Death In Heart Failure Trial Research Articles

Maximizing Survival Benefit With Primary Prevention Implantable Cardioverter-Defibrillator Therapy in a Heart Failure Population

Although implantable cardioverter-defibrillator (ICD) therapy reduces mortality in moderately symptomatic heart failure patients with an ejection fraction <or=35%, many such patients do not require ICD shocks over long-term follow-up. Using a modification of a previously validated risk prediction model based on routine clinical variables, we examined the relationship between baseline predicted mortality risk and the relative and absolute survival benefits of ICD treatment in the primary prevention Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In the placebo arm, predicted 4-year mortality grouped into 5 equal-sized risk groups varied from 12% to 50% (c statistic=0.71), whereas the proportion of SCD in those same risk groups decreased from 52% to 24% of all deaths. ICD treatment decreased relative risk of SCD by 88% in the lowest-risk group versus 24% in the highest-risk group (P=0.009 for interaction) and decreased relative risk of total mortality by 54% in the lowest-risk group versus no benefit (2%) in the highest-risk group (P=0.014 for interaction). Absolute 4-year mortality reductions were 6.6%, 8.8%, 10.6%, 14.0%, and -4.9% across risk quintiles. In highest-risk patients (predicted annual mortality >20%), no benefit of ICD treatment was seen. Projected over each patient's predicted lifespan, ICD treatment added 6.3, 4.1, 3.0, 1.9, and 0.2 additional years of life in the lowest- to highest-risk groups, respectively. A clinical risk prediction model identified subsets of moderately symptomatic heart failure patients in SCD-HeFT in whom single-lead ICD therapy was of no benefit and other subsets in which benefit was substantial.

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Review of the ICD Registry's Third Year, Expansion to include Lead Data and Pediatric ICD Procedures, and Role for Measuring Performance

ntroduction he National ICD Registry became the sole repository of CD implantation data for Medicare beneficiaries on April , 2006, and as of June 2009 had collected data from ,432 hospitals in the United States totaling over 380,000 mplants. The registry was developed through a partnership f the Heart Rhythm Society (HRS [www.HRSonline.org]) nd the American College of Cardiology Foundation ACCF [www.acc.org]) utilizing the expertise of the ational Cardiovascular Data Registry (NCDR [www. ccncdr.com]) and has made substantial progress toward everal predefined goals:

Low Referral Rate for Prophylactic Implantation of Cardioverter‐Defibrillators in a Tertiary Care Medical Center

Implantable cardioverter-defibrillators (ICDs) for primary prevention became standard of care after the publication of the second Multicenter Automatic Defibrillator Implantation Trial (MADIT-II) and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). To determine the percentage of patients in a Veterans Affairs medical center appropriately referred for primary prophylaxis ICD and to further categorize the reasons patients are not being referred. Echocardiograms obtained since the release of MADIT-II in 2002 were searched for a left ventricular ejection fraction (LVEF) < or = 35% and < or =30%. We randomly selected 120 patients per year from 2002 to 2006, for a total of 600 patients in each group. Data were reviewed to determine the number of ICD recipients and the reasons patients were not referred. In the LVEF < or = 35% group an ICD was implanted in 28% of 392 eligible patients. Nonreferral (58%) was the most common reason that eligible patients did not receive an ICD. Patients were not referred for ICD because of appropriate contraindications in 26% of cases. Overall mortality was 29% (15% with and 31% without ICD). In the LVEF < or =30% group an ICD was implanted in 33% of 388 eligible patients. Nonreferral (51%) was the most common reason that eligible patients did not receive an ICD. Patients were not referred for ICD because of appropriate contraindications in 24% of cases. Overall mortality was 28% (18% with and 32% without ICD). After the publication of MADIT-II and SCD-HeFT, only 42% of eligible patients with LVEF < or = 35% and 49% of patients with LVEF < or =30% were offered a potentially life-saving ICD between 2002 and 2006 in our medical center, sometimes with considerable delay.

