Refractory Heart Failure: A Clinical Syndrome

Heart failure as a clinical syndrome is the final pathway of many diseases that affect the heart. It begins with changes both in the way the heart operates and in neurohormonal regulation, and causes reductions in functional capacity, retention of liquids, and reduced survival.1 It is a progressive and fatal disease if left to freely develop. Once heart damage is established, a series of compensatory mechanisms are triggered which initially try to maintain cardiac output but, at the same time and in the longer term, they accelerate the deterioration of the heart muscle and cause signs and symptoms of circulatory congestion and low output. In recent years, HF has been become one of the most serious public health problems in developed countries, due to the ongoing increase in its incidence and the personal, social and economic impact that can be expected in the near future.

Heart failure is a syndrome characterised by a triad of symptoms, signs and objective evidence of cardiac dysfunction. The syndrome is divided into subtypes based on left ventricular ejection fraction (LVEF). Where the LVEF is below 40% this is termed heart failure with reduced ejection fraction (HFrEF). This differentiation from those patients with an LVEF greater than 40% (termed heart failure with mildly reduced EF (HFmrEF)) and greater than 50% (termed heart failure with preserved EF (HFpEF)) is the result of discrete LVEF cut-offs being used as inclusion/exclusion criteria in clinical trials evaluating therapeutic interventions in these patients. HFpEF represents a complex and heterogeneous group of patients, and the aetiology is largely related to comorbidities. Trials in these cohorts have failed to identify specific therapeutic strategies which influence prognosis and management is focused on achieving and maintaining euvolaemia, primarily to alleviate symptoms. Otherwise, treatment of comorbidities, anticoagulation for atrial fibrillation (AF) and strategies to reduce cardiovascular risk are recommended. Patients with HFmrEF phenotypically resemble those with HFrEF, and the clinical consensus is that they should benefit from the same drug therapies.

HFrEF is characterised by the overactivation of the neurohormonal axis—particularly of the sympathetic nervous system and the renin–angiotensin–aldosterone system. Initially this is an adaptive response but one that becomes maladaptive and results in salt and water retention and then a cascade of deleterious consequences related to haemodynamic effects and fibrosis. The importance of diuretics to relieve congestion and improve morbidity should be remembered in all patients butover the last four decades, key trials have established the importance of pharmacological antagonism of these axes in improving morbidity and mortality in patients with HFrEF.

Heart failure is not a diagnosis but a syndrome with a variety of potential causes. Symptoms generally relate to reduced cardiac output, and signs typically to elevated filling pressures. Unfortunately, the non-specific nature of symptoms means that identification of HFrEF is often made at a later stage when the patient is admitted to hospital acutely. Often, this represents the end of a long process of chronic pressure/volume overload of the left ventricle with subacute decompensation on a background of chronic myocardial disease. 

Characterization of the Symptoms

Correct identification of the patient's symptoms is important to identify those causing the main restrictions in daily life. When assessing functional limitation, the NYHA classification sometimes lacks precision (e.g. it can be difficult to distinguish between class II and III), which means that it can be useful to regularly review changes in the capacity of the patient to carry out normal activities, such as getting dressed, having a walk around the block, going up the stairs, pushing the shopping cart, etc. Symptoms of advanced or refractory HF are the result of 2 pathophysiological mechanisms, congestion and low output, and either can predominate in a given patient.

Definition of the Hemodynamic Profile

The therapeutic approach to HF differs depending on whether symptoms of congestion or low output predominate.Precisely establishing the severity of lung or systemic congestion and cardiac output requires direct determination of filling pressures and heart output via right heart catheterization.22,23 However, another practical, simple and fast method has been proposed to do this non-invasively using the 2-minute bedside assessment technique. 

Pharmacological Treatment of Advanced Heart Failure

The primary aim of HF therapy is to relieve symptoms, followed by preventing disease progression and prolonging survival. As the disease progresses, the probability of successfully achieving these objectives gradually diminishes until, in the most advanced stages, it is only possible to achieve symptomatic control. It is assumed that patients with refractory HF have had previous treatment with diuretics, ACE inhibitors, digoxin, spironolactone, and beta-blockers.

Management of Terminal Heart Failure Patients

A terminal situation is understood as an incurable disease (whether due to the lack of response to treatment, or because there is no curative treatment), that threatens the patient's life in the short-term, generally in less than 6 months, and produces progressive symptoms that seriously affect the functional capacity and emotional state of the patient and, by implication, the family's. Although many aspects related to the management of terminal situations are common to any progressive chronic disease in its final phase, in HF there are particular aspects worthy of comment.

Heart Transplantation

Progress in the medical treatment of HF, as well as in transplantation, has shown that HT especially benefits the population of patients with a high risk of death from advanced terminal HF.43,44 On the other hand, heart transplantation is limited by the insufficient number of donors and contraindications to this procedure. At present, given the progress in many aspects of HT, it is uncommon to talk in terms of absolute or relative contraindications, but rather of conditions that increase the risk of post-HT morbidity and mortality. 

The treatment of advanced HF is rapidly changing, although many decisions are based more on consensus than on controlled clinical trials. The benefits obtained with ACE inhibitors, beta-blockers, resynchronization and implantable defibrillators regarding extended survival and the quality of life of patients with mild to moderate HF has given rise to a new population of patients with terminal HF who often present kidney failure and right ventricular failure. Mechanical assist devices offer a clear advantage compared to pharmacological treatment, but are still far from improving long-term life expectations. Heart transplant continues to be the only therapy that radically changes the natural evolution of these patients, with 1-year survival around 80% and 10-year survival around 50%, but this remains an opportunity for a very small number of patients.