Beta Blockers Treatment For Cardiovascular Disease Where Do They Fit ?

1. Beta Blockers Treatment For Cardiovascular Disease Where Do They Fit? Joseph Brent Muhlestein, MD, FACC Co-Director of Cardiology Research, Intermountain Medical Center, Professor of Medicine, University of Utah Nothing to Disclose

2. Cardiovascular Disease is the major killer of the Western World Recently, significant successes have been made in developing effective primary and secondary preventative therapies Surgery Medicines Life style changes Some of these therapies have actually been shown to save lives Introduction

3. Schematic Timecourseof Human Atherogenesis • Ischemic Heart Disease • Cerebrovascular Disease • Peripheral Vascular Disease Time (years) No Symptoms ± Symptoms Symptoms

4. Pathogenesis of ACS White HD. Am J Cardiol. 1997; 80(4A):2B-10B.

5. The matrix skeleton of an unstablecoronary artery plaque fissures in the fibrous cap

6. Plaque rupture with thrombosis Fibrous cap Thrombus Lipid core FJ Schoen, BWH 1 mm

7. fatal thrombus Plaque rupture site collagenous fibrous cap thrombogenic lipid core

8. Characteristics of Unstable and Stable Plaques Lack ofInflammatory Cells Inflammatory Cells ThickFibrous Cap Thin Fibrous Cap FewSMCs MoreSMCs IntactEndothelium ErodedEndothelium ActivatedMacrophages MMP Foam Cells Unstable Stable Libby et al. Circulation 1995; 91:2844-50

9. Beta Blockers: Where do they fit?

10. Epinephrine / Norepinephrine Hypertension Hypercoagulability Vasoreacivity Fibrosis Upregulated in many situations Emotional excitement Heart Failure General anesthesia Physiology of the Sympathetic Nervous System

11. Post MI CAD Heart Failure Hypertension Non-cardiac surgery Rate Control Atrial fibrillation Inappropriate sinus tachycardia Arrhythmias Beta Blockers: Indications

12. Beta Blockers Post-MI • Rationale • Antiplatelet effect • Antiarrhthmic effect • General blood pressure effect

13. Norwegian multicenter study group (1981) 17 month follow-up Patients presenting with Q-wave MI Timolol versus placebo 44.6% reduction in sudden death 39.3% reduction in total death Beta-blocker heart attack trial (1982) 3 years follow-up Patients presenting with Q-wave MI Propranolol versus placebo 26% reduction in total mortality Evidence of Beta Blockers post MI

14. Metoprolol study (1981) 90 day follow-up metoprolol versus placebo 36% reduction in over-all mortality BBPP (1986, 9 trials pooled) 13,679 patients, a variety of beta blocker drugs 1 year follow-up 24% reduction in death ISIS I (1986) 16,027 patients, atenolol versus placebo 20 months follow-up 15% reduction in death Beta Blockers post MI (cont.)

15. Effect on sudden death of beta blockade following MI. Pooled data from 5 trials

16. HCFA cooperative cardiovascular project 201,752 patients post-MI abstracted Mortality determined at 2 years post MI 34% of all patients received beta blockers Effect of Beta-Blackade on Mortality among High-Risk and Low-risk Patients after MI

17. HCFA cooperative cardiovascular project: Results NEJM, 1998;339:489-97

18. HCFA cooperative cardiovascular project: Results NEJM, 1998;339:489-97

19. LDS Hospital Data 975 Patients with Angiographically Documented CAD Followed for >3 years (P=0.19)

20. Beta Blockers in Heart Failure

21. Vicious Cycle of Heart Failure

22. 1985, LDS Hospital, Jeffrey Anderson, et al 50 patients with IDC (EF<30%) Randomized to metoprolol (12.5-50 mg bid) versus placebo Followed for 18 months Results Low dose beta blockade tolerated by 80% of patients Death: metoprolol = 3, placebo = 8 Significant improvement in functional class The Beginning of the Beta Blocker Story

23. 383 patients with IDC (LVEF<40%) 90% were NYHA class II-III Randomized to metoprolol or Placebo (target doses: 50-75 mg po bid) Follow-up: One year Primary endpoint: Death or need for transplant Secondary endpoint: EF Metoprolol in Idiopathic Dilated Cardiomyopathy (MDC) Study Lancet, 1993, 342(8885):1441-1446