Cost-benefit analysis of primary prevention of sudden cardiac death with an implantable cardioverter defibrillator versus amiodarone in Canada

ABSTRACTBackground: Clinical trials have shown that implantable cardioverter defibrillators are effective in primary prevention of sudden cardiac death (SCD) in patients with high risk profiles.Objectives: To conduct a cost-benefit assessment of prevention of sudden cardiac death with an implantable cardioverter defibrillator (ICD) vs. amiodarone from the Canadian health-care system perspective.Methods: A simulation model that estimates the patient's course following an implantation with an ICD or initiation of amiodarone treatment was created. A thousand pairs of patients with identical characteristics in each treatment group, with similar demographic profiles as observed in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) were simulated. Based on the simulated individual patient characteristics, the model estimated the timing of severe arrhythmic events and deaths due to other causes and implemented the consequences at the time of the events. Patients might die at the time of severe arrhythmia (sudden cardiac death) or survive and become secondary prevention cases and be exposed to a higher risk of severe arrhythmia for the following 6 months. The rates of arrhythmia and death due to other causes were assumed to be the same, whereas the cases of fatality from severe arrhythmia differed between treatments. During the course of the simulation, the clinical (i.e., deaths) and economic outcomes were tallied for both treatment groups. All model parameters were obtained from the literature. The primary data source for clinical inputs was the published results of the SCD-HeFT trial which investigated the impact of ICDs on patients’ survival in primary prevention of sudden cardiac deaths compared to amiodarone and conventional therapy. The value of a statistical life (CND$ 5.8 million) was obtained from an analysis previously performed by Health Canada. The direct medical costs and monetary value of lives saved were estimated over 5 years. Sensitivity analyses on key parameters were carried out. The most important study limitation was using two different sources to derive the age dependent clinical risks. This issue was resolved by calibrating the derived risks to account for the population differences.Results: The model predicted that the overall mortality would be reduced by 19.1% (7.1% absolute reduction) with ICD compared to amiodarone over 5 years. The incremental benefit with ICD was estimated at CND$526 700 and additional cost at CND$28 300, which translated into a 0.05 cost: benefit ratio – around 1: 20 return of investment.Conclusion: In Canada, ICDs are a worthwhile alternative to amiodarone in the primary prevention of sudden cardiac death.

Is it safe to allow patients with implantable cardioverter-defibrillators to drive? Learnings from a single center experience

Implantable cardioverter-defibrillator (ICD) implant indications have widened in recent years after the publication of the Multicenter Automatic Defibrillator Implantation Trial 2 and the Sudden Cardiac Death in Heart Failure Trial. On the contrary, guidelines on resumption of driving after ICD implant were published almost 10 years ago when the ICD implant rate was much lower and candidates were generally older. The overall objective of our study was to evaluate whether patients implanted with ICDs have higher risk than the general driving population. The specific aim of the study was to verify the rate of car accidents in patients implanted with an ICD, both for primary and secondary indication, and compare this with the rate of accidents in the general population. The primary end point of the study was the annual car accident rate; the secondary end point was to determine if there were subgroups of patients with a higher risk of car accidents. All patients (612) followed up in our outpatient clinic were sent a questionnaire in which they were asked five questions regarding their driving habits before and after ICD implant and, specifically, whether they had been involved in a car accident after the implant. Two hundred eighty-six patients (47%) responded to the questionnaire. Seventy-one patients had never driven; two patients were forbidden to drive for professional reasons (one bus and one truck driver). Two hundred thirteen (74.5% of all responding) patients (201 men, mean age 62 +/- 11 years) continued to drive after ICD implant. During the follow-up (1430 +/- 920 days) 11 patients had been involved in car accidents and, importantly 10 out of 11 were innocent bystanders. Thus, in 996 patient-years, 11 events happened, yielding an annual event rate of 1.1% per patient-years (and only 0.1% in which the driver could had been responsible). Car accidents are infrequent in patients implanted with an ICD, and - in any case - not more frequent than in the general population. The old guidelines need to be updated and specific restrictions on car driving in ICD patients need to be revised to reflect the current data.

