Outcomes of implantable cardioverter-defibrillator use in patients with comorbidities: results from a combined analysis of 4 randomized clinical trials.

OBJECTIVES: The aim of this study was to determine if the benefit of implantable cardioverter-defibrillators (ICDs) is modulated by medical comorbidity. BACKGROUND: Primary prevention ICDs improve survival in patients at risk for sudden cardiac death. Their benefit in patients with significant comorbid illness has not been demonstrated. METHODS: Original, patient-level datasets from MADIT I (Multicenter Automatic Defibrillator Implantation Trial I), MADIT II, DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation), and SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) were combined. Patients in the combined population (N = 3,348) were assessed with respect to the following comorbidities: smoking, pulmonary disease, diabetes, peripheral vascular disease, atrial fibrillation, ischemic heart disease, and chronic kidney disease. The primary outcome was overall mortality, using the hazard ratio (HR) of time to death for patients receiving an ICD versus no ICD by extent of medical comorbidity, and adjusted for age, sex, race, left ventricular ejection fraction, use of antiarrhythmic drugs, beta-blockers, and angiotensin-converting enzyme inhibitors. RESULTS: Overall, 25% of patients (n = 830) had <2 comorbid conditions versus 75% (n = 2,518) with significant comorbidity (≥2). The unadjusted hazard of death for patients with an ICD versus no ICD was significantly lower, but this effect was less for patients with ≥2 comorbidities (unadjusted HR: 0.71; 95% confidence interval: 0.61 to 0.84) compared with those with <2 comorbidities (unadjusted HR: 0.59; 95% confidence interval: 0.40 to 0.87). After adjustment, the benefit of an ICD decreased with increasing number of comorbidities (p = 0.004). CONCLUSIONS: Patients with extensive comorbid medical illnesses may experience less benefit from primary prevention ICDs than those with less comorbidity; implantation should be carefully considered in sick patients. Further study of ICDs in medically complex patients is warranted.

Two simple questions to assess neurologic outcomes at 3 months after out-of-hospital cardiac arrest: experience from the public access defibrillation trial.

BACKGROUND: Two simple questions have been used to classify neurologic outcome in patients with stroke. Could they be similarly applied to patients with cardiac arrest? METHODS: As part of a randomized trial, study personnel interviewed by telephone survivors of out-of-hospital cardiac arrest to assess their outcomes 3 months after discharge. They asked two simple questions: (1) In the last 2 weeks, did you require help from another person for your everyday activities? and (2) Do you feel that you have made a complete mental recovery form your heart arrest? Next they administered the Mini-Mental State Examination (MMSE) from the Adult Lifestyles and Function Interview (ALFI) to assess cognition on a scale from 0 to 22 and the Health Utilities Index Mark 3 (HUI3) to assess quality of life on a scale from 0 (death) to 1 (perfect health). RESULTS: Based on responses to the two simple questions, 32 survivors were classified as dependent (n=5, 16%), independent (n=3, 9%) and full recovery (n=24, 75%). The mean ALFI-MMSE score was 19.1 (standard deviation 5.1), and the mean HUI3 score was 0.76 (standard deviation 0.28). The classification based on the two simple questions was significantly correlated with ALFI-MMSE (p=0.002) and HUI3 (p=0.001). Scores for the HUI3 were missing in eight survivors. CONCLUSIONS: Neurologic outcomes based on the two simple questions after cardiac arrest can be easily determined, sensibly applied, and readily interpreted. These preliminary findings justify further evaluation of this simple and practical approach to classify neurologic outcome in survivors of cardiac arrest.

A modified Wilcoxon test for non-negative distributions with a clump of zeros.

