Relations among renal function, risk of sudden cardiac death, and benefit of the implanted cardiac defibrillator in patients with ischemic left ventricular dysfunction.

Implanted cardioverter defibrillator therapy has been shown to be associated with a significant reduction in the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. However, data on the relation between renal function and SCD in this population are limited, and the effect of renal dysfunction on the implanted cardioverter defibrillator benefit has not been determined. We performed a retrospective analysis of the outcome associated with renal dysfunction, as determined by the estimated glomerular filtration rate (eGFR), in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II. Multivariate analysis in conventionally treated patients showed that for each 10-U reduction in eGFR, the risk of all-cause mortality and SCD increased by 16% (p = 0.005) and 17% (p = 0.03), respectively. Defibrillator therapy was associated with a survival benefit in each eGFR category of > or = 35 ml/min/1.73 m2 (overall risk reduction for all-cause mortality 32%, p = 0.01 and for SCD 66%, p < 0.001). However, no implanted cardioverter defibrillator benefit was shown among patients with an eGFR < 35 ml/min/1.73 m2 (all-cause mortality hazard ratio 1.09, p = 0.84; SCD hazard ratio 0.95, p = 0.95). In conclusion, in patients with high-risk cardiac disease enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II, a significant increase was found in the risk of SCD with declining renal function. Defibrillator therapy was associated with a significant survival benefit among the study patients with mild to moderate or no renal disease, but no benefit was shown among patients with more advanced renal dysfunction.

Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator.

BACKGROUND: The implanted cardioverter defibrillator (ICD) improves survival in high-risk cardiac patients. This analysis from the MADIT-II trial database examines the long-term clinical course and subsequent mortality risk of patients after termination of life-threatening ventricular tachyarrhythmias by an ICD. METHODS AND RESULTS: Life-table survival analysis was performed, and proportional hazards regression analysis was used to evaluate the contribution of baseline clinical factors and time-dependent defibrillator therapy to mortality during long-term follow-up. Of 720 patients with an ICD (average follow-up 21 months), 169 patients received 701 antiarrhythmic device therapies for ventricular tachyarrhythmias. Few baseline characteristics distinguished patients who received appropriate ICD therapy for their first ventricular tachyarrhythmic episode. The probability of survival for at least 1 year after first therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) was 80%. The hazard ratios for the risk of death due to any cause in those who survived appropriate therapy for termination of VT and VF were 3.4 (P<0.001) and 3.3 (P=0.01), respectively, compared with those who survived without receiving ICD therapy, with a high frequency of heart failure and late nonsudden cardiac death after first successful ICD therapy for VF. CONCLUSIONS: Successful appropriate therapy by an ICD for VT or VF is associated with 80% survival at 1 year after arrhythmia termination. These patients are at increased risk for heart failure and nonsudden cardiac death after device termination of VT or VF and should receive special attention for the prevention and management of progressive left ventricular dysfunction during long-term follow-up.

Analysis of mortality events in the Multicenter Automatic Defibrillator Implantation Trial (MADIT-II).

OBJECTIVES: The purpose of this study was to determine the efficacy of implantable cardiac defibrillator (ICD) therapy in preventing sudden cardiac death (SCD) in post-infarction patients with advanced left ventricular (LV) dysfunction. BACKGROUND: The Multicenter Automatic Defibrillator Implantation Trial (MADIT-II) randomized 1,232 post-infarction patients with an ejection fraction of < or =30% to ICD or conventional therapy. In the ICD group, there was a 31% decrease in the risk of total mortality. However, a better understanding of the mode of death is desirable in order to refine therapeutic interventions in high-risk populations. METHODS: We evaluated the 202 deaths, using a variation of the Hinkle-Thaler classification system as well as a clinical classification system to determine the incidence of SCD and the incidence of cardiac death due to progressive LV failure. RESULTS: The SCD rates were 10.0% in the conventional group and 3.8% in the ICD group (p < 0.01). The hazard ratio for the risk of SCD in the ICD group compared with the conventional therapy group was 0.33 (95% confidence interval 0.20 to 0.53, p < 0.0001). The ICD had no meaningful effect on non-sudden death (p = 0.32). The effect of defibrillator therapy in reducing SCD was similar in subgroup analyses stratified according to relevant baseline characteristics. CONCLUSIONS: The decrease in mortality with ICD therapy in MADIT-II is entirely due to a reduction in SCD, with similar reductions in SCD in a spectrum of subgroups stratified according to relevant baseline characteristics.