Role of Microvolt T-Wave Alternans in Assessment of Arrhythmia Vulnerability Among Patients With Heart Failure and Systolic Dysfunction

Background— Sudden cardiac death remains a leading cause of mortality despite advances in medical treatment for the prevention of ischemic heart disease and heart failure. Recent studies showed a benefit of implantable cardioverter defibrillator implantation, but appropriate shocks for ventricular tachyarrhythmias were noted only in a minority of patients during 4 to 5 years of follow-up. Accordingly, better risk stratification is needed to optimize patient selection. In this regard, microvolt T-wave alternans (TWA) has emerged as a potentially useful measure of arrhythmia vulnerability, but it has not been evaluated previously in a prospective, randomized trial of implantable cardioverter defibrillator therapy. Methods and Results— This investigation was a prospective substudy of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) that included 490 patients at 37 clinical sites. TWA tests were classified by blinded readers as positive (37%), negative (22%), or indeterminate (41%) by standard criteria. The composite primary end point was the first occurrence of any of the following events: sudden cardiac death, sustained ventricular tachycardia/fibrillation, or appropriate implantable cardioverter defibrillator discharge. During a median follow-up of 30 months, no significant differences in event rates were found between TWA-positive or -negative patients (hazard ratio 1.24, 95% confidence interval 0.60 to 2.59, P =0.56) or TWA-negative and nonnegative (positive and indeterminate) subjects (hazard ratio 1.28, 95% confidence interval 0.65 to 2.53, P =0.46). Similar results were obtained with the inclusion or exclusion of patients randomized to amiodarone in the analyses. Conclusions— TWA testing did not predict arrhythmic events or mortality in SCD-HeFT, although a small reduction in events (20% to 25%) among TWA-negative patients cannot be excluded given the sample size of this study. Accordingly, these results suggest that TWA is not useful as an aid in clinical decision making on implantable cardioverter defibrillator therapy among patients with heart failure and left ventricular systolic dysfunction.

Ejection fraction assessment and survival: An analysis of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)

Ejection fraction (EF) is an important method of mortality prediction among cardiac patients, and has been used to identify the highest risk patients for enrollment in the defibrillator primary prevention trials. Evidence suggests that measures of EF by different imaging modalities may not be equivalent. In the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), the type of imaging modality for EF assessment was not mandated. Baseline assessment of EF was performed using either echocardiography, radionuclide angiography (RNA), or contrast angiography. Multivariable analysis using a Cox proportional hazards model was used to examine whether the modality of assessing EF affected the likelihood of survival. Among the 2,521 patients enrolled in SCD-HeFT, EF was measured by RNA in 616 (24%), echocardiography in 1,469 (58%), and contrast angiography in 436 (17%). Mean EF as measured by RNA was 25.1% +/- 6.9%; by echocardiography, 23.8 +/- 6.9%; and by angiography, 21.9 +/- 6.9%. These measures were significantly different (P < .001), and each pairwise comparison differed significantly (P < .001 for each). Multivariable analysis showed no significant difference in survival between patients enrolled based on RNA versus echocardiography (HR 1.06, 95% CI 0.88-1.28), RNA versus angiography (HR 1.25, 95% CI 0.97-1.62), or echocardiography versus angiography (HR 1.18, 95% CI 0.94-1.48). Among patients enrolled in SCD-HeFT, the distribution of ejection fractions measured by radionuclide angiography differed from those measured by echocardiography or contrast angiograms. Survival did not differ according to modality of EF assessment.