Comparing two samples with a continuous non-negative score, e.g. a utility score over [0, 1], with a substantial proportion, say 50 per cent, scoring 0 presents distributional problems for most standard tests. A Wilcoxon rank test can be used, but the large number of ties reduces power. I propose a new test, the Wilcoxon rank-sum test performed after removing an equal (and maximal) number of 0's from each sample. This test recovers much of the power. Compared with a (directional) modification of a two-part test proposed by Lachenbruch, the truncated Wilcoxon has similar power when the non-zero scores are independent of the proportion of zeros, but, unlike the two-part test, the truncated Wilcoxon is relatively unaffected when these processes are dependent.

Heart rate, pacing, and outcome in the Dual Chamber and VVI Implantable Defibrillator (DAVID) trials.

BACKGROUND: Slower heart rates are believed to confer a better prognosis in heart disease. The Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial found that patients with ventricular dysfunction and isolated sinus bradycardia (rate <60 with normal PR interval) had an unusually low incidence of heart failure (HF) hospitalization and mortality when paced infrequently. OBJECTIVES: The purpose of this study was to prospectively test our hypotheses that a similar benefit from bradycardia would be conferred in DAVID II as in DAVID but that this would be nullified by the faster heart rate achieved during atrial pacing in DAVID II. METHODS: Effects of atrial versus minimal ventricular pacing on outcome in defibrillator recipients with isolated bradycardia in DAVID II were prospectively evaluated. RESULTS: Ninety-eight DAVID II patients with isolated bradycardia were similar to 502 patients without it but had less baseline HF. HF medications were used comparably in both groups at baseline and throughout the study. Overall, patients with isolated bradycardia were less likely to die or be hospitalized for HF than others (12.2% vs. 26%; P = .01). There was no evidence that atrial pacing diminished this association. Adjusted for covariates, particularly baseline HF and its treatment, isolated bradycardia patients had substantially reduced risk for HF/death (P = .018) with or without atrial pacing (relative risk 0.47 and 0.71, respectively). CONCLUSIONS: Isolated bradycardia identifies patients at lower risk for HF and mortality, an association that is not necessarily negated by accelerating heart rate with atrial pacing. This apparent conundrum challenges the use of heart rate as a therapeutic target in patients with ventricular dysfunction. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00187187.

The DAVID (Dual Chamber and VVI Implantable Defibrillator) II trial.

OBJECTIVES: The purpose of this study was to determine whether atrial pacing is a safe alternative to minimal (backup-only) ventricular pacing in defibrillator recipients with impaired ventricular function. BACKGROUND: The DAVID (Dual Chamber and VVI Implantable Defibrillator) trial demonstrated that dual chamber rate responsive pacing as compared with ventricular backup-only pacing worsens the combined end point of mortality and heart failure hospitalization. Although altered ventricular activation from right ventricular pacing was presumed to be the likely cause for these maladaptive effects, this supposition is unproven. METHODS: In all, 600 patients with impaired ventricular function from 29 North American sites, who required an implanted defibrillator for primary or secondary prevention, with no clinical indication for pacing, were randomly assigned to atrial pacing (at 70 beats/min) versus minimal ventricular pacing (at 40 beats/min) and followed up for a mean of 2.7 years. RESULTS: There were no significant differences between pacing arms in patients' baseline characteristics, use of heart failure medications, and combined primary end point of time to death or heart failure hospitalization during follow-up, with an overall incidence of 11.1%, 16.9%, and 24.6% at 1, 2, and 3 years, respectively. Similarly, the incidence of atrial fibrillation, syncope, appropriate or inappropriate shocks, and quality of life measures did not significantly differ between treatment groups. CONCLUSIONS: The effect of atrial pacing on event-free survival and quality of life was not substantially worse than, and was likely equivalent to, backup-only ventricular pacing. Atrial pacing may be considered a "safe alternative" when pacing is desired in defibrillator recipients, but affords no clear advantage or disadvantage over a ventricular pacing mode that minimizes pacing altogether. (Dual Chamber and VVI Implantable Defibrillator [DAVID] Trial II; NCT00187187).

Clinical criteria for predicting benefit of ICD/PM in post myocardial infarction patients: an AVID and CAST analysis.

