Contemporary versus tradition: Implantable cardioverter defibrillator use in nonischemic dilated cardiomyopathy

Chu-Pak Lau; Shu Zhang

doi:10.4103/IJHR.IJHR_1_18

EDITORIAL

Year : 2017 | Volume : 2 | Issue : 2 | Page : 53-57

Contemporary versus tradition: Implantable cardioverter defibrillator use in nonischemic dilated cardiomyopathy

Chu-Pak Lau¹, Shu Zhang²
¹ Department of Medicine, Division of Cardiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, Beijing, China
² The Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Date of Web Publication

31-Jan-2018

Correspondence Address:
Chu-Pak Lau
Department of Medicine, Division of Cardiology, Queen Mary Hospital, The University of Hong Kong, Suite 1303, Central Building, 1 Pedder Street, Central, Hong Kong SAR
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/IJHR.IJHR_1_18

How to cite this article:
Lau CP, Zhang S. Contemporary versus tradition: Implantable cardioverter defibrillator use in nonischemic dilated cardiomyopathy. Int J Heart Rhythm 2017;2:53-7

How to cite this URL:
Lau CP, Zhang S. Contemporary versus tradition: Implantable cardioverter defibrillator use in nonischemic dilated cardiomyopathy. Int J Heart Rhythm [serial online] 2017 [cited 2023 Jun 5];2:53-7. Available from: https://www.ijhronline.org/text.asp?2017/2/2/53/224354

Introduction

The major cardiac mortality in patients with nonischemic dilated cardiomyopathy (NIDCM) is either sudden cardiac death (SCD) or progressive heart failure. Ventricular tachyarrhythmias (VAs) due to ventricular tachycardia or fibrillation are major causes of SCD, but asystole and pulseless electrical activities become more important as heart failure progresses. Implantable cardioverter defibrillators (ICDs) are the traditional cornerstone for SCD prevention, but their efficacy in NIDCM is recently challenged by newer clinical data.

Primary Prevention

For primary prevention, both the United States AHA/ACC/HRS ^[1] and European ESC ^[2] guidelines have used left ventricular ejection fraction (LVEF) and the degree of symptomatic heart failure as criteria for ICD prescription. Patients with NIDCM and an LVEF ≤35%, with NYHA class II–III heart failure symptoms are class I candidates for ICD implantation. These are based on the cardiomyopathy trial (CAT),^[3] amiodarone versus implantable cardioverter–defibrillator trial,^[4] Defibrillators in nonischemic Cardiomyopathy Treatment Evaluation,^[5] and the SCD in Heart Failure Trial (SCD-HeFT).^[6] These studies were published before 2006 and showed a combined 31% of reduction in total mortality in the ICD versus medical therapy arm in a meta-analysis,^[7] a result mainly driven by a 56% SCD reduction.

In view of the changes in heart failure management that have occurred over the last 10 years that have included the use of the cardiac resynchronization therapy (CRT), the increase in patient longevity and comorbidities that increase the proportion of death from noncardiac causes, the role of the ICD in NIDCM has now been questioned.

The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial ^[8] randomized patients with either NIDCM or ischemic DCM who are in Class III-IV heart failure with a QRS interval of ≥120 ms to receive either medical therapy or CRT. These patients have higher baseline mortality compared to other ICD trials as Class IV heart failure patients were included. The use of CRT defibrillator (CRT-D) but not CRT reduced total mortality over medical therapy, although it was not sure if the effect was due to ICD or CRT alone. Indeed, the study did not show mortality difference between CRT-D versus CRT. The benefit of CRT/CRT-D were observed in both ischemic or NIDCM. CRT represents an important means to reduce heart failure in patients with prolonged QRS interval.

Published in 2016, the defibrillator implantation in patients with nonischemic systolic heart failure (DANISH)^[9] trial is a focus study on this issue. In 1116 patients with systolic heart failure, defibrillators were used in 556 patients, and 560 patients were assigned to usual heart failure management. In 58% of these patients who had prolonged QRS interval at baseline, a background CRT therapy was used in either arms (CRT-D vs. CRT). Defibrillator therapy was not shown to change total mortality versus control arm over a median of more than 5 years of follow up, although the SCD rate (a secondary endpoint) was significantly reduced from 8.3% to 4.3%. The study was powered to detect a difference of 25% in total mortality. According to the authors, the lack of significant mortality difference with ICD use compared to prior trials can be due to lower VAs risk in NIDCM than ischemic cardiomyopathy, the beneficial impact of CRT, and the high percentage patients using angiotensin-converting enzyme inhibitor (ACEI) and beta-blockers (BB) (both >90%) and mineralocorticoid blockers (MC) (60%) compared to older studies and vigorous exclusion of coronary artery disease. The recent AHA/ACC/HRS guideline ^[1] has not considered the results of DANISH trial in their recommendation based on the fact that over half of DANISH trial patients were eligible for CRT, and the conclusion in this study may not be applicable to the general CRT-ineligible heart failure candidates.

