1. Journey of Beta blockers
From hypertension to heart failure

2. Beta Blockers – Historical Background
Year
Scientist
Research
1948
Ahlquist
Introduced the concept of alpha & beta receptors
Lands
Subdivided beta receptors into beta1 and beta2 subtypes
1958
Powell and Slater
Described anti-adrenergic properties of a new compound, Dichloroisoproterenol
1962
Sir James W. Black
Developed Propranolol
Earned the Nobel prize for Medicine in 1989
1964
First clinical studies of the treatment of angina, arterial rhythm and hypertension disorders

3. Beta Blockers – Historical Background
Remarks by the Nobel Committee in 1988 about the research of Sir James W. Black “the greatest breakthrough when it comes to pharmaceuticals against heart illness since the discovery of digitalis 200 years ago”.
Radford et.al. NEJM, 1998, Vol. 339:

4. Beta Blockers Drugs Nonselective beta1 & beta2 adrenergic antagonists
Propranolol
Sotalol
Selective beta1 adrenergic antagonists
Atenolol
Bisoprolol
Celoprolol
Nebivolol
Metoprolol
Alpha1 & beta1 adrenergic antagonists
Carvediol
Labetolol

5. Beta Blockers Lipid solubility Peripheral vasodilation
Average daily dosage
Propranolol
High
40-80 mg
Sotalol
Low mg
Atenolol mg
Bisoprolol
Moderate mg
Celoprolol + mg
Nebivolol
2.5-5 mg
Metoprolol mg
Carvediol mg
Labetolol mg

6. Beta blockers Indications Hypertension Angina pectoris
Post-myocardial infarction
Tachyarrhythmias
Congestive heart failure

7. Beta blockers in hypertension
Atenolol has been most extensively studied in patients with essential hypertension
Reductions in blood pressure in patients with mild to severe hypertension have been associated with reduced mortality from both stroke and myocardial ischaemia.
Sethi KK et al, Cardiology Today, 2002
Recommended as first line treatment in Hypertension by
European Society of Hypertension Guidelines
British Hypertensive Society Guidelines

9. Beta-blockers in Hypertension
Established long term mortality and morbidity benefits
Beta blockers significantly reduce:
 Sudden cardiac death
 Overall coronary events
 Incidence of stroke

10. Beta Blockers The Cornerstone Of IHD Therapy
Beta blockade is a standard therapy for effort angina, mixed effort and rest angina and unstable angina.
Beta blockers decrease mortality in acute MI and in post MI period.
Beta blockers retain their position among basic therapies of numerous other conditions including hypertension, arrhythmia and cardiomyopathy.
Opie.L.H., Drugs for Heart, 2001

11. Beta Blockers In acute coronary syndromes
A summary analysis of randomized trials with threatened or evolving MI showed lower rates of progression to MI with beta-blocker treatment.
pdfs/COMMITBetaBlockerFACTSheet.pdf

12. Beta blockers in post MI
In post MI patients, beta blockers limit infarct size, reduce angina episodes, reinfarction, suppress tachyarrhythmias and sudden cardiac death and improve survival
Roy CP et al, Cardiology Today, 2002
Life saving potentials of the drugs in IHD are:
-blockers : 33%
Statins : 30%
Aspirin : 23%
Cardiac Drug Therapy, M. Gabriel Khan, Saunder; 1999

13. Beta blockers in MI
Reduce mortality during both acute and long-term management of myocardial infarction.
Howard et al., American Family Physician, 2000
Benefit occurred regardless of the patient's age or sex, infarct location and initial heart rate, or the presence or absence of ventricular arrhythmias.
Lamb RK et al, Eur Heart J Jan;9(1):32-6
Studies indicate that the most marked reduction in mortality (25 percent) occurs in the first two days after infarction.
Yusuf S. et al., JAMA Oct 14;260(14):

14. Beta blockers in MI As per ACC/AHA guidelines:
- Recommends beta blocker therapy early during an ongoing MI
- Treatment is recommended in all patients so long as contraindications does not exist, irrespective of whether the patient receives concomitant thrombolytic therapy or primary angioplasty

