Implantable Cardioverter Defibrillator - the evidence behind the guidelines
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This document summarizes a presentation on implantable cardioverter defibrillators (ICDs). It discusses the history of ICD development by pioneers Martin Mower and Michel Mirowski. Major clinical trials that established the use of ICDs for primary and secondary prevention of sudden cardiac death are summarized, including MADIT, MUSTT, and SCD-HeFT. The presentation addresses ongoing questions around appropriate patient selection and optimization of medical therapy prior to ICD implantation.
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Implantable Cardioverter Defibrillator - the evidence behind the guidelines
- 1. EBM Presentation: Implantable Cardioverter Defibrillators 5 June 2015 Koh Choong Hou Supervisor: Tan Vern Hsen
- 2. Scope • History of ICDs • Indications for ICDs • Major Trials
- 3. Pioneers of ICDs - “M&M” Martin Mower Michel Mirowski
- 4. *Dr Chow Wei En© *
- 5. Indications for ICDs (ACC)
- 6. Wait… How about medical therapy first?
- 7. SCD Prevention Trials - Antiarrhythmic Agents • CAST I [Cardiac Arrhythmia Suppression Trial (1991)] • ESVEM [Electrophysiologic Study vs ECG Monitoring (1993)] • GESICA [Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (1994)] • CHF STAT [Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy (1995)] • SWORD [Survival with Oral d-Sotalol (1996)] • CAMIAT [Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (1997)] • EMIAT (European Myocardial Infarction Amiodarone Trial (1997)]
- 9. CHF STAT
- 10. SWORD Trial
- 12. EMIAT (European MI Amiodarone Trial)
- 13. SCD Prevention Trials - ICDs • Secondary Prevention • CASH [Cardiac Arrest Study Hamburg (1994)] • AVID [Amiodarone vs Implantable Defibrillator (1995)] • CIDS [Canadian Implantable Defibrillator Study (2000)] • Primary Prevention • MADIT [Multicentre Automatic Defibrillator Implantation Trial (1996)] • CABG-PATCH (1997) • MUSTT [Multicentre Unsustained Tachycardia Trial (1999)] • MADIT II (2002) • DEFINITE (2004) • DINAMIT (2004) • SCD-HeFT (2005)
- 16. Key Trials: ICD in Secondary Prevention
- 19. • Antiarrhythmics vs ICDs • First trial of such nature to be completed • Demonstrated superiority of ICDs over AADs (primarily amiodarone) AVID Trial A Comparison of Antiarrhythmic-Drug Therapy with Implantable Defibrillators in Patients Resuscitated from Near-Fatal Ventricular Arrhythmias The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med 1997; 337:1576-1584
- 20. AVID Trial
- 21. CIDS (Canadian Implantable Defibrillator Study)
- 22. CIDS (Canadian Implantable Defibrillator Study) ICD Better Amiodarone Better
- 23. CASH (Cardiac Arrest Study Hamburg)
- 24. Sub-optimally Addressed Issues • Beta-blockade - have we really optimised medical therapy prior to device implantation? • Is 35% the magic EF? • Under-represented population - the impact of ICD in non- ischaemic CMP?
- 27. Are AADs more protective over the long term horizon? Meta-analyses of the ICD Secondary Prevention Trials. Connolly et al. European Heart Journal 2000 (21) 2071-2078
- 28. HRS/ACC/AHA Expert COnsensus Statement on the Use of ICD Therapy in Patients who are not included or not well represented in Clinical Trials. Heart Rhythm 2014; 11:1270-1303
- 29. HRS/ACC/AHA Expert COnsensus Statement on the Use of ICD Therapy in Patients who are not included or not well represented in Clinical Trials. Heart Rhythm 2014; 11:1270-1303
- 30. ICD within 40 days of AMI
- 34. Class I Indication? Not always clear cut…
- 38. Accurate & Reproducible Measurement of LV Volume & EF by Contrast Echocardiography. S Malm et al. JACC 2004:1030-5
- 39. Comparison of LVEF & Volumes in Heart Failure by Echo, Radionuclide Ventriculography & CMR. Are they interchangeable? Bellenger et al. Eur Heart J (2000) 21:1387-96
- 40. MADIT II
- 41. MADIT I & II
- 43. MUSTT
- 44. DEFINITE
- 47. ICDs prevent arrhythmic deaths but will kill you in other ways??? Shock
- 48. SCD-HeFT
- 54. Matching the Evidence to the Guidelines
- 55. Indications for ICDs (ACC) SCD HeFT
- 56. Indications for ICDs (ACC) DEFINITE
- 57. Indications for ICDs (ACC) MADIT II
- 58. Indications for ICDs (ACC) MUSTT MADIT I
- 59. Indications for ICDs (ACC) AVID, CIDS, CASH Wever EF, Hauer RN, van Capelle FL, et al. Randomized study of implantable defibrillator as first-choice therapy versus conventional strategy in postinfarct sudden death survivors. Circulation. 1995;91: 2195–203.
- 60. • The Grey Zone: 35% < EF < 40%. EPS is “useful”. • NSVT post MI, EF > 35% • NSVT post MI, EF > 35% with negative EPS • NSVT in NICMP • Elderly - what is the “age cut-off”? • Beyond EF • Dual vs Single Chamber; Programming (minimising inappropriate shocks) Unaddressed Scenarios
Editor's Notes
- The idea of the ICD came to Dr. Michel Mirowski when his friend died of SCD Concept: could a defibrillator be implanted in the body? Technological challenges: Could an implantable device deliver sufficient energy? Could leads be developed to carry that much energy? How would the device detect arrhythmias? How could defibrillation become “automated”? Dr. Harry Heller died of SCD in 1966. His friend, Dr. Michel Mirowski, knew that he might have lived had he received defibrillation immediately By 1969, Dr. Mirowski was working on the first experimental models of what would later become the ICD But it would be almost 20 years before the device was commercially available! Sinai Hospital of Baltimore recruited Dr. Mirowski and offered him opportunity to work on ICD idea At Sinai, Mirowski teamed up with Martin Mower in the research lab In 1969, experimental model First transvenous defibrillation (1969) Canine implants (1970s) First human implant: 1980 (Johns Hopkins, Baltimore)
- Technological challenges: Capacitor technology allowed small battery to store and deliver large amount of energy Transvenous defibrillation leads could carry defibrillation energy to the inside of the heart Circuitry could sense cardiac rhythms and interpret potentially dangerous ventricular tachyarrhythmias Device could be downsized enough to implant in the body
- To determine whether therapy with class Ic antiarrhythmics to suppress asymptomatic or mildly symptomatic ventricular arrhythmias after MI reduces mortality due to arrhythmia Design Multicenter, multinational; initial phase open; main phase randomized, double-blind, placebo-controlled Patients: 1725 patients with >6 ventricular premature depolarizations/h (24h Holter recording) and left ventricular ejection fraction <0.55 at <90 days after MI or <0.40 at >90 days after MI Follow up and primary end point: Mean 10 months follow up. Primary endpoint death from arrhythmia Treatment: Open titration phase (mean 15 days) to select patients in whom drug (encainide, flecainide or moricizine) suppressed arrhythmias Selected patients then randomized to three-times daily placebo, encainide 35–50 mg, flecainide 100 mg or moricizine 200–250 mg (results for moricizine not reported here) Results: Study of encainide/flecainide vs. placebo halted at mean follow up of 10 months on recommendation of CAST Data and Safety Monitoring Board because in group taking encainide or flecainide, compared with placebo group: All-cause mortality significantly higher Non-fatal cardiac arrest or death from arrhythmia significantly higher Death from other cardiac causes also higher Results consistent across all subgroups examined No confounding factors were identified to explain marked differences between encainide/flecainide and placebo Study subsequently modified to continue with moricizine (CAST II)
- A recent study24 from Argentina (Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina, or GESICA) reported a 28 percent reduction in overall mortality in the amiodarone group as compared with a control group (P 0.024). The rates of sudden death and death due to progressive heart failure were reduced by 27 and 23 percent, respectively (P0.16). The fact that the GESICA trial was not blind probably does not explain the discrepancy be- tween these results and ours. The most striking differ- ence between the two studies is that the proportion of patients with coronary artery disease in the GESICA trial was smaller (39 percent) than in our study (70percent). This difference is important, since in our study there was a trend toward a reduction in mortality among the patients with nonischemic cardiomyopathy (P0.07).
- EMIAT The EMIAT trial enrolled patients who had suffered an AMI within the last 5 to 21 days and had a left ventricular ejection fraction (LVEF) less than or equal to 40%. They were randomized to receive either amiodarone or placebo. Of the 23,493 patients screened, 3,255 patients met entry criteria, and 1,486 were enrolled into this double-blind, multicenter trial. Unlike CAMIAT, the primary endpoint for EMIAT was all-cause mortality, and the secondary endpoints were cardiac death, arrhythmic death, and resuscitated VF. In contrast to CAMIAT, the primary analysis for EMIAT was intention- to-treat, with secondary analysis using efficacy methodology. Like CAMIAT, this trial also was designed for one-sided statistical analysis. Of the 743 patients randomized to the amiodarone group, 284 (38.2%) dropped out. Of the 743 placebo patients, only 158 (21.2%) dropped out of the trial. There were no significant differences between the patient groups with respect to therapy with beta- blockers (44% in amiodarone group versus 45% in placebo group) or ACEIs (59% versus 58%). Patients were followed for a mean of 1.75 years. There was no difference in the primary endpoint of all-cause mortality (11.3% in the amiodarone group versus 12.1% in the placebo group, P=0.95) using efficacy analysis. There was no significant difference using intention-to-treat analysis. However, patients assigned to the amiodarone group did have a statistically significant reduction in VF or arrhythmic death (4.0% versus 7.9%,P=0.006 using efficacy analysis; 5.6% versus 8.2%, P=0.05 using intention-to-treat analysis).
