Introduction

Sudden cardiac death (SCD) is a major cause of mortality among patients with end-stage renal disease (ESRD). Implantable cardioverter-defibrillators (ICDs) can effectively terminate ventricular tachycardia (VT) and ventricular fibrillation (VF) and are often considered the standard of care for secondary prevention of SCD and for primary prevention in patients at risk for SCD.¹ Yet patients on dialysis were notably excluded from the pivotal trials that established the mortality benefit of ICD therapy. Hence, the utility of ICD implantation in these patients with ESRD is not clear. Furthermore, the role of ICD therapy for primary prevention of SCD in patients with ESRD without the main risk factor of a left ventricular (LV) ejection fraction ≤35% had previously not been studied. Therefore, the aim of the recently published ICD2 (Implantable Cardioverter-Defibrillator in Dialysis Patients) trial was to answer this relevant unanswered question.

SCD in Patients With ESRD

The risk of death in patients on dialysis is high, and SCD is reported to be the major cause of death among patients with ESRD. Although the exact percentage varies by source, the 2018 report by the United States Renal Data System attributed 40% of known causes of death among patients with ESRD to arrhythmia or cardiac arrest.² Overall, 22-26% of all deaths among patients on dialysis are reported as SCD.^3-5

In general, SCD is thought to result from VT/VF most commonly associated with ischemic heart disease and structural heart disease such as heart failure with reduced ejection fraction.⁶ The pathophysiology of SCD, however, has additional unique features in patients with ESRD. First, reduced ejection fraction may be less common among patients on dialysis who suffer SCD compared with the general population.⁷ On the contrary, LV hypertrophy and diastolic dysfunction are often observed in patients with ESRD, and a previous study identified worsening LV hypertrophy as the strongest predictor of SCD in patients on dialysis.⁸ Non-physiologic electrolyte and fluid shifts inherent to dialysis may also increase the risk of arrhythmias; dialysis prescription and day of the week in relation to the dialysis schedule have also been shown to alter the risk of arrhythmias among patients on dialysis.^9,10

Underrepresentation of Patients With ESRD in the Pivotal Trials

An ICD is considered the standard of care for the secondary prevention of SCD and for primary prevention of SCD in patients with LV systolic dysfunction with optimal medical therapy.¹ However, patients with ESRD were excluded from the pivotal trials that established the mortality benefit of the ICDs in these high-risk patients.^11-14 Hence, the benefit of ICD therapy in patients on dialysis who meet these guideline indications is not clear. In terms of secondary prevention, several retrospective studies have suggested improved survival of patients on dialysis with ICD therapy following sudden cardiac arrest.^15,16 Similar evidence is lacking for primary prevention in patients with LV systolic dysfunction and concomitant ESRD. In a post-hoc analysis of MADIT-II (Multicenter Automatic Defibrillator Implantation Trial-II), benefit from ICD therapy was not observed among patients with chronic kidney disease and estimated glomerular filtration less than 35 ml/min/1.73 m².¹⁷ In a propensity-matched cohort study of patients with ESRD with reduced LV dysfunction, primary prevention ICD was not associated with reduced mortality among patients with ERSD.¹⁸ Further studies are needed to establish the clinical benefit of ICD therapy in these patients with ESRD who are at risk for SCD. Currently, the international guidelines do not put forth special recommendations regarding the use of ICD specifically in patients on dialysis.^6,19

The ICD2 Trial

Patients on dialysis are at substantial risk of SCD independent of LV ejection fraction because many of these patients do not have reduced ejection fraction. Can we prevent SCD with ICD in patients with ESRD and improve overall mortality?

The ICD2 trial was a prospective, randomized controlled study of primary prevention ICD therapy among patients on dialysis without significant LV dysfunction (≥35%).²⁰ The patients underwent screening to establish that they were relatively healthy to ensure the possibility of improved mortality with ICD therapy. Patients were between 56 and 81 years of age and had been treated with dialysis for ≥90 days. Patients were excluded if they had a history of end-stage heart failure, recent myocardial infarction, human immunodeficiency virus, or another medical condition that made 1-year survival unlikely. After randomization, patients were referred to an experienced center specifically for device implantation. The primary end point was SCD. The secondary end points were all-cause mortality and adverse events related to ICD. A total of 220 patients on dialysis was screened; of those, 188 were eligible for inclusion and randomized to the ICD arm (97 patients) or to usual care (91 patients). The main analyses were performed by intention-to-treat.