Abstract 2140: Infrequent Need for Pacing Following Implantable Cardioverter-Defibrillator Shocks: Analysis of the Sudden Cardiac Death in Heart Failure Trial

Background: Implantable cardioverter-defibrillators (ICD) are routinely programmed to pace after a shock to prevent possible asystole. In those with no prior history of bradycardia, there is little data regarding the prevalence and characteristics of those who use post-shock pacing (PSP). Methods: We analyzed the occurrence of pacing within the first nine beats after the first successful ICD shock for ventricular tachycardia (VT) or ventricular fibrillation (VF) in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). All ICDs were single lead with the first PSP delivered at 1400msec and all subsequent stimuli delivered at 1200msec. We excluded patients with pacing during pre-shock rhythms and those who had pacing rates different than the protocol default rate of 50bpm (1200 msec). Results: There were 2521 patients enrolled in SCD-HeFT, of which 811 received an ICD. A total of 153 shock events were examined; 36 (23.5%) had at least one of the first nine beats paced post-shock, though only 4 (2.5%) had greater than 4 out of the 9 beats paced. No subjects needed pacing for all nine beats and only 8 (5.2%) paced for greater than 5 seconds. There were no differences in age, gender, etiology of cardiomyopathy, or NYHA class between those with PSP or not. The prevailing heart rate pre-shock was predictive of PSP; the mean cycle length of the baseline rhythm pre-shock was longer (slower rate) for those who used PSP (735 ± 228msec vs. 624 ± 158msec, P=0.001). More often, VF (vs. VT) was the rhythm shocked in those using PSP (P=0.015). A trend also was seen toward increased frequency of PSP in those receiving 30J shocks (16 of 49) versus ≤20J shocks (20 of 104, P=0.068). Conclusion: Patients infrequently require multiple paced beats post-shock for VT or VF. Patients using PSP have a slower baseline heart rate and are more likely to have VF as the shocked rhythm. While 1 or 2 paced beats out of the first nine occurred occasionally, these patients also had rapid return of their native rhythm for which the hemodynamic contribution of 1 or 2 paced beats is unclear. These data suggest that for most patients receiving a primary prevention ICD programmed for shock-only therapy, the need for PSP is limited. PSP use may reflect convention and the assumption that minor post-shock pauses are detrimental.

Evidence regarding clinical use of microvolt T-wave alternans

Microvolt T-wave alternans (MTWA) testing in many studies has proven to be a highly accurate predictor of ventricular tachyarrhythmic events (VTEs) in patients with risk factors for sudden cardiac death (SCD) but without a prior history of sustained VTEs (primary prevention patients). In some recent studies involving primary prevention patients with prophylactically implanted cardioverter-defibrillators (ICDs), MTWA has not performed as well. This study examined the hypothesis that MTWA is an accurate predictor of VTEs in primary prevention patients without implanted ICDs, but not of appropriate ICD therapy in such patients with implanted ICDs. This study identified prospective clinical trials evaluating MTWA measured using the spectral analytic method in primary prevention populations and analyzed studies in which: (1) few patients had implanted ICDs and as a result none or a small fraction (< or =15%) of the reported end point VTEs were appropriate ICD therapies (low ICD group), or (2) many of the patients had implanted ICDs and the majority of the reported end point VTEs were appropriate ICD therapies (high ICD group). In the low ICD group comprising 3,682 patients, the hazard ratio associated with a nonnegative versus negative MTWA test was 13.6 (95% confidence interval [CI] 8.5 to 30.4) and the annual event rate among the MTWA-negative patients was 0.3% (95% CI: 0.1% to 0.5%). In contrast, in the high ICD group comprising 2,234 patients, the hazard ratio was only 1.6 (95% CI: 1.2 to 2.1) and the annual event rate among the MTWA-negative patients was elevated to 5.4% (95% CI: 4.1% to 6.7%). In support of these findings, we analyzed published data from the Multicenter Automatic Defibrillator Trial II (MADIT II) and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) trials and determined that in those trials only 32% of patients who received appropriate ICD therapy averted an SCD. This study found that MTWA testing using the spectral analytic method provides an accurate means of predicting VTEs in primary prevention patients without implanted ICDs; in particular, the event rate is very low among such patients with a negative MTWA test. In prospective trials of ICD therapy, the number of patients receiving appropriate ICD therapy greatly exceeds the number of patients who avert SCD as a result of ICD therapy. In trials involving patients with implanted ICDs, these excess appropriate ICD therapies seem to distribute randomly between MTWA-negative and MTWA-nonnegative patients, obscuring the predictive accuracy of MTWA for SCD. Appropriate ICD therapy is an unreliable surrogate end point for SCD.

