Implantable cardioverter-defibrillators for primary prevention of sudden cardiac death in CKD: a meta-analysis of patient-level data from 3 randomized trials.

BACKGROUND: The benefit of a primary prevention implantable cardioverter-defibrillator (ICD) among patients with chronic kidney disease is uncertain. STUDY DESIGN: Meta-analysis of patient-level data from randomized controlled trials. SETTING & POPULATION: Patients with symptomatic heart failure and left ventricular ejection fraction<35%. SELECTION CRITERIA FOR STUDIES: From 7 available randomized controlled studies with patient-level data, we selected studies with available data for important covariates. Studies without patient-level data for baseline estimated glomerular filtration rate (eGFR) were excluded. INTERVENTION: Primary prevention ICD versus usual care effect modification by eGFR. OUTCOMES: Mortality, rehospitalizations, and effect modification by eGFR. RESULTS: We included data from the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), MADIT-II, and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). 2,867 patients were included; 36.3% had eGFR<60 mL/min/1.73m2. Kaplan-Meier estimate of the probability of death during follow-up was 43.3% for 1,334 patients receiving usual care and 35.8% for 1,533 ICD recipients. After adjustment for baseline differences, there was evidence that the survival benefit of ICDs in comparison to usual care depends on eGFR (posterior probability for null interaction P<0.001). The ICD was associated with survival benefit for patients with eGFR≥60 mL/min/1.73 m2 (adjusted HR, 0.49; 95% posterior credible interval, 0.24-0.95), but not for patients with eGFR<60 mL/min/1.73 m2 (adjusted HR, 0.80; 95% posterior credible interval, 0.40-1.53). eGFR did not modify the association between the ICD and rehospitalizations. LIMITATIONS: Few patients with eGFR<30 mL/min/1.73 m2 were available. Differences in trial-to-trial measurement techniques may lead to residual confounding. CONCLUSIONS: Reductions in baseline eGFR decrease the survival benefit associated with the ICD. These findings should be confirmed by additional studies specifically targeting patients with varying eGFRs.

Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial.

IMPORTANCE: Hospital cooling improves outcome after cardiac arrest, but prehospital cooling immediately after return of spontaneous circulation may result in better outcomes. OBJECTIVE: To determine whether prehospital cooling improves outcomes after resuscitation from cardiac arrest in patients with ventricular fibrillation (VF) and without VF. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial that assigned adults with prehospital cardiac arrest to standard care with or without prehospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation. Adults in King County, Washington, with prehospital cardiac arrest and resuscitated by paramedics were eligible and 1359 patients (583 with VF and 776 without VF) were randomized between December 15, 2007, and December 7, 2012. Patient follow-up was completed by May 1, 2013. Nearly all of the patients resuscitated from VF and admitted to the hospital received hospital cooling regardless of their randomization. MAIN OUTCOMES AND MEASURES: The primary outcomes were survival to hospital discharge and neurological status at discharge. RESULTS: The intervention decreased mean core temperature by 1.20°C (95% CI, -1.33°C to -1.07°C) in patients with VF and by 1.30°C (95% CI, -1.40°C to -1.20°C) in patients without VF by hospital arrival and reduced the time to achieve a temperature of less than 34°C by about 1 hour compared with the control group. However, survival to hospital discharge was similar among the intervention and control groups among patients with VF (62.7% [95% CI, 57.0%-68.0%] vs 64.3% [95% CI, 58.6%-69.5%], respectively; P = .69) and among patients without VF (19.2% [95% CI, 15.6%-23.4%] vs 16.3% [95% CI, 12.9%-20.4%], respectively; P = .30). The intervention was also not associated with improved neurological status of full recovery or mild impairment at discharge for either patients with VF (57.5% [95% CI, 51.8%-63.1%] of cases had full recovery or mild impairment vs 61.9% [95% CI, 56.2%-67.2%] of controls; P = .69) or those without VF (14.4% [95% CI, 11.3%-18.2%] of cases vs 13.4% [95% CI,10.4%-17.2%] of controls; P = .30). Overall, the intervention group experienced rearrest in the field more than the control group (26% [95% CI, 22%-29%] vs 21% [95% CI, 18%-24%], respectively; P = .008), as well as increased diuretic use and pulmonary edema on first chest x-ray, which resolved within 24 hours after admission. CONCLUSION AND RELEVANCE: Although use of prehospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, it did not improve survival or neurological status among patients resuscitated from prehospital VF or those without VF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00391469.

CPR during ischemia and reperfusion: a model for survival benefits.

