The most fascinating history of beta-blockers begins in 1958, ten years after Ahlquist's receptorial hypothesis, when Powell and Slater described the particular anti-adrenergic properties of a new compound, Dichloroisoproterenol. Subsequently, with the synthesis of Propranolol (1962), Sir James Black earned the Nobel prize for Medicine in 1989.
Betablockers can effectively intervene at several points in the cardiovascular continuum with extension of its role in to new indications such as CHF and prevention of coronary events in non cardiac surgery, and confirming its place in hypertension and post –MI secondary prevention.
The use of Betablockers bacome widespread worldwide in hypertension over 3 decades. These drugs are also required as first line agents in hypertension management guidelines by various authorities. Recently in 2004, controversy and doubts about the role of betablockers in primary treatment of uncomplicated hypertension surfaced when Lindhom et al reported the outcome of a meta analysis in Lancet.(1) This retrospective analysis reported increased incidence of stroke with betablockers. Possibly considering the future implications on the basis of Lindhom study, the Canadian Institute of Health Research and Stroke Foundation of Canada subsequently undertook the project of re examining this issue extensively and reviewed meta analysis of betablockers studies in hypertension (1950 - 2006). The outcome of this Canadian study (2) re-established the use of betablockers as first line agent, particularly in younger hypertensive patients below the age 60 yrs. But the NICE(National Institute of Clinical Excellence) and British Hypertension Society have changed their guidelines for management of hypertension and down graded betablockers as a fourth choice treatment after ACEIs and Calcium chanel blockers. However ESH / ESC guidelines retain beta blockers as first line treatment option for hypertension.
Recent meta-analysis of 147 randomized trials with the use of blood pressure lowering drugs in the prevention of CVD( 3 ), beta blockers in blood pressure difference trials had a special effect over and above that due to blood pressure reduction in preventing recurrent CHD events in people with a history of CHD: risk reduction 29%(95% confidence interval 22% to 34%) compared
with 15%(11% to 19%) in trials of other drugs.
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Very recently in a Cochrane review of 20 trials involving a total of 3,744 patients researchers found that adding beta-blockers as the second-line drug in combination with thiazide diuretics or calcium channel blockers, lead to an additional blood pressure reduction. The reduction was around 30% greater when the dose was doubled (4)
Use of betablockers in acute MI and post MI is very well established. In Acute MI, betablockers in pre-thrombolysis era showed reduction in mortality by 10-15% (5) and benefits were confirmed in studies performed in reperfusion era with reduction in mortality by 40%(6). In post MI patients, betablockers reduces cardiovascular events by 23% in prospective studies and upto 40% in observational studies. (7). Betablockers are the first line treatment in effort induced chronic stable angina in absence of contraindications (ACC/AHA focused update 2007)(8)
Regarding the use of betablockers in heart failure once thought to be contraindicated in patients with CHF, has now shown to reduce morbidity and mortality in these patients and strongly recommended by guidelines. (9). This is perhaps the most striking example of the application of evidence-based medicine in cardiology over the last two decades. Clinicians are now challenged to impliment this important new information in to clinical practice .The acceptance of betablockers in chronic heart failure appeared only after the publications of landmark trials CIBIS II( 1999 ), MERIT-HF( 1999 ) and lateron COPERNICUS ( 2001 ) and CAPRICORN ( 2001 ). These large randomized, controlled trials have shown that beta-blockers reduce mortality by 34 to 35 % in heart
failure patients with moderate to severe systolic dysfunction.The recent CIBIS III (The Cardiac Insufficiency Bisoprolol Study) trial (10) indicate that starting betablocker first than ACEI is as effective as starting ACEI first than a betablocker. The new data from CIBIS III clearly shows reduction in SCD with early initiation of beta blockers.