[Figure 1] shows the demographics and the SCD rates in the controlled arms of the major studies of defibrillators in NIDCM. With the exception of the COMPANION trial, which is a CRT trial in more advanced heart failure patients, the DANISH recruited the oldest patients, had the longest follow-up and the lowest annual mortality. In addition, there was an initial separation of mortality rates between the ICD versus control arms, although the two curves come together with follow-up [Figure 2]a. This is unlike the continued benefit of ICD for ischemic DCM ^[10] [Figure 2]b. This suggests that over time with progression of heart failure, or development of comorbidities or both in these patients, the benefit of ICD in NIDCM becomes attenuated. Several meta-analyses have since been published combining these trial data. Total mortality was reduced by 24% when all trials using ICD/CRT-D.^[11] Such meta-analyses that include trials performed at disparate times are limited by major difference in patients demographic and changes in heart failure treatment that have occurred over time.

Figure 1: Demographic and outcome of 5 randomized trials on implantable cardioverter defibrillator in nonischemic dilated cardiomyopathy patients: Cardiomyopathy trial (CAT),^[3] amiodarone versus implantable cardioverter–defibrillator trial (AMIOVIRT),^[4] defibrillators in nonischemic cardiomyopathy treatment evaluation DEFINITE,^[5] sudden cardiac death-Heart Failure Trial SCD-HeFT,^[6] and defibrillator implantation in patients with nonischemic systolic heart failure (DANISH).^[9] COMPANION^[8] is a trial on cardiac resynchronization therapy defibrillator versus cardiac resynchronization therapy in a more advanced heart failure population and is shown for comparison. These trials have included a total of 104, 103, 458, 2571, 1116, and 1520 patients, respectively (listed in parenthesis).^{[3],[4],[5],[6],[8],[9]} EF = ejection fraction, FU = follow-up

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Figure 2: Total mortality between implantable cardioverter defibrillator and control arm in dilated cardiomyopathy (DANISH trial^[9]) and ischemic cardiomyopathy (MADIT-II long-term outcome^[10]). The curves separate and converge overtime for nonischemic dilated cardiomyopathy (a), but continue to separate in the ischemic cardiomyopathy trial (b)

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Secondary Prevention

Three randomized controlled trials ^{[12],[13],[14]} have compared ICDs versus medical therapy in survivors of SCD or clinical VAs. While 1963 patients were enrolled in these 3 trials, only 292 (14.8%) had NIDCM. In a meta-analysis,^[7] a nonsignificant 31% reduction in all-cause mortality was observed. These trials were underpowered as NIDCM patients comprised only a small proportion of these patients. For example, in the Antiarrhythmics versus Implantable Defibrillators trial,^[12] which is the largest of these 3, 19% of 1,016 patients had NIDCM, and ICDs improved overall survival from 82.3% to 89.3%. Amiodarone was the main medication used in the medical therapy arm (>80%), and BB was used more often in the ICDs arm (~60%). In the recent 2017, AHA/ACC/HRS ^[1] guideline for the management of VAs and SCD, survivors of SCD or in those with spontaneous VAs not due to reversible causes are Class I candidates for ICDs. If VA was induced in electrophysiology study, or syncope presumed to be due to VAs, these patients have a Class II indication for ICDs, provided that they have a meaningful survival of more than 1 year. Clearly, these recommendations are based on limited trial data. However, given that survivors of SCD or the presence of VAs in NIDCM carries grave prognosis, and the inefficacy of current antiarrhythmic medications, it is unlikely that randomized trials will be performed on secondary prevention in NIDCM.

Contemporary Heart Failure Management

The differences in outcome of primary prevention trials in NIDCM reflect improvement in heart failure management, increase in proportion of progressive heart failure related death, and an aging population with noncardiac death due to comorbidities.

Failure of implantable cardioverter defibrillator therapy in treatment of arrhythmia

ICD therapies will fail in the presence of pulseless electrical activity or high defibrillator threshold. Indeed, the proportion of pulseless electrical activity in patients dying suddenly has increased. Out of hospital cardiac events due to VAs decreased from 63% to 47% over a 10 years period in the Netherlands, with increasing proportion of non-VA-related sudden death.^[15] VAs may be terminal events of heart failure. Furthermore, postshock electromechanical dissociation is increasingly recognized.^[16] In addition, with decompensated hemodynamics and patients on antiarrhythmic drugs, ICD and pacing therapy will fail even in the presence of VAs or asystole. On the other hand, appropriate ICD programming, especially in reducing unnecessary shocks may also have improved the survival benefit of ICD which was not universally considered in these trials.^[17]

Improvement in medical therapy and cardiac resynchronization therapy

[Figure 3]a shows the additional benefit of pharmacological therapy on heart failure.^[18] Additive use of ACEI, BB, and MC result in incremental survival benefit. The recent combined use of MC and neprilysin inhibitors results in a 63% reduction in survival compared to controls versus a 17% reduction with ACEI use alone.^[19] Indeed, neprilysin inhibitor with angiotensin receptor blocker reduces death compared with ACEI, and SCD comprised 32% of these deaths in Europe and America and 52% in Asians.^[20] The adherent to ACEI, BB, and MC medications was highest in the DANISH trial [Figure 3]b. This could have contributed to an annual SCD event rate lower than 2%. The use of CRT in the COMPANION trial has shown a dramatic 36% reduction of death over ICD therapy in those with prolonged QRS interval on top of optimal pharmacological therapy. Prevention of SCD using ICD therapy with such a low background event rate associated with current therapy is increasingly difficult to demonstrate.