- Primary Prevention Patients at high risk for cardiac arrest due to a defined pre-existing disease state but without clinical expression of potentially fatal arrhythmias Secondary Prevention Patients surviving cardiac arrests due to ventricular tachyarrhythmias
- Mean age 60 Mostly CAD pts INterestingly, in CASH, only VF arrest puts included, and those that had ICDs implanted did not receive amiodarone, compared to AVID and CIDS where the ICD arms still had up to 20% of pts on amiodarone
- Background Patients who survive life-threaten- ing ventricular arrhythmias are at risk for recurrent arrhythmias. They can be treated with either an implantable cardioverter–defibrillator or antiarrhyth- mic drugs, but the relative efficacy of these two treat- ment strategies is unknown. Methods To address this issue, we conducted a randomized comparison of these two treatment strategies in patients who had been resuscitated from near-fatal ventricular fibrillation or who had under- gone cardioversion from sustained ventricular tach- ycardia. Patients with ventricular tachycardia also had either syncope or other serious cardiac symptoms, along with a left ventricular ejection fraction of 0.40 or less. One group of patients was treated with implantation of a cardioverter–defibrillator; the other re- ceived class III antiarrhythmic drugs, primarily amio- darone at empirically determined doses. Fifty-six clinical centers screened all patients who presented with ventricular tachycardia or ventricular fibrillation during a period of nearly four years. Of 1016 patients (45 percent of whom had ventricular fibrillation, and 55 percent ventricular tachycardia), 507 were ran- domly assigned to treatment with implantable car- dioverter–defibrillators and 509 to antiarrhythmic- drug therapy. The primary end point was overall mortality. Results Follow-up was complete for 1013 patients (99.7 percent). Overall survival was greater with the implantable defibrillator, with unadjusted estimates of 89.3 percent, as compared with 82.3 percent in the antiarrhythmic-drug group at one year, 81.6 per- cent versus 74.7 percent at two years, and 75.4 per- cent versus 64.1 percent at three years (P0.02). The corresponding reductions in mortality (with 95 per- cent confidence limits) with the implantable defibril- lator were 3920 percent, 2721 percent, and 3121 percent. Conclusions Among survivors of VF or sustained ventricular tachycardia causing severe symptoms, the ICD is superior to antiarrhythmic drugs for increasing overall survival. (N Engl J Med 1997;337: 1576-83.)
- Background—Patients surviving ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) are at a high risk of death due to a recurrence of arrhythmia. The implantable cardioverter defibrillator (ICD) terminates VT or VF, but it is not known whether this device prolongs life in these patients compared with medical therapy with amiodarone. Methods and Results—A total of 659 patients with resuscitated VF or VT or with unmonitored syncope were randomly assigned to treatment with the ICD or with amiodarone. The primary outcome measure was all-cause mortality, and the secondary outcome was arrhythmic death. A total of 328 patients were randomized to receive an ICD. A thoracotomy was done in 33, no ICD was implanted in 18, and the rest had a nonthoracotomy ICD. All 331 patients randomized to amiodarone received it initially. At 5 years, 85.4% of patients assigned to amiodarone were still receiving it at a mean dose of 255 mg/day, 28.1% of ICD patients were also receiving amiodarone, and 21.4% of amiodarone patients had received an ICD. A nonsignificant reduction in the risk of death was observed with the ICD, from 10.2% per year to 8.3% per year (19.7% relative risk reduction; 95% confidence interval, 7.7% to 40%; P0.142). A nonsignificant reduction in the risk of arrhythmic death was observed, from 4.5% per year to 3.0% per year (32.8% relative risk reduction; 95% confidence interval, 7.2% to 57.8%; P0.094). Conclusions—A 20% relative risk reduction occurred in all-cause mortality and a 33% reduction occurred in arrhythmic mortality with ICD therapy compared with amiodarone; this reduction did not reach statistical significance.
- Background—Patients surviving ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) are at a high risk of death due to a recurrence of arrhythmia. The implantable cardioverter defibrillator (ICD) terminates VT or VF, but it is not known whether this device prolongs life in these patients compared with medical therapy with amiodarone. Methods and Results—A total of 659 patients with resuscitated VF or VT or with unmonitored syncope were randomly assigned to treatment with the ICD or with amiodarone. The primary outcome measure was all-cause mortality, and the secondary outcome was arrhythmic death. A total of 328 patients were randomized to receive an ICD. A thoracotomy was done in 33, no ICD was implanted in 18, and the rest had a nonthoracotomy ICD. All 331 patients randomized to amiodarone received it initially. At 5 years, 85.4% of patients assigned to amiodarone were still receiving it at a mean dose of 255 mg/day, 28.1% of ICD patients were also receiving amiodarone, and 21.4% of amiodarone patients had received an ICD. A nonsignificant reduction in the risk of death was observed with the ICD, from 10.2% per year to 8.3% per year (19.7% relative risk reduction; 95% confidence interval, −7.7% to 40%; P=0.142). A nonsignificant reduction in the risk of arrhythmic death was observed, from 4.5% per year to 3.0% per year (32.8% relative risk reduction; 95% confidence interval, −7.2% to 57.8%; P=0.094). Conclusions—A 20% relative risk reduction occurred in all-cause mortality and a 33% reduction occurred in arrhythmic mortality with ICD therapy compared with amiodarone; this reduction did not reach statistical significance.
- Limitations of the Study In CASH, the long recruitment time exposed the study to complexities driven by rapid changes in ICD and conven- tional therapy and by accumulation of new knowledge. Among responsible causes were the small number of participating centers and their reluctance to enroll patients for potential ICD therapy in the early phase and to deny such therapy in the late phase of the study. Also, the 0.46 mean ejection fraction reported in the whole cohort suggests a disproportional representation of relatively healthy patients in CASH, as compared with AVID.18 On the basis of these observations, we cannot exclude a selection bias that if present, might have influenced the outcome of CASH and possibly led to underestimation of the benefit of ICD therapy. In fact, although collected in more heterogeneous patient categories over a markedly shorter follow-up than in CASH, data from AVID suggest that patients who appear to most benefit from ICD treatment are those with a low (ie, 35%) rather than those with a relatively well-preserved left ventric- ular ejection fraction.18 The 19.6% 2-year all-cause mortality rate observed in the amiodarone and metoprolol groups was less than half the mortality rate used to calculate the trial sample size, thus rendering CASH underpowered to test the working hypothesis.
- Look at the low percentage of patients discharged with BB!
- OBJECTIVES We sought to assess the effect of baseline ejection fraction on survival difference between patients with life-threatening ventricular arrhythmias who were treated with an antiarrhythmic drug (AAD) or implantable cardioverter-defibrillator (ICD).BACKGROUNDThe Antiarrhythmics Versus Implantable Defibrillators (AVID) study demonstrated improved survival in patients with ventricular fibrillation or ventricular tachycardia with a left ventricular ejection fraction (LVEF) ≤0.40 or hemodynamic compromise.METHODSSurvival differences between AAD-treated and ICD-treated patients entered into the AVID study (patients presenting with sustained ventricular arrhythmia associated with an LVEF ≤0.40 or hemodynamic compromise) were compared at different levels of ejection fraction. RESULTS In patients with an LVEF ≥0.35, there was no difference in survival between AAD-treated and ICD-treated patients. A test for interaction was not significant, but had low power to detect an interaction. For patients with an LVEF 0.20 to 0.34, there was a significantly improved survival with ICD as compared with AAD therapy. In the smaller subgroup with an LVEF <0.20, the same magnitude of survival difference was seen as that in the 0.20 to 0.34 LVEF subgroup, but the difference did not reach statistical significance. CONCLUSIONS These data suggest that patients with relatively well-preserved LVEF (≥0.35) may not have better survival when treated with the ICD as compared with AADs. At a lower LVEF, the ICD appears to offer improved survival as compared with AADs. Prospective studies with larger patient numbers are needed to assess the effect of relatively well-preserved ejection fraction (≥0.35) on the relative treatment effect of AADs and the ICDs. This is where the 35% cut-off for NYHA II-II came from
- Conclusion Results from the three trials of the ICD vs amiodarone are consistent with each other. There is a 28% reduction in the relative risk of death with the ICD that is due almost entirely to a 50% reduction in arrhythmic death. This analysis demonstrates that the results of the three secondary prevention ICD trials are consistent with one another. It initially might have appeared that the studies had different results, as the AVID study reported a statistically significant reduction in mortality with the ICD compared to medical therapy, while the other two studies did not demonstrate a statistically significant difference in risk of death. The lack of any evidence of heterogeneity among the studies in the fixed effects analysis indicates that these differences in treatment benefit are not major and are likely due to play of chance. All three studies observed some reduction in death from the ICD, with the benefit being almost twice as large in the AVID study as it was in the other two studies. The AVID study, however, was stopped early due to observation of a greater than expected benefit of the ICD. Early study termination because of benefit does create a bias in favour of reporting larger treatment effects; which could partly explain the discrepancy between the results of the AVID and the other two studies. It might appear that the meta-analysis adds little to our knowledge because the AVID study was positive and it was the largest of the three trials. However, the AVID study was relatively short in duration and although it has a large number of patients it contributed only 202 of the 455 deaths that occurred in the three studies. As it is the actual outcome events that directly affect statistical power, only 45% of the power of the pooled analysis comes from AVID study patients. AVID by stopping early due to an observed benefit may have over- estimated the effect of the ICD. Combining the results of all three studies gives the most precise and unbiased estimate of the efficacy of the ICD vs amiodarone. The ICD is expected to exert its benefit on mortality specifically by prevention of deaths due to ventricular arrhythmia. The fact that the ICD had a very large effect on the outcome of arrhythmic death, and almost no effect (compared to amiodarone) on non-arrhythmic deaths, adds biological plausibility to the findings of this overview. Arrhythmic death was rather dramatically reduced, with a relative risk reduction of 50% in favour of ICD compared to amiodarone. The steady divergence of the survival curves depicting arrhythmic death for the ICD and amiodarone treatment arms contrasts with the lack of divergence after 3 years of the curves depicting the effect on death from any cause. This suggests that competing non-arrhythmic causes of death may, over time, reduce the benefit of the ICD. It has been recently suggested that the lack of statistically significant ICD benefit in CASH and CIDS indicates a lack of certainty that the ICD is superior to amiodarone[12]. This meta-analysis clearly indicates that the three studies are indeed consistent and that the ICD is more effective than amiodarone. This analysis pro- vides the most precise estimate of the benefit of the ICD over amiodarone for prevention of death, which is a relative risk reduction of 27%. The annual death rate was reduced by the ICD from 12·3% per year to 8·8% per year, an absolute reduction of 3·5% per year. Thus an ICD would have to be implanted in 29 patients to save one life per year of follow-up. The effectiveness of the ICD over amiodarone is not large as, over 6 years of follow-up, the prolongation of life is only just over a third of a year. The AVID study has reported that the prolongation of life with the ICD during a 3 year follow-up, is modest. The present analysis now extends that finding to a follow-up period of 6 years.
