I Allah Merciful Beneficial: N The Name of The Most and

In the name of Allah the Most Merciful and Beneficial
Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

Vadil (Carvedilol)
Beta Blockade and Beyond

Heart Failure:
How Big is the Problem Really?
 A leading risk factor for mortality, and is ranked 5th as a cause of
disability-adjusted life-years.
 Heart Failure deaths have increased by 145% in 20years.1
 More than 20 million people have heart failure worldwide, and the
prevalence of heart failure in developed countries is estimated as 2%. 2
 In developed countries, about 6–10% population over 65 years age have

Heart Failure. 2
 Congestive Heart Failure accounts for 50% deaths per year.
 2 million new cases of Congestive Heart Failure diagnosed every year.
Dr. Adnan Ahmed Ansari 1. Journal of Oiterrial Medicine 1995: 237: 135-141 , 2. J Cardiovasc Dis Diagn, Volume 1 • Issue 5 Tabros Pharma (Pvt.) Ltd.
Prevalence of Heart Failure by Age and Sex
16
14.7
14 12.8
12
Percent of Population
10 9.1
8
6 4.9
4
1.9 1.4
2
0.3 0.2
0
20-39 40-59 60-79 80+
Men Women
Dr. Adnan Ahmed Ansari (NHANES: 2003-2006). Source: NCHS and NHLBI. Tabros Pharma (Pvt.) Ltd.
Heart Failure:
How Big is the Problem Really?
 There is an escalating trend of heart failure admissions in our

local population. 4
 Heart Failure has increased from 14.75% to 22.87% in 3 years time

period in Pakistan.4
 It has increased due to un-affordability, or the improper management

of HF patients by quacks in rural areas, accounting for multiple
readmissions with worsening of HF.4
Dr. Adnan Ahmed Ansari 4. Pak J Physiol 2012;8(1) Tabros Pharma (Pvt.) Ltd.
TODAY’S NEED?
An Ideal & FDA Recommended Drug of Choice Should .....
 Effectively control the heart rate.
 Provides cardio protection.
 Lowers the blood pressure
 Safe & well tolerated.
B-Blockers fulfill all the needs making it an ideal choice for CHF
Patients…
2013 ACCF/AHA Heart Failure Guideline
 In patients with MI and reduced EF, evidence-based beta blockers
should be used to prevent HF.
 Long term treatment with beta blockers can lessen the symptoms of
HF.
 Use of 1 of the 3 beta blockers proven to reduce mortality (e.g,

Bisoprolol, Carvedilol, and Metoprolol) is recommended for all patients
with current or prior symptoms of HFrEF, unless contraindicated, to
reduce morbidity and mortality.
 These benefits of beta blockers were seen in patients with or without

CAD and in patients with or without diabetes mellitus.
 Beta blockers can be safely started before discharge even in patients

hospitalized for HF.

Circulation. 2013;128:1810-1852.
Choosing Beta Blocker in
CONGESTIVE HEART FAILURE
Atenolol
Carvedilol
Bisoprolol Metoprolol
Labetolol
Propranolol
Nebivolol

The only Carvedilol in
Pakistan with all
Strength

Properties of -Blockers
b-1 a- Increases Other ancillary
Name Lipophilic
Selective blockade ISA properties
Atenolol Yes No No No No
Bisoprolol Yes No Weak No No
Antioxidant, effects
Carvedilol No Yes Yes No on endothelial
function
Metoprolol Yes No Yes No No
Membrane stabilizing
Propranolol No No Yes No
Effect
Timolol No No Weak No Anti-platelet effects

Carvedilol in Heart Failure
 Effective receptor-blockade approach to heart failure.

 Negative inotropic effect counteracted by vasodilation.
 Provides anti-proliferative, anti-arrhythmic activity and
inhibition of apoptosis.
 Prevents renin secretion.
Dr. Adnan Ahmed Ansari Drugs of Today 1998; 34 (Suppl B): 1-23. Tabros Pharma (Pvt.) Ltd.
Comparison of carvedilol and metoprolol on clinical outcomes in patients with
chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET)
17% Reduction 40%