OBJECTIVE: Manual CPR improves the likelihood of neurologically intact survival following cardiac arrest. The mechanism of this benefit is not completely understood. We propose a mechanism whereby manual CPR simultaneously limits ischemia and specifically protects against reperfusion injury. We derive a conceptual framework that describes cell survival as it relates to the ischemic and reperfusion stages and CPR effects. RESULTS: Based on a synthesis of basic science and clinical information, we propose that the benefit of the subnormal circulation produced by manual CPR is multifaceted and specifically includes attenuating reperfusion injury by providing graded blood flow to the heart and brain. Although manual CPR produces reperfusion pathophysiology, the low flow from CPR limits reperfusion injury specifically through mechanisms of post-ischemic conditioning which include attenuating peak levels of oxidative substrate and activating pathways that protect against oxidative stress. CONCLUSIONS: If such a hypothesis of post-ischemic conditioning is borne out, CPR may be considered a dose-sensitive therapy whereby certain physiologic states would be best served by different levels of circulation and hence distinct grades of CPR.

The relationship between shocks and survival in out-of-hospital cardiac arrest patients initially found in PEA or asystole.

OBJECTIVE: To describe survival rates from out-of-hospital cardiac arrest for patients who present with pulseless electrical activity or asystole according to whether they remained in a non-shockable rhythm or converted to ventricular fibrillation and were shocked appropriately. RESULTS: Observational analysis of a cardiac arrest registry collected as part of a randomized trial. SETTING: Five urban/suburban cities in the United States and Canada. PARTICIPANTS: Trial subjects (adult, treated, non-traumatic) whose first documented heart rhythm/state following cardiac arrest was asystole or pulseless electrical activity. INTERVENTION: Periodic pauses to assess for shockable rhythm. MAIN OUTCOME MEASURE: Survival to hospital discharge. RESULTS: Of 1377 cardiac arrest patients, 738 presented with an initial arrest rhythm/state of either pulseless electrical activity or asystole. Of the 738, 78% (n=574) subsequently remained in a non-shockable rhythm/state at each evaluation throughout the resuscitation (No-Shock group) while 22% (n=164) converted to ventricular fibrillation and were shocked by emergency medical service (Shock group). Survival to hospital discharge was significantly greater in the No-Shock group (4.9% versus 0.6%, p=0.01). Shock group remained a predictor (odds ratios=0.18, p=0.036) of death after adjustment for potential confounders. CONCLUSIONS: These results suggest that patients with cardiac arrest who develop VF during the course of treatment for initially observed pulseless electrical activity or asystole do not benefit from conventional approaches to treatment such as defibrillation. Further study is warranted to define the optimal treatment of this patient cohort.

Consent in resuscitation trials: benefit or harm for patients and society?

CONTEXT: Research in an emergency setting is challenging because there may not be sufficient opportunity or time to obtain informed consent from the patient or their legally authorized representative. Such research can be conducted without prior consent if specific criteria are met. However consent is sometimes required for continued participation and may bias the results of the study. OBJECTIVE: To review regulations related to waiver of consent in emergency research, and evidence of whether such regulations introduce bias. RESULTS: Emergency research can be conducted without consent, either through community disclosure and consultation followed by patient or family notification and consent for continued participation after the intervention was applied, or under a minimal risk waiver. Review of the clinical record is necessary to determine important outcomes such as survival to discharge. If consent is required for this review but not granted, then these data are missing during analysis. If seriously ill or disadvantaged patients are less likely to assent, then investigators cannot determine reliably whether these vulnerable patients were harmed by the intervention. If missing data are different from complete data, then the analysis is susceptible to bias, and the conclusions could be misleading. Extrapolation from non-consent rates in resuscitation studies to results from the DAVID trial demonstrates that the rate of absence of data and information due to lack of assent can influence whether there is a significant difference between treatment groups (survival of control versus intervention: p=0.04 for complete data; p=0.08 for 10.8% lack of assent; p=0.40 for 19.7% lack of assent). CONCLUSIONS: Exception from consent for emergency research should extend to review of the hospital record as the standard in emergency research. The only potential risk to patients associated with review of the clinical record after the intervention is loss of privacy and confidentiality. Appropriate safeguards can be taken to minimize this risk.

Manual chest compression vs use of an automated chest compression device during resuscitation following out-of-hospital cardiac arrest: a randomized trial.

