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Triumph of the trials: ACC 2002

Triumph of the trials: ACC 2002. Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, Massachusetts James Ferguson MD Associate Director, Cardiology

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Triumph of the trials: ACC 2002

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  1. Triumph of the trials: ACC 2002 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, Massachusetts James Ferguson MD Associate Director, Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, Texas Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, New York

  2. Subjects MADIT II ICDs for post-MI patients with low EF Atrial fibrillation Rate vs rhythm Coated stents The end of restenosis?

  3. MADIT II • Multicenter Automatic Defibrillator Implantation Trial II • 1232 post-MI patients with moderate LV dysfunction (EF 30%) randomized to ICD or conventional medical therapy • Arrhythmia was not an inclusion criteria, did not require previous EP testing

  4. MADIT II: All-cause mortality P=0.016 19.8% 14.2% Moss et al. N Engl J Med 2002;346(12):877-83.

  5. MADIT II: Additional discussion HospitalizationsICD group had more hospitalizations Drug treatmentThe patients received the proper drug regimen CostDo we put ICDs in everyone?

  6. MADIT II: Diverging curves • Percent reduction in rate of death on ICD therapy • Nominal 95% CI • Time • 1 year • -47-20 • 12 • 28 • 2 years • 4-46 • 28 • 3 years • 5-46 Moss et al. N Engl J Med 2002;346(12):877-83.

  7. MADIT II: Increased hospitalizations • # patients hospitalized • # patients hospitalized/1000 hours follow-up • Patient group • Conventional therapy group • 9.4 • 73 (14.9%) • Defibrillator group • 148 (19.9%) • 11.3 Nominal p=0.09 "If you save lives in sick people, they are going to require more hospital resources." Ferguson Moss et al. N Engl J Med 2002;346(12):877-83.

  8. MADIT II: Medications • ICD (n=742) • Medical therapy (n=490) • Medication at last contact • ACE-inhibitors • 68% • 72% • Beta-blockers • 70% • 70% • Statins • 67% • 64% • Diuretics • 72% • 81% Moss et al. N Engl J Med 2002;346(12):877-83.

  9. MADIT II: Performance We don't yet have details on how often the ICDs actually fired in the patients. VENTAK PRIZM 2 ICDSource: Guidant

  10. MADIT II: Mortality by event • ICD (n=742) • Medical therapy (n=490) • Cause of death • Noncardiac • 26 • 20 • Cardiac • 74 • 67 • Arrhythmic • 27 (3.6%) • 46 (9.4%) • Nonarrhythmic • 41 • 18 Moss et al. N Engl J Med 2002;346(12):877-83.

  11. MADIT II: Fuster's hypothesis • "I bet that what is happening is the group that otherwise might have been induced into ventricular tachycardia is the group that has benefit." • Fuster VENTAK PRIZM 2 ICDSource: Guidant

  12. MADIT-II: MUSTT • EF < 40% • CAD • spontaneous nonsustained ventricular tachycardia (VT-NS) Entry Criteria Buxton et al. N Engl J Med 1999;341(25):1882-90.

  13. MADIT II: The patient • Patient with low EF, previous MI, and the patient asked for a defibrillator ICDs cost $25-35,000 • Found a normal result on signal-averaging, so I sent him home • Fuster VENTAK PRIZM 2 ICDSource: Guidant

  14. MADIT II: Risk stratification • "The idea of risk stratification to try and identify those who benefit most has become absolute dogma in clinical practice in acute coronary syndromes." • Cannon • Inducibility makes sense as a good marker of the risk of arrhythmic death • How recent is the MI? • Arrhythmic burden might be useful

  15. MADIT II: True costs • We will eventually have to have risk stratification • What is cost/quality of year of life saved? • We need data extending out for 2-3 years Weber

  16. MADIT II: Science takes its course • "The truth is that whenever we do anything that prolongs life we are going to be rewarded by horrifying increases in cost. And if we save them completely from heart disease they are going to get cancer." • "In a way it's a futile and frustrating discussion." Weber