All Cause Mortality
Duration of Study = 58 M
34%
Carvedilol Metoprolol
n= 1511, Dose 25 mg BD n= 1518, Dose 50 mg BD
Carvedilol used for treatment of chronic heart failure, has a significantly greater beneficial
effect on survival than metoprolol.
Dr. Adnan Ahmed Ansari THE LANCET• Vol 362 • July 5, 2003 Tabros Pharma (Pvt.) Ltd.
The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS)
35% Reduction
18.5%
All Cause Mortality
Duration of Study = 316 Days

11.4%
Carvedilol Placebo
n= 1156 n= 1133
Dr. Adnan Ahmed Ansari Curr Control Trials Cardiovasc Med. 2001; 2(1): 20–23. Tabros Pharma (Pvt.) Ltd.
Effect of Carvedilol on outcome after myocardial infarction in patients with
left-ventricular dysfunction (CAPRICORN)
1.00 Reduced All-Cause Mortality
Carvedilol (n=975)
.90
Proportion Event-Free
.80  23%
Placebo (n=984)
Risk Reduction
.70
.60
0
0 0.5 1 1.5 2 2.5
Years
Dr. Adnan Ahmed Ansari THE LANCET • Vol 357 • May 5, 2001 Tabros Pharma (Pvt.) Ltd.
The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic
Heart Failure (US Carvedilol Study)
1.00 Reduced All Cause Mortality
Carvedilol (n=696)
.90
.80  65%
Survival
Placebo (n=398)
Risk Reduction
.70
.60
0
0 0.5 1 1.5 2 2.5
Years
Dr. Adnan Ahmed Ansari N Engl J Med 1996;334:1349-55 Tabros Pharma (Pvt.) Ltd.
Carvedilol : Superior than all Beta Blockers
Meta-Analysis of Carvedilol Versus Beta 1 Selective Beta-Blockers
(Atenolol, Bisoprolol, Metoprolol, and Nebivolol)
Study Design:
Randomized, controlled, direct comparison trials that included adults receiving
atenolol, bisoprolol, metoprolol, nebivolol, or carvedilol to evaluate the effects of
carvedilol compared to other BBs on mortality, cardiovascular events, and hospital
readmissions in the setting of AMI or systolic HF.
CONCLUSION:
 Carvedilol, as compared against atenolol, bisoprolol, metoprolol
and nebivolol significantly reduced all-cause mortality in systolic HF
patients.
Carvedilol significantly reduced all-cause mortality compared with b1-

selective BBs in AMI patients.
Dr. Adnan Ahmed Ansari Am J Cardiol 2013;111:765-769 Tabros Pharma (Pvt.) Ltd.
Only FDA Approved Beta Blocker for all Stages of
Heart Failure
Class I Class II Class IV

Class III
CAPRICORN COPERNICUS
(carvedilol) US Carvedilol (carvedilol)
(carvedilol)

Congestive Heart Failure
Benefits of Carvedilol in Associated

Co-morbidities
 CAD
 Stroke
 Renal function–worsening HF
 Diabetes
 Arrhythmias

Carvedilol : Beta Blockade and Beyond
Vasodilation:
Hemodynamic effect: • α-1 receptor blockade by Carvedilol decreases peripheral
vascular resistance.2
Potent antioxidant effect more than vitamin E:

Anti-oxidant activity: • Carvedilol is a potent anti-oxidant, 10-fold more than vit E.
• Cavedilol’s metabolites are 30 – 80 times more potent than
Carvedilol and up to 1000-fold more potent than vitamin E.1,3
Anti-proliferative & • Carvedilol in vitro and in vivo has been shown to have anti
Anti-apoptotic activity: proliferative effects on smooth muscle cells.4
•β2-receptor blockade may prevent arrhythmias and,

Anti-arrhythmic effect: consequently, sudden cardiac death.2
• α1-receptor blockade by carvedilol reduces the potential for
arrhythmias.2
1) Am J Cardiol, 1997;82(1A):41L-45L 2) Expert Rev Cardiovasc Ther. 2009;7(5):483-498