- Figure 1 Survival curves for the ICD-only primary prevention trials in patients with cardiomyopathy (CM) due to coronary artery disease (CAD) or acute myocardial infarction (MI), heart failure, or nonischemic CM. All curves represent mortality/survival. MADIT 1⁄4 Multicenter Automatic Defibrillator Trial; MUSTT 1⁄4 Multicenter Unsustained Tachycardia Trial; CABG-Patch 1⁄4 Coronary Artery Bypass Graft-Patch; DINAMIT 1⁄4 Defibrillator in Acute Myocardial Infarction Trial; IRIS 1⁄4 Immediate Risk Stratification Improves Survival Study; SCD-HeFT 1⁄4 Sudden Cardiac Death in Heart Failure Trial; DEFINITE 1⁄4 Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation Trial. Randomized Controlled Trials of ICD Therapy for Primary Prevention of Sudden Cardiac Death Seven large randomized trials have evaluated the use of ICDs in patients at risk of sudden cardiac death due to heart failure or left ventricular dysfunction in the setting of prior MI (Table 2 and Figure 1).1,2,10–12 Each of the trials evaluated slightly different patient groups, and all of the trials, with the exception of the Coronary Artery Bypass Graft (CABG)- Patch trial, identified a patient population in whom the ICD conferred a survival benefit or reduced death from arrhyth- mia. Of the randomized trials, the CABG-Patch was unique in that all patients received revascularization with CABG at the time of randomization. In CABG-Patch, 900 patients with an ejection fraction (EF) o0.36 and an abnormal signal-averaged ECG who were undergoing bypass surgery were randomized to receive an ICD using epicardial patches or not.12 After an average follow-up of 32 months, the hazard ratio (HR) for death from any cause was 1.07 (95% confidence interval [CI]: 0.81–1.42, P 1⁄4 .64). ICD implan- tation was associated with a higher rate of postoperative infections (ICD: 12.3% vs control: 5.9%; P o.05) and deep sternal wound infections (ICD: 2.7% vs 0.4%, P o.05). Patients were excluded if they had prior significant ventric- ular arrhythmias or poorly controlled diabetes. The Multi- center Unsustained Tachycardia Trial (MUSTT) enrolled 2202 patients with coronary artery disease, an EF r0.40, and nonsustained ventricular tachycardia (NSVT) Z3 beats, of whom 704 had sustained ventricular tachycardia (VT) inducible by programmed electrical stimulation.10 The patients with inducible sustained VT were randomized to no antiarrhythmic therapy or antiarrhythmic therapy guided by electrophysiologic (EP) study. After a median follow-up of 39 months, the 5-year estimates for overall mortality were 42% and 48%, respectively (relative risk: 0.80; 95% CI: 0.64–1.01). Within the EP-guided therapy group, 161 patients received an ICD (after one or more failed antiar- rhythmic drug trials), and in this group, the adjusted relative risk of mortality was 0.40 (95% CI: 0.27–0.59). In the Multicenter Automatic Defibrillator Trial (MADIT), 196 patients with prior myocardial infarction, EF r0.35, and inducible nonsuppressible ventricular arrhythmias at electro- physiologic testing were randomized to receive an ICD or medical therapy alone.11 After an average follow-up of 27 months, the ICD was associated with a significant reduction in mortality (HR: 0.46; 95% CI: 0.26–0.82; P 1⁄4 .009). In the Multicenter Automatic Defibrillator Trial II (MADIT-II) 1232 patients with an EF r0.30 due to prior myocardial infarction were randomized to ICD therapy or medical therapy alone.2 During an average follow-up of 20 months, the ICD was associated with a significant reduction in mortality (HR: 0.69; 95% CI: 0.51–0.93; P 1⁄4 .016). Finally, the Sudden Cardiac Death in Heart Failure Trial (SCD- HeFT) randomized 2521 patients with an ejection fraction r0.35 and Class II or III heart failure symptoms to ICD therapy, placebo, or amiodarone. In SCD-HeFT slightly more than 50% of patients had cardiac dysfunction and heart failure due to coronary artery disease. After a median follow- up of 45 months, ICD therapy was associated with a significant reduction in mortality (HR: 0.77; 97.5% CI: 0.62–0.96; P 1⁄4 .007).1 It is instructive to examine the clinical characteristics of patients who were actually enrolled in the trials (Table 2).1,2,10–12 The median age of enrolled patients was 63–67 years, and patients 475 years accounted for 554 (11%) of the patients enrolled in MUSTT, MADIT-I, MADIT-II, and SCD-HeFT.13 The trials predominantly studied men, with women accounting for only 8%–24% of enrollees. Ethnic background was identified in the MUSTT and SCD-HeFT trials. Nonwhite patients accounted for 9% of patients in MUSTT and 24% of patients in SCD-HeFT. The baseline cardiovascular characteristics varied between the trials. Although EF was similar for all five trials, ranging from 0.23–0.30, 80% of patients in MUSTT had Class I or II heart failure symptoms, 70% of patients in MADIT II had Class I or II heart failure symptoms, and 67% of patients in MADIT and 100% of patients in SCD-HeFT had Class II or III heart failure symptoms. Prior revascularization with CABG also varied among the three studies, at approximately 50% of patients with ischemic cardiomyopathy in SCD-HeFT, 45% in MADIT, 56% in MUSTT, 57% in MADIT-II, and of course 100% in CABG-Patch. NSVT was part of the inclusion criteria for MADIT and MUSTT and thus was present in all patients but was present in only 23% of patients in SCD- HeFT. The incidence of NSVT was not provided in initial or subsequent reports on the CABG-Patch or MADIT-II trials. Two trials have evaluated the use of ICDs in patients in the acute period after MI.14,15 In the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), 674 patients were randomized between 6 to 40 days after an MI to receive an ICD or no ICD therapy.14 Additional inclusion criteria included a left ventricular ejection fraction (LVEF) r0.35 and impaired cardiac autonomic function. After a mean follow-up of 30 months, there was no mortality benefit associated with the ICD implant (HR: 1.08; 95% CI: 0.76– 1.55; P 1⁄4 .66). In the Immediate Risk-Stratification Improves Survival (IRIS) trial, 898 patients were randomized between 5to31daysafteranMItoreceiveanICDornoICD therapy.15 Unlike DINAMIT, patients could be enrolled in IRIS under two clinical scenarios, either an LVEF r0.40 associated with an initial sinus rate 490 bpm, or NSVT (43 beats at a rate 4150 bpm) identified by 24-hour ambulatory ECG. After a mean follow-up of 37 months, ICD therapy was not associated with a significant reduction in mortality (HR: 1.04; 95% CI: 0.81–1.35; P 1⁄4 .78). Similar to the primary prevention trials discussed previously, both studies predominantly enrolled men (76%–77%) who were in their early 60s (average age 61–63 years). As expected, the average LVEF was higher in IRIS (0.35) when compared with DINAMIT (0.28) because 23% of patients were enrolled in IRIS based on the presence of NSVT. In both studies, anterior wall MIs accounted for two-thirds of the index MIs. Reperfusion therapy in DINAMIT was performed in approximately 60% of patients, evenly split between thrombolysis and PCI. Reperfusion therapy was attempted in 77% of patients in IRIS, with three-fourths of these patients receiving PCI. Two large studies on ICD therapy in patients with nonischemic cardiomyopathy have been completed.1,16 In SCD-HeFT, 1211 patients (slightly less than 50% of the total group) had heart failure due to nonischemic cardiomyopathy. In a prespecified analysis of this patient group, ICD therapy conferred a trend toward a survival advantage (HR: 0.73; 97.5% CI: 0.50–1.07; P 1⁄4 .06). The apparent decrease in the magnitude of benefit conferred by the ICD is in part explained by the lower event rate observed in patients with nonischemic cardiomyopathy when compared with patients with ischemic cardiomyopathy (5-year event rate with ICD therapy: ischemic 0.359 vs nonischemic 0.214). The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial evaluated only patients with nonischemic cardiomyopathy.16 A total of 458 patients with nonischemic cardiomyopathy, LVEF o0.36, and frequent premature ventricular contractions or NSVT were random- ized to ICD therapy or no ICD therapy. After a mean follow- up of 29 months, there was a trend toward improved survival with ICD (HR: 0.64; 95%CI: 0.40–1.06; P 1⁄4 .08) and a significant reduction in deaths due to arrhythmia with ICD therapy (HR: 0.20; 95% CI: 0.06–0.71; P 1⁄4 .006). The patients enrolled in DEFINITE were younger (average age 58 years) and had a lower ejection fraction (0.21) than the patients enrolled in the trials that evaluated the benefits of ICD therapy in patients with coronary artery disease.
