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MADIT II The EP Show: MADIT II Eric Prystowsky MD Director, Clinical Electrophysiology Laboratory St Vincent Hospital The Care Group (private clinic) Indianapolis, Indiana Arthur Moss MD Professor of Medicine University of Rochester Medical Center Rochester, New York EP Show – April 2002 MADIT II Background Identified low EF as primary determinant of mortality post-MI in 1970s Repetitive ventricular ectopic beats (salvos) also contribute to risk •BHAT (JAMA 1982;247:1707-1714) •ACE inhibitors (NEJM 1992;327:669-77) •CAST (NEJM 1991;324:781-788) EP Show – April 2002 MADIT II 1990's In 1990s we had good treatment for left ventricular dysfunction but no effective therapy for preventing sudden cardiac death Moss EP Show – April 2002 MADIT II ICD benefit in previous studies Relative reduction 2-year all-cause mortality (%) 40 39% 51% 54% Control 30 ICD 20 10 0 AVID EP Show – April 2002 MUSTT MADIT MADIT II MADIT II: Description Multicenter Automatic Defibrillator Implantation Trial II •MI > 4 weeks •LVEF 30% 1232 patients randomized to ICD or conventional medical therapy Arrhythmia was not an inclusion criteria, did not require previous EP testing EP Show – April 2002 MADIT II MADIT II: All-cause mortality 25% P=0.016 20% 15% 19.8% 14.2% 10% 5% 0% ICD EP Show – April 2002 Medical therapy Moss et al. N Engl J Med 2002;346(12):877-83. MADIT II Serial drug testing EP testing began in Philadelphia in the early 1980s •Arrhythmias could be induced and then suppressed by anti-arrhythmic agents •Despite no long-term follow-up, it made physiologic sense to think this provided survival benefit Moss EP Show – April 2002 MADIT II MUSTT Entry Criteria • EF < 40% • CAD • spontaneous nonsustained ventricular tachycardia (VT-NS) Total mortality (5 years) ICDs (n=161) Drug therapy (n=153) P value 24% 55% <0.001 EP Show – April 2002 Buxton et al. N Engl J Med 1999;341(25):1882-90. MADIT II EP testing MUSTT and CAST have shaken the confidence in EP testing as a good risk stratifier in coronary disease •MADIT II sub-study is looking for any patients who did benefit from EP studies Moss EP Show – April 2002 MADIT II MADIT II: Medications ICD (n=742) Medical therapy (n=490) ACE-inhibitors 68% 72% Beta-blockers 70% 70% Statins 67% 64% Diuretics 72% 81% Medication at last contact EP Show – April 2002 Moss et al. N Engl J Med 2002;346(12):877-83. MADIT II ICD benefit in MADIT and MUSTT 2-year all-cause mortality (%) 40 Relative reduction 51% 54% Control 30 ICD 20 10 0 MUSTT EP Show – April 2002 MADIT MADIT II Patient populations MUSTT and MADIT both required documented ventricular arrhythmias and had to be inducible in the lab •A higher risk population •Medical therapy available to control group was not as good as in MADIT II Moss EP Show – April 2002 MADIT II MADIT II: Medications ICD (n=742) Medical therapy (n=490) ACE-inhibitors 68% 72% Beta-blockers 70% 70% Statins 67% 64% Diuretics 72% 81% Medication at last contact EP Show – April 2002 Moss et al. N Engl J Med 2002;346(12):877-83. MADIT II ICD benefit ICDs benefit is now superimposed on very aggressive drug management •The control group has an improved outcome •The relative ICD benefit is now only 30% compared to 50% in earlier trials Moss EP Show – April 2002 MADIT II MADIT II vs MADIT and MUSTT 2-year all-cause mortality (%) 40 Relative reduction 31% 51% 54% Control 30 ICD 20 10 0 MADIT II EP Show – April 2002 MUSTT MADIT MADIT II Inducible patients “There probably is a little more, not dramatic, additive risk stratification if you are inducible positive in the lab.” Prystowsky “I think [EP testing] does add an increment. Its not as large an increment as what we thought and one needs a larger population now to see it.” Moss EP Show – April 2002 MADIT II Two peculiarities Two peculiarities noted in the MADIT-II manuscript •Superimposable survival curves for the first 6-7 months •Increased heart failure in the ICD group EP Show – April 2002 MADIT II MADIT II: Diverging curves Probability of survival Time ICD patients Control 1 year 0.91 0.90 2 years 0.84 0.78 3 years 0.78 0.69 EP Show – April 2002 Moss et al. N Engl J Med 2002;346(12):877-83. MADIT II Delay in survival benefit A physiological explanation •Curves are almost identical to original ACE inhibitor trials •Patients were probably enrolled with previous symptoms •The patients are high enough risk that the ICD doesn't show a difference in the first 6 months Moss EP Show – April 2002 MADIT II Delay in survival benefit A statistical explanation •Statisticians find the effect is just part of the "wobble" of a clinical trial •Pattern of difference between the curves is consistent over time Moss EP Show – April 2002 MADIT II Explaining the delay Two ongoing explanations •Physiological effect – the sickest patients die equally in both arms in the first 6 months •Statistical