CONTEXT: High-quality cardiopulmonary resuscitation (CPR) may improve both cardiac and brain resuscitation following cardiac arrest. Compared with manual chest compression, an automated load-distributing band (LDB) chest compression device produces greater blood flow to vital organs and may improve resuscitation outcomes. OBJECTIVE: To compare resuscitation outcomes following out-of-hospital cardiac arrest when an automated LDB-CPR device was added to standard emergency medical services (EMS) care with manual CPR. DESIGN, SETTING, AND PATIENTS: Multicenter, randomized trial of patients experiencing out-of-hospital cardiac arrest in the United States and Canada. The a priori primary population was patients with cardiac arrest that was presumed to be of cardiac origin and that had occurred prior to the arrival of EMS personnel. Initial study enrollment varied by site, ranging from late July to mid November 2004; all sites halted study enrollment on March 31, 2005. INTERVENTION: Standard EMS care for cardiac arrest with an LDB-CPR device (n = 554) or manual CPR (n = 517). MAIN OUTCOME MEASURES: The primary end point was survival to 4 hours after the 911 call. Secondary end points were survival to hospital discharge and neurological status among survivors. RESULTS: Following the first planned interim monitoring conducted by an independent data and safety monitoring board, study enrollment was terminated. No difference existed in the primary end point of survival to 4 hours between the manual CPR group and the LDB-CPR group overall (N = 1071; 29.5% vs 28.5%; P = .74) or among the primary study population (n = 767; 24.7% vs 26.4%, respectively; P = .62). However, among the primary population, survival to hospital discharge was 9.9% in the manual CPR group and 5.8% in the LDB-CPR group (P = .06, adjusted for covariates and clustering). A cerebral performance category of 1 or 2 at hospital discharge was recorded in 7.5% of patients in the manual CPR group and in 3.1% of the LDB-CPR group (P = .006). CONCLUSIONS: Use of an automated LDB-CPR device as implemented in this study was associated with worse neurological outcomes and a trend toward worse survival than manual CPR. Device design or implementation strategies require further evaluation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00120965.

Effect of prehospital induction of mild hypothermia on 3-month neurological status and 1-year survival among adults with cardiac arrest: long-term follow-up of a randomized, clinical trial.

BACKGROUND: Randomized trials of prehospital cooling after cardiac arrest have shown that neither prehospital cooling nor targeted temperature management differentially affected short-term survival or neurological function. In this follow-up study, we assess the association of prehospital hypothermia with neurological function at least 3 months after cardiac arrest and survival 1 year after cardiac arrest. METHODS AND RESULTS: There were 508 individuals who were discharged alive from hospitals in King County, Washington; 373 (73%) were interviewed by telephone 123±43 days after the initial event. Overall, 59% of the treatment group and 58% of the control group had Cerebral Performance Category (CPC) 1 or 2 (P=0.70), and 50% of the treatment group and 49% of the control group had slight disability or better by the Modified Rankin Scale (MRS; (P=0.35). One-year survival was 87% in the treatment group and 84% in the control group (P=0.42). Of those with CPC 1 at hospital discharge, 68% had CPC 1 or 2 at follow-up, and 59% had MRS of slight disability or better. Of 41 patients with CPC 3 or 4 at discharge, only 12% had CPC 2 at follow-up, and just 5% had MRS of slight disability or better. One-year survival was 92% for CPC 1 at discharge, but only 40% for CPC 4. CONCLUSION: In addition to excellent survival, patients who had good neurological function at discharge continued to have good function at least 3 months after the event. CLINICAL TRIAL REGISTRATION: URL: Clinicaltrials.gov. Unique identifier: NCT00391469.

Survival benefit of the primary prevention implantable cardioverter-defibrillator among older patients: does age matter? An analysis of pooled data from 5 clinical trials.

BACKGROUND: The impact of patient age on the risks of death or rehospitalization after primary prevention implantable cardioverter-defibrillator (ICD) placement is uncertain. METHODS AND RESULTS: Data from 5 major ICD trials were merged: the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), the Multicenter UnSustained Tachycardia Trial (MUSTT), the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation Trial (DEFINITE), and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Median age at enrollment was 62 (interquartile range 53-70) years. Compared with their younger counterparts, older patients had a greater burden of comorbid illness. In unadjusted exploratory analyses, ICD recipients were less likely to die than nonrecipients in all age groups: among patients aged <55 years: hazard ratio 0.48, 95% posterior credible interval 0.33 to 0.69; among patients aged 55 to 64 years: hazard ratio 0.69, 95% posterior credible interval 0.53 to 0.90; among patients aged 65 to 74 years: hazard ratio 0.67, 95% posterior credible interval, 0.53 to 0.85; and among patients aged ≥75 years: hazard ratio 0.54, 95% posterior credible interval 0.37 to 0.78. Sample sizes were limited among patients aged ≥75 years. In adjusted Bayesian-Weibull modeling, point estimates indicate ICD efficacy persists but is attenuated with increasing age. There was evidence of an interaction between age and ICD treatment on survival (two-sided posterior tail probability of no interaction <0.01). Using an adjusted Bayesian logistic regression model, there was no evidence of an interaction between age and ICD treatment on rehospitalization (two-sided posterior tail probability of no interaction 0.44). CONCLUSIONS: In this analysis, the survival benefit of the ICD exists but is attenuated with increasing age. The latter finding may be because of the higher burden of comorbid illness, competing causes of death, or limited sample size of older patients. There was no evidence that age modifies the association between ICD treatment and rehospitalization.

