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

• • • • • •

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

Schematic Timecourse of Human Atherogenesis

• Ischemic Heart Disease • Cerebrovascular Disease • Peripheral Vascular Disease Time (years)

No Symptoms ± Symptoms Symptoms

White HD.

Am J Cardiol.

1997; 80(4A):2B-10B.

Pathogenesis of ACS

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

Plaque rupture with thrombosis

Thrombus Fibrous cap 1 mm FJ Schoen, BWH Lipid core

Plaque rupture site fatal thrombus collagenous fibrous cap thrombogenic lipid core

Characteristics of Unstable and Stable Plaques

Few SMCs Thin Fibrous Cap Inflammatory Cells More SMCs Thick Fibrous Cap Lack of Inflammatory Cells Eroded Endothelium Activated Macrophages Unstable MMP Libby et al. Circulation 1995; 91:2844-50 Intact Endothelium Foam Cells Stable

Beta Blockers: Where do they fit?

• • • • • • • • •

Physiology of the Sympathetic Nervous System

Epinephrine / Norepinephrine Hypertension Hypercoagulability Vasoreacivity Fibrosis Upregulated in many situations Emotional excitement Heart Failure General anesthesia

• • • • • • •

Beta Blockers: Indications

Post MI CAD Heart Failure Hypertension Non-cardiac surgery Rate Control Atrial fibrillation Inappropriate sinus tachycardia Arrhythmias

Beta Blockers Post-MI

• Rationale Antiplatelet effect Antiarrhthmic effect General blood pressure effect

Evidence of Beta Blockers post MI

• • 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

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

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

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

HCFA cooperative cardiovascular project: Results

2 Year Mortality Based on Initial EF 40% 35% 30% 25% 20% 15% 10% 5% 0% >50% 20-49% Beta blocker <20% No beta blocker

NEJM, 1998;339:489-97

HCFA cooperative cardiovascular project: Results

2 Year Mortality Based on Type of MI 14% 12% 10% 8% 6% 4% 2% 0% Q-wave Beta blocker Non Q-wave No beta blocker

NEJM, 1998;339:489-97

LDS Hospital Data 975 Patients with Angiographically Documented CAD Followed for >3 years

14% 12% 10% 8% 6% 4% 2% 0% Mortality by whether post-MI patients (n=242) were placed on a beta blocker

(P=0.19)

12% 6% Beta blocker No beta blocker

Beta Blockers in Heart Failure

Vicious Cycle of Heart Failure

• • • • •

The Beginning of the Beta Blocker Story

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

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: 50-75 mg po bid) Follow-up: One year • Primary endpoint: Death or need for transplant • Secondary endpoint: EF Lancet, 1993, 342(8885):1441-1446

Death or Transplant

Change In Ejection Fraction

Change in Functional Status

Study Results

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 )

• • • • • •

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  Supine systolic BP  68 bpm 100 mm Hg

Study Design

Titrated from 12.5 mg/25 mg to 200 mg once daily* Metoprolol XL n=1990 Placebo Run-in Placebo n=2001 2 Single blind 0 2468 12 Weeks 6 9 12 15 Months Double-blind 18 21 *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.

Mean Dose at Study Closure

179 mg 200 160 120 80 40 0 159 mg Placebo Metoprolol XL

Combination Beta and Alpha Antagonists

Carvedilol

Survival 1.0

0.9

Mortality in US Carvedilol Heart Failure Program

Patients (%) 4 3.3

 3 3.8

† 

P

=.001

†

P

<.05

0.8

0.7

0.6

0 0 Placebo (n=398) Carvedilol Risk reduction=65% (n=696) P<.001

100 200 Days 300 400 2 1 0.7

1.7

0 Progressive HF Sudden cardiac death Adapted from Packer et al, NEJM, 1996.

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?

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

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

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 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: All-Cause Mortality

100 90 80 70 60 P = 0.00013

0 0 3 6 9 12 Months 15 18 21 Carvedilol Placebo

COPERNICUS: Effect During First 8 Weeks

Death, Hospitalization and Permanent Withdrawal 20 15 Placebo 10 5 Carvedilol 0 0 2 4 6 Weeks After Randomization Krum H et al. JACC 2002 8

COPERNICUS: Effect During First 8 Weeks

Death, Hospitalization and Withdrawal in Highest Risk Patients 30 Placebo 20 10 Carvedilol 0 0 2 4 6 Weeks After Randomization 8

•

Reasons Given for Not Using

b

-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 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

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.

Carvedilol or Metoprolol in Heart Failure: Which is Best?

• • • •

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

• • • •

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

10 5 0

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

20 15 Death MI No Beta-blocker Death/MI Beta-blocker

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.

Beta Blockers in Hypertension

Atenolol Versus Placebo Meta-analysis

Atenolol versus other Antihypertensive agents: Meta-analysis

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.

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

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 • NEJM 1996 Peri-operative MI

Peri-operative Beta Blockers

Peri-operative Beta Blockers

Peri-operative Beta Blockers

2007 National Guidelines

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.

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.

• • • • •

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

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.