- PP = pt population Patient Population #2: Patients within 40 days of acute MI who have known left ventricular dysfunction and who have previously satisfied criteria for implantation of a primary prevention ICD. Patient Population #4: Patients within 40 days of an MI who subsequently present sustained or hemodynamically significant ventricular tachyarrhythmias. Patient Population #5: Patients who, within 40 days of an MI (but 448 hours), present with syncope likely due to ventricular tachyarrhythmia, and in whom there is no evidence of ongoing ischemia.
- DINAMIT and CABG PATCH - negative trials
- A quick run through of the various primary prevention trials. MADIT. Looked population with prior MI and ICMP with poor EF <35% or inducible VT/VF at EPS, with a “wash out” period of 3 weeks to 3 months post MI/CABG or PCI. Overall, a statistically significant mortality benefit with ICDs CABG PATCH. Patient group with poor EF (<35%) and abnormal SAECG undergoing CABG. Showed no difference in survival between ICD vs non-ICD at time of CABG. However, majority of deaths in both arms were attributed to non-arrhythmic causes (70%). MUSTT. Patients shortly post MI (4 days only) with NSVT. SCD incidence reduced with ICDs. MADIT II. Very poor EF < 30% group with “wash out” of 3 months post reverse (average EF 23%). 5.6% absolute decrease in mortality in ICD arm. DEFINITE. Only early trial looking purely at NICMP subgroup, but NYHA I-III and with NSVT/PVCs. ICDs significantly reduced arrhythmic SCDs. SCD HeFT. NYHA II-III with EF < 35% (this is where the Class I recommendation was derived). Lower mortality in ICD group.
- 7. DINAMIT. Post MI EF < 35%, mostly anterior MIs. No global decrease in mortality difference, but ICD group less arrhythmic deaths (counter intuitively, increase risk of non-arrhythmic deaths) 8. IRIS. Post MI EF < 40% with NSVT. No difference in mortality - ICD group decreased SCD but more non sudden cardiac death?!
- Let’s look at EFs - this magical number that guides all therapies and decision making. All primary prevention trials.
- Our findings indicate that measurements of LV volumes and EF in a non-selected patient population are more accurate and reproducible using a second-generation intra- venous contrast agent, even compared to state-of-the-art tissue harmonic imaging. Contrast injections have previ- ously been shown to improve measurement of LV volumes and EF compared to fundamental imaging (4). Tissue harmonic imaging was indeed used by Thomson et al. (5) studying patients post-myocardial infarction, but the sample size was relatively small (n 26) and the reference method was computed tomography, which is less documented by prospective clinical EF studies. Our study is the first to show that LVO is in better agreement with MRI compared to tissue harmonic imaging results. Echo volume underestimation before contrast was more pronounced for diastolic than systolic volumes (Fig. 2). With contrast, underestimation was reduced, especially for diastolic volumes. Accordingly, the accuracy of EF measure- ment improved with significant reduction in limits of agreement. This also indicates that despite tissue harmonic imaging, it is difficult to identify “true” endocardial borders. The contrast agent is filling the intertrabecular spaces, thus improving definition of the outermost endocardial lining (Fig. 1). But the addition of contrast did not eliminate volume underestimation made by echocardiography, reflect- ing some of the inherent limitations of transthorasic 2D- echo such as image plane positioning errors, foreshortening of the LV long axis, geometric assumptions, and cardiac translation (1,12). Our data demonstrated a clear improvement in reproduc- ibility of EF measurements by using contrast, both between observers with different training and at repeated measurements by the same observer. The limits of agreement were reduced to one-third with contrast compared to baseline. This indicates that contrast echo has the potential to improve the confidence of less experienced investigators, making the interpretation of LV systolic function less operator dependent. In contrast to Hundley et al. (4), we found that the advantage of contrast was also evident for patients with good image quality. According to the ASE Task Force Guidelines, contrast studies for LVO should be performed in patients with suboptimal baseline echo studies, in which at least two of six contiguous segments in a standard apical view are not visual- ized (13). However, according to our results, contrast should be considered whenever accurate EF or absolute volumes are required for clinical decision making. Contrast should be particularly useful in serial monitoring of smaller volume or EF changes over time, as in post-MI LV remodeling, end-stage heart failure, heart transplants, cardiotoxic chemotherapy, and timing of valve replacement in valve regurgitation. Contrast should also be considered when LV EF or volumes are used as inclusion or randomization criteria and outcome parameters in clinical trials. Conclusions. The 2D-echocardiographic evaluation of LV volumes and EF by tissue harmonic imaging was found to be more accurate and reproducible when performed after adding intravenous contrast in non-selected cardiac pa- tients. Our results support that contrast enhancement should be considered not only in very difficult-to-image patients, but whenever it is considered important to have precise and repeatable measurements of LV size and global systolic performance.
- Aims To prospectively compare the agreement of left ven- tricular volumes and ejection fraction by M-mode echocar- diography (echo), 2D echo, radionuclide ventriculography and cardiovascular magnetic resonance performed in patients with chronic stable heart failure. It is important to know whether the results of each technique are interchang- able, and thereby how the results of large studies in heart failure utilizing one technique can be applied using another. Some studies have compared cardiovascular magnetic resonance with echo or radionuclude ventriculography but few contain patients with heart failure and none have com- pared these techniques with the current fast breath-hold acquisition cardiovascular magnetic resonance. Methods and Results Fifty two patients with chronic stable heart failure taking part in the CHRISTMAS Study, underwent M-mode echo, 2D echo, radionuclude ventricul- ography and cardiovascular magnetic resonance within 4 weeks. The scans were analysed independently in blinded fashion by a single investigator at three core laboratories. Of the echocardiograms, 86% had sufficient image quality to obtain left ventricular ejection fraction by M-mode method, but only 69% by 2D Simpson’s biplane analysis. All 52 patients tolerated the radionuclude ventriculography and cardiovascular magnetic resonance, and all these scans were analysable. The mean left ventricular ejection fraction by M-mode cube method was 39 16% and 29 15% by Teichholz M-mode method. The mean left ventricular ejec- tion fraction by 2D echo Simpson’s biplane was 31 10%, by radionuclude ventriculography was 249% and by car- diovascular magnetic resonance was 30 11. All the mean left ventricular ejection fractions by each technique were significantly different from all other techniques (P<0·001), except for cardiovascular magnetic resonance ejection fraction and 2D echo ejection fraction by Simpson’s rule (P = 0·23). The Bland–Altman limits of agreement encom- passing four standard deviations was widest for both car- diovascular magnetic resonance vs cube M-mode echo and cardiovascular magnetic resonance vs Teichholz M-mode echo at 66% each, and was 58% for radionuclude ventricu- lography vs cube M-mode echo, 44% for cardiovascular magnetic resonance vs Simpson’s 2D echo, 39% for radio- nuclide ventriculography vs Simpson’s 2D echo, and smallest at 31% for cardiovascular magnetic resonance– radionuclide ventriculography. Similarly, the end-diastolic volume and end-systolic volume by 2D echo and cardiovas- cular magnetic resonance revealed wide limits of agreement (52 ml to 216 ml and 11 ml to 188 ml, respectively). Conclusion These results suggest that ejection fraction measurements by various techniques are not interchange- able. The conclusions and recommendations of research studies in heart failure should therefore be interpreted in the context of locally available techniques. In addition, there are very wide variances in volumes and ejection fraction between techniques, which are most marked in comparisons using echocardiography. This suggests that cardiovascular magnetic resonance is the preferred technique for volume and ejection fraction estimation in heart failure patients, because of its 3D approach for non-symmetric ventricles and superior image quality. Discussion In view of the important prognostic and therapeutic implications of both cardiac volumes and ejection frac- tion, as well as the increasing availability and use of cardiovascular magnetic resonance, it is important to know how interchangeable are the results obtained from echo, radionuclide ventriculography and cardiovascular magnetic resonance. The mean ejection fraction by each technique was shown to differ significantly from the other techniques in all but the cardiovascular magnetic resonance–Simpson’s biplane 2D echo comparison. Although there was no significant difference between the mean ejection fractions in this last group, the Bland–Altman plot reveals wide limits of agreement for this and all groups. These wide limits of agreement are consistent with previous studies (Table 4) but this rep- resents the first comparison of 2D echo, radionuclide ventriculography and the current standard cardio- vascular magnetic resonance analysis in patients with chronic, stable heart failure. The results suggest that an assessment of ejection fraction by one method cannot be assumed to be universal. Although some discrepancy exists, most of the published data on comparison of these techniques would suggest that, irrespective of the patient population studied, cardiovascular magnetic resonance tends to give a higher ejection fraction than radionuclide ventriculography and echo gives a higher ejection fraction than either cardiovascular