Should patients with congenital heart disease and a systemic ventricular ejection fraction less than 30% undergo prophylactic implantation of an ICD?

Areduced left ventricular (LV) ejection fraction (EF) is established as one of the strongest risk factors for sudden and total cardiac mortality in adults with ischemic and nonischemic heart disease.1,2 Based on the Multicenter Automatic Defibrillator Implantation Trial II and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) clinical trials, patients with an LVEF <30% are at a significantly increased risk for sudden cardiac death (SCD) and thus warrant an implantable cardioverter defibrillator (ICD).3,4 At the same time, increasing numbers of patients with congenital heart disease (CHD) continue to survive complex repairs or palliations of their heart defects, allowing survival beyond adolescence and into adulthood. However, it is uncertain whether the risks of systemic ventricular dysfunction and the benefits of primary prevention ICDs demonstrated in adult clinical trials extend to patients with CHD. Clarification regarding this issue is important because in the current era, the majority of ICD implantations in patients with CHD are for primary prevention of SCD.5 Response by Triedman see p 307 In this article, we argue that patients with CHD and a systemic ventricular EF <30% should undergo prophylactic implantation of an ICD. Although large-scale randomized clinical ICD trials are unlikely to be performed in these patients, data from adult studies with other forms of heart disease as well as observational and registry studies in CHD patients provide consistent support for the proposal that advanced systemic ventricular dysfunction is a significant risk factor for SCD in CHD patients and thus provides a rational basis for prophylactic implantation of an ICD. Several major randomized clinical trials have been reported regarding the efficacy of ICDs for the primary prevention of SCD in adults with ischemic and nonischemic heart disease and have been the subject of several meta-analyses and reviews.3,4,6–8 These studies include a total …

Publicly Reporting Implantable Cardioverter Defibrillator Outcomes

The past decade has seen a dramatic increase in efforts by both payors and governmental agencies to measure and publicly report patient outcomes to ensure that patients receive appropriate, high-quality care. As a result, terms such as outcomes, quality, report cards, and benchmarking have entered the lexicon of clinical medicine, and both physicians and hospitals are increasingly being held accountable for the outcomes of their patients. This movement shows no sign of slowing down. In May 2008, the Centers for Medicare and Medicaid Services proposed increasing the total number of inpatient hospital measures from 40 to 73,1 and numerous physician measures are in various phases of development. In the current environment, it is likely that implantable cardioverter defibrillators (ICDs), which reduce the risk of sudden cardiac death,2 will soon emerge as a high-priority target for the development of performance measures, given that the procedure is expensive, performed on severely ill patients, and associated with significant risk of complications. Article see p 240 Accordingly, the findings published by Al-Khatib et al3 in this issue of Circulation: Arrhythmia and Electrophysiology warrant consideration in the context of current efforts to publicly report patient outcomes using Medicare claims data. In this excellent article, the authors used data from Centers for Medicare and Medicaid Services standard analytic files to determine the 90-day postprocedure complication rates and 1-year mortality rates of 8581 Medicare beneficiaries who had an ICD implanted by one of 1959 implanting physicians. The authors note that the complication rate declined from 18.8% in 2002 to 14.2% in 2005 and further identified specific factors associated with an increased risk of complication such as chronic lung disease, dementia, and renal disease. Of interest, physician experience as measured by procedure volume was not significantly associated with the risk of complication, although an earlier …

Implantable Cardioverter Defibrillator Therapy in Patients with Prior Coronary Revascularization in the Sudden Cardiac Death in Heart Failure Trial (SCD‐HeFT)

