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Nephrology Times:
doi: 10.1097/01.NEP.0000415986.18372.fe
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Implantable Cardioverter Defibrillators: Need for Randomized Trials in Kidney Disease

Bansal, Vinod K. MD

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Vinod K. Bansal, MD, a member of the Nephrology Times Editorial Board, is Professor of Medicine in the Division of Nephrology and Hypertension at Loyola University Chicago Stritch School of Medicine. His areas of focus include hypertension and diabetic nephropathy.

Sudden cardiac death accounts for 25% of all deaths in patients with chronic kidney disease (CKD). In those on dialysis, the incidence is even greater—about two-thirds of cardiovascular deaths.1

Vinod K. Bansal, MD...
Vinod K. Bansal, MD...
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The risk of sudden cardiac death is estimated to be 7% per year in patients on dialysis—higher than that of individuals enrolled in randomized clinical trials of defibrillator therapy for primary prevention.2 Studies from the Duke Databank for Cardiovascular Disease (DDCD) indicates a progressive increase in sudden cardiac death risk as the estimated glomerular filtration rate (eGFR) drops in patients with Stage 3–5 CKD and coronary artery disease.3

Given these formidable rates, determining the most effective way to prevent sudden cardiac death in the kidney disease population is critical.

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Primary and Secondary Prevention

Prevention of sudden cardiac death can be primary or secondary. Primary prevention is used in individuals without a history of cardiac arrest or sustained ventricular arrhythmia, while secondary prevention targets patients who survived such an event. Those with a history of cardiac disease and syncope are placed in the secondary prevention category because ventricular arrhythmia is considered the presumptive cause of syncope.4

The most effective way to prevent sudden cardiac death is to place an implantable cardioverter defibrillator (ICD). Primary indications for such a device are ventricular arrhythmias and progressive heart failure.4

Particularly in the case of primary prevention, ICD therapy is recommended for patients who have received optimal medical management and have a reasonable expectation for survival of a year or more. Survival may be very difficult to predict, especially in patients with advanced CKD or ESRD plus multiple comorbidities. Patients with repeated heart failure and renal dysfunction are at a markedly higher risk for early death.5

Another challenging aspect of heart failure management is assessing the true degree of left ventricular ejection fraction (LVEF). The American College of Cardiology/American Heart Association recommendations for primary prevention are based on an LVEF of 40% or less.4 Clinical trials testing the effectiveness of an implantable cardioverter defibrillator have used an LVEF of 40% or less, 30% or less, and intermediate thresholds.6,7

It is important that the parameters for left ventricular ejection fraction be clearly defined and consistent across patient populations. The indications for an ICD as secondary prevention are simpler, as they are defined by the history of cardiac arrest or the presence of sustained ventricular arrhythmia.

Data on the use of an ICD is very limited in patients with end-stage renal disease, and even more limited in those with chronic kidney disease. Almost all clinical trials have excluded these patients.8

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Retrospective Studies

For the most part, what have been reported are retrospective studies with relatively small numbers of patients, presenting challenges for the development of guidelines in patients with CKD or ESRD. Despite the absence of outcome studies and the lack of clinical guidelines, the use of implantable cardioverter defibrillators has continued to increase in patients on dialysis.9

In a retrospective study of 229 patients who had an ICD placed for the primary prevention of sudden cardiac death, 35 had chronic kidney disease (15.3%).10 The patients were followed for 18.0 +/- 15.2 months, and the primary endpoint was death.

The mortality rate was statistically significantly higher in patients who had chronic kidney disease compared with those who did not—48.6% versus 8.2%—and one-year survival was lower—61.2 % and 96.3%, respectively. A Cox regression analysis controlling for age, sex, comorbidities, ejection fraction, and medications established chronic kidney disease as the strongest independent predictor of death, with a hazard ratio of 10.5.

Another retrospective study of patients with CKD, which included individuals on dialysis, compared survival rates in patients with a left ventricular ejection fraction of 35% or less who did or did not receive an implantable cardioverter defibrillator.11 Among the 33 patients with chronic kidney disease who were not on dialysis (mean glomerular filtration rate [GFR] 39 mL/min), two-year survival was significantly better with an ICD—80%, versus 54% in those without an ICD. The benefit persisted after adjustment for gender, race, GFR, digoxin use, and presence of coronary disease, heart failure, or hypertension. Among the 45 dialysis patients, however, there was no survival advantage with an ICD.

Additional studies also have examined the relationship among the severity of kidney disease, the use of an implantable cardioverter defibrillator, and the risk of sudden cardiac death.

According to a sub-analysis of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) by Goldenberg et al, the risk of all-cause mortality increased by 16% for each 10-unit decrease in estimated glomerular filtration rate.12 There was a significant risk reduction with ICD use in patients who had an eGFR greater than 35 mL/min/1.73 m2, but none in those with lower kidney function.

In a more recent report from the Duke Electrophysiology Genetic and Genomic Studies (EPGEN), Williams et al analyzed a cohort of 199 patients with an eGFR less than 60 mL/min.2 The annual mortality rate was 12.2%, and the annual rate of appropriate ICD use was 7%. Lower glomerular filtration rate was a statistically significant predictor of death, with a 10-mL/min decrease in GFR leading to a 48% increase in risk of death. Further adjustment for appropriate ICD therapy did not modify the association of lower eGFR with mortality, the authors concluded.

