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