BACKGROUND: Three clinical factors from the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial-heart failure, left ventricular dysfunction and certain historical features defined a subgroup in which an implantable cardioverter defibrillator (ICD/PM) has a mortality advantage over amiodarone. METHODS: These three factors were jointly evaluated in the AVID cohort with ischemic heart disease (IHD) and the results applied in placebo-treated post-infarction patients in the cardiac arrhythmia suppression trial (CAST). RESULTS: Similar predictive power was noted in AVID patients with IHD. In CAST the factors defined three groups; one group (5.8%), corresponding to AVID patients that had high risk and benefited from an ICD/PM and another group (17.2%) corresponding to patients in AVID where the risk was moderate and ICD/PM and amiodarone had equal efficacy, demonstrated a two-fold higher risk of sudden arrhythmic than non-arrhythmic death and hence would be expected to benefit from antiarrhythmia therapy. The third group, corresponding to AVID patients with low risk of arrhythmia, demonstrated similar and low risks of sudden arrhythmic and non-arrhythmic death. Thus this group (77%) is unlikely to benefit from indiscriminate antiarrhythmia therapy. Onset of risk of death in CAST patients was offset from randomization by 3 to 6 months. CONCLUSIONS: Readily available clinical criteria identify a small group likely to benefit from an ICD/PM after recent myocardial infarction (MI) and the remainder unlikely to benefit from nonselective ICD/PM therapy. Additional risk stratification should focus on the latter patients and be timed to allow ICD/PM implantation between 2 and 6 months after MI.

Effect of pacing for soft indications on mortality and heart failure in the dual chamber and VVI implantable defibrillator (DAVID) trial.

BACKGROUND: The dual chamber and VVI implantable defibrillator (DAVID) trial demonstrated that dual chamber (DDDR) pacing in defibrillator candidates with impaired ventricular function and no established indication for pacing resulted in worsened congestive heart failure (CHF) or death. Many patients had abnormalities for which pacing is often advocated to improve the management of ventricular dysfunction. OBJECTIVES: Evaluate the impact and interaction of nonessential but potentially justifiable reasons to pace ("soft indications"), together with pacing mode, on outcome. METHODS: DAVID patients were stratified by those with and without "soft indications" for pacing (rate < 60 beats/min or first-degree atrioventricular block) (n = 169; n = 335, respectively). This analysis also stratified patients by normal and abnormal QRS conduction (QRS >or= 110 ms), who were previously found to be affected differently by DDDR pacing. Groups were analyzed according to the combined endpoint of mortality or CHF hospitalization. RESULTS: When assigned to treatment that promoted pacing (DDDR), the incidence of death or CHF tended to be higher in patient subgroups with and without "soft indications," consistent with results from DAVID. Patients with, compared to those without, these abnormalities neither benefited nor were less adversely affected when actively paced. The presence or absence of "soft indications" also provided no additional explanation for the differing outcomes in patient cohorts with and without abnormal QRS conduction. CONCLUSIONS: Sinus bradycardia or first-degree atrioventricular block did not ameliorate the poor outcomes associated with dual-chamber compared with VVI pacing, and do not justify conventional dual-chamber pacing in defibrillator recipients with ventricular dysfunction.

Pearls and perils of an implantable defibrillator trial using a common control: implications for the design of future studies.