The trial was stopped early for futility reasons after inclusion of 188 patients. Overall survival probability at 5 years was 52.4% and was similar between the 2 groups: 50.6% in the ICD group and 54.5% in the control group with a hazard ratio of 1.02 (95% confidence interval, 0.69-1.52; p = 0.92). Cumulative incidence of SCD at 5 years was 8.9% and was also similar between the 2 groups: 9.7% in the ICD group and 7.9% in the control group, resulting in a hazard ratio of 1.32 (95% confidence interval, 0.53-3.29; p = 0.55). Eleven patients (13.8%) received appropriate ICD therapy following implantation (4 for VF and 8 for transient VT, successfully terminated in 3). Cause of death was reported to be similar between the 2 groups. Surprisingly, the most common cause of death was attributed to infectious disease in both groups, followed by SCD.

There are several possible explanations for the outcome of this study. First, the prevalence of SCD was lower in this study (n = 19, 10.1%) compared with the previous reports.^2-5 Although the discrepancy could be a result of selection bias (selection of relatively healthier patients on dialysis in this study), it could also point to issues such as misclassification of cause of death in studies and registries, attributable to inconsistent definitions and non-standardized methods of assessment of the cause of death. In a meta-analysis of 42 trials and studies, the reported incidence of SCD among patients with ESRD ranged from 0.4 to 10.04 deaths per 100 person-years.²¹ The study identified wide heterogeneity in definitions and adjudication methods across studies. Furthermore, although in general VT/VF are thought to be the most common causes of SCD, the true incidence of VT/VF among patients on dialysis is not clear. A recent prospective study using implantable loop recorders demonstrated bradyarrhythmia as the most common and significant arrhythmic event in patients with ESRD.²² If the true incidence of VT/VF was previously overestimated in patients on dialysis, it is feasible that ICD therapy would not improve survival. Second, despite the lower incidence of SCD in this study, overall mortality was still substantial (47.6% mortality at 5 years), with the most prevalent cause attributed to infection (29%). Hence, the significant comorbidities of patients on dialysis and the competing causes of non-cardiac death may blunt the effect of ICD therapy on patient mortality. Third, the study demonstrated significant rates of ICD complications among patients on dialysis:

• 25 adverse events occurred in 22 patients (27.5%)
• 11 re-interventions occurred in 10 patients
• Device extraction occurred in 6 patients (7.5%), 4 due to recurrent bacteremia

A retrospective analysis of The National Cardiovascular Data Registry ICD Registry data also found that risk of mortality following primary prevention ICD was proportional to the severity of renal dysfunction.²³ Another retrospective study demonstrated an independent association of ESRD with in-hospital complications following ICD implantation.²⁴ The higher risk of complication with ICD implantation may further blunt the effect of defibrillation therapy on clinical outcomes in patients on dialysis.

Conclusion

The authors of the ICD2 trial should be commended on the rigorous study methodologies used to answer, once and for all, the question of whether ICD therapy can save the lives of patients on dialysis without depressed LV ejection fraction. The study suggests that the much-needed answer is no. Despite the generally reported high burden of SCD among patients with ESRD, in this prospective randomized trial of patients on dialysis without significant LV dysfunction, ICD therapy did not lead to improved survival or reduction in SCD. This study also pointed to lower incidence of SCD than previously reported and high rate of ICD-related complication in patients on dialysis, both of which may have mitigated the mortality benefit of defibrillation therapy in these patients. Uncertainties remain in terms of ICD therapy for secondary prevention of SCD in patients on dialysis and primary prevention of SCD among patients with LV dysfunction and comorbid ESRD. The findings from the ICD2 trial, nonetheless, offer important insights into the role of ICD therapy in patients with ESRD.