2) 3) Expert Opin Drug Metab Toxicol. 2010:6(2):237-250. 4) Am J Hypertens 1998;11:15S–22S
Anti-Adrenergic Activity:
 Not only the 1 receptor, but also the 2 & α1 receptor are linked to
downstream cellular signaling pathways in cardiac remodeling. 1
 Consequently, blocking only the 1 receptor, leaves the heart unprotected to
remodeling signals triggered by stimulation of the other adrenergic receptors. 1
 Non-failing myocardium is dominated by the β1 receptor subtype, whereas
failing myocardium exhibits a mixture of receptor subtypes with β2 and α1
receptor subtype comprising approximately 50% of the total population. 2
 In the failing heart, the β2 receptor represents 35%-40% of the total β receptor
population. 2
 These data would suggest that β1 selective blocker may have inherent
limitations in their ability to inhibit the adverse biological effects of elevated
cardiac adrenergic drive in the failing human heart. 2
Dr. Adnan Ahmed Ansari 1. Cadiovasc Drug Ther, 2010; 24:351-358, 2. Eur Heart J, 1996;17 (Suppl B): 8-16 Tabros Pharma (Pvt.) Ltd.
Anti-Adrenergic Activity:
Sympathetic Activation
Atenolol
Bisoprolol 1 receptors 2 receptors α1 receptors
Metoprolol
Nebivolol
Propranolol
Carvedilol
Anti-remodelling effects – Less progression heart failure
 Blockers 1 blockade 2 blockade α1 blockade Ancillary Effects

Carvedilol +++ +++ +++ +++a
Metoprolol +++
Bisoprolol +++
Nebivolol +++ ++b
Dr. Adnan Ahmed Ansari 1. Cadiovasc Drug Ther, 2010; 24:351-358 a : anti-oxidant, anti-apoptotic, anti-endothelin b : NO generation Tabros Pharma (Pvt.) Ltd.
Metabolic Effect:
Glucose Control Lipid Metabolism
HbA1c Carvedilol TC
Insulin Sensitivity HDL-C , LDL-C
New Onset of DM TG
Beneficial Metabolic Effect
Dr. Adnan Ahmed Ansari 1) Vascular Health and Risk Management 2008:4(1) 23–30 2) JAMA. 2004;292:2227-2236 Tabros Pharma (Pvt.) Ltd.
Metabolic Effect:
Effect on Insulin Sensitivity:
Effect on Insulin Sensitivity in Patients with Hypertension
Carvedilol 13%
Atenolol -22%
Metoprolol -21%
Propranolol -33%
-40% -20% 0% 20% 40%

Change Above or Below Baseline (%)

Am J Hypertens 1998;11:1258–1265
Carvedilol Offers Substantial Benefits in Hypertension
Patients with Type 2 DM Vs Metoprolol
Metabolic Effect:
Mean Change from Baseline at 5 Months.

10.3
6.4
0.15 0.02 Insulin Sensitivity
HbA1c Microalbuminurea
-2
Metoprolol Carvedilol -9.1
Dr. Adnan Ahmed Ansari JAMA 2004; 292: 2227-2236 Tabros Pharma (Pvt.) Ltd.
Carvedilol Offers Substantial Benefits in Hypertension
Patients with Type 2 DM Vs Atenolol
Metabolic Effect:
Mean Change from Baseline at 6 Months.
12 10
8
4
3
-1
-2
-3 -3
-5 Atenolol Carvedilol
-20 -10
TC TG HDL Glucose HbA1c Insulin
Rev Cardiovasc Med, 2004; 5 Suppl 1:S18-S27
Renal Effect:
Effect on Chronic Kidney Disease
Renal Effects in Chronic Kidney Disease (CKD)
Carvedilol Atenolol Propranolol Metoprolol Labetolol

Renal Vascular Resistance
Renal Blood Flow
GFR

Kidney Int, 2006; 70 (11): 1905-1913
Carvedilol Offers Superior Double Digit
Antihypertensive Effect than Atenolol
SBP DBP
-6
-8
-11
-12
Carvedilol Atenolol
Dr. Adnan Ahmed Ansari J Clin Pharmacol, 1990:38, Suppl 2; S143-6 Tabros Pharma (Pvt.) Ltd.
Advantage of VADIL
A Unique β-Blocker
 Carvedilol is the only drug with -blocking activity that provides
comprehensive adrenergic blockade.
 Carvedilol is more beneficial than conventional
-blocking agents in mild-to-moderate heart failure.
 Carvedilol is the only drug with -blocking activity proven to be
effective at lower doses.
 COPERNICUS enrolled the most severely affected heart failure
population of any trial of  blockade.
 Carvedilol significantly reduces mortality in severe heart failure
patients.
Advantage of VADIL
A Unique β-Blocker
 Once-daily dosing.
 No dosage adjustment in patients with impaired renal

function.
 Cab be effectively co-administered with calcium

antagonists and ACE inhibitors.
 Frequency of side effect not higher than placebo.