AIMS: Implantable defibrillators are considered life-saving therapy in heart failure (CHF) patients. Surprisingly, the recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) reached an opposing conclusion from that of numerous other trials about their survival benefit in patients with advanced CHF. A critical analysis of common control trial design may explain this paradoxical finding, with important implications for future studies. METHODS AND RESULTS: Common control trials compare several intervention groups to a single rather than separate control groups. Though potentially requiring fewer patients than trials using separate controls, variation in the common control group will influence all comparisons and creates correlations between findings. During subgroup analyses, this dependency of outcomes may increase belief in the presence of a real subgroup effect when, in fact, it should increase skepticism. For example, a high (r = 0.92), statistically unlikely (p = 0.052) correlation between comparisons was observed across the subgroups reported in SCD-HeFT. Such concordance between amiodarone and a defibrillator across subgroups was unexpected, given how much the effects of these treatments significantly differed from one another in the main study. This suggests the study's subgroup findings (specifically the absence of benefit from defibrillators in advanced CHF) were not necessarily a consequence of treatment; more likely, they resulted from variation in what the treatments were compared against, the common control. CONCLUSION: Common control trials can be more efficient than other designs, but induce dependence between treatment comparisons and require cautious interpretation.

Psychosocial status predicts mortality in patients with life-threatening ventricular arrhythmias.

BACKGROUND: Quality-of-life (QoL) instruments evaluate various aspects of physical, mental, and emotional health, but how these psychosocial characteristics impact long-term outcome after cardiac arrest and ventricular tachycardia (VT) is unknown. OBJECTIVE: The purpose of this study was to evaluate the relationship of baseline QoL scores with long-term survival of patients enrolled in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial. METHODS: Formal QoL measures included SF-36 mental and physical components, Patient Concerns Checklist, and Ferrans and Powers Quality-of-Life Index-Cardiac Version. Multivariate Cox regression was used to assess the association of survival and these measures, adjusting for index arrhythmia type, gender, race, age, ejection fraction, history of congestive heart failure, antiarrhythmic therapy, and beta-blocker use. RESULTS: During mean follow-up of 546 +/- 356 days, 129 deaths occurred among 740 patients. Higher baseline SF-36 physical summary scores (P <.001), higher baseline QoL Index summary scores (P = .015), and lower baseline Patient Concerns Checklist summary scores (P = .047) were associated with longer survival, even after adjustment for clinical variables. When QoL measures were examined simultaneously, only the SF-36 physical summary score remained significant (P = .002). CONCLUSION: During recovery after sustained VT or cardiac arrest, formal baseline QoL assessment provides important prognostic information independent of traditional clinical data.

A history of heart failure predicts arrhythmia treatment efficacy: data from the Antiarrythmics versus Implantable Defibrillators (AVID) study.

BACKGROUND: In survivors of life-threatening ventricular tachycardia (VT), a history of CHF (HxCHF) before the VT episode may provide different prognostic information than their measured left ventricular ejection fraction (LVEF). METHODS: We evaluated outcomes from patients in the AVID study. Patients were included in the study if they presented with ventricular fibrillation, VT with syncope or VT with hemodynamic compromise, and LVEF < or = 40%. Treatment options included implantable cardioverter defibrillator (ICD) or antiarrhythmic drugs (AAD), usually amiodarone. RESULTS: As expected, a HxCHF is associated with an increased and high risk of arrhythmic and nonarrhythmic death. However, an interaction was observed between arrhythmia treatment (ICD or AAD) and HxCHF status: the survival advantage with an ICD, as compared with AAD therapy, is largely restricted to HxCHF patients. CONCLUSIONS: The ICD is no better than AAD therapy in preventing arrhythmic death in patients with no HxCHF. In this data set, a HxCHF is somewhat more accurate in predicting prognosis and the response to therapy than a reduced LVEF.

What is the appropriate outcome for studies of treatments for out-of-hospital cardiac arrest?