We conducted this study to examine the effect of the ICD on the outcomes of patients with prior coronary revascularization enrolled in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and to assess the association of time from coronary revascularization to enrollment with death and sudden cardiac death (SCD). We included in this analysis patients with ischemic heart disease not randomized to the amiodarone arm. Cox proportional hazards models were used to examine the association of prior CABG and of prior PCI with each outcome. Interactions between randomized treatment and each revascularization type and time were tested in each model. Of the 882 patients who met these inclusion criteria, 255 (29%) had no prior revascularization, 178 (20%) had prior PCI only, 284 (32%) had prior CABG only, and 165 (19%) had prior PCI and CABG. There was no significant difference in ICD benefit across the revascularization subgroups (all P > 0.1). There was a trend toward improved survival with an ICD in patients who had their CABG > 2 years before randomization (HR [CI] = 0.71 [0.49, 1.04]) that was not observed in patients who had their CABG < or = 2 years before randomization (HR [CI] = 1.40 [0.61, 3.24]). In SCD-HeFT, there was no significant difference in ICD benefit across the revascularization subgroups. Patients who had their CABG > 2 years before randomization showed a trend toward improved survival with an ICD that was not observed in patients who had their CABG < or = 2 years before randomization.

Life and Death after ICD Implantation

Randomized trials have established that the prophylactic use of implantable cardioverter–defibrillators (ICDs) prolongs survival in patients with left ventricular dysfunction that is due to myocardial infarction1 or associated with heart failure from any cause.2 One of the pivotal trials, the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) (ClinicalTrials.gov number, NC0609), compared ICD therapy or amiodarone with placebo in 2521 patients with symptomatic heart failure due to ischemic or nonischemic left ventricular dysfunction.2 That trial showed that among patients who had an ICD as compared with those who received a placebo, there was an absolute reduction in mortality of 7.2 . . .

Review of the Registry's Second Year, Data Collected, and Plans to Add Lead and Pediatric ICD Procedures

esenc F d m l b t G t N d s Q o M N h a c p i t t i e r i e t a e y p c e t t b T t ntroduction he National ICD Registry became the sole repository of CD implantation data for Medicare beneficiaries April 1, 006 and as of June 2008 had collected data from 1,448 ospitals in the United States totaling over 270,373 imlants. This registry was developed through a partnership of he Heart Rhythm Society (HRS; www.HRSonline.org) and he American College of Cardiology Foundation (ACCF; ww.acc.org) utilizing the expertise of the National C iovascular Data Registry (NCDR; www.accncdr.com). he National ICD Registry is accruing ICD implants at the ate of 10,000 per month with 88% of implants being done n hospitals that enter all patients receiving ICDs including oth primary and secondary prevention indications in all ge groups. A rigorous Data Quality Reporting process is in lace to ensure data accuracy and hospital auditing will egin the summer of 2008. Six abstracts have been pr ed, and four manuscripts are in development utilizing ata generated from the National ICD Registry answering ey clinical questions elicited from the growing ICD imlant patient database ( http://www.accncdr.com). Funding or the Longitudinal ICD Registry Study has been procured, nd the study will begin in 2008. The scope of the National CD registry is being expanded to include data on new trial, ventricular, defibrillation, and left-heart leads placed t the time of ICD implant and whenever existing leads are epositioned, replaced, extracted or abandoned. These data ill assist the Food and Drug Administration (FDA) with urveillance of lead performance. Pediatric ICD implantaions will be followed in the Registry; and the Registry is eing positioned to serve as a performance reporting tool to ssist with quality measures.

Patients with heart failure who require an implantable defibrillator should have cardiac resynchronisation routinely

Should patients with heart failure who require an implantable cardiac defibrillator (ICD) get a device capable of delivering cardiac resynchronisation therapy (CRT-D) routinely? For those that like to read the...