  17. MADIT II: Extending the boundaries • What we're doing is defining the boundaries of where ICDs work and don't work • "What MADIT II has done is take the stake and move it a little farther out in terms of post-MI patients with low ejection fraction." • Ferguson

  18. MADIT II: Drilling into the data • We will find a population that benefits and a population that does not • Inducible VT is a completely reasonable hypothesis for defining the benefit population • Putting ICDs in everyone who qualifies for MADIT is "potentially backbreaking" • Ferguson

  19. MADIT II: Signal-averaging • Used signal-averaging because it was a strong predictor of high-risk in MUSTT • At this point in time, don't put an ICD in patients who qualify for MADIT II who have normal signal-averaging • "We have to face these patients today." • Fuster

  20. MADIT II: QRS interval • Hazard ratio • QRS interval • < 0.12 sec • 0.12-0.15 sec • >0.15 sec 0.2 0.4 0.6 0.8 1.2 1.0 Conventional therapy better Defibrillator better Moss et al. N Engl J Med 2002;346(12):877-83.

  21. MADIT II: Assessing patients • We don't have enough information to predict who will benefit most • "Seat of the pants indicators" such as QRS intervals or the number of extra systoles should be helpful for now VENTAK PRIZM 2 ICDSource: Guidant Weber

  22. MADIT II: Fundamental approach • "The fundamental approach that one takes with these patients is 'are they guilty until proven innocent' or are they 'innocent until proven guilty'?" • "Am I going to put a defibrillator in this guy unless there is a reason not to or do I require a reason to put a defibrillator in this individual?" • Ferguson

  23. MADIT II: Reasons to put an ICD in • "I still need a reason to put a defibrillator in an individual." • Signal-averaged ECG • Frequency of VPDs • Heart-rate variability is a possibility • Probably would not take someone to provocative EP testing Ferguson

  24. MADIT II: Cost • MADIT II entry criteria would lead to an additional 300,000 patients for ICDs, a $9 billion market • ICDs cost $25-35,000 • "When you have something good, industry competes and costs go down." • Fuster VENTAK PRIZM 2 ICDSource: Guidant

  25. MADIT II: Cheaper ICDs • As demand grows, costs should drop • These ICDs are the "BMW 7-series" versions, with all the hi-tech bells and whistles • Cheaper, simpler ICDs could be used in patients with uncomplicated arrhythmic history • Cannon

  26. MADIT II: Lay press concerns • Extending Life, Defibrillators Can Prolong Death Could we unintentionally torture patients with ICDs? Rare, but not impossible

  27. Atrial fibrillation : Quality of Life • While making guidelines, everyone said that AFFIRM and RACE would give all the answers • "I was disappointed" • The issue is quality of life, not mortality, but that wasn't studied

  28. Atrial fibrillation : AFFIRM design • Atrial Fibrillation Follow-up Investigation of Rhythm Management • Conducted at 213 centers in the US and Canada • Randomized 4060 patients to rate control therapy or to rhythm control therapy All patients enrolled in the trial were able to tolerate either rate or rhythm control therapy at baseline

  29. Atrial Fibrillation: AFFIRM results • Rate control • Rhythm Control • Endpoint • P value • 0.058 • Mortality • 306 • 356 • 79 • Stroke • 84 • NS Wyse DG, ACC 2002

  30. Atrial Fibrillation: RACE design • RAte Control vs Electrical cardioversion for persistent atrial fibrillation (RACE) • 522 patients randomized to medical rate control (n=256) or electrical cardioversion rhythm control (n=266) • 3 years follow-up • Primary endpoints: morbidity and mortality • Secondary endpoints: quality of life and cost of therapy

  31. Atrial Fibrillation: RACE results • Rate control (n=256) • Rhythm Control (n=266) • Endpoint • Combined mortality and morbidity* • 17.2% • 22.6% • 7.0% • 6.7% • Cardiovascular mortality *cardiovascular death, hospitalization for heart failure, thromboembolic complications, severe bleeding, pacemaker implantation, or severe drug side effects