BACKGROUND: A good outcome following out-of-hospital medical care for cardiac arrest is survival to hospital discharge. Because a large number of patients are required to detect a minimum clinically important difference in survival, an intermediate outcome such as hospital admittance is commonly used. For an intermediate outcome to be a useful surrogate, the survival rate conditional on achieving the intermediate outcome should not depend upon the field treatment. If so, an advantage of the intermediate outcome may be a smaller sample size. However, recent trials demonstrate that survival conditional on admittance may depend upon the field treatment. Even if the resources are available to power a study for survival, is survival the right outcome? For example, no increase in survival and a large increase in admittance could be considered a bad result, as it represents a substantial waste of resources. Similarly no increase in mortality and a decrease in admittance should be considered a good result, as it represents a substantial cost savings without any sacrifice of life. Both admittance and survival are important outcomes and need to be considered jointly, that is, as a bivariate outcome. METHODS: Cost-effectiveness concepts are used to distinguish between a good and bad (bivariate) outcome. Simulations are conducted to compare the impact of the univariate and the bivariate outcomes in a variety of trial scenarios. A table of sample sizes is computed for the bivariate outcome across a range of trial scenarios. RESULTS: The bivariate outcome outperforms both univariate outcomes for most alternatives. The required sample size for the joint outcome of admittance and survival may be substantially, over 50%, less than that for the survival outcome alone. CONCLUSION: Use of the bivariate outcome could provide more informed decision making about resuscitation strategies and at less cost then the current gold standard of hospital survival.

Location of cardiac arrests in the public access defibrillation trial.

BACKGROUND: The Public Access Defibrillation (PAD) Trial found an overall doubling in the number of out-of-hospital cardiac arrest (CA) survivors when a lay responder team was equipped with an automated external defibrillator (AED), compared with cardiopulmonary resuscitation (CPR) alone. OBJECTIVES: To describe the types of facilities that participated in the trial and to report the incidence of CA and survival in these different types of facilities. METHODS: In this post-hoc analysis of PAD Trial data, the physical characteristics of the participating facilities and the numbers of presumed CAs, treatable CAs, and survivors are reported for each category of facilities. RESULTS: There were 625 presumed CAs at 1,260 participating facilities. Just under half (n = 291) of the presumed CAs were classified as treatable CAs. Treatable CAs occurred at a rate of 2.9 per 1,000 person-years of exposure; rates were highest in fitness centers (5.1) and golf courses (4.8) and lowest in office complexes (0.7) and hotels (0.7). Survival from treatable CA was highest in recreational complexes (0.5), public transportation sites (0.4), and fitness centers (0.4) and lowest in office complexes (0.1) and residential facilities (0.0). CONCLUSIONS: During the PAD Trial, the exposure-adjusted rate of treatable CA was highest in fitness centers and golf courses, but the incidence per facility was low to moderate. Survival from treatable cardiac arrest was highest in recreational complexes, public transportation facilities, and fitness centers.

Percent right ventricular pacing predicts outcomes in the DAVID trial.

BACKGROUND: The Dual-Chamber and VVI Implantable Defibrillator (DAVID) trial demonstrated a worse outcome in patients with implantable cardioverter-defibrillators (ICDs) programmed to DDDR at 70 bpm compared with patients who had ICDs programmed to VVI backup pacing at 40 bpm. Pacing was more frequent in the DDDR group. OBJECTIVES: The purpose of this study was to determine whether right ventricular pacing (RV) is an independent predictor of outcome in the DAVID trial. METHODS: We evaluated the relationship of percent RV pacing to the composite endpoint of death or hospitalization for congestive heart failure. Patients who had a 3-month follow-up and who had not yet reached an endpoint were included in the study. Using Cox regression analysis (VVI group N = 195; DDDR group N = 185), we examined multiple factors, including percent RV pacing at 3-month follow-up, that might be associated with adverse outcomes. RESULTS: Percent RV pacing as a continuous variable was correlated with the primary endpoint. As a dichotomous variable, the best separation for predicting endpoints occurred with DDDR RV pacing > 40% vs DDDR RV pacing < or = 40% (P = .025). Patients with DDDR RV pacing < or = 40% had similar or better outcomes to the VVI backup group (P = .07). Correction for baseline variables predictive of the composite outcome in the (nonpaced) VVI group (use of nitrates, increased heart rate, and increased age) did not change the findings for RV pacing (P = .008). In contrast, atrial pacing was not predictive of worse outcomes. CONCLUSION: These results suggest, but do not prove, a causal relationship between frequent RV pacing and adverse outcomes in patients with left ventricular ejection fraction < or = 40%.

