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.

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.

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.

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.

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.

Cost-effectiveness of the implantable cardioverter-defibrillator versus antiarrhythmic drugs in survivors of serious ventricular tachyarrhythmias: results of the Antiarrhythmics Versus Implantable Defibrillators (AVID) economic analysis substudy.

BACKGROUND: The implantable cardioverter-defibrillator (ICD) is an effective but expensive device. We used prospectively collected data from a large randomized clinical trial of secondary prevention of life-threatening ventricular arrhythmias to determine the cost-effectiveness of the ICD compared with antiarrhythmic drug (AAD) therapy, largely with amiodarone. METHODS AND RESULTS: Charges for initial and repeat hospitalizations, emergency room, and day surgery stays and the costs of antiarrhythmic drugs were collected on 1008 patients. Detailed records of all other medical encounters and expenses were collected on a subgroup of 237 patients. Regression models were then created to attribute these expenses to the rest of the patients. Charges were converted to 1997 costs using standard methods. Costs and life years were discounted at 3% per year. Three-year survival data from the Antiarrhythmics Versus Implantable Defibrillators trail were used to calculate the base-case cost-effectiveness (C/E) ratio. Six-year, twenty-year, and lifetime C/E ratios were also estimated. At 3 years, total costs were $71 421 for a patient taking AADs and $85 522 for a patient using an ICD, and the ICD provided a 0.21-year survival benefit over AAD treatment. The base-case C/E ratio was thus $66 677 per year of life saved by the ICD compared with AAD therapy (95% CI, $30 761 to $154 768). Six- and 20-year C/E ratios remained stable between $68 000 and $80 000 per year of life saved. CONCLUSIONS: The ICD is moderately cost-effective for secondary prevention of life-threatening ventricular arrhythmias, as judged from prospectively collected data in a randomized clinical trial.

Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Antiarrhythmics versus Implantable Defibrillators (AVID) trial.

OBJECTIVES: This study sought to evaluate the antiarrhythmic effects of lipid-lowering drug therapy as assessed by ventricular tachyarrhythmia (ventricular tachycardia [VT]/ventricular fibrillation [VF]) recurrences recorded by an implantable cardioverter defibrillator (ICD) in patients with atherosclerotic heart disease (ASHD). BACKGROUND: Randomized trials of lipid-lowering drugs suggest reduction of sudden death (SD) in patients with ASHD. Because SD is usually secondary to VT/VF, this observation suggests that lipid-lowering therapy has antiarrhythmic effects. METHODS: The probability of VT/VF recurrence in patients with ASHD treated with an ICD in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial who did not receive lipid-lowering drug therapy (n = 279) was compared with that in patients who received early and consistent lipid-lowering therapy (n = 83). In addition, all-cause mortality and cardiac mortality of all patients in the AVID trial with ASHD who did not receive lipid-lowering therapy (n = 564) were compared with that of those who received early and consistent lipid-lowering therapy (n = 149). RESULTS: Using multivariate analyses, lipid-lowering therapy was associated with a reduction in the relative hazard for VT/VF recurrence of 0.40 (95% confidence interval [CI] 0.15 to 0.58) (adjusted p = 0.003) in the ICD subgroup. Lipid-lowering therapy was also associated with a reduction in the relative hazard for all-cause mortality of 0.36 (95% CI 0.15 to 0.68) (adjusted p = 0.03) and a reduction in the relative hazard for cardiac mortality of 0.39 (95% CI 0.16 to 0.78) (adjusted p = 0.04) in the larger study population. CONCLUSIONS: In patients with ASHD who have received an ICD, lipid-lowering therapy is associated with reduction in the probability of VT/VF recurrence, suggesting that part of the benefit of lipid-lowering therapy may be due to an antiarrhythmic effect.

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.

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%.

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.

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.

Risk of sudden versus nonsudden cardiac death in patients with coronary artery disease.

BACKGROUND: Patients at high risk of sudden cardiac death, yet at low risk of nonsudden death, might be ideal candidates for antiarrhythmic drugs or devices. Most previous studies of prognostic markers for sudden cardiac death have ignored the competitive risk of nonsudden cardiac death. The goal of the present study was to evaluate the ability of clinical factors to distinguish the risks of sudden and nonsudden cardiac death. METHODS: We identified all deaths during a 3.3-year follow-up of 30,680 patients discharged alive after admission to the cardiac care unit of a Seattle hospital. Detailed chart reviews were conducted on 1093 subsequent out-of-hospital sudden deaths, 973 nonsudden cardiac deaths, and 442 randomly selected control patients. RESULTS: Patients who died in follow-up (suddenly or nonsuddenly) were significantly different for many clinical factors from control patients. In contrast, patients with sudden cardiac death were insignificantly different for most clinical characteristics from patients with nonsudden cardiac death. The mode of death was 20% to 30% less likely to be sudden in women, patients who had angioplasty or bypass surgery, and patients prescribed beta-blockers. The mode of death was 20% to 30% more likely to be sudden in patients with heart failure, frequent ventricular ectopy, or a discharge diagnosis of acute myocardial infarction. A multivariable model had only modest predictive capacity for mode of death (c-index of 0.62). CONCLUSION: Standard clinical evaluation is much better at predicting overall risk of death than at predicting the mode of death as sudden or nonsudden.

