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Treatment For Cardiovascular Disease

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Presentation on theme: "Treatment For Cardiovascular Disease"— Presentation transcript:

1 Treatment For Cardiovascular Disease
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 Schematic Timecourse of Human Atherogenesis
• Ischemic Heart Disease • Cerebrovascular Disease • Peripheral Vascular Disease Time (years) No Symptoms ± Symptoms Symptoms

4 Pathogenesis of ACS Pathogenesis of ACS
Exposure of the vascular subendothelium leads to adhesion of circulating platelets at the site of plaque rupture. The material present in the plaque core is highly thrombogenic, leading to platelet activation and subsequent aggregation. Aggregated platelets form a partially occlusive thrombus and facilitate activation of the coagulation pathway and deposition of fibrin, possibly leading to formation of a totally occlusive thrombus, consisting of a platelet core and red blood cells entrapped in the surrounding fibrin mesh. 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
Fibrous cap Thrombus Lipid core FJ Schoen, BWH 1 mm

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

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

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 44.6% reduction in sudden death 39.3% reduction in total death Beta-blocker heart attack trial (1982) 3 years follow-up 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
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) This large-scale study was designed to investigate the effect of metoprolol XL when added to standard therapy in patients with decreased ejection fraction and symptoms of heart failure (New York Heart Association [NYHA] Class II–IV). The primary study end points were total mortality and the combined end point of all-cause mortality and all-cause hospitalization. Randomization began February 14, 1997 and ended April 14, The Independent Safety Committee was to monitor total mortality at approximately 25%, 50%, and 75% of the total number of expected deaths. On September 21, 1998, the Independent Safety Committee undertook the secondary interim analysis of the MERIT-HF data. The Committee found that the previously defined criteria for termination of the study for mortality reduction had been met and exceeded (z = versus 2.98 as defined in the protocol). The study was closed prematurely on October 31, 1998, because of significant benefit in the metoprolol XL arm.

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 Men and women ages 40–80 years were eligible for enrollment. Patients had to have symptomatic heart failure, defined as NYHA Class II–IV, for at least 3 months before randomization and had to be receiving standard therapy at enrollment. Standard therapy was defined as any combination of diuretics and an ACE inhibitor. If an ACE inhibitor was not tolerated, hydralazine/long-acting nitrate, or an angiotensin receptor blocker could be used. Digitalis could also be prescribed. Patients had to have a ventricular ejection fraction of 40% or less within months of recruitment. Patients with ejection fraction between 36% and 40% were eligible only if their maximum walking distance during a 6-minute walk test was 500 yards or less. Patients also had to have a resting heart rate of at least 68 beats per minute (bpm) and a supine systolic blood pressure of at least 100 mm Hg.

30 Titrated from 12.5 mg/25 mg to 200 mg once daily*
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 2 4 6 8 12 6 9 12 15 18 21 Months Weeks This double-blind, placebo-controlled, randomized study, began with a single-blind, 2-week placebo run-in period. It is important to note that MERIT-HF included a placebo run-in period rather than run-in with active drug, the results may more accurately reflect normal clinical practice. The study was approved by local ethical committees. All patients gave written informed consent. Randomization was balanced for investigational site, age, sex, ethnicity, cause of heart failure, previous acute myocardial infarction, time since last myocardial infarction, diabetes mellitus, ejection fraction, and NYHA functional class. Patients were not immediately excluded because of intolerance. With a target enrollment of 1600 patients in each group and an average follow-up of 2.4 years, MERIT-HF would have 80% power to detect a 30% relative-risk reduction in all-cause mortality. The primary statistical analyses included log-rank test for the comparison of the two randomization groups and Cox proportional hazards model for relative risk. Prespecified subgroup analyses were to be performed in any subgroup in which at least 180 total deaths in the two randomization groups had occurred. With 180 deaths there was at least a 70% power to detect a 30% increase in risk. 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
2 179 mg 159 mg 1 6 1 2 Mean dose (mg) 8 4 A substantial number of patients were able to tolerate high doses of metoprolol XL; 87% received 100 mg or more, with 64% reaching the maximum dose of 200 mg once daily. The mean dose of metoprolol XL was 159 mg. In the placebo group, the mean dose achieved was 179 mg, and 82% of patients received the maximum dose. Placebo Metoprolol XL





36 Combination Beta and Alpha Antagonists

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

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

43 COPERNICUS: Effect During First 8 Weeks
Death, Hospitalization and Permanent Withdrawal 20 15 Placebo % Patients with event 10 Carvedilol 5 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 10 Carvedilol 2 4 6 8 Weeks After Randomization

45 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

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 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 Antihypertensive agents:
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

70 Peri-operative Beta Blockers

71 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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