Presentation on theme: "Treatment For Cardiovascular Disease"— Presentation transcript:
1Treatment For Cardiovascular Disease Beta BlockersTreatment For Cardiovascular DiseaseWhere Do They Fit?Joseph Brent Muhlestein, MD, FACCCo-Director of Cardiology Research,Intermountain Medical Center,Professor of Medicine, University of UtahNothing to Disclose
2IntroductionCardiovascular Disease is the major killer of the Western WorldRecently, significant successes have been made in developing effective primary and secondary preventative therapiesSurgeryMedicinesLife style changesSome of these therapies have actually been shown to save lives
3Schematic Timecourse of Human Atherogenesis • Ischemic HeartDisease• CerebrovascularDisease• PeripheralVascularDiseaseTime (years)No Symptoms ± Symptoms Symptoms
4Pathogenesis 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.
5The matrix skeleton of an unstable coronary artery plaque fissures inthe fibrous cap
6Plaque rupture with thrombosis Fibrous capThrombusLipid coreFJ Schoen, BWH1 mm
10Physiology of the Sympathetic Nervous System Epinephrine / NorepinephrineHypertensionHypercoagulabilityVasoreacivityFibrosisUpregulated in many situationsEmotional excitementHeart FailureGeneral anesthesia
13Evidence of Beta Blockers post MI Norwegian multicenter study group (1981)17 month follow-upPatients presenting with Q-wave MITimolol versus placebo44.6% reduction in sudden death39.3% reduction in total deathBeta-blocker heart attack trial (1982)3 years follow-upPropranolol versus placebo26% reduction in total mortality
14Beta Blockers post MI (cont.) Metoprolol study (1981)90 day follow-upmetoprolol versus placebo36% reduction in over-all mortalityBBPP (1986, 9 trials pooled)13,679 patients, a variety of beta blocker drugs1 year follow-up24% reduction in deathISIS I (1986)16,027 patients, atenolol versus placebo20 months follow-up15% reduction in death
15Effect on sudden death of beta blockade following MI Effect on sudden death of beta blockade following MI. Pooled data from 5 trials
16Effect of Beta-Blackade on Mortality among High-Risk and Low-risk Patients after MI HCFA cooperative cardiovascular project201,752 patients post-MI abstractedMortality determined at 2 years post MI34% of all patients received beta blockers
22The Beginning of the Beta Blocker Story 1985, LDS Hospital, Jeffrey Anderson, et al50 patients with IDC (EF<30%)Randomized to metoprolol ( mg bid) versus placeboFollowed for 18 monthsResultsLow dose beta blockade tolerated by 80% of patientsDeath: metoprolol = 3, placebo = 8Significant improvement in functional class
23Metoprolol in Idiopathic Dilated Cardiomyopathy (MDC) Study 383 patients with IDC (LVEF<40%)90% were NYHA class II-IIIRandomized to metoprolol or Placebo(target doses: mg po bid)Follow-up: One yearPrimary endpoint: Death or need for transplantSecondary endpoint: EFLancet, 1993, 342(8885):
28Primary Objectives To determine whether metoprolol XL reduces: Total mortalityThe 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.
29Inclusion Criteria Age 40–80 years NYHA Class II–IV Standard treatment for HF for at least 2 weeks before randomizationEF 35%, or 36% to 40% with a 6-minute walk test 450 metersResting heart rate 68 bpmSupine systolic BP 100 mm HgMen 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.
30Titrated from 12.5 mg/25 mg to 200 mg once daily* Study DesignTitrated from 12.5 mg/25 mg to 200 mg once daily*Metoprolol XLn=1990Placebo Run-inPlacebon=200122468126912151821MonthsWeeksThis 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- blindDouble-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.