magnetic resonance or radionuclide ventriculography (Table 4). Echo is widely used in large trials within the heart failure population but is considerably disadvantaged by the reliance on geometric assumptions. These do not hold true as the left ventricle undergoes progressive dilatation in heart failure. As the left ventricular volume increases the left ventricle becomes more spherical and the relationship between length and diameter is altered[31]. As a result, as the left ventricle diameter increases, the 95% confidence interval of prediction of left ventricular volume from the diameter rapidly increases[33]. Echo is also unreliable in the presence of regional asynergy, as it assumes that the area where the echo measurements are taken is representative of the entire left ventricle[9,34]. The Simpson’s biplane 2D echo method is regarded as more accurate than M-mode methods[35], but it still extrapolates data from a limited sampling of the left ventricle. In clinical practice the biplane method is often not used as it is time consuming and even more dependent on good endocardial border definition. Our study is consistent with this, in that 86% of patients had images of sufficient quality to be analysed by M-mode echo, compared to 69% for the 2D Simpson’s biplane method. Echo also suffers from errors introduced by gain-dependent edge identification and transducer position during imaging. These sources of error may contribute to the difference between echo and both radionuclide ventriculography and cardiovascular magnetic resonance. Furthermore, they may explain why the Bland–Altman limits of agreement between the cube M-mode echo and Simpson’s 2D echo method were 14·6 to 31·7% in this study. Radionuclide ven- triculography suffers from poor resolution, the need for background correction and errors from overlapping structures. radionuclide ventriculography analysis is also centre dependent, with the lower limit of the normal range of ejection fraction ranging from 35% to 75%[36]. Cardiovascular magnetic resonance, by comparison, acquires high resolution tomographic images that are free of geometric assumptions, without the need for ionizing radiation. Cardiovascular magnetic resonance has been shown to be both accurate and reproducible in both normal and dilated hearts[13,15,37,38]. This, together with the limitations of echo and radionuclide ven- triculography, would suggest that cardiovascular magnetic resonance is the method of choice for the evaluation of left ventricular volumes and function, especially in dilated hearts. Gated SPECT can also be used to measure volumes and ejection fraction in the heart either with a manual analysis[39], or with an automated analysis programme[40]. One study using automated analysis showed a reasonable corre- lation of volumes and ejection fraction derived from gated SPECT compared to cardiovascular magnetic resonance, although the limits of agreement were wide, with non-zero differences between the techniques (sys- tematic bias)[41]. Comparisons with other techniques, such as first pass radionuclide ventriculography similarly show wide agreement limits and systematic bias in volume estimation[42]. The inter-study reproducibility of ejection fraction measurements with gated SPECT is good[43]. More experience is required with this tech- nique before its clinical application compared with cardiovascular magnetic resonance can be defined. While these problems of each technique may explain the difference, the choice of technique used is often governed more by the availability of local resources and the important practical issue may not be which method is better, but that the techniques do not provide com- parable results[44]. If a cut-off figure for ejection fraction is used for risk stratification or as a guide to treatment, the differing techniques will have considerable impact on who is treated, with both clinical and financial consequences. Naik et al.[22] argued that because a patient with an ejection fraction of 40% could have an ejection fraction of between 20 and 60% by radionuclide ventriculography, a second method could be used to provide more confidence in the estimate. Alternatively, if cardiovascular magnetic resonance offers greater accuracy and reproducibility[12,15], in one examina- tion, albeit at greater initial cost, then there may be arguments to suggest that one cardiovascular magnetic resonance scan would provide a more cost effective assessment. The important difference between the repro- ducibility of cardiovascular magnetic resonance and other techniques is highlighted by the number of patients required to detect a clinical change. For example, Bottini et al.[45] found that to detect a 10 g difference in mass with a power of 90% and an error of 0·05 would require 505 patients by echo and 14 by cardiovascular magnetic resonance. Study limitations Variability can occur in both the acquisition and the analysis of data. Errors in acquisition were minimized by following standard guidelines and by ensuring that the same investigator performed all the data acquisition for one technique for each site. As both the echo and radionuclide ventriculography data were acquired by two centres, the potential exists for greater variability of acquisition than for the cardiovascular magnetic reso- nance that was acquired at only one site; however, both centres had considerable experience with both imaging techniques. Variability in analysis was minimized by the use of core laboratories. Despite this, the use of taped echo data rather than on-line or digital analysis may have had a detrimental effect on echo quality, compared to the digital MR data. The patient population was selected by the fact that the CHRISTMAS study required adequate echo views for wall motion analysis. In studies not requiring wall motion analysis, worse image quality may be accepted, which may result in even greater difference between echocardiography and the other imaging modalities.
- Mortality over an average follow-up of 20 months • There was a 31% reduction in the risk of death at any interval among patients in the defibrillator group as compared with patients in the conventional-therapy group. • The cumulative survival curves represent a relative decrease in death rates in the defibrillator group (95% confidence limits) of 12% at 1 year (-27 to 40%), 28% at 2 years (4 to 46%), and 29% at 3 years (5 to 46%). Methods Over the course of four years, we en- rolled 1232 patients with a prior myocardial infarc- tion and a left ventricular ejection fraction of 0.30 or less. Patients were randomly assigned in a 3:2 ratio to receive an implantable defibrillator (742 patients) or conventional medical therapy (490 patients). Inva- sive electrophysiological testing for risk stratification was not required. Death from any cause was the end point. Results The clinical characteristics at base line and the prevalence of medication use at the time of the last follow-up visit were similar in the two treatment groups. During an average follow-up of 20 months, the mortality rates were 19.8 percent in the conven- tional-therapy group and 14.2 percent in the defibrilla- tor group. The hazard ratio for the risk of death from any cause in the defibrillator group as compared with the conventional-therapy group was 0.69 (95 percent confidence interval, 0.51 to 0.93; P=0.016). The effect of defibrillator therapy on survival was similar in sub- group analyses stratified according to age, sex, ejec- tion fraction, New York Heart Association class, and the QRS interval. Conclusions In patients with a prior myocardial in- farction and advanced left ventricular dysfunction, prophylactic implantation of a defibrillator improves survival and should be considered as a recommend- ed therapy. (N Engl J Med 2002;346:877-83.)
- MADIT I When MADIT I was designed in 1991, ICDs required a thoracotomy for implantation - due to this invasive nature, eligibility criteria for enrolment into the ICD arm for MADIT I was very stringent and required puts to be at externally high risks for SCD. Studies prior to 1991 (Mirowski et al “Termination of malignant ventricular arrhythmias with implanted automatic defibrillator in human beings” NEJM 1980) indicated that CAD puts with LV dysfunction and NSVT would meet such criterion. Furthermore, it was widely believed that CAD puts with inducible ventricular arrhythmias that were non suppressible with AADs at EPS were considered to be at particular high risk for SCD. With that in mind, MADIT I was designed as a proof-of-concept study to determine through an RCT if ICD would improve survival in this high risk profile group, compared against conventional medical therapy of the time. Over 4 years, 196 puts were enrolled, with the trial halted in 1996 due to significantly improved survival in the ICD arm. Due to small sample size and limited number on mortality events, only a few secondary sub studies were possible. One important secondary investigation evaluated ICD efficacy in various high risk sub sets - EF < 25%, QRSd > 120ms, those wit hCCF - analyses revealed that the sicker the pts, the more the benefits from ICD. These set the stage for design and initiation of MADIT II. MADIT II With MADIT I establishing the efficacy of ICDs, MADIT II now set about to further refine the subgroups that received the greatest mortality benefits, by selecting puts with CAD and advanced LV dysfunction (EF<30%). Pilot data also showed that CAD pts this degree of impairment had higher frequency of ventricular ectopy - thus it was reasoned that detection of ecotype need not be required for eligibility. Of note, there was aslo a paradigm shift to NOT require EP indelibility of V-arrhythmias for eligibility into MADIT II. However, EPS was recommended at time of ICD implant in those randomised to device therapy. It was this reasoning that led to the design of a 3:2 ICD-to-non ICD radomization so that a high level secondary hypothesis relating to inducibility and appropriate ICD utilisation could be tested. MADIT II was initiated in 1997 and stopped in 2001 after enrolment of 1232 puts. ICD therapy was a/w 31% reduction in mortality risk compared to medical therapy. It should be noted that 70% of both Rx groups received OMT with BB abd ACE-I.