A comparison of the AVID and DAVID trials of implantable defibrillators.

We compared 2 studies of implantable cardiac defibrillators (ICDs) to determine the effects of device mode on outcomes. The Antiarrhythmics Versus Implantable Defibrillators (AVID) trial (1993 to 1997) demonstrated improved survival with the ICD compared with antiarrhythmic drug therapy. The Dual-chamber And VVI Implantable Defibrillator (DAVID) trial (2000 to 2002) showed that VVI pacing at 40 beats/min in patients with ICDs reduced the combined end point of death and hospitalization for congestive heart failure compared with DDDR pacing at 70 beats/min. Patients in the AVID trial (631 of 1,016) and the DAVID trial (221 of 506) meeting common inclusion and all exclusion criteria were studied. The major end points were the time to death, and the composite end point of time to death or hospitalization for congestive heart failure. Patients in the AVID and DAVID trials were similar, but more AVID patients had coronary artery disease (p = 0.04), history of myocardial infarction (p = 0.005), and previous ventricular arrhythmias (p = 0.03). DAVID patients underwent more previous revascularization procedures (coronary artery bypass surgery, p = 0.03; percutaneous coronary intervention, p = 0.001), and were more often taking beta-blocking drugs at hospital discharge (p <0.001). The backup VVI ICD groups in both studies had similar outcomes (p = 0.4), even when corrected for the previous demographic differences. The time-to- composite end point was similar in AVID patients treated with antiarrhythmic drugs and DAVID patients treated with DDDR ICDs (p = 0.6). Despite improved pharmacologic therapy and revascularization, outcomes have not improved with backup VVI pacing ICDs. If DDDR ICDs had been used in the AVID trial, benefit from ICDs for patients with serious ventricular arrhythmias could have been missed.

Characteristics of heart beat intervals and prediction of death.

OBJECTIVE: To assess the value for improving risk stratification of measures, unadjusted and adjusted for heart rate, of heart rate variability (HRV) and heart rate turbulence (HRT) based on 2- to 24-h ambulatory electrocardiographic recordings; and to relate this to the decision to use an implantable cardiac defibrillator (ICD) and the attendant consequences on effectiveness and cost-effectiveness. BACKGROUND: Risk stratification for high risk or low risk of lethal ventricular arrhythmic events, and hence for a decision about defibrillator implant, most commonly utilizes the left ventricular ejection fraction (LVEF). Electrocardiographic (ECG) approaches include 24-h ambulatory ECG recordings, with counts of ventricular premature contractions (VPCs), measures of heart rate variability (HRV), and heart rate turbulence (HRT). HRT has two components: turbulence onset (TO) and turbulence slope (TS). METHODS AND RESULTS: We evaluated the qualifying ambulatory ECG recordings from 744 patients in the active treatment arms of the Cardiac Arrhythmia Suppression Trial (CAST). Beat characteristics, VPC counts, normal-to-normal beat intervals, and time-domain measures of HRV and HRT were calculated. Tachograms were rescaled to a heart rate of 75 and the resulting "normalized" measures evaluated as risk predictors for death, compared to unnormalized measures. Measures based on 2-h ECGs were also evaluated as risk predictors. The most powerful univariate predictor of survival was the normalized turbulence slope. The best multivariate prediction model had six components: history of angina, hypertension, diabetes, and absence of post-myocardial infarction revascularization, the log of LVEF, normalized TS, HR, and an interaction term of HR and normalized TS. Gains in effectiveness from use of this model cost between $0 and $4000 per year of life saved. CONCLUSIONS: Turbulence slope substantially exceeded other ECG-based measures in improving prediction of subsequent death in models which included LVEF, and other clinical parameters. Use of this model would improve the effectiveness and cost-effectiveness of the ICD.

