Description of the condition

Heart failure (HF) is a public health concern and its burden has increased over the past decades. It is estimated that as of 2016, more than 37.7 million people are affected by this disease globally (Ziaeian 2016). The annual global economic burden of the disease was estimated at USD 108 billion per annum in 2012, with direct costs to healthcare systems accounting for USD 65 billion and indirect costs (through lost productivity, morbidity, premature mortality, etc.) accounting for USD 43 billion (Ambrosy 2014). While the discovery of several evidence‐based drug and device therapies has improved the outcomes for ambulatory HF patients, postdischarge mortality and readmission rates of hospitalised HF patients have not changed in the past two decades (Ambrosy 2014).

HF is a clinical syndrome that is characterised by an impaired systemic delivery of blood, whereby the heart fails to pump enough blood to meet the body's metabolic demand (McMurray 2012). HF can result from many cardiac diseases, which had led to a multitude of classifications for this syndrome based on anatomy (disease of the myocardium, pericardium, or endocardium), pathophysiological mechanism (systolic vs diastolic dysfunction), and etiology (ischaemic vs non‐ischaemic), with the latter being the most commonly used in the clinical setting (Maron 2006). Ischaemic HF is caused by myocardial ischaemia due to an underlying coronary artery disease (Ho 1993). Various potential causes leading to non‐ischaemic cardiomyopathy (NICM) are described in the literature, which are classified into four main categories: dilated cardiomyopathy (DCM) (idiopathic, viral illness, alcoholism, etc.), hypertrophic cardiomyopathy (genetic factors and hypertension), restrictive cardiomyopathy (amyloidosis, sarcoidosis, haemochromatosis, etc.), and arrhythmogenic right ventricular dysplasia (Wu 2007). DCM is characterised by systolic dysfunction leading to a reduced Left Ventricular Ejection Fraction (LVEF) (Daughenbaugh 2007). While not all patients with DCM display signs of HF, it is believed that long‐standing DCM eventually leads to HF (McNally 2013; Dass 2015). In fact, patients with DCM can be either asymptomatic (New York Heart Assocation (NYHA) class I), or can display signs and symptoms of HF (e.g. dyspnoea, fatigue, fluid retention) (NYHA class II‐IV depending on severity) in which case they are considered to have non‐ischaemic systolic HF (Yancy 2013; Ponikowski 2016).

HF patients, whether ischaemic or non‐ischaemic, are at increased risk of developing ventricular arrhythmias due to underlying structural and mechanical factors (e.g. increased inward sodium and calcium currents due to myocardial stretch) (Wu 2007). These can range from non‐sustained ones, such as premature ventricular beats, to life‐threatening ones such as ventricular fibrillation (VF) that leads to sudden cardiac death (SCD). SCD is defined as a rapid and fatal cardiovascular decompensation in a previously haemodynamically stable patient that happens within one hour, and its risk increases as the LVEF falls below 40% (Yap 2005; Shiga 2009; Mosterd 2001). SCD has long been considered the leading cause of death in HF patients (Bardy 2005; Packer 2009). However, new evidence suggests that this has changed over the last few years. In fact, a recent study (CERTITUDE) has shown that progressive HF is now the leading cause of death in cardiac resynchronisation therapy (CRT) patients (Marijon 2015). Other studies have also shown that mortality due to progressive HF and to non‐cardiovascular causes were more common than SCD in HF patients (Henkel 2008; Pons 2010). Nevertheless, current medical and device therapies are directed towards preventing and terminating arrhythmic events before their progression to fatal VF and SCD (Derfler 2004).

HF patients can also present with sudden severe symptoms (acute decompensated HF) or with an insidious onset (chronic HF). The two conditions are managed differently: acute HF therapy is mainly managed pharmacologically (diuretics, vasodilators, etc.) while chronic HF is managed through both device and medical therapy (Ponikowski 2016). Since our analysis focuses on device therapy, our target population are patients with chronic HF.