Prognostic value of baseline electrophysiology studies in patients with sustained ventricular tachyarrhythmia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial.

OBJECTIVES: We sought to determine the value of electrophysiology (EP) testing in patients with ventricular fibrillation (VF), ventricular tachycardia (VT) with syncope, or sustained VT in the setting of left ventricular dysfunction. BACKGROUND: Traditionally, EP testing is part of the workup of patients with sustained VT or VF. Recently, some have suggested that EP testing is unnecessary in these patients, many of whom are likely to receive an implantable cardioverter-defibrillator (ICD). METHODS: Within a multicenter trial (Antiarrhythmics Versus Implantable Defibrillators) designed to evaluate whether drugs or ICD resulted in a better outcome, data were analyzed regarding EP testing. Although this testing was not required, it was performed in >50% of patients. Information regarding the results of EP testing was correlated to baseline clinical characteristics and outcome. RESULTS: Of 572 patients subjected to an EP test, 384 (67%) had inducible sustained VT or VF. Inducible patients were more likely to have coronary artery disease, previous infarction, and VT as their index arrhythmic event. Inducibility of VT or VF did not predict death or recurrent VT or VF. CONCLUSIONS: Information derived from EP testing in this patient population, particularly those with VF, is of limited value and may not be worth the risks and costs of the procedure, particularly in those patients likely to receive an ICD.

Effect of surgical revascularization in patients with coronary artery disease and ventricular tachycardia or fibrillation in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Registry.

BACKGROUND: Patients who undergo resuscitation from near-fatal ventricular arrhythmias often have significant coronary artery disease, and revascularization has been shown to reduce myocardial ischemia and cardiac arrest episodes in this patient population. The magnitude of benefit attributed to revascularization has varied by study, and the use of adjunct implantable cardioverter defibrillator (ICD) therapy has not been well-characterized. METHODS AND RESULTS: The Antiarrhythmics Versus Implantable Defibrillators (AVID) registry included 3117 patients with life-threatening ventricular arrhythmias, of whom 2321 (77%) had documented coronary artery disease and 281 (17%) underwent a coronary artery bypass grafting revascularization procedure after the index event. Patients who underwent a revascularization procedure were younger, had a lower incidence rate of prior myocardial infarction and ventricular arrhythmia, had a higher left ventricular ejection fraction, had less congestive heart failure, and were more likely to have had ventricular fibrillation as the presenting arrhythmia. Patients who underwent revascularization had a better survival rate than did those who did not undergo such a procedure after the index event, and adjustment for differing baseline patient covariates did not alter the relative survival rate benefit. Further, ICD implantation offered a similar survival rate advantage to those patients in the AVID registry with coronary artery disease independent of revascularization. CONCLUSION: Coronary revascularization in the AVID registry patients with coronary artery disease effected a survival rate benefit that was not attributable to differences in baseline patient characteristics. The benefit of ICD on patient survival rate was not attenuated by a revascularization procedure.

Dispatcher assisted CPR: implementation and potential benefit. A 12-year study.

OBJECTIVES: Our objectives are to describe details of the dispatcher assisted cardiopulmonary resuscitation (CPR) instruction program we implemented during a 12 years study and to provide estimates of the potential number of out-of-hospital cardiac arrests that might benefit from such instruction based on data from the last 77 months. METHODS: Basic data were obtained for all episodes of out-of-hospital cardiac arrest in the city of Seattle, as well as all emergency medical services (EMS) dispatches for suspected cardiac arrest. In addition to EMS run reports, data sources included audio tapes of dispatches, and interviews of callers. These data were used in a potential benefit analysis. RESULTS: Over a period of 77 months, 54% (3320/6130) of cardiac arrests received advanced cardiac life support (ACLS) by Seattle Fire Department emergency medical technicians (EMTs) and paramedics. We estimated that 29.9% (994/3320) of cardiac arrests in Seattle treated by EMS could have theoretically benefited from dispatcher assisted CPR. No serious adverse consequences of a dispatcher assisted CPR program were observed. Failure to identify a cardiac arrest by dispatchers was largely attributed to deviation from a well-defined protocol. However, non-arrests identified, initially as arrests appeared to be unavoidable. CONCLUSIONS: In the city of Seattle, some 29.9% of all out-of-hospital cardiac arrest victims who received ACLS had the potential to benefit from dispatcher assisted CPR.

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.

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.

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.