Place of Beta blockers in arrhyhthmias is very well established , they are not only good for supraventricular tachyarrhythmias but also effective in ventricular arrhythmias. European trial has shown that metoprolol was as effective as other electrophysiologically guided antiarrhythmic therapy.(10) Patients with life threatening ventricular tachyarrhythmias, long term betablocker therapy was successful especially in those with left ventricular ejection fraction exceeding 45%. More recently the results of several trials have suggested an anti-arrhythmic mechanism for at least part of their mortality benefit in the treatment of chronic congestive heart failure. More
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over pre-operative institution of βB results in lesser incidence of post-operative arrhythmias (11)
Despite improvement in perioperative care, severe cardiac complications like death or myocardial infarction, still occur in 0.5-1% of patients after non cardiac surgery. Perioperative use of beta blockers has the strongest level of evidence in this setting. It is an important extension of the well known role of beta blockers in CAD. Randomised trials and the large cohort studies have demostrated that the perioperative use of betablockers reduces the occurance of myocardial infarction or cardiac death in high risk surgery, in particular vascular surgery. Low risk patients do not seems to benefit from systemic perioperative betablocker prescription. However DECREASE IV study( 12-13) confirms that intermediate risk patients also benefit from peri operative betablockade with bisoprolol. New data from DECREASE V evident that, with tight control of heart rate, pre operative revascularization is not necessary in high risk patients. (14). More over ACC/AHA 2007 guidelines give class I indication for perioperative beta blockade only for patients with known CAD undergoing vascular surgery and who are already on chronic betablocker therapy(15). Although the recent data from POISE trial (16) casting more doubt on the benefits of perioperative beta blockers.
At last the issues ralated to the safety and tolerability of betablockers have been a great challenge. The myth regarding harm in diabetes looks to be more extrapolation. Apart from cardiovascular adverse effects, the emeregence of new onset diabetes and sexual impotence are the key concerns. Is it a reality with highly selective Beta 1 blockers also ? This issue needs to be addressed. Betablockers are infact been underused in old age, diabetes and COPD, however with the advent of new generation betablockers viz. Nebivolol, Carvedilol, Bisoprolol, physicians should not be deprived of using beta blockers in broad group of patients.
We are hopeful that some more data in coming future will continue to emerge, refining and extending their role as powerful interventions at multiple points for cardiovascular disease prevention.
REFFRENCES
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2. Khan N, McAlister FA—Re-examining the efficacy of betablockers, for the treatment of hypertension: a meta analysis. CMAJ. 174(12): 1737-1742, 2006
3. MRLaw, JK Morris, NJ Wald, use of blood pressure lowering drugs in the prevention of cardio vascular disease : meta analysis of 147 randomized trials in the context of expectations from prospective epidemiological trials. BMJ 2009;338:1665
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4. Hypertension :betablockers effective in cobinaton therapy. Cochrane library Jan 20, 2010
5. ISIS-1—Randomized trial of intravenous atenolol among 16027 cases of suspected AMI:ISIS-1, Lancet 1986:2;57
6. Silvet H,Spencer F, Yarzebeski J,etal. Cummunity wide trends in the use and outcomes associated with beta blockers in the patients with AMI: Worcester Heart Attack Study. Arch Intern Med 2003;163:2175
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9. Foody, Betablocker therapy in heart failure, scientific review, JAMA, 2002: 287(7): 883-89
10. G Steinbeck, D Andresen, P Bach, R Haberl, M Oeff, E Hoffmann, and ER von Leitner. A comparison of electrophysiologically guided antiarrhythmic drug therapy with beta-blocker therapy in patients with symptomatic, sustained ventricular tachyarrhythmias. NEJM, 1992;327:987-992
11. Willenheimer R, Erdman E, Follath F, Krum H, Ponikowaski P, Silke B, Verkenne P, Lechat P. comparision of treatment initiation with bisoprolol v/s enalapril in chronic heart failure patients: rationale and design of CIBIS III. Eur Heart Fail 2004;6: 493-500
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14. Boersma E etal. Perioperative cardiovascular mortality in non cardiac surgery: validation of the Lee cardiac risk index. Am J Med 2005: 118: 1134-1141
15. Poldermans D, Schouten O, Vidakovic R, Bax JJ, Thomson IR, Hoeks SE, Feringa HH, Dunkelgrun M, de Jaegere P, Maat A, van Sambeek MR, Kertai MD, Boersma E; DECREASE Study Group. A clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery. J Am Coll Cardiol 2007;49:1763–9
16. Feisher LA, Beckman JA, Brown KA, et al. ACC / AHA 2007 guidelines on perioperative cardiovascular evaluation and care for non cardiac surgery
17. Devereaux PJ, Yang H, Yusuf S, et al; POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet 2008;371:1839−47.
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