Description of the intervention

The standard of care for the treatment of HF patients is defined by a guideline recommended approach (primarily Class I), which consists of optimal medical therapy (OMT) as a first‐line treatment, either with or without device therapy (Yancy 2013; Ponikowski 2016). OMT is a multidimensional approach to managing people with HF, which consists of pharmacological treatment of HF and co‐morbidities (e.g. hypertension) and lifestyle modifications, all of which serve to improve patients' outcome by reducing the risk of HF hospitalisation and death. Treatment with Angiotensin Converting Enzyme inhibitors (ACE‐I) or Angiotensin Receptor Blockers (ARBs) in addition to a beta‐blocker (Class I level A) is the mainstay for the pharmacological treatment of HF with reduced ejection fraction (i.e. LVEF ≤ 40%) (Yancy 2013; Ponikowski 2016). Studies have linked the use of these drugs with a decreased morbidity and mortality in patients with HF, by decreasing the workload on the heart (Heran 2012; Chatterjee 2013). If symptoms persist despite treatment with ACE‐I and a beta‐blocker, a mineralocorticoid receptor antagonist (MRA) is recommended (Class 1 Level A) to reduce the risk of HF hospitalisation and death (Yancy 2013; Ponikowski 2016). Long‐term control of weight, blood pressure, glucose and lipid levels, and reduction in smoking and alcohol consumption also improves patients' survival and reduces the risk of HF in at‐risk patients (McMurray 2012).

Implantable Cardioverter Defibrillators (ICDs) are implantable devices that deliver electrical energy to the heart during episodes of ventricular arrhythmias, thus ending the life‐threatening event and resetting the sinus rhythm. They have been effective in reducing mortality in patients with tachycardia, fibrillation, and other arrhythmic anomalies (Kuck 2000; Young 2003; Josephson 2004). The very first guidelines that discussed the use of ICD in clinical practice were based on the Antiarrhythmics versus Implantable Defibrillators (AVID) study, a large multicenter trial which showed a reduction in all‐cause mortality in cardiac arrest survivors (AVID investigators 1997). Hence, a Class I recommendation was established by the American College of Cardiology (ACC)/American Heart Association (AHA) for the use of ICD in secondary prevention in patients meeting enrolment criteria for AVID (Poole 2014). The Canadian Implantable Defibrillator Study (CIDS) and the Cardiac Arrest Study Hamburg (CASH) trials supported the results of this trial. While these studies lacked statistical significance, a pattern of mortality reduction in ICD‐treated patients started to emerge (Connolly 2000; Kuck 2000).

It was not until after the MADIT II trial that guidelines upgraded ICD from a secondary to a primary and secondary prevention therapy (Moss 2002). Furthermore, guidelines were once again updated in 2006 based on the results of the SCD‐Heft trial, assigning Class I recommendation for ICD implantation in non‐ischaemic HF patients as well. As a matter of fact, the recommendations have not changed since: ICD implantation is a Class I recommendation for the primary and secondary prevention of SCD due to VT/VF in more severe cases of non‐ischaemic HF (LVEF ≤ 35% despite ≥ three months of optimal medical therapy) as an adjunct to medical therapy (Yancy 2013; Ponikowski 2016).

The recommendations for the prophylactic use of ICDs in non‐ischaemic HF were based on subgroup analyses and small trials of low quality evidence. Indeed, the DANISH study, which is the largest randomised control on patients with non‐ischaemic HF, showed that there is no long‐term beneficial effect from ICD implantation in terms of mortality reduction (Kober 2016).

Patients who meet the criteria for ICD implantation may present with a pre‐existing device therapy: a cardiac re‐synchronisation therapy device (CRT). CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS interval — the deflections seen on an electrocardiogram corresponding to the depolarisation of the right and left ventricles of the heart — duration ≥ 150 msec (normal 80 to 100 msec) and left bundle branch block (LBBB) QRS morphology and with LVEF ≤ 35% despite OMT in order to improve symptoms and reduce morbidity and mortality (Yancy 2013; Ponikowski 2016). In fact, ICDs can be implanted alone, or in conjunction with a CRT device, in which case the device is upgraded to a CRT defibrillator (CRT‐D), maintaining its initial function as a pacemaker, and also taking on a new function which is that of the defibrillator. In other words, if these patients to whom a pacemaker (CRT‐P) was already implanted meet the criteria for ICD implantation, their device is upgraded to a CRT‐D.