- The central questions raised by this trial, the AVID Trial, and MADIT are why mortality differed among the trials and why the group assigned to implanted- defibrillator therapy did not have lower mortality than the non-defibrillator group in our trial, as it did in the AVID Trial and MADIT. These differences must be due to differences in the patients at enroll- ment or differences in treatment during follow-up. The patients were similar in terms of age, sex, prevalence of heart failure, and average LVEF in the three trials. One critical difference was the indicator of arrhythmia used to qualify patients for the study. The AVID Trial (a secondary-prevention trial) required spontaneous sustained ventricular tachyarrhythmias to enroll patients; MADIT used inducible sustained ventricular tachyarrhythmias that were not suppressed by intra- venous procainamide; and we used abnormalities on a signal-averaged electrocardiogram (MADIT and our trial were primary-prevention trials). Comparison of the results of these trials suggests that the occurrence of sustained ventricular arrhythmias, either natural or induced, is a better marker than abnormalities on the SAECG of a high risk of sudden death that might be prevented by the prophylactic implantation of a defibrillator. The failure of implanted-defibrillator therapy to improve survival in our trial, in contrast to the results in the AVID Trial and MADIT, implies that patients selected for the latter two trials had more episodes of arrhythmia in which death was preventable with implanted-defibrillator therapy. Differences in the treatment of ischemia may also have contributed to the differences in the response to implanted-defibrillator therapy among these trials. Patients in our trial underwent complete revascularization on the day of randomization. In the AVID Trial and MADIT, fewer patients underwent coronary bypass surgery or angioplasty, and revascularization was, on average, performed longer before recruitment for these trials. Some controlled data on patients with angina, along with uncontrolled experience in treating survivors of cardiac arrest or recipients of implanted defibrillators, suggest that coronary bypass surgery decreases the risk of sudden death. It is possible that ischemic triggering is im- portant in the genesis of lethal ventricular tachyarrhythmias in coronary heart disease and that revas- cularization in our trial decreased the incidence of ischemically triggered arrhythmias far below the in- cidence in the other two trials. Also, it is possible that coronary bypass surgery beneficially altered the autonomic nervous input to the heart. The events committee of the Multicenter Post-Infarction Program estimated that 58 percent of deaths due to arrhythmia were preceded by acute myocardial is- chemia,36 and the Cardiac Arrhythmia Pilot Study estimated that proportion at 35 percent. That mor- tality was lower in our trial than in MADIT and the AVID Trial, despite similar age,LVEF, and rate of heart failure among the patients, is consistent with a significant benefit of cardiac revascularization in terms of survival.
- Background The mortality rate among patients with coronary artery disease, abnormal ventricular function, and unsustained ventricular tachycardia is high. The usefulness of electrophysiologic testing for risk stratification in these patients is unclear. Methods We performed electrophysiologic testing in patients who had coronary artery disease, a left ventricular ejection fraction of 40 percent or less, and asymptomatic, unsustained ventricular tachycardia. Patients in whom sustained ventricular tachyarrhyth- mias could be induced were randomly assigned to receive either antiarrhythmic therapy guided by elec- trophysiologic testing or no antiarrhythmic therapy. The primary end point was cardiac arrest or death from arrhythmia. Patients without inducible tachyar- rhythmias were followed in a registry. We compared the outcomes of 1397 patients in the registry with those of 353 patients with inducible tachyarrhyth- mias who were randomly assigned to receive no an- tiarrhythmic therapy in order to assess the prognos- tic value of electrophysiologic testing. Results Patients were followed for a median of 39 months. In a Kaplan–Meier analysis, two-year and five-year rates of cardiac arrest or death due to ar- rhythmia were 12 and 24 percent, respectively, among the patients in the registry, as compared with 18 and 32 percent among the patients with inducible tachy- arrhythmias who were assigned to no antiarrhyth- mic therapy (adjusted P<0.001). Overall mortality af- ter five years was 48 percent among the patients with inducible tachyarrhythmias, as compared with 44 per- cent among the patients in the registry (adjusted P= 0.005). Deaths among patients without inducible tach- yarrhythmias were less likely to be classified as due to arrhythmia than those among patients with induc- ible tachyarrhythmias (45 and 54 percent, respective- ly; P=0.06). Conclusions Patients with coronary artery disease, left ventricular dysfunction, and asymptomatic, un- sustained ventricular tachycardia in whom sustained ventricular tachyarrhythmias cannot be induced have a significantly lower risk of sudden death or cardiac arrest and lower overall mortality than similar patients with inducible sustained tachyarrhythmias.
- Therapy with an ICD significantly reduced the risk of sudden death from arrhythmia (hazard ratio, 0.20; P=0.006) and resulted in a reduction in the risk of death from any cause that approached but did not reach statistical significance (hazard ratio, 0.65; P=0.08). As in prior trials, the ICD was highly effective at preventing sudden death from cardiac causes. The difference in mortality between the standard- therapy group and the ICD group was almost entirely due to a difference in the incidence of death from cardiac arrhythmia. On the basis of data available at the time the study was designed, more than 50 per- cent of the deaths were expected to be due to arrhythmia, and thus, the trial was powered to detect a 50% difference in the rates of death from any cause. However, only approximately one third of the deaths in the standard-therapy group were due to arrhythmia. Eighty-five percent of the patients in this study were treated with ACE inhibitors and beta- blockers — a higher compliance rate than in other studies.4-7 The lower-than-expected rate of sudden death from arrhythmia may have been due to the high rate of use of beta-blockers and ACE inhibi- tors and may thus have resulted in the nonsignificant reduction in deaths from any cause. Sub-group analyses revealed that the implantation of an ICD significantly reduced the risk of death among patients who had NYHA class III heart failure and among men. Prior large-scale studies evaluating the effect of prophylactic implantation of an ICD for the preven- tion of sudden death have focused on patients with coronary disease. Our trial was designed to evaluate the effect of an ICD on the risk of death among patients with nonischemic cardiomyopathy who were receiving standard therapy, usually including ACE inhibitors and beta-blockers. The second Mul- ticenter Automatic Defibrillator Implantation Trial (MADIT II) reported a decrease in the relative risk of death from any cause of 31% among patients who received an ICD — which was similar to our finding of a 35% decrease
- background Implantablecardioverter–defibrillator(ICD)therapyhasbeenshowntoimprovesurviv- al in patients with various heart conditions who are at high risk for ventricular arrhyth- mias. Whether benefit occurs in patients early after myocardial infarction is unknown. methods We conducted the Defibrillator in Acute Myocardial Infarction Trial, a randomized, open-label comparison of ICD therapy (in 332 patients) and no ICD therapy (in 342 pa- tients) 6 to 40 days after a myocardial infarction. We enrolled patients who had reduced left ventricular function (left ventricular ejection fraction, 0.35 or less) and impaired cardiac autonomic function (manifested as depressed heart-rate variability or an elevat- ed average 24-hour heart rate on Holter monitoring). The primary outcome was mor- tality from any cause. Death from arrhythmia was a predefined secondary outcome. results During a mean (±SD) follow-up period of 30±13 months, there was no difference in over- all mortality between the two treatment groups: of the 120 patients who died, 62 were in the ICD group and 58 in the control group (hazard ratio for death in the ICD group, 1.08; 95 percent confidence interval, 0.76 to 1.55; P=0.66). There were 12 deaths due to arrhythmia in the ICD group, as compared with 29 in the control group (hazard ratio in the ICD group, 0.42; 95 percent confidence interval, 0.22 to 0.83; P=0.009). In con- trast, there were 50 deaths from nonarrhythmic causes in the ICD group and 29 in the control group (hazard ratio in the ICD group, 1.75; 95 percent confidence interval, 1.11 to 2.76; P=0.02). conclusions Prophylactic ICD therapy does not reduce overall mortality in high-risk patients who have recently had a myocardial infarction. Although ICD therapy was associated with a reduction in the rate of death due to arrhythmia, that was offset by an increase in the rate of death from nonarrhythmic causes. In this randomized trial of high-risk patients who had recently had a myocardial infarction, overall survival was not improved by prophylactic implan- tation of an ICD. The study groups were well bal- anced with respect to their baseline clinical charac- teristics and the early use of reperfusion therapy. There was a high rate of use of appropriate medical therapy.Itisunlikelythatthesimilaritybetweenthe two groups in the rate of death from all causes rep- resents a false negative result due to inadequate sample size. The 95 percent confidence interval of the hazard ratio for death from any cause rules out a reduction in mortality of 25 percent or greater. The ICD group, as compared with the control group, had a large, statistically significant reduction (by more than 50 percent) in the risk of death due to arrhythmia; however, this effect was offset by a significant increase, of similar magnitude, in the rate of death from nonarrhythmic causes. The ICD is expected to reduce mortality by preventing sudden cardiac deaths due to ventricular fibrillation without any effect on death from nonarrhythmic causes. This pattern has been consistently observed in pre- vious trials of ICD therapy in patients at high risk. In several trials of ICD therapy — the Canadian Im- plantable Defibrillator Study, the Antiarrhythmics versus Implantable Defibrillators trial, and the Car- diac Arrest Study Hamburg — there was a 50 per- cent reduction in the rate of death from arrhythmia and almost no effect on the rate of death from other causes; the net effect was a 25 percent reduction in overall mortality.17 In the Multicenter Automatic Defibrillator Implantation Trial I (MADIT I) and MADIT II,1,2 which evaluated prophylactic ICD therapy in patients with chronic ischemic heart dis- ease, the rate of death due to arrhythmia was mark- edly reduced and the rate of death from other causes was not increased. In DINAMIT, the reduction in the rate of arrhyth- mia-related death was very similar to that observed in previous trials of ICD therapy. However, in contrast to the previous trials, DINAMIT revealed a statistically significant