Filling the Gap
A. BARANCHUK, C. MORILLO
Introduction
Sudden cardiac death (SCD) remains a major public health challenge in both North America and Europe. Identifying high-risk patients is of paramount importance in order to correctly select the population that derives the great- est benefit from ICD implantation. Unfortunately, risk markers developed to date are not universally applied and have low sensitivity and predictive val- ues, limiting their use. Financial restraints on health care systems vary wide- ly among different countries, adding complexity to global recommendations.
Cardiovascular disease is responsible for 40 000 deaths annually in Canada, and SCD related to ventricular tachyarrhythmias causes 50% of this mortality [1]. In the United States the annual figures for SCD range between 300 000 and 450 000 [2]. In addition, around 5 000 000 people live with chronic heart failure, with 550 000 new cases added every year. Almost 10%
will die annually of either progressive pump failure or SCD [3]. The global incidence of SCD is difficult to estimate in Europe, but the Maastricht study showed an annual incidence of out-of-hospital SCD of 1 in 1000 inhabitants, which is similar to that reported in North America [4].
Several guidelines and recommendations have been published by most of the leading cardiovascular societies [5]. However, it is important to recognise that SCD is a moving target, and in the past 3 years important clinical trials not included in current guidelines have been reported. A thorough review of SCD guidelines is out of the scope of this review. This chapter will focus on the most recently published and presented trials and will place this new information in the framework of current SCD guidelines.
Department of Medicine, Arrhythmia Service, McMaster University, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada
Indications for ICD for Primary Prevention
Several studies have assessed the effec t iveness of implantable cardioverter–defibrillators (ICDs) for the prevention of SCD in high-risk populations. These studies may be classified according to the underlying anatomical substrate:
1. Coronary artery disease + left ventricular ejection fraction (LVEF) <
30–35%: MADIT I, MADIT II, MUSTT, DINAMIT [6–9]
2. Non-ischaemic dilated cardiomyopathy + depressed LVEF: CAT, AMIOVIRT, DEFINITE [10–12]
3. LVEF ≤ 35% + NYHA class II/III regardless of the aetiology of the car- diomyopathy SCD-HeFT [13, 14]
Overall a 39% relative risk reduction in all-cause mortality [31% in non ischaemic dilated cordiomyopathy (NICM)] is achieved in the setting of pri- mary prevention of SCD [15, 16] Current guidelines should be updated as follows:
1. Class I: Ischaemic heart disease with or without mild to moderate heart failure symptoms and LVEF ≤ 30%, measured at least 1 month after myocardial infarction and 3 months after coronary revascularisation pro- cedure [percutaneous coronary interventions (PCI) and/or coronary artery bypass graft (CABG)] (level of evidence: A)
2. Class IIa:
a) Patients with ischaemic heart disease and LV dysfunction (LVEF = 31–35%), measured at least 6 weeks after myocardial infarction and 3 months after coronary revascularisation procedure (PCI and/or CABG) with inducible ventricular fibrillation (VF)/sustained ventric- ular tachycardia (VT) at electrophysiology study (level of evidence: B) b) Patients with non-ischaemic cardiomyopathy ≥ 9 months, LVEF ≤ 30%,
and NYHA functional class II–III heart failure (level of evidence: B) c) Patients with familial or inherited conditions such as but not limited
to long QT syndrome, hypertrophic cardiomyopathy, Brugada syn- drome, or arrhythmogenic right ventricular dysplasia (ARVD) and at a high risk for life-threatening ventricular tachyarrhythmias (level of evidence: B)
3. Class IIb:
a) Patients with ischaemic heart disease, prior myocardial infarction, LV dysfunction (LVEF = 31–35%), with either no inducible VF/sustained VT at electrophysiology study, or without an electrophysiology study (level of evidence: C)
b) Patients with non-ischaemic cardiomyopathy present for at least 9 months, LV dysfunction (LVEF = 31–35%) and NYHA functional class II–III heart failure (level of evidence: C)
ICD Indications after an Acute Myocardial Infarction
The first 6–12 months after an acute myocardial infarction (AMI) are a peri- od of high risk for SCD. However, the benefit of ICDs in this setting has not been fully studied. The DINAMIT study was a randomised, open-label study that compared ICD therapy to no ICD therapy in 674 patients during the immediate period after an AMI (6–40 days). Inclusion criteria were: LVEF
≤ 35%, heart rate variability standard deviation of normal RR intervals (SDNN) ≤ 70 ms or a mean RR interval ≤ 750 ms (heart rate ≥ 80 bpm) by 24-h Holter monitoring. The primary outcome was total mortality. There was no difference in overall mortality between the two groups (95% CI, 0.76 to 1.55; P
= 0.66; follow-up 30 ± 13 months). However, there was a reduction in arrhythmic deaths that was manifested by an increase in non-arrhythmic deaths in the ICD group [9].
Based on the DINAMIT study findings, the decision to implant an ICD should be delayed for at least 6 weeks and possibly more in patients with a recent myocardial infarction and reduced LV function. Reassessment of LV function is required in order to define the need for an ICD.
