journey of beta blockers from hypertension to heart failure

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  • Journey of Beta blockers From hypertension to heart failure
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  • Beta Blockers Historical Background YearScientistResearch 1948AhlquistIntroduced the concept of alpha & beta receptors LandsSubdivided beta receptors into beta1 and beta2 subtypes 1958Powell and Slater Described anti-adrenergic properties of a new compound, Dichloroisoproterenol 1962Sir James W. Black Developed Propranolol Earned the Nobel prize for Medicine in 1989 1964First clinical studies of the treatment of angina, arterial rhythm and hypertension disorders
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  • 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 NEJM, 1998, Vol. 339:551-553
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  • 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
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  • Beta Blockers Lipid solubility Peripheral vasodilation Average daily dosage PropranololHigh40-80 mg SotalolLow160-320 mg AtenololLow25-100 mg BisoprololModerate2.5-10 mg CeloprololModerate+200-600 mg NebivololModerate+2.5-5 mg MetoprololHigh50-100 mg CarvediolModerate+3.125-50 mg LabetololLow+200-800 mg
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  • Beta blockers Indications Hypertension Angina pectoris Post-myocardial infarction Tachyarrhythmias Congestive heart failure
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  • 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
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  • Beta-blockers in Hypertension Established long term mortality and morbidity benefits Beta blockers significantly reduce: Sudden cardiac death Overall coronary events Incidence of stroke
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • Beta blockers continue to surprise us Cruikshank, Eur. Heart J., 2000
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  • Use of beta-blockers in hypertensive diabetic CLINICAL EVIDENCE
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  • 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
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  • 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.
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  • Clinical end pointAbsolute risk (events per 1000 patient years) Captopril Absolute risk (events per 1000 patient years) Atenolol p value Any diabetes related end-point 53.3484043 Deaths related to diabetes 15.2120028 All-cause mortality238208044 Myocardial infarction202169035 Stroke6861074 Peripheral vascular disease 1611059 Microvascular disease135104030
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  • 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
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  • Use of beta-blockers in heart failure
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  • A Bayesian Meta-Analysis 22 trials 10 135 patients James M. Brophy et al, Ann Intern Med. 2001;134:550-560.
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  • StudyYearDrugDurationNYHA class Anderson et al1985Metoprolol19IIIV Engelmeier et al.1985Metoprolol12IIIV Pollock et al.1990Bucindolol3IIIV Woodley et al.1991Bucindolol3IIIII Paolisso et al.1992Metoprolol3IIV Waagstein et al.1993Metoprolol18IIIII Wisenbaugh et al.1993Nebivelol3IIIV
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  • StudyYearDrugDurationNYHA class Fisher et al1994Metoprolol6IIIV Bristow et al.1994Bucindolol3IIV CIBIS-I1994Bucindolol23IIIIV Eichhorn et al.1994Metoprolol3IIIII Metra et al.1994Carvediol3IIIII Olsen et al.1995Carvediol4IIIV Krum et al.1995Carvediol4IIIV
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  • StudyYearDrugDurationNYHA class Bristow et al1996Carvediol6IIIV Packer et al.1996Carvediol6IIIV Colucci et al.1996Carvediol15IIIII Cohn et al.1997Carvediol8IIIV Aust/Nz1997Carvediol19IIIII CIBIS-II1999Bisoprolol15IIIIV MERIT-HF1999Metoprolol12IIIV RESOLVED2000Metoprolol6IIIV
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  • Significantly less no. of deaths PlaceboBeta-blocker therapy Deaths624/ 4862444 /5273 % of deaths128 4 lives saved per 100 patients James M. Brophy et al, Ann Intern Med. 2001;134:550-560.
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  • Significantly less hospitalization PlaceboBeta-blocker therapy Patients requiring hospitalization 754/ 4862540 /5273 % Patients requiring hospitalization 1511 4 fewer hospitazations per 100 patients James M. Brophy et al, Ann Intern Med. 2001;134:550-560.
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  • 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. The probability that beta-blocker therapy reduced total mortality and hospitalizations for congestive heart failure was almost 100%. James M. Brophy et al, Ann Intern Med. 2001;134:550-560.
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  • 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)
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  • 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)
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  • 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
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  • METOPROLOL Metoprolol, a relatively select