From a clinical point of view, any unexpected death can be thought of as 'sudden death' and can include. conditions as diverse as arrhythmias, aortic dissection, subarachnoid hemorrhage, acute myocardial infarction or massive pulmonary embolism.. Traumatic death is normally excluded from this category. For prognostic and therapeutic differences (i.e. from subarachnoid hemorrhage or pulmonary embolism), a distinct subcategory, known as 'sudden cardiac death' (SCD) is recognised. A widely accepted definition is "natural death due to cardiac causes, heralded by abrupt loss of consciousness within an hour of the onset of acute symptoms; pre‐existing heart disease may have been known to be present, but the time and mode of death are unexpected" (Myerburg 2004).

SCD is one of the leading causes of cardiac death. The incidence increases with age and is three to four times more frequent in men of all ages than women (Kannel 1998; MMWR 2002). Accurately estimating its real incidence is difficult, but according to data obtained from death certificates, 63.4% of total cardiac mortality is attributed to SCD in the US (MMWR 2002). Probably this data overestimates SCD prevalence, as it is based only on clinical presentation (MMWR 2002; Zheng 2001). Incidence rates varying from 0.36 to 1.28/100000 patients per year have been reported from some emergency room services, but these tend to underestimate the real incidence, as it only refers to patients who survive to reach the hospital (Priori 2001). A prospective observational study reported that 5.6% of overall mortality in general population of all ages was due to SCD (Chugh 2004).

The main cause of SCD in Western society is coronary heart disease, comprising 60 to 80% of all SCD events (Kannel 1982; MMWR 2002 ; Spaulding 1997; Zheng 2001). The remaining causes correspond to other types of cardiopathy (i.e. hypertrophic cardiomyopathy, non‐ischemic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, etc). Only 5% of SCD occur in patients with no structural abnormality (Consensus 1997). Most commonly (80%), SCD is caused by the sudden onset of monomorphic Ventricular Tachycardia (VT) that degenerates into Ventricular Fibrillation (VF). Less frequently it is initiated by polymorphic VT/VF directly and only a minority occurs as bradyarrhythmias or heart blocks (Priori 2001).

In this context, electrophysiological (EP) testing with intracardiac recording and electrical stimulation at baseline and with drugs has been used for arrhythmia assessment and risk stratification for SCD. EP testing has been used to document the inducibility of VT, guide ablation, evaluate drug effects, assess the risks of recurrent VT or SCD, and assess the indications for ICD therapy. In patients with coronary heart disease (CHD), asymptomatic non‐sustained VT, and an ejection fraction (EF) less than 40%, inducibility of sustained VT ranges from 20 to 40%. Therefore, inducibility confers worse prognosis in these patients (Buxton 2000). However, in patients with CHD and a low EF (less than 30%), non‐inducibility doesn't portend a good prognosis (Buxton 2002), and persistent inducibility while receiving antiarrhythmic drugs confers worse prognosis (Wilber 1990).

There are two main and complementary strategies to deal with SCD:
‐ treating cardiovascular risk factors and coronary heart disease (i.e. ischemia), and
‐ using drugs or devices that reduce the risk of ventricular arrhythmias, either by preventing them or by reducing the frequency of events.

According to current evidence, implantable cardiac defibrillators (ICD) reduce mortality compared with antiarrhythmics for primary prevention in high risk patients with reduced left ventricular ejection fraction in both coronary artery disease and non‐ischemic cardiopathy, and in secondary prevention of SCD (AVID 1997; Connolly 2000; Desai 2004; Kuck 2000). In spite of the evidence, the elevated costs of ICD, do not allow this treatment to be readily available in the health systems of low and middle income countries.

While ICD may improve survival in selected patient populations, it may diminish the patient's quality of life (Gehi 2006). In a study comparing ICD versus no ICD in patients who underwent coronary artery bypass graft surgery, the use of ICD was associated with lower levels of psychological well‐being and reduced physical and emotional role functioning than the group who didn't receive an ICD (Namerow 1999). However, a recent analysis from the Sudden Cardiac Death ‐ Heart Failure Trial (SCD‐HeFT) showed that subjective measures of physical function did not differ significantly between the ICD and placebo groups at any time point, but that there was a short‐term increase in psychological well‐being among patients with ICDs throughout the first year after implantation, a benefit that did not persist to 30 months (Mark 2008). The occurrence of ICD shocks reduced the quality of life, but only if quality of life was measured within one to two months after the shock (Mark 2008).

Amiodarone has been proposed as an alternative to ICD, being categorized as a IIa level of evidence for prophylaxis of SCD in patients with coronary heart disease (Priori 2001). However, evidence favouring this drug is controversial: some studies have shown moderate efficacy (Heidenreich 2002; Strickberger 2003), but others have not (Bardy 2005). A recent systematic review concluded that ICD discharges were reduced in patients with ICD and amiodarone compared to patients with ICD without amiodarone. Assuming ICD discharges follow ventricular arrhythmias it could be assumed that amiodarone reduces the number of arrhythmic episodes (Ferreira 2007). If amiodarone proves to be beneficial in SCD prevention, it would constitute a valid alternative in situations where economic constraints limit the widespread use of ICD.

The use of amiodarone, however, is not free of adverse effects. Its use has been associated with toxicity involving the lungs, thyroid gland, liver, eyes, skin and nerves (Connolly 1997), the pulmonary toxicity being its most serious potential adverse effect (it has been described in some series as frequent as 17%, but the incidence when compared with placebo is <1%) (Pollak 1999), and thyroid toxicity the most common complication that requires intervention, being described in up to 10% of patients receiving long‐term amiodarone therapy. The frequency of most adverse effects is related to total amiodarone exposure (Siddoway 2003). Minor adverse effects are nausea, anorexia, photosensitivity, and a blue discoloration of the skin (Siddoway 2003).

Chronic treatment with antiarrhythmic drugs is also associated with severe adverse effects, including the potential induction of life‐threatening arrhythmias e.g. increased mortality is associated with the long term use quinidine (Coplen 1990).

Furthermore, data collected during the last 20 years has convincingly proven that beta‐blocking treatment is associated with an improved clinical outcome in several patient groups. The efficacy of this treatment in post‐MI patients relates to a drug‐associated reduction in all‐cause mortality and is not necessarily related to the time after the acute event when therapy is started (Yusuf 1985). Patients with a history of congestive heart failure or depressed left ventricular function tend to show the greatest benefit in mortality reduction.

Data suggests that in patients post‐MI, potasium channel blockers such as d‐sotalol (Waldo 1996) or dofetilide (Køber 2000; Torp‐Pedersen 1999) have a neutral or even harmful effects regarding to all‐cause mortality. However, calcium‐channel blockers such as verapamil have shown favorable effects only in the population without heart failure (DAVIT II 1990).

As the risk of SCD in patients with an ICD is much lower than the risk in patients without, one might assume that they are two different populations in terms of their baseline risk, and therefore interpretting the pooled results from trials of the effects of amiodarone in patients with and without ICDs might be misleading, so we'll conduct a different analysis for each population.

The aim of this review is to assess the role of amiodarone in primary and secondary prevention of sudden cardiac death in high‐risk patients, with and without ICD, compared to placebo or other antiarrhythmic drugs.