Primary Prevention with Defibrillator Therapy in Women: Results from the Sudden Cardiac Death in Heart Failure Trial

The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter defibrillator (ICD) therapy reduced overall mortality in patients with class II or III heart failure and left ventricular ejection fraction (LVEF) <or= 35%, while amiodarone had no effect on survival. There are limited data regarding the influence of gender on outcome of patients receiving ICDs for primary prevention. We examined gender differences in response to treatment and outcome in this cohort. Women comprised 23% of the SCD-HeFT cohort, with similar percentages in the amiodarone, ICD, and placebo groups. Compared with men, women were more likely to be non-Caucasian, to have class III heart failure, and nonischemic heart disease. After adjustment for baseline differences, overall mortality risk was lower in women than in men. The gender difference in overall mortality was seen in the placebo group, while no gender difference in overall mortality was seen in the ICD group. There was a significantly lower absolute risk of death in the placebo arm women, compared with the placebo arm men (annual mortality rate approximately 4% vs. 6%). The impact of ICD therapy appears to differ between men and women in this trial, with a smaller ICD benefit among women. However, the test for an interaction between gender and therapy was not significant. The lower overall mortality risk in women in the placebo group and the smaller number of women enrolled may help to explain why treatment differences in women were much smaller and difficult to detect.

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

AimsImplantable 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 ResultsCommon 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.ConclusionCommon control trials can be more efficient than other designs, but induce dependence between treatment comparisons and require cautious interpretation.

CA1 ECONOMIC ANALYSIS OF IMPLANTABLE CARDIOVERTER DEFIBRILLATORS INTHE PRIMARY PREVENTION OF SUDDEN CARDIAC DEATH—A CANADIAN PERSPECTIVE

CA1 ECONOMIC ANALYSIS OF IMPLANTABLE CARDIOVERTER DEFIBRILLATORS INTHE PRIMARY PREVENTION OF SUDDEN CARDIAC DEATH—A CANADIAN PERSPECTIVE Deniz B, Sadri H United BioSource Corporation, Concord, MA, USA, Medtronic of Canada Ltd,Toronto, ON, Canada OBJECTIVE: To conduct a cost-benefit analysis (CB) for the Implantable Cardioverter Defibrillators (ICDs) in the primary prevention of Sudden Cardiac Death (SCD) compared to amiodarone.METHODS: A discrete event simulation model was built to determine the cost-benefit ratio associated with ICDs from a societal perspective in Canada using the “value of life” approach as a measure of “benefit”. The clinical inputs were derived from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and the Amiodarone Trial Analysis (ATMA) studies. The related costs were derived from the Ontario Health Insuranace Plans’ (OHIP) schedule of benefits and fees, Ontario Drug Benefit formulary (ODB) and published data. The value of life in Canada (CND$5.8Mil.), as determined by Health Canada, was used in the model. One hundred replicaitons of 1000 identical twin pairs over 7 years, aligned with the average life of an ICD, were run. The costs (year 2006) and outcomes ere discounted at 3%. Sensitivity Analysis (SAs) were performed for key input parameters. RESULTS: The absolute all-cause mortality was reduced by eight percent with ICD over seven years compared to amiodarone. The average costs associated with ICD and amiodarone treatments were estimated as CND$32,000 and CND$6400 per patient, respectively. The predicted cost-benefit ratio (CBR) was 0.04. This figure suggests that for every $1 spent for ICD in the primary prevention of SCD the society will gain $25 in “value” by human lives saved. SAs showed that results were robust (CBR: 0.035–0.044). CONCLUSION: IDs reduce the risk of SCD due to arrhythmia compared to amiodarone. The estimated CBR suggests that ICDs are worthwhile investment from a societal perspective in Canada. The initial investment for ICD in primary prevention of SCD in Canada is comparable and in many cases lower when compared to other societal programs for saving lives.