Pre-randomization and de-randomization in emergency medical research: new names and rigorous criteria for old methods.

Clinical trials are performed to determine if a therapy is effective in the treatment of a disease. The methods of randomization and blinding are used to assure that the only planned difference between the two groups is the therapy itself, and differences in outcome cannot be attributed to bias. Emergency medical conditions, and in particular therapies that must be administered in an emergency, present challenges to inclusion, exclusion, randomization, and blinding that are at times insurmountable in the context of available resources. Pre-randomization (that is, assigning the therapy to be used before the event occurs) and de-randomization (that is, removing randomized cases that do not meet established inclusion criteria) may address some of the challenges resulting from emergency enrollment but have the potential to create bias. We describe these techniques, and provide criteria that should be employed if pre-randomization and/or de-randomization are being considered. It is possible to use these techniques to successfully complete clinical trials that would not have been possible using only standard methodology and still ensure that results are without bias.

Structural relationships between measures based on heart beat intervals: potential for improved risk assessment.

Decreased left ventricular ejection fraction is the most commonly used risk factor for identification of patients at high-risk for lethal ventricular arrhythmic events. Twenty-four-hour electrocardiographic (ECG) approaches to risk stratification include: counts of ventricular premature contractions (VPCs), measures of heart rate variability (HRV), and heart rate turbulence (HRT) which has two components, turbulence onset and turbulence slope (TS). Refinement of these ECG risk stratifiers could enhance their clinical utility. We explored the structural relationships between heart rate (HR) and HRV and HRT measures. Our goal was to separate out the component of these measures due to the underlying average heart rate (HR), thus potentially reducing the variability of the measures and increasing their power to stratify risk. We proposed re-scaling tachograms of heart-beat intervals so that the re-scaled tachogram has a HR of 75 (or equivalently an average interval of 800 ms) and calculating HRV and HRT from the rescaled time series. We also explored the relationship between the number of VPCs and HRT. We showed that TS is structurally related to the number of VPCs (and hence to the length of the ECG recording). We proposed an adjusted TS that is independent of the number of VPCs. We also addressed the ability of shorter ECG recording to estimate HRV and HRT measures. We evaluated standard and rescaled HRV and HRT measures using qualifying ambulatory ECG recordings from 744 patients in the Cardiac Arrhythmia Suppression Trial. We found that measures based on the rescaled tachogram had reduced variance (20% to 40%). Correlations between measures were also substantially reduced. We also found substantial circadian effects on some, but not all HRV indices, not explained by the circadian pattern in HR and possibly pointing to additional measures for risk prediction. In conclusion, we found that adjusting for HR and the number of VPCs in heart-beat related ambulatory ECG measures has the potential to significantly improve the power of these measures to risk stratify cardiac patients.

Measuring survival rates from sudden cardiac arrest: the elusive definition.