15. “Beta blockers continue to surprise us”
Cruikshank, Eur. Heart J., 2000

16. Use of beta-blockers in hypertensive diabetic
CLINICAL EVIDENCE

17. UKPDS THE UK PROSPECTIVE DIABETES STUDY
LANDMARK STUDY
Multi-center randomized controlled trial of different therapies of type II diabetes
Clinical centers: 23
Type II diabetic patients: 5102
Person years follow up:

18. UKPDS BLOOD PRESSURE CONTROL STUDY
To determine whether
Tight blood pressure control policy can reduce the morbidity and mortality in type II diabetes patients
ACE inhibitor(Captopril) or beta blocker (Atenolol) is advantageous in reducing the risk of development of clinical complications.

23. Clinical end point
Absolute risk (events per 1000 patient years)
Captopril
Absolute risk (events per 1000
patient years)
Atenolol
p value
Any diabetes related end-point
53.3
48·4
0·43
Deaths related to diabetes
15.2
12·0
0·28
All-cause mortality
23·8
20·8
0·44
Myocardial infarction
20·2
16·9
0·35
Stroke
6·8
6·1
0·74
Peripheral vascular disease
1·6
1·1
0·59
Microvascular disease
13·5
10·4
0·30

24. UKPDS BLOOD PRESSURE CONTROL STUDY
Conclusion
ACE inhibitors and beta blockers were equally effective in lowering mean blood pressure in hypertensive patients with type II diabetes and in reducing the risk of
any diabetes related endpoints
diabetes related deaths
microvascular end-points

25. Use of beta-blockers in heart failure

26. Use of beta-blockers in heart failure
A Bayesian Meta-Analysis
22 trials
patients
James M. Brophy et al, Ann Intern Med. 2001;134:

27. Study
Year
Drug
Duration
NYHA class
Anderson et al
1985
Metoprolol 19
II–IV
Engelmeier et al. 12
Pollock et al.
1990
Bucindolol 3
Woodley et al.
1991
II–III
Paolisso et al.
1992
I–IV
Waagstein et al.
1993 18
Wisenbaugh et al.
Nebivelol

28. Study
Year
Drug
Duration
NYHA class
Fisher et al
1994
Metoprolol 6
II–IV
Bristow et al.
Bucindolol 3
I–IV
CIBIS-I 23
III–IV
Eichhorn et al.
II–III
Metra et al.
Carvediol
Olsen et al.
1995 4
Krum et al.

29. Study
Year
Drug
Duration
NYHA class
Bristow et al
1996
Carvediol 6
II–IV
Packer et al.
Colucci et al. 15
II–III
Cohn et al.
1997 8
Aust/Nz 19
CIBIS-II
1999
Bisoprolol
III–IV
MERIT-HF
Metoprolol 12
RESOLVED
2000

30. Significantly less no. of deaths
Placebo
Beta-blocker therapy
Deaths
624/ 4862
444 /5273
% of deaths 12 8
4 lives saved per 100 patients
James M. Brophy et al, Ann Intern Med. 2001;134:

31. Significantly less hospitalization
Placebo
Beta-blocker therapy
Patients requiring hospitalization
754/ 4862
540 /5273
% Patients requiring hospitalization 15 11
4 fewer hospitazations per 100 patients
James M. Brophy et al, Ann Intern Med. 2001;134:

32. The probability that beta-blocker therapy reduced total mortality and hospitalizations for congestive heart failure was almost 100%.
Beta-Blocker therapy is associated with clinically meaningful reductions in mortality and morbidity in patients with stable congestive heart failure and should be routinely offered to all patients similar to those included in trials.
James M. Brophy et al, Ann Intern Med. 2001;134:

33. Tolerability of Beta Blockers
In a meta-analysis of 90 comparative studies of angina, beta blockers were found to be associated with a lower incidence of adverse effects than calcium antagonists.
(Heidenreich et al, JAMA May 26;281(20):
1-selective blockers such as atenolol appear to be better tolerated than nonselective agents
(Dahlof et al, Circulation, 1991)