Letter by de Boer and van Veldhuisen Regarding Article, “Risk of Thromboembolism in Heart Failure: An Analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)”

HomeCirculationVol. 117, No. 1Letter by de Boer and van Veldhuisen Regarding Article, “Risk of Thromboembolism in Heart Failure: An Analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by de Boer and van Veldhuisen Regarding Article, “Risk of Thromboembolism in Heart Failure: An Analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)” Rudolf A. de Boer and Dirk J. van Veldhuisen Rudolf A. de BoerRudolf A. de Boer University Medical Center Groningen, Thoraxcenter, Department of Cardiology, Groningen, The Netherlands Search for more papers by this author and Dirk J. van VeldhuisenDirk J. van Veldhuisen University Medical Center Groningen, Thoraxcenter, Department of Cardiology, Groningen, The Netherlands Search for more papers by this author Originally published1 Jan 2008https://doi.org/10.1161/CIRCULATIONAHA.107.725440Circulation. 2008;117:e7To the Editor:We read with interest the recent article from Freudenberger et al.1 The major observation in this article is the incidence of thromboembolism in patients receiving contemporary heart failure management. The increased risk for thromboembolism in heart failure has been appreciated for quite some time, but whether preventive treatment with antiplatelet or anticoagulant agents is indicated in heart failure remains a controversial issue. Current American Heart Association/American College of Cardiology guidelines for the treatment of heart failure do not recommend standard treatment with antiplatelet or anticoagulant agents, except in patients with additional diseases such as coronary artery disease, atrial fibrillation, or ventricular thrombus, or with prosthetic valves.Much to our surprise, treatment with anticoagulant agents (warfarin) was not associated with a lower rate of thromboembolic events in the analysis of Freudenberger et al.1 From the data presented, it remains somewhat unclear which patients are struck by thromboembolism, as the authors do not present data on what percentage of the patients using either antiplatelet or anticoagulant or no antithrombotic therapy developed a thromboembolic event. The authors speculate that the number of embolic events, mainly consisting of ischemic stroke, may have primarily been driven by hypertension and atherosclerosis rather than by cardiogenic embolism. Such a mechanism may have been predominant, because the current analysis excluded patients with prior atrial fibrillation or atrial flutter. Nevertheless, from a pathophysiological perspective, oral anticoagulants should theoretically reduce the occurrence of thromboembolism.These data are important because they add to the currently scarce database on anticoagulant therapy in heart failure. Several (retrospective) analyses from heart failure cohorts2–4 have suggested that anticoagulant agents may reduce heart failure–associated mortality. Thus, next to amiodarone and an implantable cardioverter-defibrillator, available observational evidence suggests that treatment with anticoagulants may reduce morbidity and mortality in heart failure. A large prospective randomized trial testing the efficacy of antiplatelet and anticoagulant therapy in heart failure5 is eagerly awaited.DisclosuresNone. References 1 Freudenberger RS, Hellkamp AS, Halperin JL, Poole J, Anderson J, Johnson G, Mark DB, Lee KL, Bardy GH; SCD-HeFT Investigators. Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation. 2007; 115: 2637–2641.LinkGoogle Scholar2 Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, Lamas GA, Moyé LA, Goldhaber SZ, Pfeffer MA. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med. 1997; 336: 251–257.CrossrefMedlineGoogle Scholar3 Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Warfarin anticoagulation and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol. 1998; 31: 749–753.CrossrefMedlineGoogle Scholar4 de Boer RA, Hillege HL, Tjeerdsma G, Verheugt FW, van Veldhuisen DJ. Both antiplatelet and anticoagulant therapy may favorably affect outcome in patients with advanced heart failure. A retrospective analysis of the PRIME-II trial. Thromb Res. 2005; 116: 279–285.CrossrefMedlineGoogle Scholar5 Pullicino P, Thompson JL, Barton B, Levin B, Graham S, Freudenberger RS; on behalf of the WARCEF Investigators. Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail. 2006; 12: 39–46.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 1, 2008Vol 117, Issue 1 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.107.725440PMID: 18172042 Originally publishedJanuary 1, 2008 PDF download Advertisement SubjectsAnticoagulantsCerebrovascular Disease/StrokeCongenital Heart Disease