Survival benefit of primary prevention implantable cardioverter-defibrillator therapy after myocardial infarction: does time to implant matter? A meta-analysis using patient-level data from 4 clinical trials.

BACKGROUND: Whether there is an optimal time to place an implantable cardioverter-defibrillator (ICD) more than 40 days after myocardial infarction (MI) in guideline-eligible patients is unknown. OBJECTIVE: To evaluate the effect of time from MI to randomization on mortality, rehospitalizations, and complications. METHODS: Individual data on patients enrolled in 9 primary prevention ICD trials were provided. Clinical trials were eligible for the current analysis if they enrolled patients with an MI more than 40 days prior to randomization to primary prevention ICD therapy vs usual care: Multicenter Automatic Defibrillator Implantation Trial I, Multicenter UnSustained Tachyardia Trial, Multicenter Automatic Defibrillator Implantation Trial II, and Sudden Cardiac Death in Heart Failure Trial. RESULTS: ICD recipients died less frequently than nonrecipients at 5 years across all subgroups of time from MI to randomization. In unadjusted Cox proportional hazards regression, a survival benefit was evident in most subgroups. Adjusted Bayesian Weibull survival modeling yielded hazard ratio (HR) 0.50, 95% posterior credible interval (PCI) 0.20-1.25 41-180 days after MI; HR 0.98, 95% PCI 0.37-2.37 181-365 days after MI; HR 0.22, 95% PCI 0.07-0.59>1-2 years after MI; HR 0.42, 95% PCI 0.17-0.90>2-5 years after MI; HR 0.55, 95% PCI 0.25-1.15>5-10 years after MI; and HR 0.48, 95% PCI 0.20-1.02>10 years after MI. There was no evidence of an interaction between time from MI and all-cause mortality, rehospitalizations, or complications. CONCLUSIONS: In this meta-analysis, there was scant evidence that the efficacy of primary prevention ICD therapy depends on time to implantation more than 40 days after MI. Similarly, there was no evidence that the risks of rehospitalizations or complications depend on time more than 40 days after MI.

Role of the implantable defibrillator among elderly patients with a history of life-threatening ventricular arrhythmias.

AIMS: The implantable defibrillator (ICD) reduces arrhythmic and all-cause mortality in patients with a history of life-threatening ventricular arrhythmias. However, its effectiveness in elderly patients is uncertain, given their competing risk of non-arrhythmic death. METHODS AND RESULTS: Individual patient data from all three secondary prevention trials comparing the ICD to amiodarone were pooled. Patients were divided into two groups based on age < 75 and > or = 75 years. Patient characteristics were reported and the effect of the ICD on all-cause mortality and arrhythmic death was determined for each group. The effect of age on these outcomes was determined by evaluating the interaction term (age-treatment). A total of 1866 patients were included in this analysis. Their mean age was 63.7 +/- 10.4 years (intra-quartile range 58-71 years). There were 252 patients > or = 75 years old (13.5% of total). Patients > or = 75 years old had a similar left ventricular (LV) ejection fraction (EF)(32.6 +/- 13.7 vs. 33.8 +/- 14.9%, P = 0.20) and baseline prevalence of NYHA class 3 or 4 heart (12.3 vs. 11.8%, P = 0.38) failure as younger patients, but were less likely to have ventricular fibrillation as their presenting arrhythmia (39 vs. 53%, P = 0.0001). Over a mean follow-up of 2.3 years, older patients were more likely to die of non-arrhythmic death (8.74% per year vs. 3.96% per year, P = 0.001) and arrhythmic death (6.73% per year vs. 3.84% per year, P = 0.03). The ICD significantly reduced all-cause and arrhythmic death in patients < 75 years old (all-cause death HR = 0.69, 95% CI: 0.56-0.85, P < 0.0001; arrhythmic death HR = 0.44, 95% CI: 0.32-0.62, P < 0.0001), but not in patients > or = 75 years old (all-cause death HR = 1.06, 95% CI: 0.69-1.64, P = 0.79; arrhythmic death HR = 0.90, 95% CI: 0.42-1.95, P = 0.79). The interaction between age > or = 75 and ICD use was of borderline significance in each case (P = 0.09 and P = 0.11, respectively). CONCLUSION: Elderly patients with a history of life-threatening ventricular arrhythmias have a high incidence of non-arrhythmic death. In these patients, the ICD may not afford the same survival advantage over amiodarone that is seen in younger patients. ICD therapy should not be withheld based on age alone; however, physicians should carefully consider the risk of non-arrhythmic death among elderly patients when selecting the appropriate therapy for an individual.