34. Tolerability of Beta Blockers
1-selective blockers are generally equivalent to the ACE inhibitors and calcium antagonists in terms of impact on quality of life.
(Landray MJ et al, J Clin Pharm Ther Aug;27(4): Review)

35. In patients with reactive airway disease
Meta-analysis of 19 clinical studies
Cardioselective beta-blockers do not produce clinically significant adverse respiratory effects in patients with mild to moderate reactive airway disease. The results were similar for patients with concomitant chronic airways obstruction.
Given their demonstrated benefit in such conditions as heart failure, cardiac arrhythmias, and hypertension, cardioselective beta-blockers should not be withheld from patients with mild to moderate reactive airway disease.
Salpeter SR et al, Ann Intern Med Nov 5;137(9):715-25

36. METOPROLOL
AT A GLANCE

37. METOPROLOL
Metoprolol, a relatively selective beta1-blocker, is devoid of intrinsic sympathomimetic activity and possesses weak membrane stabilising activity.
Prakash A et al, Drugs Sep;60(3):647-78

38. METOPROLOL Well established in cardiovascular medicine
Particularly useful in the management of hypertension and ischaemic heart disease.
Plosker GL et al, Drugs Mar;43(3):

39. METOPROLOL
In hypertension, post-myocardial infarction and idiopathic dilated cardiomyopathy
Beneficial effects on morbidity and mortality, or closely-related end-points.
Improves quality of life
Peters DH SR et al, Pharmacoeconomics Oct;6(4):

40. METOPROLOL Controlled release metoprolol
Release the drug at a relatively constant rate over a 24-hour period
Producing sustained and consistent metoprolol plasma concentrations and beta 1-blockade while retaining the convenience of once daily administration.
Plosker GL et al, Drugs Mar;43(3):

41. METOPROLOL Controlled release metoprolol
Similar or lesser degree of adverse effects related to the central nervous system compared with atenolol or long acting propranolol.
Less pronounced beta 2-mediated bronchoconstrictor effects than atenolol in asthmatics, and less general fatigue and leg fatigue in healthy subjects.
These results are presumably due to the beta 1-selectivity of metoprolol in addition to the the avoidance of high peak plasma concentrations.
Plosker GL et al, Drugs Mar;43(3):

42. METOPROLOL IN HEART FAILURE
Trials in mild to moderate (NYHA functional class II to III) chronic heart failure
MERIT-HF
Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure trial
RESOLVD
Randomized Evaluation of Strategies for Left Ventricular Dysfunction pilot study.
Prakash A et al, Drugs Sep;60(3):647-78

43. METOPROLOL IN HEART FAILURE
MERIT-HF
Treatment with metoprolol CR/XL was initiated at a low dosage of 12.5 to 25 mg once daily and gradually increased at 2-weekly intervals until the target dosage (200 mg once daily) or maximal tolerated dosage had been attained in patients receiving standard therapy for heart failure.
Prakash A et al, Drugs Sep;60(3):647-78

44. METOPROLOL IN HEART FAILURE
MERIT-HF
At 12 months, metoprolol CR/XL was associated with a 34% reduction in relative risk of all-cause mortality in patients with chronic heart failure due to ischaemic or dilated cardiomyopathy in the MERIT-HF trial.
The incidence of sudden death and death due to progressive heart failure were both significantly decreased with metoprolol CR/XL.
Prakash A et al, Drugs Sep;60(3):647-78

45. METOPROLOL IN HEART FAILURE
MERIT-HF
The drug is well tolerated when treatment is initiated in low dosages and gradually increased at intervals of 1 to 2 weeks.
Conclusions of the study was Metoprolol CR/XL effectively decreases mortality and improves clinical status in patients with stable mild to moderate (NYHA functional class II or III) chronic heart failure due to left ventricular systolic dysfunction, and the drug is effective in patients with ischaemic or dilated cardiomyopathy.
Prakash A et al, Drugs Sep;60(3):647-78

46. THANK YOU