In patients on dialysis, cardiovascular mortality rates remain very high, and these rates are not explained by traditional risk factors. This elevated risk may be due in part to a much higher incidence of sudden cardiac death (SCD).
The mechanisms and causes underlying SCD are not precisely known, and its prevention with implantable cardioverter-defibrillators (ICDs) remains poor in this patient population. Survival rates after resuscitation are dismal, with a mortality rate much higher than that in patients not on dialysis.
What's in a Name
Sudden cardiac death has been variously defined, but consensus appears to be death within one hour of symptom onset.1 The definition is of critical importance when comparing SCD rates.
In the general population, the rate of sudden cardiac death is reported to be about one per 1,000 patient-years, or about 6% to 13.0% of all deaths in the United States, using the one-hour definition.1,2
The United States Renal Data System (USRDS) reported an SCD rate of 55 per 1,000 patient-years, representing 26.1% of all deaths in patients with end-stage renal disease (ESRD).3 The USRDS includes deaths from confirmed arrhythmias and from cardiac arrest of unknown cause, but without any time specification, under the SCD umbrella. Although this approach may overestimate true incidence, it emphasizes chronic kidney disease (CKD) as an independent risk factor for sudden cardiac death.4
Other retrospective studies in the kidney disease population have also examined incidence of sudden cardiac death. For example, the three-year cumulative incidence of SCD was 22 per 1,000 patient-years, or 19% of total deaths, in a cohort of 476 prevalent dialysis patients.5 In a report of 5,830 dialysis patients who underwent coronary artery bypass surgery, the death rate from SCD was 76 per 1,000 patient-years, or about 25% of all-cause deaths, 6 and a single-institution study reported a sudden cardiac death rate of 4.6 events per 1,000 patient-years in 19,440 patients with varying degrees of CKD who underwent cardiac catheterization.7 A higher death rate with increasing CKD severity also was noted.
Most of the studies have not distinguished between sudden cardiac death and sudden death that may be due to noncardiac causes, such as pulmonary embolism or massive stroke. However, in dialysis patients, it would be difficult to differentiate between the two, and perhaps all sudden deaths are cardiac in nature because of the high risk and incidence of cardiac disease in this cohort. SCD rates are similar in the hemodialysis and peritoneal dialysis populations.
Risks Poorly Defined
The risk factors behind the increased SCD incidence in patients on dialysis are not well delineated. In the general population, coronary artery disease and congestive heart failure are the most common culprits, but this is not necessarily true in end-stage renal disease.
While very few prospective studies have examined the drivers of sudden cardiac death in patients on hemodialysis, and only one prospective study has done so in those on peritoneal dialysis, it is obvious that the presence of multiple risk factors put the patient with ESRD at greatly increased risk.
These risk factors include cardiac risks, such as left ventricular hypertrophy (LVH), congestive heart failure, low ejection fraction, vascular calcification, electrographic abnormalities, hyperkalemia during the intradialytic period, cellular shift during dialysis, and possibly hypokalemia postdialysis; calcium and phosphorus disorders; unspecified inflammatory markers; iron overload; and sleep apnea and sympathetic overactivity.
Serum potassium levels vary in ESRD patients depending on dialysis schedule. Genovesi et al reported an increased incidence of sudden cardiac death with serum potassium levels of 6.0 mmol/L or greater,5 while Kovesdy et al found predialysis levels of 4.6 mEq/L to 5.3 mEq/L to be associated with greatest survival.8
One intriguing observation found that hemodialysis patients most commonly die of cardiac arrest and arrhythmias during the last 12 hours of the longer interdialytic period.9 Other studies have reported a significant increase in sudden cardiac death after the start of a dialysis session.5,10 In data from Fresenius Medical Care North America dialysis units, a low concentration of potassium in the dialysis bath—0 mmol/L or 1 mmol/L—was associated with SCD.11
Using echocardiography and a biomarker panel, Wang et al examined the role of left ventricular mass index and ejection fraction in predicting SCD.12 While the study was restricted to peritoneal dialysis patients at a regional center in Hong Kong, the findings are likely to have the same significance in hemodialysis patients. During a follow-up period of five years, cardiac troponin T, N-terminal pro-brain natriuretic peptide, and left ventricular (LV) ejection fraction of 48% or less were all significantly associated with SCD. In another study done in hemodialysis patients, a progressive increase in LV mass index was more predictive of SCD than was LVH alone.13
Two excellent reviews of sudden death in patients with kidney disease have recently been published and are highly recommended.11,14
In patients with ESRD, the treatment approach for sudden cardiac death should target the multiple risk factors present. As many of the described risks have only a weak association with SCD, the problem lies in determining how to weight each (Passman 2011).15 Undoubtedly, a global strategy for identifying and controlling these risk factors would be ideal. Such an approach may include:
* 1. Normalize fluid balance, avoiding frequent fluid overloads, and normalize blood pressure, which together may lead to LVH regression. The role of inflammatory markers remains undefined.
* 2. Avoid the use of dialysis baths that have low or no potassium. Calcium, phosphorus, and parathyroid hormone correction are part of every unit's quality indicators, but a significant number of patients remain outside recommended parameters.