References

1. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2013;61:e6-75.
2. Chapter 5: Mortality (United States Renal Data System website). 2019. Available at: https://www.usrds.org/2018/view/v2_05.aspx. Accessed August 8, 2019.
3. Cheung AK, Sarnak MJ, Yan G, et al. Cardiac diseases in maintenance hemodialysis patients: Results of the HEMO Study. Kidney Int 2004;65:2380-9.
4. Parekh RS, Plantinga LC, Kao WHL, et al. The association of sudden cardiac death with inflammation and other traditional risk factors. Kidney Int 2008;74:1335-42.
5. Jadoul M, Thumma J, Fuller DS, et al. Modifiable practices associated with sudden death among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Clin J Am Soc Nephrol 2012;7:765-74.
6. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: Executive Summary. Circulation 2018;138:e210-71.
7. Genovesi S, Valsecchi MG, Rossi E, et al. Sudden death and associated factors in a historical cohort of chronic haemodialysis patients. Nephrol Dial Transplant 2009;24:2529-36.
8. Paoletti E, Specchia C, Di Maio G, et al. The worsening of left ventricular hypertrophy is the strongest predictor of sudden cardiac death in haemodialysis patients: a 10 year survey. Nephrol Dial Transplant 2004;19:1829-34.
9. Karnik JA, Young BS, Lew NL, et al. Cardiac arrest and sudden death in dialysis units. Kidney Int 2001;60:350-7.
10. Pun PH, Lehrich RW, Honeycutt EF, Herzog CA, Middleton JP. Modifiable risk factors associated with sudden cardiac arrest within hemodialysis clinics. Kidney Int 2011;79:218-27.
11. Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000;101:1297-302.
12. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877-83.
13. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37.
14. Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997;337:1576-83.
15. Herzog CA, Li S, Weinhandl ED, Strief JW, Collins AJ, Gilbertson DT. Survival of dialysis patients after cardiac arrest and the impact of implantable cardioverter defibrillators. Kidney Int 2005;68:818-25.
16. Wan C, Herzog CA, Zareba W, Szymkiewicz SJ. Sudden cardiac arrest in hemodialysis patients with wearable cardioverter defibrillator. Ann Noninvasive Electrocardiol 2014;19:247-57.
17. Goldenberg I, Moss AJ, McNitt S, et al. Relations among renal function, risk of sudden cardiac death, and benefit of the implanted cardiac defibrillator in patients with ischemic left ventricular dysfunction. Am J Cardiol 2006;98:485-90.
18. Pun PH, Hellkamp AS, Sanders GD, et al. Primary prevention implantable cardioverter defibrillators in end-stage kidney disease patients on dialysis: a matched cohort study. Nephrol Dial Transplant 2015;30:829-35.
19. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36:2793-867.
20. Jukema JW, Timal RJ, Rotmans JI, et al. Prophylactic Use of Implantable Cardioverter-Defibrillators in the Prevention of Sudden Cardiac Death in Dialysis Patients. Circulation 2019;139:2628-38.
21. Ramesh S, Zalucky A, Hemmelgarn BR, et al. Incidence of sudden cardiac death in adults with end-stage renal disease: a systematic review and meta-analysis. BMC Nephrol 2016;17:78.
22. Roberts PR, Zachariah D, Morgan JM, et al. Monitoring of arrhythmia and sudden death in a hemodialysis population: The CRASH-ILR Study. PLoS One 2017;12:e0188713.
23. Hess P, Hellkamp AS, Peterson E, et al. Survival after primary prevention implantable cardioverter-defibrillator placement among patients with chronic kidney disease. Circ Arrhythm Electrophysiol 2014;7:793-9.
24. Aggarwal A, Wang Y, Rumsfeld JS, Curtis JP, Heidenreich PA; National Cardiovascular Data Registry. Clinical characteristics and in-hospital outcome of patients with end-stage renal disease on dialysis referred for implantable cardioverter-defibrillator implantation. Heart Rhythm 2009;6:1565-71.

Keywords: Arrhythmias, Cardiac, Retrospective Studies, Prospective Studies, Defibrillators, Implantable, Ventricular Fibrillation, Risk Factors, Bradycardia, Secondary Prevention, Selection Bias, Medical Futility, Fluid Shifts, Intention to Treat Analysis, Standard of Care, Stroke Volume, Renal Dialysis, Death, Sudden, Cardiac, Tachycardia, Ventricular, Arrhythmias, Cardiac, Heart Failure, Primary Prevention, Kidney Failure, Chronic, Myocardial Ischemia, Registries, Renal Insufficiency, Chronic, Comorbidity, Bacteremia, Myocardial Infarction, Electrolytes, Hypertrophy

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