Atherosclerotic risk genotypes and recurrent coronary events after myocardial infarction.

The association of a group of prespecified atherosclerotic risk genotypes with recurrent coronary events (coronary-related death, nonfatal myocardial infarction, or unstable angina) was investigated in a cohort of 1,008 patients after infarction during an average follow-up of 28 months. We used a carrier-ship approach with time-dependent survivorship analysis to evaluate the average risk of each carried genotype. Contrary to expectation, the hazard ratio for recurrent coronary events per carried versus noncarried genotype was 0.89 (95% confidence interval 0.80 to 0.99, p = 0.03) after adjustment for relevant genetic, clinical, and environmental covariates. This hazard ratio, derived from the 7 prespecified genotypes, indicated an average 11% reduction in the risk of recurrent coronary events per carried versus noncarried genotype. At 1 year after hospital discharge, the cumulative probability of recurrent coronary events was 26% in those who carried < or =1, 20% for those with 2 to 4, and 13% for those with > or =5 of these genotypes (p = 0.02). This unexpected risk reversal is a likely consequence of changes in the mix of risk factors in pre- and postinfarction populations. In conclusion, this under appreciated, population-based, risk-reversal phenomenon may explain the inconsistent associations of genetic risk factors with outcome events in previous reports involving coronary populations with different risk attributes.

Temporal aspects of improved survival with the implanted defibrillator (MADIT-II).

The present study retrospectively explored the reasons for delay in the onset of survival benefit from the implanted cardioverter defibrillator (ICD) in the Second Multicenter Automatic Defibrillator Implantation Trial. The cumulative probability of cause-specific death over time was estimated by the Kaplan-Meier method and by proportional hazards regression analysis. Early cardiac death survival curves were similar by treatment assignment in the 0- to 12-month period (p = 0.76). Late cardiac death survival curves by treatment assignment in the >12- to 52-month follow-up period were divergent with a lower probability of late cardiac death in the ICD arm compared with conventional therapy group (p <0.001). The time-specific hazard ratios of ICD to conventional therapy for cardiac death in the early and late periods were significantly different from each other (nominal p = 0.004). There was a significant decrease in sudden cardiac death with ICD therapy in the early (p = 0.012) and late (p <0.001) groups. In the early period, the rate of nonsudden cardiac death was significantly higher in the ICD group than in the conventional therapy group (p = 0.003). Rates of late nonsudden cardiac death were similar in the 2 treatment arms (p = 0.11).

Interfraction and intrafraction changes in amplitude of breathing motion in stereotactic liver radiotherapy.