31Mean Dose at Study Closure 2179 mg159 mg1612Mean dose (mg)84A 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.PlaceboMetoprolol XL
36Combination Beta and Alpha Antagonists Carvedilol
37Mortality in US Carvedilol Heart Failure Program SurvivalPatients(%)1.043.8†P=.0013.30.93†P<.050.8Placebo (n=398)20.71.7Carvedilol (n=696)Risk reduction=65% P<.0010.610.7100200300400ProgressiveHFSudden cardiacdeathDaysAdapted from Packer et al, NEJM, 1996.
38COPERNICUS: 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?
39COPERNICUS: Study design 2289 patients enrolledIncusion criteriaIschemic or non-ischemic cardiomyopathySevere (Class III-IV) CHFLVEF <25%ExclusionAllergic to carvedilolAlready on beta blocker therapyFluid over-loadOn IV inotropes
40COPERNICUS: High-Risk Subgroup Hospitalised at time of randomisationHospitalised 3 times or more for CHF within last yearLV ejection fraction < 15%Fluid retention (ascites, rales or oedema)Required IV positive inotropic agent or vasodilator within last 2 weeksPacker M et al. N Engl J Med 2001
41COPERNICUS: Study course Patients stabilized with diuretics and ACE inhibitor therapyPatients may be given digoxin and amiodarone but not requiredPatients slowly titrated with carvedilol therapy as toleratedStart with mg po bidInitial titration often performed while in the hospitalUp-titrate dose about every two weeksPatients followed for 2 years
43COPERNICUS: Effect During First 8 Weeks Death, Hospitalization and Permanent Withdrawal2015Placebo% Patients with event10Carvedilol52468Weeks After RandomizationKrum H et al. JACC 2002
44COPERNICUS: Effect During First 8 Weeks Death, Hospitalization and Withdrawal inHighest Risk Patients30Placebo20% Patients with event10Carvedilol2468Weeks After Randomization
45Reasons Given for Not Using b-Blockers in Patients With Severe Heart Failure: All proven wrong by COPERNICUSLack of appreciation for disease processMy patient has terminal disease. There is nothing I can do to help him / herMisunderstanding about efficacyI can accomplish what I need to do with other CHF drugs without having to use a b-blockerExcessive concern about safetyMy patient is too unstable for a b-blocker. It would be best to delay treatment for a while until he / she is more stable
46COPERNICUS: 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.
47Carvedilol or Metoprolol in Heart Failure: Which is Best?
58Beta Blockers in CAD Beta blockers are good for post-MI Beta blockers are good for CHFWhat about run-of-mill CAD?Beta blockers are good anti-anginal agentsBut do they save lives?No randomized trialsWithout data, national guidelines recommend it for USA
59LDS Hospital Study4,304 patients with angiographically-confirmed coronary artery diseaseNo history of CHFNo history of MIData 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 recordedPatients were followed for an average of 3±1.9 years for outcomes of all-cause death and myocardial infarction.AHA, 2002
60Univariate Effect of Beta-Blockade on Death, MI, and Death/MI Percent
62LDS 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.
65Antihypertensive agents: Atenolol versus otherAntihypertensive agents:Meta-analysis
66Recent 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.
67Beta Blockers in Non-Cardiac Surgery General anesthesia produces significant sympathetic responses.Peri-operative MI is significant in older patients undergoing non-cardiac surgeryBeta blockade may be helpful
68Peri-operative Beta Blockers in Non-cardiac Surgery Study 200 elderly patients undergoing non-cardiac surgeryRandomized to atenolol versus placeboFollowed for up to two yearsDeathPeri-operative MINEJM 1996
85Revised 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.
86Perioperative 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.
87Miscellaneous Other Uses of Beta Blockers for Cardiovascular Patients Rate control for atrial fibrillationPrevention of supraventricular tachycardiaTreatment of inappropriate sinus tachycardiaTreatment and prevention of non-sustained ventricular tachycardiaTreatment of thyroid storm associated hypertension and tachycardia
88ConclusionsBeta blocker therapy continues to be a very important strategy in the management of a wide variety of cardiovascular patientsIt 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.