Indications for ICD for Secondary Prevention
There is conclusive evidence supporting the superiority of ICDs over drugs for the secondary prevention of SCD [17–19]. A meta-analysis of secondary prevention trials reported a 28% relative risk reduction in all-cause mortali- ty. This reduction was almost entirely due to a 50% relative risk reduction in arrhythmic deaths. Greater benefit is derived in patients with an LVEF <
35% [20]. Current guidelines support the use of ICDs in patients surviving a cardiac arrest or having presented with symptomatic sustained VT with reduced LV function regardless of aetiology.
ICD Indications for Infrequent Clinical Conditions
The less common cardiac disorders such as hypertrophic cardiomyopathy, Brugada syndrome, long QT, and arrhythmogenic right ventricular dysplasia are difficult to include in general guidelines due to their low incidence.
However, sudden death is relatively frequent and is a devastating clinical pre- sentation that could affect young people, and ICDs are sometimes the only available alternative [21, 22] (Table 1). Risk stratification of diseases with low prevalence is challenging. However, some useful recommendations based on small non-randomised studies and expert opinions may be proposed.
The diagnosis of Brugada syndrome [23] is based on typical 12-lead ECG
findings (ST segment elevation in leads V1–V3) in subjects with either a family history of unexplained SCD or syncope or presenting with symptoms.
The role of an electrophysiology study in determining the risk of death remains uncertain; however, ICD implantation is recommended in patients who survive an episode of VT/VF [24]. The evidence is in favour of including as high-risk patients those with a previous history of syncope and a familial history of SCD.
SCD may frequently be the primary manifestation of the long QT syn- drome. There are clinical indicators such as history of syncope, ECG charac- teristics, cardiac arrest and torsades de pointes, and genetic markers that may help identify subjects at higher risk. ICD is recommended for secondary prevention while primary prevention is based mostly in the treatment with beta-blockers and life-style changes [25].
Arrhythmogenic right ventricular dysplasia may be a cause of SCD in the younger groups. Evidence identify ing high-risk subgroups is sparse.
Nonetheless, ICD is indicated in patients with VT/VF that are refractory to anti-arrhythmic agents. Patients with LV involvement or severe compromise of the right ventricle are at higher risk [26].
There is sparse evidence to provide definitive recommendations regard- ing the role of ICD in patients with catecholaminergic polymorphic VT.
Nonetheless, it is reasonable to recommend an ICD for secondary prevention or after beta-blockers have failed [27].
The level of evidence for all of these disorders is C, and larger studies assessing the role of primary prevention and better means for risk stratifica- tion are certainly needed. Careful assessment of family history, searching for early unexplained deaths, ‘seizures’, and recurrent syncope, may aid individ- ualising the decision to implant an ICD in a young subject.
Table 1.ICD recommendation for infrequent cardiac disorders
Disease Primary prevention Secondary prevention
Long QT – Class I
ARVD Class IIa Class I
HCM Class IIa Class I
Brugada Class Ia Class I
CPVT – Class I
ARVD, arrhythmogenic right ventricular dysplasia; HCM, hypertrophic cardiomy- opathy; CPVT, catecholaminergic polymorphic VT
a Patients with syncope and no documented VT
ICD or ICD and Cardiac Resynchronisation Therapy
A number of cardiac resynchronisation therapy (CRT) studies have demon- strated an improvement in quality of life, exercise tolerance, and NYHA class in patients with heart failure and prolonged QRS. However, the benefits in relation to mortality have not been clearly established. The COMPANION study was designed to evaluate the role of the addition of ICD therapy to CRT. The primary outcome was a composite of total mortality and hospitali- sations related to heart failure. COMPANION showed a significant reduction in the primary outcome for both CRT and CRT-ICD. However, mortality was significantly reduced only in the CRT-ICD arm, a 40% relative risk reduction [28, 29, 31]. This effect was significant regardless of the aetiology of heart failure.
It still remains unclear whether the effect of CRT-ICD is due to a syner- gistic effect between the different therapies or if it is only caused by a reduc- tion in arrhy thmic deaths due to the presence of an ICD in high-risk patients. Ongoing studies are currently addressing this issue. Current evi- dence supports the use of CRT-ICD in patients who fulfill both criteria. This is a class IIa indication with level of evidence A.
Health-Economic Considerations
The economic implications of ICD implantation are unquestionable [31, 32].
The issue is rather how to scientifically and economically judiciously use the limited resources available. Further refining of risk-stratifying markers such as T wave alternans may aid in this decision. However, a prospective trial using a ‘risk score’ may need to be developed. Compared to other medical therapies, ICDs may be economically sound. Figure 1 shows the calculated number needed to treat to save one life in the different ICD-CRT clinical tri- als. These should provide a general perspective on the potential economic justification of ICD therapy. It is important to recognise that clinical trials are limited by the fact that they do not take into account the relentless pro- gression of the disease in patients with impaired LV function. Nevertheless, the benefit is clear, and physicians and health authorities should team up to create responsible policies that should be adapted to each country’s resources.
Conclusions
Evidence-based large clinical trials have undoubtedly demonstrated the ben- efits of ICD in specific populations. Guidelines are intended only as a tool to aid in the decision whether to implant an ICD or CRT device. The responsi- bility of physicians is primarily towards their patients, but judicious use of health care resources is critical to be able to provide a fair share to all the patients in need of these devices.
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