Journey of Beta blockers From hypertension to heart failure

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

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. 339:551-553

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

Beta Blockers Lipid solubility Peripheral vasodilation Average daily dosage Propranolol High 40-80 mg Sotalol Low 160-320 mg Atenolol 25-100 mg Bisoprolol Moderate 2.5-10 mg Celoprolol + 200-600 mg Nebivolol 2.5-5 mg Metoprolol 50-100 mg Carvediol 3.125-50 mg Labetolol 200-800 mg

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

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

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

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

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. www.acc.org/clinical/practice_advisory/ pdfs/COMMITBetaBlockerFACTSheet.pdf

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

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. 1988 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. 1988 Oct 14;260(14):2088-93

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 http://circ.ahajournals.org/cgi/reprint/100/9/1016.pdf

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

Use of beta-blockers in hypertensive diabetic CLINICAL EVIDENCE

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: 53000

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.

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

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

Use of beta-blockers in heart failure

Use of beta-blockers in heart failure A Bayesian Meta-Analysis 22 trials 10 135 patients James M. Brophy et al, Ann Intern Med. 2001;134:550-560.

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

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.

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

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;134:550-560.

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;134:550-560.

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;134:550-560.

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. 1999 May 26;281(20):1927-36. 1-selective blockers such as atenolol appear to be better tolerated than nonselective agents (Dahlof et al, Circulation, 1991)

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. 2002 Aug;27(4):233-42. Review)

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. 2002 Nov 5;137(9):715-25

METOPROLOL AT A GLANCE

METOPROLOL Metoprolol, a relatively selective beta1-blocker, is devoid of intrinsic sympathomimetic activity and possesses weak membrane stabilising activity. Prakash A et al, Drugs. 2000 Sep;60(3):647-78

METOPROLOL Well established in cardiovascular medicine Particularly useful in the management of hypertension and ischaemic heart disease. Plosker GL et al, Drugs. 1992 Mar;43(3):382-414

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. 1994 Oct;6(4):370-400

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. 1992 Mar;43(3):382-414

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. 1992 Mar;43(3):382-414

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. 2000 Sep;60(3):647-78

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. 2000 Sep;60(3):647-78

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. 2000 Sep;60(3):647-78

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. 2000 Sep;60(3):647-78

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