascular fluid. (See 'Approach to refractory volume overload' above and "Use of diuretics in patients with heart failure", section on 'Refractory congestion' and "Causes and treatment of refractory edema in adults".)

●Approach to low cardiac output – For patients with refractory HF and low cardiac output with evidence of hypoperfusion, therapy includes vasodilators and inotropes. Patients with refractory HFrEF despite optimum pharmacologic and device therapy should be evaluated for candidacy for mechanical circulatory support and cardiac transplantation. (See 'Approach to low cardiac output' above.)