  32. Atrial fibrillation : No answers • My original question wasn't answered • Patients with systolic or diastolic dysfunction who don't have atrial kick weren't included in the study • Fuster

  33. Atrial fibrillation : Disappointing • "I'm not an electrophysiologist, so I've been waiting for guidelines to tell me what to do for some time." • "It's a little disappointing that […] those people who might have benefited probably didn't even get into the study." Weber

  34. Atrial fibrillation : AFFIRM drugs • Rhythm control • amiodarone (39%) • sotalol (33%) • propafenone (10%) • Ablation and pacemakers were given in the rhythm arm, if necessary

  35. Atrial fibrillation : AFFIRM drugs • Rate control • digoxin (51%) • beta-blockers (49%) • calcium-channel blockers (41%) • There was no specific drug regimen

  36. Atrial fibrillation : Drug safety • "At least the drugs that maintained normal sinus rhythm didn't kill the patients." • Maybe amiodarone is protective • Fuster • It could be that the fact these were patients with atrial fibrillation played a role • Ferguson

  37. Atrial Fibrillation: Low mortality • Patients who need atrial kick are the toughest atrial fibrillation patients to work with • The good news is mortality favored rate control slightly – this looks pretty safe Cannon

  38. Atrial Fibrillation: Warfarin • "I came away with the notion that A-Fib and coumadin are very good partners." • Most strokes in AFFIRM occurred in patients who either stopped warfarin or had an INR below 2.0 • The idea you should convert A-Fib patients so they can get off anti-coagulation doesn't hold up Cannon

  39. Atrial fibrillation : Anticoagulation • "The concept that you convert to normal sinus rhythm and therefore off of anticoagulants is really a dream." • I do Holter monitoring 3 months later because most patients you can see there are still a few beats of atrial fibrillation Fuster

  40. Atrial Fibrillation: Anticoagulation • Atrial fibrillation developing after cardiac surgery often reverses itself • You should still follow up patients with a Holter to document that the patient has stable sinus rhythm Cannon

  41. Atrial Fibrillation: Guidelines • The guidelines urge great caution about discontinuing anticoagulants • You should continue anticoagulation unless something convinces you otherwise • ACC/AHA/ESC GUIDELINES FOR THE MANAGEMENT OF PATIENTS WITH ATRIAL FIBRILLATIONJ Am Coll Cardiol 2001;38:1266i-1xx Fuster

  42. Atrial fibrillation: Anticoagulation • "The big winner in this seemed to be coumadin. Because if you want to use rhythm control because you think you are reducing the need for anticoagulation you're probably making a mistake." Ferguson

  43. Coated stents: FIM

  44. Coated stents: RAVEL

  45. Coated stents: Stopping cell growth • "[Ending restenosis] is an idea people have been looking for, and stopping cell growth locally looks like a real winner." Cannon

  46. Coated stents: Stopping cell growth • "It's probably a victory for vascular biologists everywhere to say the shotgun approach or crude approaches we've used in the past have not worked." • Not all coated stents will work, we need to look long at hard at the data • We need to look at the SIRIUS trial Ferguson

  47. Coated stents: Early pathology • Brazil data makes you believe the subsequent pathology is determined at the time of procedure • "I assume most of the value of the coated stent is a local effect that takes place soon after the stent is put in." Weber

  48. Coated stents: New study • >2000 pts Diabetics with multi-vessel disease lesions (15-30 mm long, 2.5-3.5 mm diameter) Randomized to sirolimus stent or CABG • This study has been submitted to NIH and is under consideration

  49. Coated stents: End of CABG? • Finding clinical effect on high-risk patients is the most important study to do • BARI used balloon angioplasty without antiplatelet therapy • Can diabetics with multi-vessel disease be stented or must they use surgery? • It even raises questions about stenting patients with stable angina Cannon

  50. Coated stents: 6-month QCA in diabetics

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