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Carvedilol in the management of MI and
Heart Failure
Dr.Pankaj JariwalaFellow, ICPS, Paris, France
Consultant Interventional CardiologistKamineni Hospitals, King Koti,
Hyderabad
Preamble
Carvedilol is a B1, B2 and α1 blocking agent while metoprolol has only B1 blocking action
Carvedilol is also known to have anti-oxidant and anti-proliferative action which are not seen in other B blockers
Here we discuss clinical benefits of carvedilol Vs metoprolol (also Vs other B blockers) in patients with
myocardial infarction (MI) and congestive heart failure (CHF)
Carvedilol Vs Metoprolol in Acute MI
A study enrolled 313 patients with anterior AMI and LVEF < 45%,
randomised to carvedilol or metoprolol.
Patients were followed-up for mean of 13.4
months.
End point: • time to composite adverse
events (t-CAE). • time to composite hard
events (t-CHE) and • health-related quality of
life.Am Heart J
2007;154:116-22
Carvedilol Vs Metoprolol in Acute MI
Event Free time
Am Heart J 2007;154:116-22
Carvedilol Vs Metoprolol in Acute MIQuality of Life
Compared to metoprolol, Carvedilol improved death free time and
quality of life
Am Heart J 2007;154:116-22
Carvedilol Vs other B blockers in MI patients
treated with DES: COREA–AMI registry
The registry included 4748
acute MI patients
undergoing PCI with DES
in South Korea
2921 patients received
carvedilol, 664 patients
received other B blockers
Primary End Point: All
cause deathFollow up: 3
years
COREA–AMI registry : Baseline characters
COREA–AMI registry : CV outcomes
All cause death and CV death were 42% and 77% more in non-
carvedilol B blockers compared to carvedilol
COREA–AMI registry : KM Curve for mortality
Carvedilol Vs Other B blockers in acute MI: A meta-analysis
A systematic review and meta-analysis of
randomized, controlled, trials on atenolol, bisoprolol,
metoprolol, nebivolol, carvedilol to evaluate effects of carvedilol Vs other BBs on
mortality, CV events, and hospital readmissions in
Acute MI.
3 randomized trials were included
Am J Cardiol 2013;111:765e769
Carvedilol Vs Other B blockers in acute MI: A meta-analysis
Forest plot of relative risk for all-cause mortality in patients with AMIs.
In AMI patients, carvedilol patients has 45% lower mortality compared to other
B blockersAm J Cardiol 2013;111:765e769
GEMINI: Carvedilol Vs Metoprolol in DM + HT
Participants were randomized to receive a 6.25 mg-25 mg carvedilol (n=498) or 50-200 mg metoprolol tartrate (n=737),
each twice daily.Primary End Point: Change in HbA1c
Other parameters: effect on insulin sensitivity, and microalbuminuria (ACR: Albumin to creatinine ratio)
Follow up: 5 months
JAMA. 2004;292:2227-2236
GEMINI - Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives
GEMINI: effect on HbA1c
HbA1c was significantly lower in carvedilol group Vs Metoprolol
group
JAMA. 2004;292:2227-2236
GEMINI: Insulin resistance and proteinuria
HOMA-IR ACR
-16-14-12-10
-8-6-4-2024
-9.1
-14
-2
2.5
Carvedilol Metoprolol
% C
hang
e
Insulin resistance and proteinuria were reduced significantly better in carvedilol Vs Metoprolol
JAMA. 2004;292:2227-2236
GEMINI: Effect on BP
Systolic BP Diastolic BP
-20-18-16-14-12-10-8-6-4-20
-18.1
-9.9
-16.9
-9.5CarvedilolMetoprolol
Chan
ge in
BP
(mm
Hg)Both Carvedilol and metoprolol
were equally effective for BP reduction
JAMA. 2004;292:2227-2236
Carvedilol(target dose 25 mg twice
daily) A multiple adrenergic
inhibitor(n = 1,511)
Metoprolol tartrate(target dose 50 mg twice
daily) A beta-1 blockade agent
(n = 1,518)Endpoints (mean follow-up 58 months):
Primary – 1) All-cause mortality and 2) All-cause mortality or all-cause hospitalization
Secondary – Composite of all cause mortality or cardiovascular hospitalization; Composite of cardiovascular death, non-fatal acute MI, or heart transplantation; Worsening of heart failure; Cardiovascular death; NYHA class
COMET : Carvedilol Vs Metoprolol in CHF
3,029 patients with Class III-IV heart failure
Enrolled at 317 centers in 15 European countries
Lancet 2003; 362: 7–13
COMET Trial: Primary Endpoint Analysis
Series10%
10%
20%
30%
40%
50%
33.9%39.5%
Carvedilol Metopro-lol
All-cause mortality
HR 0.8395% CI 0.74-0.93
p=0.0017
Lancet 2003; 362: 7–13
Carvedilol group had 17% lower all cause mortality than
Metoprolol in CHF
COMET : Carvedilol Vs Metoprolol
↓56%↓16%
J Am Coll Cardiol 2007;49:963–71
OPTIMIZE-HFCarvedilol in hospitalized patients
with heart failure
Subjects: hospitalized with new-onset/worsening HF as primary cause of admission or those who developed significant symptoms of HF during
hospitalization.
2373 (87.2%) patients at discharge were randomized to carvedilol or placebo.
End points: Mortality and rehospitalisation rates at 60- and 90-day
Am Heart J 2007;153:82-9.
OPTIMIZE-HF: Results
53% reduction in death
Am Heart J 2007;153:82-9.