A separate study by Hage et al found that chronic kidney disease was independently associated with higher mortality when an implantable cardioverter defibrillator was used for primary prevention (43% vs. 15%) but not for secondary prevention.1 The reason for this distinction was left unexplained.

The difference in ICD survival benefit between patients with CKD who are not on dialysis and those on dialysis may be due to disease severity and the corresponding higher prevalence of coronary artery disease. Left ventricular hypertrophy, frequent fluid overload, and electrolytes disturbances may increase the propensity for arrhythmias.13

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Risk for Complications

One concern that has been raised with ICD placement in patients who have chronic kidney disease is a higher incidence of complications.

For example, Tompkins et al reported statistically significantly higher incidences of infection (12.5% vs. 0.2%) and bleeding (21.9% vs. 3.2%) following ICD placement in patients who had ESRD compared with patients who did not.14 The complication rates were slightly lower in patients with chronic kidney disease who were not on dialysis.

In another recent study, Charytan et al analyzed data from the United States Renal Data System (USRDS) on patients who received an implantable cardioverter defibrillator between 1994 and 2006.9 Early in the time period, ICD placement was for secondary prevention, while in more recent times, ICDs were also used for primary prevention.

The mortality rate was high throughout the observation period, reaching 53.4%, with most deaths attributed to cardiovascular causes. The authors also noted a high incidence of infection but didn't comment on whether or not there was a difference in bleeding complications. This study differs from others because data were administratively collected, meaning reporting may have varied from unit to unit.

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Need for Randomized Trial

The reason for poor prognosis after implantable cardioverter defibrillator placement in patients with chronic kidney disease and end-stage renal disease remains elusive. Almost all studies have confirmed that there is increased cardiovascular disease at all stages of chronic kidney disease, and the risk seems to be related to the degree of decline in glomerular filtration rate.

The factors cited for this increased mortality are many and include pathophysiological changes such as hypercoagulability, endothelial dysfunction, arterial calcification, and left ventricular hypertrophy.15 An ICD benefit may not be seen in these patients because of competing mortality risks. However, these observations predominantly are based on retrospective reports, small observational studies, and analyses of USRDS data.

What is required is a prospective randomized study that can provide data for the development of evidence-based guidelines on indications for ICD use in chronic kidney disease and end-stage renal disease. In the absence of such a study, one has to go by what has been developed for patients with normal renal function, expecting a somewhat lesser benefit, but the intervention may still be valuable.

Any reduction in sudden cardiac death events in patients on dialysis will help reduce the already very high annual mortality in this population. Randomized trials that include or focus on patients with chronic kidney disease and end-stage renal disease might help in the development of specific recommendations for implantable cardioverter defibrillator placement.

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1. Hage FG, Aljaroudi W, Aggarwal H, et al. Outcomes of patients with chronic kidney disease and implantable cardiac defibrillator: primary versus secondary prevention. Int J Cardiol 2011 Sept 8 [Epub ahead of print].

2. Williams ES, Shah SH, Piccini JP, et al. Predictors of mortality in patients with chronic kidney disease and an implantable defibrillator: an EPGEN substudy. Europace 2011;13:1717–1722.

3. Pun PH, Smarz TR, Honeycutt EF, et al. Chronic kidney disease is associated with increased risk of sudden cardiac death among patients with coronary artery disease. Kidney Int 2009;76:652–658.

4. Epstein AE, DiMarco JP, Ellenbogen KA, et al. The ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. Circulation 2008;117:e350-e408.

5. Mozaffarian D, Anker SD, Anand I, et al. Prediction of mode of death in heart failure: the Seattle Heart Failure Model. Circulation 2007;116:392–398.

6. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G, for the Multicenter Unsustained Tachycardia Trial Investigators. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999;341:1882–1890.

7. Moss AJ, Zareba W, Hall WJ, et al, for the Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–883.

8. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA 2006;296: 1377–1384.

9. Charytan DM, Patrick AR, Liu J, et al. Trends in the use and outcomes of implantable cardioverter-defibrillators in patients undergoing dialysis in the United States. Am J Kidney Dis 2011;58:409–417.

10. Cuculich PS, Sánchez JM, Kerzner R, et al. Poor prognosis for patients with chronic kidney disease despite ICD therapy for the primary prevention of sudden death. Pacing Clin Electrophysiol 2007;30:207–213.

11. Khan F, Adelstein E, Saba S. Implantable cardioverter defibrillators confer survival benefit in patients with renal insufficiency but not in dialysis-dependent patients. J Intervent Cardiac Electrophysiol 2010;28:117–123.

12. Goldenberg I, Moss AJ, McNitt S, et al, for the Multicenter Automatic Defibrillator Implantation Trial-II Investigators. 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;98:485–490.

13. Robin J, Weinberg K, Tiongson J, et al. Renal dialysis as a risk factor for appropriate therapies and mortality in implantable cardioverter-defibrillator recipients. Heart Rhythm 2006;3:1196–1201.

14. Tompkins C, McLean R, Cheng A, et al. End-stage renal disease predicts complications in pacemaker and ICD implants. J Cardiovasc Electrophysiol 2011;22:1099–1104.

15. Agarwal R, Bunaye Z, Bekele DM, Light RP. Competing risk factor analysis of end-stage renal disease and mortality in chronic kidney disease. Am J Nephrol 2008;28:569–575.

© 2012 Lippincott Williams & Wilkins, Inc.