ICD implantation is associated with a series of adverse events that are both physical (e.g. haemothorax, pneumothorax) and psychological (Rosenqvist 1998). ICD is only effective in patients who are at high risk of SCD; otherwise, patients are exposed to unnecessary adverse events from device implantation that reduce their quality of life (QoL) without benefiting from its action. While the AVID trial showed that ICD reduces all‐cause mortality in cardiac arrest survivors, patients randomised to the ICD arm of the study showed significant decline in QoL manifested by a decrease in physical functioning and mental well‐being and increased anxiety (Schron 2002). ICDs deliver unexpected shocks to the patients without warning, which creates distress to them and their family members (Dunbar 1993; Dougherty 1995). Patients live in a state of anxiety, constantly anticipating an electric shock, which results in an elevated incidence of anxiety disorders and panic attacks (Sears 2002). Finally, Post‐traumatic stress disorder has also been reported to be elevated in patients with ICD, causing them to re‐experience the events of shock and manifest emotions associated with them (Hamner 1999; Ladwig 2008).

Hence, careful evaluation of patients' profile and ensuring they meet the guidelines' criteria for implantation is critical in preventing patients' exposure to unnecessary harm through overprescription of ICD therapy.

How the intervention might work

Beta‐blockers suppress the firing of these action potentials by blocking the sodium and calcium channels. However, ICDs work through a different mechanism: while beta‐blockers prevent the abnormal firing of cardiomyocytes, ICDs work to stop the chain reaction created by the abnormal pacemaker cells. During episodes of arrhythmias, they deliver an electric shock that depolarises all the cardiac cells simultaneously, thereby halting the progression of the arrhythmia. Thus, the primary purpose of ICDs is to end life‐threatening ventricular arrhythmias and reduce SCD or arrhythmia‐related complications. Therefore, we can only expect a relevant reduction in mortality rate in subgroups of HF patients with high incidence of sustained ventricular arrhythmias leading to cardiac arrest if not terminated.

In non‐ischaemic HF, currents that are abnormally generated in the ventricle can be immediately stopped through the delivery of a therapeutic dose of electric energy from an ICD device.

Why it is important to do this review

Several studies have assessed the effectiveness of ICD treatment in NICM patients (Kadish 2000; Desai 2004); however, these studies had conflicting results, with some showing significant improvement in primary outcome (e.g. COMPANION trial) while others showed no benefit (e.g. CAT and AMIOVIRT trials) (Bansch 2002; Strickberger 2003; Bristow 2004).

A meta‐analysis of 1854 patients from five ICD primary prevention trials concluded that ICD treatment in NICM patients significantly improves mortality rate when compared to medical therapy alone (Desai 2004). Moreover, the ACC and Euopean Society of Cardiology (ESC) guidelines for device‐based therapy recommend ICD implantation in patients with non‐ischaemic HF with LVEF ≤ 35% (Yancy 2013; Ponikowski 2016).

A recently published large randomised control trial — the DANISH study — defied current guidelines and the 2004 meta‐analysis, supporting the evidence that ICD use in NICM patients does not reduce the all‐cause mortality rate (Kober 2016). Hence, the purpose of this Cochrane Review is to assess the benefit of ICD use in NICM patients using a meta‐analysis of trials tackling this subject, including the Danish study, and thus provide a framework for future guideline updates.

While several systematic reviews have been published on this topic after the publication of the DANISH results, the measured outcomes were all mortality‐related (SCD mortality, all‐cause mortality, etc.) (Al‐Khatib 2017; Golwala 2017; Luni 2017; Shun‐Shin 2017; Wolff 2017). None of these studies assessed the adverse events versus benefits of ICD implantation and the cost of this therapy. Moreover, none of these reviews assessed the benefits of ICDs in different patient subgroups (e.g. age, gender, baseline ejection fraction, etc.). This is of critical importance since the DANISH study showed that there was a significant treatment‐by‐subgroup interaction for age, with all‐cause mortality being significantly lower in younger patients on ICD, compared to older patients who did not derive any benefit from ICD implantation (Kober 2016). Finally, some of the studies performed a ʽRisk of bias' assessment; however, none assessed the quality of the evidence.

To this end, this Cochrane Review will be the first to: measure mortality‐related outcomes in addition to adverse events vs added benefits and cost; assess the risk of bias using the Cochrane tool and the quality of evidence using the GRADE approach; and perform an analysis on different patient subgroups in a single study.

Finally, we will also search for unpublished studies which may add evidence so far unknown.