Differential Advantages
VADIL vs Other β-Blocker
 Consistently high response rates.
 No negative effects on lipid or glucose metabolism.
 Preserve peripheral perfusion - no cold extremities.
 Antioxidant effects-many folds potent than other Beta blocker.
 Can be safely and effectively used in hypertensive patients

with heart failure.
 Only FDA approved Beta-Blocker for heart failure.

VADIL vs α-Blocker
 Consistently high response rate.
 No reflex activation of the sympathetic nerve – no tachycardia.
 Anti-atherosclerotic potential through effectively inhibiting

low density lipoproteins from oxidation.
 Exhibits anti-anginal/anti ischemic effect in patients with

concomitant coronary artery disease.

VADIL vs ACE Inhibitors
 Consistently high response rate.
 Anti-atherosclerotic potential through effective inhibiting low

density lipoproteins from oxidation.
 As good as ACE inhibitors in quality of life assessments,

without irritating cough.
 Can be used without further precaution in patients with

impaired renal function.

Conclusions
Carvedilol is a unique cardioprotective agent, useful

for comorbidities in heart failure patients:
 CAD
 Stroke
 Diabetes
 Atrial fibrillation
 Sudden death

Dosage Titration Vadil (Carvedilol)
Essential 12.5 mg OD 25 mg OD 50 mg (OD or in 2

Hypertension Start With For 2 days For 2 days divided doses) if
required
Chronic Heart 3.125 mg BD 6.25 mg BD

Failure Start With For 2 weeks & Titrate For 2 weeks
12.5 mg BD 25 mg BD Stop here 50 mg BD for

For 2 weeks if patient’s weight patient’s weight
<85 kg >85 kg (max dose)

Only Carvedilol in Pakistan with
all Strengths


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In the name of Allah the Most Merciful and Beneficial

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

Beta Blockade and Beyond

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

 Heart Failure deaths have increased by 145% in 20years.1

 In developed countries, about 6–10% population over 65 years age have

 2 million new cases of Congestive Heart Failure diagnosed every year.

 There is an escalating trend of heart failure admissions in our

 Heart Failure has increased from 14.75% to 22.87% in 3 years time

 It has increased due to un-affordability, or the improper management

 Effectively control the heart rate.

 Provides cardio protection.

 Lowers the blood pressure

 Safe & well tolerated.

 Use of 1 of the 3 beta blockers proven to reduce mortality (e.g,

 These benefits of beta blockers were seen in patients with or without

 Beta blockers can be safely started before discharge even in patients

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

CONGESTIVE HEART FAILURE

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

Bisoprolol Yes No Weak No No

Metoprolol Yes No Yes No No

Timolol No No Weak No Anti-platelet effects

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

 Effective receptor-blockade approach to heart failure.

17% Reduction 40%

Duration of Study = 316 Days

1.00 Reduced All-Cause Mortality

1.00 Reduced All Cause Mortality

Carvedilol significantly reduced all-cause mortality compared with b1-

Class I Class II Class IV

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

Benefits of Carvedilol in Associated

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

Potent antioxidant effect more than vitamin E:

•β2-receptor blockade may prevent arrhythmias and,

1) Am J Cardiol, 1997;82(1A):41L-45L 2) Expert Rev Cardiovasc Ther. 2009;7(5):483-498

Anti-remodelling effects – Less progression heart failure

 Blockers 1 blockade 2 blockade α1 blockade Ancillary Effects

Glucose Control Lipid Metabolism

Insulin Sensitivity HDL-C , LDL-C

Beneficial Metabolic Effect

Effect on Insulin Sensitivity in Patients with Hypertension

-40% -20% 0% 20% 40%

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

Mean Change from Baseline at 5 Months.

0.15 0.02 Insulin Sensitivity

Metoprolol Carvedilol -9.1

Effect on Chronic Kidney Disease

Renal Effects in Chronic Kidney Disease (CKD)

Carvedilol Atenolol Propranolol Metoprolol Labetolol

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.

 No dosage adjustment in patients with impaired renal

 Cab be effectively co-administered with calcium

 Frequency of side effect not higher than placebo.

Dr. Adnan Ahmed Ansari Tabros Pharma (Pvt.) Ltd.