increase in the rate of death from nonarrhythmic causes among patients as- signed to receive an ICD. Most of these deaths (78 percent) were cardiovascular in nature. It appears that in this trial, as in previous trials of ICD therapy, the ICD prevented death from ventricular fibrilla- tion. However, preventing death from ventricular fibrillation did not reduce overall mortality in these patients. The reason for the unexpected and unprecedent- ed increase in mortality from causes other than arrhythmia in patients assigned to receive an ICD is not clear. The most likely explanation is that the patients “saved” from an arrhythmia-related death by ICD therapy are also at high risk for death from other cardiac causes. There was no sign of an in- creased rate of death in association with the surgi- cal procedure or complications with the use of the ICD. It is unlikely that the increased rate of deaths from cardiac, nonarrhythmic causes were due to ex- cessive pacing, as in the Dual-Chamber and VVI Im- plantable Defibrillator Trial,18 because the backup pacing was programmed at a very low rate in almost all the patients in the ICD group. It has been speculated that ICDs might, by shocking ventricular fibrillation, merely transform sudden death to eventual death from pump failure, without significantly prolonging life, especially when ventricular fibrillation is occurring in a patient with end-stage heart failure or a large acute myo- cardial infarction. There is some evidence that such a possibility may have factored into the results of the Coronary Artery Bypass Graft Patch Trial,19 and it provides a reasonable hypothesis for the results of DINAMIT. The mean left ventricular ejection fraction in DINAMIT was significantly reduced (at 0.28) and did not increase appreciably six weeks later. How- ever, the mean ejection fraction was somewhat higher than that in MADIT II (0.23)2 — a difference that may explain the higher overall mortality ob- served in MADIT II. The main differences between patients in DINAMIT and those in previous trials is the temporal proximity to acute infarction and the abnormal results of autonomic-function tests at baseline. In DINAMIT, the ratio of death due to ar- rhythmia to death from any cause was 34 percent, similar to the ratio in other ICD trials. A recent analysis of the MADIT II trial, which also enrolled patients with a previous myocardial infarction, sup- ports the main finding of DINAMIT — that pa- tients who have recently had an infarction do not benefit from ICD.20 In MADIT II, the mean time from the most recent infarction to enrollment in the study was 6.5 years; the subgroup of patients with the most recent infarction did not benefit at all from ICD therapy.20 This finding was in marked contrast to the outcome in patients whose infarction had occurred in the remote past, in whom the benefit from the ICD was large. Although several clinical studies had indicated that the results of tests of autonomic function carry prognostic implications after myocardial infarc- tion,7-11 the recently published Azimilide Post Infarct Survival Evaluation,21 which provided definitive information on the prognostic value of heart- rate variability, has demonstrated that impaired heart-rate variability is associated with increased mortality but not specifically mortality from ar- rhythmic causes. Nonetheless, the proportion of deaths in the DINAMIT control group that were at- tributable to arrhythmia was 50 percent — as high as in any previous trial of ICD therapy for second- ary or primary prevention. Use of amiodarone was more common in the control group than it was in the ICD group. Most likely, this difference is a reflection of physicians’ desire in this unblinded study to provide additional optimal therapy in the absence of an ICD. However, as recently demonstrated in a large, randomized trial, amiodarone does not offer any survival bene- fit if given for primary prevention in patients with ischemic or nonischemic cardiomyopathy and re- duced ventricular function.22 Most likely, amioda- rone had no effect on survival in our trial as well.
- In DINAMIT, the reduction in the rate of arrhythmia-related death was very similar to that observed in previous trials of ICD therapy. However, in contrast to the previous trials, DINAMIT revealed a statistically significant increase in the rate of death from nonarrhythmic causes among patients assigned to receive an ICD. Most of these deaths (7%) were cardiovascular in nature. It appears that in this trial, as in previous trials of ICD therapy, the ICD prevented death from VF. However, preventing death from VF did not reduce overall mortality in these patients. The reason for the unexpected and unprecedented increase in mortality from causes other than arrhythmia in patients assigned to receive an ICD is not clear. The most likely explanation is that the patients “saved” from an arrhythmia-related death by ICD therapy are also at high risk for death from other cardiac causes. There was no sign of an in- creased rate of death in association with the surgi- cal procedure or complications with the use of the ICD. It is unlikely that the increased rate of deaths from cardiac, nonarrhythmic causes were due to ex- cessive pacing, as in the Dual-Chamber and VVI Im- plantable Defibrillator Trial,18 because the backup pacing was programmed at a very low rate in almost all the patients in the ICD group. It has been speculated that ICDs might, by shocking ventricular fibrillation, merely transform sudden death to eventual death from pump failure, without significantly prolonging life, especially when ventricular fibrillation is occurring in a patient with end-stage heart failure or a large acute myo- cardial infarction. There is some evidence that such a possibility may have factored into the results of the Coronary Artery Bypass Graft Patch Trial,19 and it provides a reasonable hypothesis for the results of DINAMIT. complications of icd therapy The average time between randomization and ICD implantation was 6.3±7.3 days. Of the 332 patients assigned to receive an ICD, 310 actually received a device. The time between ICD implantation and dis- charge from the hospital averaged 4.7±6.4 days. In- hospital device-related complications occurred in 25 patients; the most common of these complications were lead dislodgment, pneumothorax, and inap- propriate shocks. There were no deaths related to device implantation. To prevent inappropriate pac- ing, bradycardia pacing was typically programmed to 40 to 45 beats per minute (maximum, 55 beats per minute).
- methods Werandomlyassigned2521patientswithNewYorkHeartAssociation(NYHA)classII or III CHF and a left ventricular ejection fraction (LVEF) of 35 percent or less to conven- tional therapy for CHF plus placebo (847 patients), conventional therapy plus amioda- rone(845patients),orconventionaltherapyplusaconservativelyprogrammed,shock- only,single-leadICD(829patients).Placeboandamiodaronewereadministeredina double-blind fashion. The primary end point was death from any cause. results The median LVEF in patients was 25 percent; 70 percent were in NYHA class II, and 30 percent were in class III CHF. The cause of CHF was ischemic in 52 percent and nonis- chemic in 48 percent. The median follow-up was 45.5 months. There were 244 deaths (29 percent) in the placebo group, 240 (28 percent) in the amiodarone group, and 182 (22 percent) in the ICD group. As compared with placebo, amiodarone was associated with a similar risk of death (hazard ratio, 1.06; 97.5 percent confidence interval, 0.86 to 1.30; P = 0.53) and ICD therapy was associated with a decreased risk of death of 23 per- cent (0.77; 97.5 percent confidence interval, 0.62 to 0.96; P=0.007) and an absolute decrease in mortality of 7.2 percentage points after five years in the overall population. Results did not vary according to either ischemic or nonischemic causes of CHF, but they did vary according to the NYHA class. conclusions In patients with NYHA class II or III CHF and LVEF of 35 percent or less, amiodarone has no favorable effect on survival, whereas single-lead, shock-only ICD therapy reduces overall mortality by 23 percent. Discussion Our study has two principal findings. First, therapy with a conservatively programmed, shock-only ICD significantly decreased the relative risk of death by 23 percent, resulting in an absolute reduction of 7.2 percentage points at five years among patients with CHF who received state-of-the-art background medical therapy, and the benefit did not vary ac- cording to the cause of CHF. Second, amiodarone had no beneficial effect on survival, despite the use of appropriate dosage and reasonable compliance rates over longer periods than in other placebo- controlled trials.1,9,10 Our findings raise the standard of care for many patients with CHF by substantiating evidence from earlier trials in favor of ICD therapy in patients with ischemic CHF and by providing evidence of a sur- vival benefit associated with such therapy in patients with nonischemic CHF. ICD therapy had a signifi- cant benefit in patients in NYHA class II but not in those in NYHA class III CHF. In contrast, amioda- rone therapy had no benefit in patients in NYHA class II and decreased survival among patients in NYHA class III CHF, as compared with those who received placebo. Subgroup effects, however, are considered most credible if they are prespecified, have a significant interaction with treatment, and are considered bio- logically plausible. The NYHA subgroups were pre- specified, and the results of the interaction tests were significant. Moreover, the results of the six- minute walk test (Fig. 4) support the findings with respect to NYHA class, not only for ICD therapy but also for amiodarone. Nevertheless, it is worth point- ing out that this subgroup effect was not anticipat- ed before data analysis. Rather, the general trend in prior trials had been for the relative treatment ef- fect to be nearly constant and, thus, for the treat- ment benefit to be larger in absolute terms for sick- er patients. Whether the treatment differences that we observed in NYHA-class subgroups are biologi- cally plausible is uncertain. The traditional view of clinical trialists is that the results of subgroup analysis are inherently mislead- ing and should be interpreted very conservatively until replicated elsewhere. In the absence of repli- cation, the findings of other trials can guide the in- terpretation of this particular subgroup effect. In the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II),17 a study of patients who had had a myocardial infarction, and in the Antiarrhyth- mics versus Implantable Defibrillators (AVID) study,6 a secondary prevention trial, the worse the ejection fraction, the greater the benefit of ICD ther- apy. In a post hoc analysis, MADIT II showed a ben- efit of ICD therapy in terms of survival that was sim- ilar to the overall trial results when the groups were stratified according to the NYHA class (I, II, or III) (MADIT II Executive Committee: personal commu- nication). In the Defibrillators in Non-Ischemic Car- diomyopathy Treatment Evaluation (DEFINITE) tri- al, patients in NYHA class III derived the largest survival benefit from ICD therapy.4 Thus, we do not believe that the unanticipated subgroup effect we found is a sufficient basis for withholding ICD ther- apy from patients in NYHA class