effect – the overlap is just an artifact that resolves itself over time Moss EP Show – April 2002 MADIT II Explaining the delay Third possible explanation •Drug treatment effect – it took some time for medical therapy to reach the appropriate level, and the delay is reflected in the overlap of the curves Moss EP Show – April 2002 MADIT II MADIT II: Increased hospitalizations Patient group # patients hospitalized # patients hospitalized/1000 hours follow-up Conventional therapy group 73 (14.9%) 9.4 148 (19.9%) 11.3 Defibrillator group Nominal p=0.09 EP Show – April 2002 Moss et al. N Engl J Med 2002;346(12):877-83. MADIT II Explaining the rise in CHF We encourage physicians who put in ICDs to be vigilant for the development of subtle heart failure •Patients who live longer have more chances to develop heart failure •Backup ventricular pacing may contribute to LV dysfunction •Each shock releases myocardial enzyme, this may signal damage Moss EP Show – April 2002 MADIT II A disease of medical progress AVID trial also had an increased number of hospitalizations for heart failure in the ICD patients “I would look upon this is a disease of medical progress. That is, as you reduce mortality due to one cause, you're naturally going to have morbidity and mortality from other causes that will creep up. But over time, it takes longer for that to become manifest." Doctor EP Show – April 2002 MADIT II Effect of pacing rate Do people who developed heart failure have a greater percentage of time pacing? •Could be an important clinical observation •Data on this should be available in the near future EP Show – April 2002 MADIT II Cardiac death in the USA Endpoint # Deaths Death rate (per 100 000) 1998 724 859 268.2 1999 725 192 265.9 2000* 709 894 257.9 *preliminary data EP Show – April 2002 National Vital Statistics Reports. CDC 2002 MADIT II The future Sudden death remains a major epidemiological problem •We are moving toward AEDs everywhere •Should we consider ICDs before people present with serious problems? Prystowsky EP Show – April 2002 MADIT II Should everyone get ICDs? "One can raise a similar type of question, 'Should everyone have a coronary angiogram or should everyone have an exercise tolerance test?' And I think one has to put this in good clinical judgment and the answer is 'no' " Moss EP Show – April 2002 MADIT II Risk stratification We are required as good clinicians to do risk stratification •Do they have symptoms? •Exercise tolerance tests after 50 We need appropriate, relevant, clinical risk stratification Moss EP Show – April 2002 MADIT II Risk stratification Should everyone with an MI have an ICD? •Not at that level of evidence yet •Previous MI and LVEF 30% probably should get one Moss EP Show – April 2002 MADIT II MADIT III Multicenter Automatic Defibrillator Implantation Trial III •Adults with type 2 diabetes •LVEF 30%-40% Planned trial for the future to look at this risk population EP Show – April 2002 MADIT II Other risk populations Populations outside of coronary disease may benefit from ICDs •Hypertrophic cardiomyopathy •Brugada syndrome •Long-QT syndrome •Arrhythmagenic right ventricular dysplasia EP Show – April 2002 Moss MADIT II Progress We will continue to identify populations where the ICD is useful •An expanding population, but not likely to become a cure-all "I wouldn't put [an ICD] in yet but I think you ought to have an exercise tolerance test, just like I think President Bush ought to have an exercise tolerance test." Moss EP Show – April 2002 MADIT II Money We in the US have not had quotas on lifesaving therapies •MADIT II opens up a large population for ICD implantation •Talk of how it is too expensive and might bankrupt the health care system Prystowsky EP Show – April 2002 MADIT II Repeat of the CABG debate This is the same argument that appeared in 1982 about CABG •Editorials said CABG would bankrupt the system •CABG continued and is now a multibillion dollar part of health care Moss EP Show – April 2002 MADIT II Future of ICDs Future ICD market in the range of 300 000 per year •3 million by prevalence alone •2-300 000 new cases meet MADIT II criteria every year As volume increases, market forces will bring the cost down to pacemaker range ($3000) Moss EP Show – April 2002 MADIT II Future costs As the volume increases, market forces should lower the cost •ICD cost in 5 years should be $3000 "I'm not an economist, I'm a clinician and an investigator and I think the first thing we have to do is show the clear cut benefit and then the market forces will come into play." Moss EP Show – April 2002 MADIT II The EP Show: MADIT II Eric Prystowsky MD Director, Clinical Electrophysiology Laboratory St Vincent Hospital The Care Group (private clinic) Indianapolis, Indiana Arthur Moss MD Professor of Medicine University of Rochester Medical Center Rochester, New York EP Show – April 2002