Heart failure (HF) morbidity and mortality constitute an important burden for patients and for the healthcare systems in both developed and developing countries.Patients with HF are frequently hospitalised and have a high mortality risk because of a poor prognosis or an unexpected death, termed sudden cardiac death (SCD). In people diagnosed with HF, SCD occurs at 6–9 times the rate of the general population.

                    Almost 20% and 80% of patients die within one year and eight years of initial diagnosis, respectively.  Risk factors of SCD were reported to be similar to cardiovascular diseases. However, the most studied and proven predictor of SCD in patients with HF is left ventricular ejection fraction. Potential drug interventions in patients with heart failure with reduced ejection fraction (HFrEF) include beta-blockers (BBs), angiotensin-converting enzyme inhibitors (ACE-i), angiotensin receptor blockers (ARBs), antialdosterones or mineralocorticoid receptor antagonists, amiodarone, other antiarrhythmic agents, combined ARB/neprilysin inhibitors, statins and fish oil supplementation.Some of these interventions aimed at improving survival and reducing total mortality and SCD in HF.

             For instance, a newly licensed drug (sacubitril/valsartan) in PARADIGM-HF trial (Prospective Comparison of angiotensin neprilysin inhibitor (ARNI) with ACE-i to Determine Impact on Global Morbidity and Mortality in Heart Failure) showed around 20% SCD reduction compared with enalapril.Nevertheless, optimal strategies for SCD prevention in HF are warranted if we take into account the high portion of mortality that still occurs in this population. Had a practitioner identified a patient with high risk of SCD, it would be important to know which drug is effective or not in SCD prevention other than non-drug interventions such as implantable cardioverter defibrillators (ICDs). However, the large amount of information and the multiple and sometimes discordant systematic reviews on drug interventions could be misleading.

Therefore, it is vital to identify the pharmacological agents that confer the greatest benefit in SCD risk reduction particularly in high-risk patients and if any optimisation of therapeutic strategies to those patients is possible accordingly. Thus, we decided to conduct an overview of systematic reviews to summarise and synthesise the available evidence about the effectiveness of drug interventions in the prevention of SCD in HFrEF and categorised the evidence into effective, ineffective and unclear evidence of effectiveness.

                Our overview indicates that only three drug interventions (BBs, antialdosterones, combined ARB/neprilysin inhibitors) significantly reduce SCD and improve overall survival among individuals with HF and reduced ejection fraction. However, there is no evidence of effectiveness of ARBs to reduce neither all-cause mortality nor SCD (with a low quality of evidence), and ACE-i do not significantly reduce SCD events. When the goal of drug therapy is to reduce SCD, especially in high-risk patients, our synthesis supports the use of the most effective regimen.