Carvedilol in severe chronic HFCOPERNICUS Trial
Multicentre, double-blind, randomized trial.
Subjects (n=2289) with severe HF (presence of dyspnoea or fatigue at rest or with minimal
exertion, LVEF≤25% despite treatment with ACE-I or ARB.
Mean duration of follow-up: 10.4 months
NEJM 2001;344(22):1651.
COPERNICUS: time to hospitalization/ death for CHF
31% ↓
Circulation 2002;106(17): 2194-99
P < 0.001
COPERNICUS : Patients with recent/recurrent decompensation /very low LVEF (<15%)
↓33% P=0.002
↓33% P=0.002
Circulation 2002;106(17): 2194-99
COPERNICUS: Adverse Events
Circulation 2002;106(17): 2194-99
Carvedilol: CAPRICORN
in LVD after AMISubjects: Patients clinically stable and had experienced a
MI in previous 3-21 days .
Randomized to carvedilol vs placebo
Mean duration of follow-up: 1.3 years.
End Points: Change in • LVEDV (Left Ventricle End Diastolic Volume)• LDESV (Left Ventricle End Systolic Volume)
• LVEF (Left Ventricular Ejection Fraction)
Carvedilol: CAPRICORN Myocardial
remodelingAll differences are statistically significant
Circulation 2001 Oct; 104 (17 Suppl.): 517
Carvedilol: CAPRICORN
in LVD after AMI
All cause mortality
CV mortality
Recurrent nonfatal MI
All cause mortality or nonfatal MI
Lancet 2001;357:1385-90
P=0.031
P=0.024P=0.014
P=0.002↓23%↓23%↓29%
↓41%↓25%
Carvedilol & Enalapril: CARMEN trial
Myocardial remodeling
Carvedilol
CAR+ENA Enalapril-6-4-20246
-4.7-6
6
Change in LVESVI (mL/m2) from baseline
CAR monotherapy, n=161CAR+ENA, n=158ENA monotherapy n=160Duration: 18 months
* **
•*p<0.006 vs. baseline•** p< 0.001 vs. baseline
Remme WJ et al, 2003
Carvedilol vs Metoprolol in CHF: A meta-analysis
Effect on LVEFA meta-analysis was done of all 19 randomized controlled
trials of carvedilol or metoprolol that measured left ventricular ejection fraction before and after treatment in
2184 CHF patients
Mean Follow up: 8.3 ± 0.1 months
Studies comparing both drugs directly as well as those comparing them to placebo were compared
Am Heart J 2001;141:899-907
Carvedilol vs Metoprolol in CHF: A meta-analysis
Am Heart J 2001;141:899-907
Carvedilol improved LVEF better than metoprolol in both direct and indirect comparisons
Carvedilol Vs Other B blockers in CHF: A meta-analysis
A systematic review and meta-analysis of randomized, controlled, trials including patients on atenolol, bisoprolol, metoprolol, nebivolol, or carvedilol to evaluate effects of
carvedilol Vs other BBs on mortality, cardiovascular events, and hospital readmissions in CHF.
8 randomized trials including 4563 patients were included
4 HF trials compared metoprolol Vs carvedilol (n = 3,376).
Am J Cardiol 2013;111:765e769
Carvedilol Vs Other B blockers in CHF: A meta-
analysisCarvedilol reduced all cause mortality by 15% vs other B
blockers in CHF
Am J Cardiol 2013;111:765e769
Carvedilol reduced all cause mortality by 14% vs metoprolol in
CHF
Carvedilol vs Metoprolol in CHF:
A 2015 meta-analysis of 4 prospective studies
Effect on All cause mortality
Carvedilol reduced all cause mortality by 20% compared to
metoprolol in CHF Am J Cardiol 2015, http://dx.doi.org/10.1016/j.amjcard.2015.01.545
Possible mechanisms of CV benefits of carvedilol over metoprolol
Carvedilol blocks B1, B2
and α1 receptors,
while metoprolol
blocks only B1 receptors
In CHF, B1 receptors are downregulated, whereas b2
and a1 receptors are upregulated.
B1 and B2 receptors ratio
is normally 70:30, which
becomes 60:40 in CHF
Selective overexpression of B2 or α1
receptors causes cardiac hypertrophy and CHF in
animal models
Expert Rev. Cardiovasc. Ther. 2012; 10(1):13-25
Possible mechanisms of benefits of carvedilol over
metoprololPresynaptic B2
receptors cause the release of
norepinephrine (NE) which can worsen
CHF.
Carvedilol inhibits presynaptic NE
release by inhibiting B2 receptor. This is
not done by B1-selective blockers.
Carvedilol has more persistent binding and
a higher binding affinity to B receptors
Vs metoprolol succinate
Endothelin-1 and oxidative stress are
involved in NE induced ventricular
hypertrophy, both are inhibited by carvedilol
Expert Rev. Cardiovasc. Ther. 2012; 10(1):13-25
USFDA Approved Indications
Hypertension
Angina Pectoris
CHF (NYHA II-III)
Hypertension
Post-MI LV Dysfunction
Mild to severe CHF (NYHA I-
IV)
Metoprolol Carvedilol
Take Home Message
Carvedilol has broad spectrum sympatholytic effects (Vs Metoprolol)
In Post-MI patients, carvedilol reduce mortality and improve quality of life
Metabolic adverse events (dyslipidemia, dysglycemia) are less common in carvedilol vs
metoprololIn CHF patients, improvement in LVEF and reduction in mortality are better with carvedilol Vs MetoprololThus, carvedilol is a better choice for patients with
MI & CHF