24. Death or Transplant

25. Change In Ejection Fraction

26. Change in Functional Status

27. Study Results

28. To determine whether metoprolol XL reduces: Total mortality The combined end point of all-cause mortality and all-cause hospitalizationin patients with HF (NYHA Class II–IV) Primary Objectives

29. Age 40–80 years NYHA Class II–IV Standard treatment for HF for at least 2 weeksbefore randomization EF  35%, or 36% to 40% with a 6-minute walk test 450 meters Resting heart rate  68 bpm Supine systolic BP  100 mm Hg Inclusion Criteria

30. Study Design Titrated from12.5 mg/25 mgto 200 mgonce daily* MetoprololXL n=1990 PlaceboRun-in Placebo n=2001 2 0 2 4 6 8 12 6 9 12 15 18 21 Months Weeks Single-blind Double-blind *The recommended starting dose was 12.5 mg of blind medicine in patients with NYHA Class III–IV heart failure and 25 mg in Class II heart failure.

31. Mean Dose at Study Closure 179 mg 2 0 0 159 mg 1 6 0 1 2 0 Mean dose (mg) 8 0 4 0 0 Placebo Metoprolol XL

36. Combination Beta and Alpha Antagonists Carvedilol

37. Mortality in US Carvedilol Heart Failure Program Survival Patients (%) 1.0 3.8† 4 P=.001 3.3 0.9 3 †P<.05 0.8 Placebo (n=398) 2 1.7 0.7 Carvedilol (n=696) Risk reduction=65% P<.001 1 0.6 0.7 0 0 200 300 400 100 0 Sudden cardiac death Progressive HF Days Adapted from Packer et al, NEJM, 1996.

38. Can the sickest (class IV) CHF patients be safely and effectively treated with carvedilol? Can carvedilol therapy be initiated during the hospitalization for CHF? COPERNICUS: Major questions

39. 2289 patients enrolled Incusion criteria Ischemic or non-ischemic cardiomyopathy Severe (Class III-IV) CHF LVEF <25% Exclusion Allergic to carvedilol Already on beta blocker therapy Fluid over-load On IV inotropes COPERNICUS: Study design

40. Hospitalised at time of randomisation Hospitalised 3 times or more for CHF within last year LV ejection fraction < 15% Fluid retention (ascites, rales or oedema) Required IV positive inotropic agent or vasodilator within last 2 weeks COPERNICUS: High-Risk Subgroup Packer M et al. N Engl J Med 2001

41. Patients stabilized with diuretics and ACE inhibitor therapy Patients may be given digoxin and amiodarone but not required Patients slowly titrated with carvedilol therapy as tolerated Start with 3.125 mg po bid Initial titration often performed while in the hospital Up-titrate dose about every two weeks Patients followed for 2 years COPERNICUS: Study course

42. COPERNICUS: All-Cause Mortality 100 90 80 Carvedilol % Survival 70 Placebo 60 P = 0.00013 0 0 3 6 9 12 15 18 21 Months

43. COPERNICUS: Effect During First 8 Weeks Death, Hospitalization and Permanent Withdrawal 20 15 Placebo 10 % Patients with event Carvedilol 5 0 0 2 4 6 8 Weeks After Randomization Krum H et al. JACC 2002

44. COPERNICUS: Effect During First 8 Weeks Death, Hospitalization and Withdrawal in Highest Risk Patients 30 Placebo 20 % Patients with event Carvedilol 10 0 0 2 4 6 8 Weeks After Randomization

45. Lack of appreciation for disease process My patient has terminal disease. There is nothing I can do to help him / her Misunderstanding about efficacy I can accomplish what I need to do with other CHF drugs without having to use a b-blocker Excessive concern about safety My patient is too unstable for a b-blocker. It would be best to delay treatment for a while until he / she is more stable Reasons Given for Not Using b-Blockersin Patients With Severe Heart Failure:All proven wrong by COPERNICUS

46. This study demonstrates that, even in the most sick CHF patients, carvedilol therapy results in significant clinical benefit. Also, this life-saving therapy can be initiated very early after volume stabilization, often-times even during initial hospitalization. COPERNICUS: Conclusions

47. Carvedilol or Metoprolol in Heart Failure: Which is Best?