Upload
others
View
6
Download
0
Embed Size (px)
Citation preview
9/24/2013
1
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 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
9/24/2013
2
Time (years)
No Symptoms ± Symptoms Symptoms
• Ischemic HeartDisease
• CerebrovascularDisease
• PeripheralVascularDisease
Schematic Timecourseof Human Atherogenesis
Pathogenesis of ACS
White HD. Am J Cardiol. 1997; 80(4A):2B-10B.
9/24/2013
3
The matrix skeleton of an unstablecoronary artery plaque
fissures inthe fibrous cap
Plaque rupture with thrombosis
1 mm FJ Schoen, BWH
ThrombusThrombus Fibrous cap
Lipid coreLipid core
9/24/2013
4
Plaque rupture
site
fatal thrombus
collagenous fibrous cap
thrombogenic lipid core
Characteristics of Unstable and Stable Plaques
Thin Fibrous Cap
Inflammatory Cells
FewSMCs
Unstable
ErodedEndotheliumActivated
Macrophages
ThickFibrous Cap
Lack ofInflammatory Cells
Foam Cells
IntactEndothelium
MoreSMCs
Stable
Libby et al. Circulation 1995; 91:2844-50
MMP
9/24/2013
5
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
9/24/2013
6
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
9/24/2013
7
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
9/24/2013
8
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
9/24/2013
9
HCFA cooperative cardiovascular project: Results
NEJM, 1998;339:489-97
HCFA cooperative cardiovascular project: Results
NEJM, 1998;339:489-97
9/24/2013
10
LDS Hospital Data975 Patients with Angiographically Documented CAD Followed for >3 years
(P=0.19)
Beta Blockers in Heart Failure
9/24/2013
11
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
9/24/2013
12
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: EFLancet, 1993, 342(8885):1441-1446
Death or Transplant
9/24/2013
13
Change In Ejection Fraction
Change in Functional Status
9/24/2013
14
Study ResultsStudy Results
Primary Objectives• 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)
9/24/2013
15
Inclusion Criteria• 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
Study DesignStudy 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 from12.5 mg/25 mg
to 200 mgonce daily*
Placebo
MetoprololXL
211812 159612246802
PlaceboRun-in
Weeks
9/24/2013
16
Mean Dose at Study Closure
0
40
80
120
160
200M
ean
dose
(m
g)179 mg
159 mg
Placebo Metoprolol XL
9/24/2013
17
9/24/2013
18
Combination Beta and Alpha Antagonists
Carvedilol
9/24/2013
19
Adapted from Packer et al, NEJM, 1996.
Placebo (n=398)Carvedilol (n=696)
Days
Risk reduction=65% P<.001
Survival
1.0
0.9
0.8
0.7
0.6
00 100 200 300 400 Progressive
HFSudden cardiac
death
Patients(%)
3.8†
3.3
0.7
1.7
4
3
2
1
0
P=.001
†P<.05
Mortality in US Carvedilol Heart Failure Program
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?
9/24/2013
20
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
9/24/2013
21
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
% S
urvi
val
00
3 6 9 12 15 18 21
Months
100
90
80
60
70
P = 0.00013
Carvedilol
Placebo
COPERNICUS: All-Cause Mortality
9/24/2013
22
COPERNICUS: Effect During First 8 Weeks
Krum H et al. JACC 2002
Death, Hospitalization and Permanent Withdrawal
Carvedilol
00 2 4 6 8
% P
atie
nts
with
eve
nt20
10
5
15Placebo
Weeks After Randomization
COPERNICUS: Effect During First 8 Weeks
Placebo
Carvedilol
30
20
10
00 2 4 6 8
% P
atie
nts
with
eve
nt
Death, Hospitalization and Withdrawal inHighest Risk Patients
Weeks After Randomization
9/24/2013
23
Reasons Given for Not Using -Blockersin 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
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.
9/24/2013
24
Carvedilol or Metoprolol in Heart Failure: Which is Best?
9/24/2013
25
9/24/2013
26
9/24/2013
27
9/24/2013
28
9/24/2013
29
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
9/24/2013
30
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
Per
cent
Univariate Effect of Beta-Blockade on Death, MI, and Death/MI
9/24/2013
31
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.
9/24/2013
32
Beta Blockers in Hypertension
Atenolol Versus Placebo Meta-analysis
9/24/2013
33
Atenolol versus otherAntihypertensive 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.
9/24/2013
34
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
• Peri-operative MINEJM 1996
9/24/2013
35
Peri-operative Beta Blockers
Peri-operative Beta Blockers
9/24/2013
36
Peri-operative Beta Blockers
2007 National Guidelines
9/24/2013
37
9/24/2013
38
9/24/2013
39
9/24/2013
40
9/24/2013
41
9/24/2013
42
9/24/2013
43
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.
9/24/2013
44
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.