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Beta Blockers Treatment For Cardiovascular Disease Where Do They Fit? Joseph Brent Muhlestein, MD, FACC Co-Director of Cardiology Research, Intermountain.

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Presentation on theme: "Beta Blockers Treatment For Cardiovascular Disease Where Do They Fit? Joseph Brent Muhlestein, MD, FACC Co-Director of Cardiology Research, Intermountain."— Presentation transcript:

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 Introduction 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

3 Time (years) No Symptoms ± Symptoms Symptoms Ischemic Heart Disease Cerebrovascular Disease Peripheral Vascular Disease Schematic Timecourse of Human Atherogenesis

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

5 The matrix skeleton of an unstable coronary artery plaque fissures in the fibrous cap

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

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

8 Characteristics of Unstable and Stable Plaques Thin Fibrous Cap Inflammatory Cells Few SMCs Unstable Eroded Endothelium Activated Macrophages Thick Fibrous Cap Lack of Inflammatory Cells Foam Cells Intact Endothelium More SMCs Stable Libby et al. Circulation 1995; 91: MMP

9 Beta Blockers: Where do they fit?

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

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

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

13 Evidence of Beta Blockers post MI Norwegian multicenter study group (1981) - 17 month follow-up - Patients presenting with Q-wave MI - Timolol versus placebo % reduction in sudden death % 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

14 Beta Blockers post MI (cont.) 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

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

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

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 The Beginning of the Beta Blocker Story 1985, LDS Hospital, Jeffrey Anderson, et al 50 patients with IDC (EF<30%) Randomized to metoprolol ( 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

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

24 Death or Transplant

25 Change In Ejection Fraction

26 Change in Functional Status

27 Study Results

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

29 Inclusion Criteria Age 40–80 years NYHA Class II – IV Standard treatment for HF for at least 2 weeks before 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

30 Study Design *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. Single- blind Double-blind Months n=2001 n=1990 Titrated from 12.5 mg/25 mg to 200 mg once daily* Placebo Metoprolol XL Placebo Run-in Weeks

31 Mean Dose at Study Closure Mean dose (mg) 179 mg 159 mg PlaceboMetoprolol XL





36 Combination Beta and Alpha Antagonists Carvedilol

37 Adapted from Packer et al, NEJM, Placebo (n=398) Carvedilol (n=696) Days Risk reduction=65% P<.001 Survival Progressive HF Sudden cardiac death Patients (%) 3.8 † 3.3   P=.001 † P<.05 Mortality in US Carvedilol Heart Failure Program

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

39 COPERNICUS: Study design 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

40 COPERNICUS: High-Risk Subgroup 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 Packer M et al. N Engl J Med 2001

41 COPERNICUS: Study course 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 mg po bid - Initial titration often performed while in the hospital - Up-titrate dose about every two weeks - Patients followed for 2 years

42 % Survival Months P = Carvedilol Placebo COPERNICUS: All-Cause Mortality

43 COPERNICUS: Effect During First 8 Weeks Krum H et al. JACC 2002 Death, Hospitalization and Permanent Withdrawal Carvedilol % Patients with event Placebo Weeks After Randomization

44 COPERNICUS: Effect During First 8 Weeks Placebo Carvedilol % Patients with event Death, Hospitalization and Withdrawal in Highest Risk Patients Weeks After Randomization

45 Reasons Given for Not Using  -Blockers in Patients With Severe Heart Failure: All proven wrong by COPERNICUS 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  -blocker Excessive concern about safety - My patient is too unstable for a  -blocker. It would be best to delay treatment for a while until he / she is more stable

46 COPERNICUS: Conclusions 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.

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











58 Beta Blockers in CAD Beta blockers are good for post-MI Beta blockers are good for CHF What about run-of-mill CAD? - Beta blockers are good anti-anginal agents But do they save lives? - No randomized trials - Without data, national guidelines recommend it for USA

59 LDS Hospital Study 4,304 patients with angiographically-confirmed coronary artery disease - No history of CHF - No history of MI Data recorded included baseline demographics, socioeconomic status, cardiac risk factors, clinical presentation, therapeutic procedures. Certain cardiac medications including beta-blockers which were prescribed at discharge were recorded Patients were followed for an average of 3±1.9 years for outcomes of all-cause death and myocardial infarction. AHA, 2002

60 Percent Univariate Effect of Beta-Blockade on Death, MI, and Death/MI


62 LDS Hospital Study: Conclusions Prescription of beta-blockers at hospital discharge seems protective against all- cause death for patients with coronary artery disease even if they do not have history of heart failure or myocardial infarction. Prescription of beta-blockers in these patients does not appear protective against future myocardial infarction.

63 Beta Blockers in Hypertension

64 Atenolol Versus Placebo Meta-analysis

65 Atenolol versus other Antihypertensive agents: Meta-analysis

66 Recent Guidelines Changes Regarding Beta Blockers and Hypertension In early versions of JNC, beta-blockers were considered first-line therapy. But in JNC 7, beta-blockers were considered only either as add-on therapy to thiazide-type diuretics, or as initial therapy in patients with compelling other indications. Recent European hypertension guidelines have relegated beta-blockers to fourth-line agents, after diuretics, RAAS blockers, and CCBs in patients with uncomplicated hypertension.

67 Beta Blockers in Non- Cardiac Surgery General anesthesia produces significant sympathetic responses. Peri-operative MI is significant in older patients undergoing non-cardiac surgery Beta blockade may be helpful

68 Peri-operative Beta Blockers in Non-cardiac Surgery Study 200 elderly patients undergoing non- cardiac surgery Randomized to atenolol versus placebo Followed for up to two years Death Peri-operative MI NEJM 1996

69 Peri-operative Beta Blockers



72 2007 National Guidelines













85 Revised Meta-analysis Conclusions: - Guideline bodies should retract their recommendations based on fictitious data without further delay. - The well-conducted trials indicate a statistically significant 27% increase in mortality from the initiation of perioperative β-blockade that guidelines currently recommend.

86 Perioperative Beta Blocker Therapy: Brent’s Opinion If patients are already on beta blocker therapy, leave them on it through the entire perioperative period. If they are not, then probably leave them that way. We hoped beta blockers would help, and indeed they do prevent heart attacks, but unfortunately they also increase the risk of strokes and death.

87 Miscellaneous Other Uses of Beta Blockers for Cardiovascular Patients Rate control for atrial fibrillation Prevention of supraventricular tachycardia Treatment of inappropriate sinus tachycardia Treatment and prevention of non- sustained ventricular tachycardia Treatment of thyroid storm associated hypertension and tachycardia

88 Conclusions Beta blocker therapy continues to be a very important strategy in the management of a wide variety of cardiovascular patients It remains one of a very few agents that has actually been shown to save lives. The major change from the past is that beta blockers are now lower priority for the primary treatment of hypertension.

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