III. Another pertinent finding of our study was that single-lead ICDs proved beneficial despite a 5 per- cent rate of acute device-related complications and 9 percent rate of chronic complications. It is not sur- prising that ICD therapy has complications related to surgery and long-term management limitations, but the survival benefit associated with simple, shock-only ICD therapy outweighs any shortcom- ings of this approach. Placing our findings in relation to those of other trials of ICD therapy poses some difficulties. Two previous studies have examined the role of ICD therapy in patients with CHF — the Amiodarone versus Implantable Cardioverter–Defibrillator Trial (AMIOVIRT)3 and the DEFINITE trial4 — but only among those with nonischemic cardiomyopathy. AMIOVIRT randomly assigned 103 patients in NYHA class I, II, or III who had an LVEF of 35 per- cent or less and had nonsustained ventricular tachy- cardia during ambulatory monitoring to amioda- rone or dual-chamber ICDs programmed as VVI shock only (Strickberger A: personal communica- tion). No mortality advantage had been observed when the trial was aborted after two years. Back- ground use of beta-blockers was somewhat lower in AMIOVIRT than in our trial (53 percent vs. 69 per- cent at randomization). Differences in outcome be- tween the two trials are probably due to differences in the number of patients enrolled and the duration of follow-up. The DEFINITE trial randomly assigned 458 pa- tients to ICD or standard therapy and did not find a significant survival benefit (P=0.08). The study used nonsustained ventricular tachycardia and frequent ectopy as entry criteria, and 22 percent of the pa- tients were in NYHA class I. In addition, the thresh- old for pacing was higher than in our study (40 vs. 34 beats per minute), and the heart rate prompting intervention was lower (180 vs. 187 beats per min- ute). Moreover, the death rate was higher at two years than among our patients with nonischemic CHF (14 percent vs. 10 percent), suggesting that there may have been fundamental differences in the two study populations. It is critical to emphasize that the effect of ICD therapy in patients with CHF may differ substantial- ly depending on the programming of the device; whether single-, dual-, or triple-chamber devices are used; whether antibradycardia pacing or rate- responsive pacing is used; which detection algo- rithm is used; and whether antitachycardia pacing maneuvers are used for ventricular tachycardia. Al- though physicians understand that different drugs lead to different outcomes, they may fail to realize that the same is true for ICD therapy. ICD therapy cannot be considered a single intervention, given the numerous possible permutations of this ap- proach. Consequently, we cannot emphasize too strongly that we evaluated only very conservatively programmed ICDs with a conservative detection al- gorithm and shock-only therapy. We found strong evidence that this approach works; however, con- siderable caution should be used in extrapolating our results to other approaches to ICD therapy, such as those involving dual-chamber or biventricular pacing, since, as reported previously,3,8,18 they may not afford the same benefit or, for that matter, any benefit. Our findings may also be pertinent to constrain- ing the costs of ICD therapy. ICDs were inserted on an outpatient basis, and testing of the devices was very limited. Outpatient insertion is certainly less expensive than inpatient insertion and can easily be translated to routine practice. Moreover, given the finding that no patient who underwent ICD testing required more than the maximal output of the de- vice to terminate ventricular fibrillation, a reason- able argument can be made that defibrillation test- ing is unwarranted in this population. The risk and cost of defibrillation testing are likely to outweigh the remote possibility that a rare patient might ben- efit from it. A simplified, effective approach to the implantation of single-lead, shock-only ICDs such as ours should translate into cost savings. In conclusion, amiodarone does not improve survival among patients with mild-to-moderate sys- tolic CHF. Simple, shock-only ICD therapy improves survival beyond the improvement afforded by state- of-the-art drug therapy. Our approach to ICD ther- apy is widely applicable and should have a positive public health effect on the population of patients with CHF.
- Objectives The purpose of this study was to assess the incidence, predictors, and outcome of inappropriate shocks in implantable cardioverter-defibrillator (ICD) patients. Background Despite the benefits of ICD therapy, inappropriate defibrillator shocks continue to be a significant drawback. The prognostic importance of inappropriate shocks outside the setting of a clinical trial remains unclear. Methods From 1996 to 2006, all recipients of defibrillator devices equipped with intracardiac electrogram storage were included in the current analysis and clinically assessed at implantation. During follow-up, the occurrence of inappropriate ICD shocks and all-cause mortality was noted. Results A total of 1,544 ICD patients (79% male, age 61 ± 13 years) were included in the analysis. During the follow-up period of 41 ± 18 months, 13% experienced ≥1 inappropriate shocks. The cumulative incidence steadily increased to 18% at 5-year follow-up. Independent predictors of the occurrence of inappropriate shocks included a history of atrial fibrillation (hazard ratio [HR]: 2.0, p < 0.01) and age younger than 70 years (HR: 1.8, p = 0.01). Experiencing a single inappropriate shock resulted in an increased risk of all-cause mortality (HR: 1.6, p = 0.01). Mortality risk increased with every subsequent shock, up to an HR of 3.7 after 5 inappropriate shocks. Conclusions In a large cohort of ICD patients, inappropriate shocks were common. The most important finding is the association between inappropriate shocks and mortality, independent of interim appropriate shocks. In SCD HeFT (2005): icd shocks Of the 829 patients in the ICD group, 259 (31%) were known to have received shocks from their device for any cause, with 177 (68% of those shocked, or 21% of the ICD group) receiving shocks for rapid ventricular tachycardia or fibrillation. During five years of follow-up, the average annual rate of ICD shocks was 7.5%. For appropriate shocks only (i.e.,shocks for rapid,sustained ventricular tachycardia or fibrillation), the average annual rate of ICD shocks was 5.1 percent.
- Single-chamber ICDs versus dual-chamber ICDs versus cardiac resynchronization therapy defibrillators. With su- praventricular arrhythmias as the principal cause of inappro- priate shocks, one might hypothesize that additional sensing information would improve discrimination between supraven- tricular tachyarrhythmias and ventricular tachyarrhythmias to prevent inappropriate therapy. Therefore, in theory, dual- chamber ICDs should perform better than single-chamber ICDs. However, in the literature, there are doubts regarding the performance of devices with extra sensing/pacing leads compared with single-chamber ICDs. Theuns et al. (34) performed a prospective, randomized study to evaluate the performance of tachyarrhythmia detection algorithms in single- and dual-chamber ICDs, but did not find a significant reduction in the number of inappropriate arrhythmia classifi- cations. Other studies found similar results (20,35,36). In contrast, a randomized trial conducted by Friedman et al. (37) demonstrated a small but significant reduction of inappropriate supraventricular tachyarrhythmias detection (8.6%) when using optimized programmed dual-chamber ICDs compared with single-chamber ICDs. These findings were supported by Soundarraj et al. (29). In the present study, no significant differences were observed in the incidence of inappropriate shocks when comparing the 3 different device types.
- To better inform patients and physicians of the expected risk of adverse events and to assist hospitals’ efforts to improve the outcomes of patients undergoing implantable cardioverter-defibrillator (ICD) implantation, we developed and validated a risk model using data from the NCDR (National Cardiovascular Data Registry) ICD Registry. ICD prolong life in selected patients, but ICD implantation carries the risk of periprocedural complications. We analyzed data from 240,632 ICD implantation procedures between April 1, 2010, and December 31, 2011 in the registry. The study group was divided into a derivation (70%) and a validation (30%) cohort. Multivariable logistic regression was used to identify factors associated with in-hospital adverse events (complications or mortality). A parsimonious risk score was developed on the basis of beta estimates derived from the logistic model. Hierarchical models were then used to calculate risk-standardized complication rates to account for differences in case mix and procedural volume. Overall, 4,388 patients (1.8%) experienced at least 1 in-hospital complication or death. Thirteen factors were independently associated with an increased risk of adverse outcomes. Model performance was similar in the derivation and validation cohorts (C-statistics 1⁄4 0.724 and 0.719, respectively). The risk score characterized patients into low- and-high risk subgroups for adverse events ( 10 points, 0.3%; !30 points, 4.2%). The risk-standardized complication rates varied significantly across hospitals (median: 1.77, interquartile range 1.54, 2.14, 5th/95th percentiles: 1.16/3.15). We developed a simple model that predicts risk for in-hospital adverse events among patients undergoing ICD placement. This can be used for shared decision making and to benchmark hospital performance. (J Am Coll Cardiol 2014;63:788–96) a 2014 by the American College of Cardiology Foundation
- subgroup analysis Although the study was not powered to detect differences within subgroups, several prespecified analyses were performed regarding variables that could affect survival (Fig. 2). A Cox proportional- hazards model was used to analyze differences in survival in predefined subgroups. Men had a rela- tive risk of death from any cause of 0.49 (95 percent confidence interval, 0.27 to 0.90; P = 0.018) after the implantation of an ICD. Patients with NYHA class III heart failure had a relative risk of death of 0.37 (95 percent confidence interval, 0.15 to 0.90; P= 0.02) after receiving an ICD (Fig. 3).
- MUSTT: Methods We performed electrophysiologic testing in patients who had coronary artery disease, a LVEF 40 percent or less, and asymptomatic, unsustained ventricular tachycardia. Patients in whom sustained ventricular tachyarrhythmias could be induced were randomly assigned to receive either antiarrhythmic therapy guided by electrophysiologic testing or no antiarrhythmic therapy. The primary end point was cardiac arrest or death from arrhythmia. Patients without inducible tachyar- rhythmias were followed in a registry. We compared the outcomes of 1397 patients in the registry with those of 353 patients with inducible tachyarrhyth- mias who were randomly assigned to receive no an- tiarrhythmic therapy in order to assess the prognos- tic value of electrophysiologic testing. MADIT I: Proof of concept study in 1996 to determine through a RCT whether ICD would improve survival in CAD puts at high risk of SCD cf conventional OMT. Showed 54% risk reduction of death.