BACKGROUND: Measuring survival from sudden out-of-hospital cardiac arrest (OOH-CA) is often used as a benchmark of the quality of a community's emergency medical service (EMS) system. The definition of OOH-CA survival rates depends both upon the numerator (surviving cases) and the denominator (all cases). PURPOSE: The purpose of the public access defibrillation (PAD) trial was to measure the impact on survival of adding an automated external defibrillator (AED) to a volunteer response system trained in CPR. This paper reports the definition of OOH-CA developed by the PAD trial investigators, and it evaluates alternative statistical methods used to assess differences in reported "survival." METHODS: Case surveillance was limited to the prospectively determined geographic boundaries of the participating trial units. The numerator in calculating a survival rate should include only those patients who survived an event but who otherwise would have died except for the application of some facet of emergency medical care-in this trial a defibrillatory shock. Among denominators considered were: total population of the study unit, all deaths within the study unit, and documented ventricular fibrillation cardiac arrests. The PAD classification focused upon cases that might have benefited from the early use of an AED, in addition to the likely benefit from early recognition of OOH-CA, early access of EMS, and early cardiopulmonary resuscitation (CPR). Results of this classification system were used to evaluate the impact of the PAD definition on the distribution of cardiac arrest case types between CPR only and CPR + AED units. RESULTS: Potential OOH-CA episodes were classified into one of four groups: definite, probable, uncertain, or not an OOH-CA. About half of cardiac arrests in the PAD units were judged to be definite OOH-CA events and therefore potentially treatable with an AED. However, events that occurred in CPR-only units were less likely to be classified as definite or probable OOH-CA events than those in CPR + AED units (43% versus 55%, odds ratio 0.78, 95% confidence interval 0.57-1.07). The study retained sufficient power to permit a statistical analysis of the alternative hypothesis that the CPR + AED method results in twice as many survivors as a CPR-only approach. The result is critically dependent on the denominator used for calculating survival rates; but the analysis does not require a denominator as the numerators will have identical Poisson distributions (counts for rare events) under the null hypothesis since randomization distributes the risk of cardiac arrest evenly between the two arms. CONCLUSION: Reported OOH-CA rates and survival rates vary widely, depending upon the definitions applied to events. Rigorous assessment of treatments applied to improve survival can be obscured by inappropriate definitions. Large-scale randomized interventions designed to improve survival from OOH-CA can be evaluated based upon the absolute numbers of patients surviving, rather than a change in the proportion surviving.

Lower observed versus expected (based on U.S. age and gender specific rates) survival in patients treated for near-fatal ventricular arrhythmias.

Implantable cardioverter defibrillators (ICDs) have improved survival for patients with ventricular fibrillation (VF) or sustained vertricular tachycardia (VT). However, the survival of these patients compared to the general population has not been assessed. Observed survival rates for patients randomized to either antiarrhythmic drug therapy (mainly amiodarone) arm or ICD arm were compared to expected rates, calculated using age and sex-specific survival rates derived from the 1989-1991 US population life tables and applied to the age and sex distribution of patients in each arm. Consistent with the results of the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, patients randomized to receive ICDs experienced significantly higher survival than those in the drug arm; however, both groups experienced significantly lower survival than expected using age and gender matched U.S. survival rates. Within arms, the difference between the observed and expected rates increased over 3 years of follow-up from 7.7% to 15.3% for the ICD arm, and from 14.6% to 26.4% for the drug arm. These results quantify the improvements in survival that can be expected for VF or VT patients using drug or ICD therapies and underscore the need for continued research into methods for further improving the overall level of health of these patients.

Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial.

INTRODUCTION: The implantable cardioverter defibrillator (ICD) is commonly used to treat patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Arrhythmia recurrence rates in these patients are high, but which patients will receive a therapy and the forms of arrhythmia recurrence (VT or VF) are poorly understood. METHODS AND RESULTS: The therapy delivered by the ICD was examined in 449 patients randomized to ICD therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. Events triggering ICD shocks or antitachycardia pacing (ATP) were reviewed for arrhythmia diagnosis, clinical symptoms, activity at the onset of the arrhythmia, and appropriateness and results of therapy. Both shock and ATP therapies were frequent by 2 years, with 68% of patients receiving some therapy or having an arrhythmic death. An appropriate shock was delivered in 53% of patients, and ATP was delivered in 68% of patients who had ATP activated. The first arrhythmia treated in follow-up was diagnosed as VT (63%), VF (13%), supraventricular tachycardia (18%), unknown arrhythmia (3%), or due to ICD malfunction or inappropriate sensing (3%). Acceleration of an arrhythmia by the ICD occurred in 8% of patients who received any therapy. No physical activity consistently preceded arrhythmias, nor did any single clinical factor predict the symptoms of the arrhythmia. CONCLUSION: Delivery of ICD therapy in AVID patients was common, primarily due to VT. Inappropriate ICD therapy occurred frequently. Use of ICD therapy as a surrogate endpoint for death in clinical trials should be avoided.