* 3. Consider possible drug therapies for the prevention of arrhythmia, such as beta blockers and, possibly, renin-angiotensin system (RAS) blockers. In dialysis patients with dilated cardiomyopathy, Cice et al reported increased two-year survival with carvedilol.16 In another retrospective study, patients taking beta blockers had a higher survival rate after cardiac arrest.17While randomized trials of beta blockers in dialysis patients are lacking, given the presence of multiple risk factors and the available evidence from retrospective studies, use of these agents should be seriously considered in patients with dilated cardiomyopathy.Two small studies reported better survival in dialysis patients on RAS blockers,17,18 but other studies have failed to identify a cardiovascular benefit.19,20
* 4. Evaluate implantable cardioverter-defibrillators in patients with end-stage renal disease. These devices are the most effective therapy for SCD prevention in the general population, but most studies of their use have excluded patients with CKD.1
Patients with advanced chronic kidney disease may be less responsive to ICDs because of the increased defibrillation thresholds required.21 Major complications with ICD include pneumothorax, pocket infection, and thrombosis. Serum creatinine has been reported to be an independent predictor of time to first appropriate ICD shock.22
In a meta-analysis, Sakhuja and colleagues examined data from seven published studies encompassing a total of 2,516 patients, including 89 patients on dialysis, and reported a 2.7-fold increased mortality risk in those on dialysis.23 They also observed that beta blockers were less protective than ICDs in patients on dialysis.
Using a decision analysis model, Amin et al determined that, in chronic kidney disease, the benefits of ICDs for primary prevention are age and CKD stage dependent.24 In Stage 5 CKD, the ICD favored patients younger than 65. Further studies are needed to truly assess the roles of serum creatinine and age in determining the efficacy of ICD in the dialysis population.
Need for Trials
The efficacy of beta blockers, renin–angiotensin system blockers, and implantable cardioverter-defibrillators need to be tested in randomized trials of dialysis patients before guidelines can be developed.
Meanwhile, we should focus on achieving dry weight, normalizing blood pressure, avoiding fluid overload, keeping electrolytes (calcium, phosphorus, and potassium) normal, and avoiding very low potassium dialysate. Patients on dialysis should be evaluated for ICD just like those with normal renal function are, and the device may be required in particular patients.
Zipes DP, Camm AJ, Borggrefe M, et al, for the American College of Cardiology/American Heart Association Task Force, European Society of Cardiology Committee for Practice Guidelines, European Heart Rhythm Association, and Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation
Chugh SS, Jui J, Gunson K, et al. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large US community. J Am Coll Cardiol
US Renal Data System. USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2010.
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
Genovesi S, Valsecchi MG, Rossi E,et al. Sudden death and associated factors in a historical cohort of chronic hemodialysis patients. Nephrol Dial Transplantation 2009;24:2529-2536.
Herzog CA, Strief JW, Collins AJ, Gilbertson DT. Cause-specific mortality of dialysis patients after coronary revascularization: why don't dialysis patients have better survival after coronary intervention? Nephrol Dial Transplantation 2008;23:2629-2633.
Pun PH, Smarz TR, Honeycutt EF, Shaw LK, Al-Khatib SM, Middleton JP. Chronic kidney disease is associated with increased risk of sudden cardiac death among patients with coronary artery disease. Kidney Int
Kovesdy CP, Regidor DL, Mehrotra R, et al. Serum and dialysate potassium concentrations and survival in hemodialysis patients. Clin J Am Soc Nephrol 2004;2:999-1007.
Wanner C, Krane V, März W, et al, for the German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med
Bleyer AJ, Hartman J, Brannon PC, Reeves-Daniel A, Satko SG, Russell G. Characteristics of sudden death in hemodialysis patients. Kidney Int 2006;88:2268-2273.
Shamseddin MK, Parfrey PS. Sudden cardiac death in chronic kidney disease: epidemiology and prevention. Nat Rev Nephrol
Wang AY, Lam CW, Chan IH, Wang M, Lui SF, Sanderson JE. Sudden cardiac death in end-stage renal disease patients: a five-year prospective analysis. Hypertension
Paoletti E, Specchia C, Di Maio G, et al. The worsening of left ventricular hypertrophy is the strongest predictor of sudden cardiac death in hemodialysis patients: a 10-year survey. Nephrol Dial Transplantation 2004;19:1829-1834.
Green D, Roberts PR, New DI, Kalra PA. Sudden cardiac death in hemodialysis patients: an in-depth review. Am J Kidney Dis
Passman R, Herzog CA. End-stage renal disease: sudden cardiac death: stratifying risk in dialysis patients. Nat Rev Nephrol
Cice G, Ferrara L, D'Andrea A, et al. Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J Am Coll Cardiol
Pun PH, Lehrich RW, Smith SR, Middleton JP. Predictors of survival after cardiac arrest in outpatient hemodialysis clinics. Clin J Am Soc Nephrol 2007;2:491-500.
Takahashi A, Takase H, Toriyama T, et al. Candesartan, an angiotensin II type 1 receptor blocker reduces cardiovascular events in patients on chronic hemodialysis—a randomized study. Nephrol Dial Transplantation 2006;21:2507-2512.
Zannad F, Kessler M, Lehert P, et al. Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies. Kidney Int
Ishani A, Herzog CA, Collins AJ, Foley RN. Cardiac medications and their association with cardiovascular events in incident dialysis patients: cause or effect? Kidney Int
Dasgupta A, Montalvo J, Medendorp S, et al. Increased complication rates of cardiac rhythm management devices in ESRD patients. Am J Kidney Dis
Hreybe H, Razak E, Saba S. Effect of end-stage renal failure and hemodialysis on mortality rates in implantable cardioverter-defibrillator recipients. Pacing Clin Electrophysiol
Sakhuja R, Keebler M, Lai TS, McLaughlin Gavin C, Thakur R, Bhatt DL. Meta-analysis of mortality in dialysis patients with an implantable cardioverter defibrillator. Am J Cardiol
Amin MS, Fox AD, Kalahasty G, Shepard RK, Wood MA, Ellenbogen KA. Benefit of primary prevention implantable cardioverter-defibrillators in the setting of chronic kidney disease: a decision model analysis. J Cardiovasc Electrophysiol