PURPOSE: Interfraction and intrafraction changes in amplitude of liver motion were assessed in patients with liver cancer treated with kV cone beam computed tomography (CBCT)-guided stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: A total of 314 CBCTs obtained with the patient in the treatment position immediately before and after each fraction, and 29 planning 4DCTs were evaluated in 29 patients undergoing six-fraction SBRT for unresectable liver cancer, with (n = 15) and without (n = 14) abdominal compression. Offline, the CBCTs were sorted into 10 bins, based on phase of respiration. Liver motion amplitude was measured using liver-to-liver alignment from the end-exhale and end-inhale CBCT and four-dimensional CT reconstructions. Inter- and intrafraction amplitude changes were measured from the difference between the pre-SBRT CBCTs relative to the planning four-dimensional CT, and from the pre-SBRT and post-SBRT CBCTs, respectively. RESULTS: Mean liver motion amplitude for all patients (range) was 1.8 (0.1-7.0), 8.0 (0.1-18.8), and 4.3 (0.1-12.1) mm in the mediolateral (ML), craniocaudal (CC), and anteroposterior (AP) directions, respectively. Mean absolute inter- and intrafraction liver motion amplitude changes were 1.0 (ML), 1.7 (CC), and 1.6 (AP) mm and 1.3 (ML), 1.6 (CC), and 1.9 (AP) mm, respectively. No significant correlations were found between intrafraction amplitude change and intrafraction time (range, 4:56-25:37 min:sec), and between inter- and intrafraction amplitude changes and liver motion amplitude. Intraobserver reproducibility (sigma, n = 29 fractions) was 1.3 (ML), 1.4 (CC), and 1.4 (AP) mm. CONCLUSIONS: For the majority of liver SBRT patients, the change in liver motion amplitude was minimal over the treatment course and showed no apparent relationships with the magnitude of liver motion and intrafraction time.

Inter- and intrafraction variability in liver position in non-breath-hold stereotactic body radiotherapy.

PURPOSE: The inter- and intrafraction variability of liver position was assessed in patients with liver cancer treated with kilovoltage cone-beam computed tomography (CBCT)-guided stereotactic body radiotherapy. METHODS AND MATERIALS: A total of 314 CBCT scans obtained in the treatment position immediately before and after each fraction were evaluated from 29 patients undergoing six-fraction, non-breath-hold stereotactic body radiotherapy for unresectable liver cancer. Off-line, the CBCT scans were sorted into 10 bins, according to the phase of respiration. The liver position (relative to the vertebral bodies) was measured using rigid alignment of the exhale CBCT liver with the exhale planning CT liver, following the alignment of the vertebrae. The interfraction liver position change was measured by comparing the pretreatment CBCT scans, and the intrafraction change was measured from the CBCT scans obtained immediately before and after each fraction. RESULTS: The mean amplitude of liver motion for all patients was 1.8 mm (range, 0.1-5.7), 8.0 mm (range, 0.1-18.8), and 4.3 mm (range 0.1-12.1) in the medial-lateral (ML), craniocaudal (CC), and anteroposterior (AP) directions, respectively. The mean absolute ML, CC, and AP interfraction changes in liver position were 2.0 mm (90th percentile, 4.2), 3.5 mm (90th percentile, 7.3), and 2.3 mm (90th percentile, 4.7). The mean absolute intrafraction ML, CC, and AP changes were 1.3 mm (90th percentile, 2.9), 1.6 mm (90th percentile, 3.6), and 1.5 mm (90th percentile, 3.1), respectively. The interfraction changes were significantly larger than the intrafraction changes, with a CC systematic error of 2.9 and 1.1 mm, respectively. The intraobserver reproducibility (sigma, n = 29 fractions) was 1.3 mm in the ML, 1.4 mm in the CC, and 1.6 mm in the AP direction. CONCLUSION: Interfraction liver position changes relative to the vertebral bodies are an important source of geometric uncertainty, providing a rationale for prefraction soft-tissue image guidance. The intrafraction change in liver position from the beginning to the end of each fraction was small for most patients.

Association of prolonged QRS duration with ventricular tachyarrhythmias and sudden cardiac death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).

BACKGROUND: There is conflicting literature on the relationship between prolonged QRS duration (QRSd) and arrhythmic events, including sudden cardiac death (SCD), in heart failure patients with or without implantable cardioverter-defibrillators (ICDs). OBJECTIVE: The purpose of this study was to evaluate the prognostic significance of prolonged QRSd relative to arrhythmic outcomes in medically and ICD-treated patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II. METHODS: Using a Cox proportional hazards model adjusting for ejection fraction, heart failure class, and blood urea nitrogen, we estimated the association of prolonged QRSd >/=140 ms with SCD in the medically treated arm and SCD or first appropriate ICD therapy for rapid ventricular tachycardia/fibrillation (VT/VF; cycle length