Figure 3: Improvement in medical therapy and CRT. (a) Benefit of incremental medical therapy on heart failure survival. (b) Utilization rate of pharmacological therapy in ICD trials (Trials reference as in legend of Figure 1). CRT = cardiac resynchronization therapy, ICD = implantable cardioverter defibrillator, ACEI = angiotensin-converting enzyme (ACE) inhibitor, ARB = angiotensin receptor blockers, BB = beta-blocker, ARNI = angiotensin receptor-neprilysin inhibitors, MC = mineralocorticoid blockers

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Heart failure progression, aging, and sudden cardiac death

With better management of heart failure, patient survival is now longer, and many of them will progress to a more advanced stage of heart failure. It is well recognized that as NYHA class worsened, the proportion of death that is sudden will fall compared to those with a better NYHA class.^[21] Even among the SCD group, more will die of asystole and pulseless electrical activities that ICD therapy does not benefit. Importantly, with advanced age, more of them will suffer from noncardiac death due to comorbidities and non-SCD causes.^[22] In fact, the benefit of ICD will decrease as the age of the patient increase in all ICD trials.^[23]

Evolving Management of Sudden Cardiac Death in Nonischemic Dilated Cardiomyopathy

ICD implantation carries significant implant and long-term risks. Given the reduced benefit of ICD use in currently well-managed patients with NIDCM for SCD, there is a need to improve the cost/efficacy of ICD therapy.

Genetic predisposition

Familial type of DCM can be due to mutations in sarcomere and desmosomal protein gene; proteins that directly affect cardiac contractile muscle. An important gene is the lamin A/C mutations, in which patients present with asymptomatic conduction disease for decades, followed by atrial arrhythmias and VAs and DCM. In the setting of a familial occurrence of DCM and conduction disturbance, screening of lamin A/C mutation and SCN5A genes are recommended. A mutation-specific screening is indicated in family members if a patient has documented mutation in a DCM-related genes, as recommended by the combined Heart Rhythm Society and European Heart Rhythm Society.^[24]

Noninvasive predictors of sudden cardiac death

The majority of DCM patients do not have a familial occurrence. Hence, predictors of future VAs have relied on risk factors evaluation. These risk factors include (1) autonomic parameters; (2) structural/functional parameters such as LVEF and left ventricular dimensions; and (3) arrhythmia indicators such as electrophysiology testing and electrocardiographic (ECG) depolarization and repolarization abnormalities. In a meta-analysis of 12 conventional parameters involving 45 trials in 6088 patients,^[25] autonomic parameters were found to be unpredictive. Structural/functional and ECG parameters are helpful, but their overall specificities range only from 36.2% to 87.3%, with sensitivities between 28.8% and 91.0%. Indeed, LVEF, the basis on which ICD therapy is prescribed, has only a sensitivity and specificity of 71.7% and 50.5% and a positive predictive accuracy of 21.9%.

VAs originated from trigger or reentry, often from fibrous tissues that develop in the myocardium of DCM. The use of late gadolinium enhancement (LGE) to detect LV scarring has been proposed as a marker of VA. Indeed, positive LGE in the LV increases the VA risk almost 10 folds, both in patients with LVEF below and above 35%.^[26] In a recent cohort studies that include only patients with mildly impaired LVEF of ≥40%, the 4-year arrhythmic risk was 17.8% versus 2.3% in those with and without LGE.^[27] LGE defines the VA substrate and may emerge as a good marker to predict SCD independent of the LVEF.

Ventricular tachycardia ablation

Triggers for VA such as hypokalemia, thyrotoxicosis, and new-onset ischemia should be promptly diagnosed and treated. VA ablation can be performed, but due to the often patchy fibrosis that can involve multiple myocardial layers, the success rate of VA ablation is less durable than VA ablation in cardiomyopathy due to ischemic heart disease,^[28] notwithstanding the reported low acute success rate of 22.2%.

Conclusion

The benefit of primary prevention ICDs for mortality in DCM is now significantly reduced due to better medical care and the use of CRT. Nevertheless, the benefit on SCD prevention remains valid. Better identification of patients with higher risk of SCD such as younger age and those with positive left ventricular LGE may allow a better cost performance of ICD. Prospective trials using parameters such as myocardial scar assessment to decide on the best ICD strategies will be need.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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