Do arrhythmia patients improve survival by participating in randomized clinical trials? Observations from the Cardiac Arrhythmia Suppression Trial (CAST)and the Antiarrhythmics Versus Implantable Defibrillators Trial (AVID).

It is debatable whether patients benefit directly from participation in a randomized clinical trial. We attempt to address this question for participants in the Cardiac Arrhythmia Suppression Trial (CAST) and the Antiarrhythmics Versus Implantable Defibrillators (AVID) studies. Survival rates were compared between eligible patients who enrolled in the trials and eligible patients who did not enroll, adjusting for baseline covariates. In CAST, despite that the active therapy was found to confer an almost threefold increased risk of death, survival was similar between the 3163 enrolled and the 1363 nonenrolled eligible patients. However, when patients were under study management, their risk of death was approximately 20% lower than when they left study management. In AVID, overall survival was similar between the 1016 enrolled and the 1246 nonenrolled eligible patients. However, mortality was substantially higher among patients not enrolled because the referring physician mandated the type of therapy. Overall these observational analyses suggest a net improvement in survival for the participants in these two trials.

Survival of antiarrhythmic or implantable cardioverter defibrillator treated patients with varying degrees of left ventricular dysfunction who survived malignant ventricular arrhythmias.

INTRODUCTION: The relative effectiveness of the implantable cardioverter defibrillator (ICD) and antiarrhythmic drugs (AADs) varies with left ventricular ejection fraction (LVEF). However, once an ICD or AAD treatment strategy is chosen, the degree to which the LVEF influences survival is unknown. This article addresses that question. METHODS AND RESULTS: Using patient data from the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, the impact of LVEF on prognosis of patients who were treated with either an ICD or AAD was assessed. Survival within each quintile of LVEF was estimated by the method of Kaplan-Meier for patients treated with either the ICD or AADs. The Cox proportional hazards model was used to investigate the prognostic value of LVEF for estimating survival after adjustment for other baseline covariates among all patients in the subgroups treated by ICD or AAD. In the highest two quintiles of LVEF, survival was comparable in AAD-treated and ICD-treated patients. In the AAD-treated patients, higher LVEF was significantly and independently associated with survival free of all-cause mortality and arrhythmic death. In the ICD-treated patients, however, the statistical significance of the association was lost and only a trend toward greater survival was present. Death due to congestive heart failure remained independently and significantly associated with survival in both AAD-treated and ICD-treated patients. CONCLUSION: In patients treated with AADs but not patients treated with ICDs, survival is strongly associated with LVEF. The absence of a statistically significant association in the ICD patients is likely related to the effectiveness of the ICD in treating malignant ventricular arrhythmias, but a chance lack of association cannot be excluded.

Factors determining ICD implantation in drug therapy patients after termination of antiarrythmics versus implantable defibrillators trial.

Because of a significant survival benefit in the defibrillator arm of the Antiarrhythmics versus Implantable Defibrillator (AVID) Trial, patients in the antiarrhythmic drug (AAD) arm were advised to undergo ICD implantation. Despite this recommendation, ICD implantation in AAD patients was variable, with a large number of patients not undergoing ICD implantation. Patients were grouped by those who had been on AAD < 1 year (n = 111) and those on AAD > 1 year (n = 223). Multiple clinical and socioeconomic factors were evaluated to identify those who might be associated with a decision to implant an ICD. The primary reason for patients not undergoing ICD implantation was collected, as well as reasons for a delayed implantation, occurring later than 3 months from study termination. Of 111 patients on AAD for less than 1 year, 53 received an ICD within 3 months compared to 40/223 patients on AAD for more than 1 year (P < 0.001). Patient refusal was the most common reason to not implant an ICD in patients on drug < 1 year; physician recommendation against implantation was the most common in patients on drug > 1 year. Multivariate analysis showed ICD recipients on AAD < 1 year were more likely to be working and have a history of myocardial infarction (MI), while those on AAD > 1 year were more likely to be working, have a history of MI and ventricular fibrillation, and less likely to have experienced syncope, as compared to those who did not get an ICD. Having private insurance may have played a role in younger patients receiving an ICD.