BETA BLOCKERS IN HYPERTENSION

Beta blockers are not recommended as initial treatment of

uncomplicated hypertension

beta-blockers had a reduced ability to protect against stroke,

though being equally effective for protection from coronary

events and mortality

Administration of beta-blockers is beneficial in patients with

angina pectoris, heart failure and a recent myocardial

infarction

Introduction

In a meta-analysis of over 24,000 hypertensive patients aged 52-70

years, atenolol was found inferior to other anti-hypertensive drugs

with higher total mortality (RR 1.13, 1.02-1.25), cardiovascular

mortality (RR 1.16, 1.00-1.34) and stroke (RR1.30, 1.12-1.50) in

patients on atenolol

Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension : is it a wise choice? Lancet 2004; 364: 1684-89.

A recent Cochrane review of over 95,000 hypertensive patients in 13

trials showed that beta-blockers do not reduce mortality and are

inferior to other antihypertensive drugs suggesting that they should

not be initiating drugs in hypertension

Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Mbewu A, Opie LH. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2012; 11: CD002003.

The inferiority of beta-blockers compared with that of other

antihypertensive agents was established by the LIFE study

and the ASCOT study

They showed superiority of an ACE inhibitor and, a calcium

antagonist over therapy initiated by a b-blocker as far as

stroke (LIFE) or stroke and mortality (ASCOT) were

concerned

In the LIFE study 9000 hypertensive patients with left

ventricular hypertrophy were randomized to either losarten or

atenolol

Similar reduction in systolic and diastolic BP were achieved

with both drugs

Despite similar BP reduction atenolol was associated with

25% higher incidence of stroke but not with higher incidence

of MI

LIFE STUDY

There was 25% lower incidence of new onset diabetes in the

losartan group

In the subgroup of patients with diabetes the 24% reduction in

primary endpoint was linked with reduction in cardiovascular

and total mortality

ASCOT trial Suggested that BP in the central aorta might be

an explanation for increase stroke in beta blocker group

In this trial atenolol based regimen was less efficacious in

reducing central aortic pressure than amlodipine based

regimen

Williams Bet al: differential impact of blood pressure lowering drugs on central aortic pressure and clinicaL outcomes CAFÉ study . CIRCULATION 113:1213,2006

The difference in central aortic pressure is largely explained

by heart rate lowering effect of beta blockers

Slowing heart rate will increase central augmentation index

and in turn diminish central BP lowering effect of beta

blockers

Williams B, Lacy PS. Impact of heart rate on central aortic pressures and hemodynamics: analysis from the CAFE (Conduit Artery Function Evaluation) study: CAFE-Heart Rate. J Am Coll Cardiol 2009;54:705–713.

These findings cannot be directly extrapolated to other β-blockers, such as nebivolol and carvedilol, which have vasodilating effect in the peripheral circulation and less heart-rate–slowing effect in the heart

Impact of Heart Rate on Central Hemodynamics and Stroke: A Meta-Analysis of β-Blocker Trials Feng-Hua Ding1, Yan Li1, Li-Hua Li1, Ji-Guang Wang1 American Journal of Hypertension 26(1) January 2013

In a recent meta analysis of 9 trials (n = 754), β-blockers were less efficacious in reducing cAI than all the other classes of drugs (8.6%, P < 0.001).

Baseline-adjusted difference in HR between randomized groups was associated with cAI (7.0% increase for each 10 bpm decrease in HR, P = 0.02), which was associated with cSBP (1.2 mm Hg increase for each 1% increase in cAI, P = 0.009)

Beta blockers does not reduce cental aortic pressure equally

They reduces heart rate and increase peripheral resistance so that the arterial wave reflection from the periphery returns during systole rather than during diastole

This leads to systolic augmentation of BP

Williams Bet al: differential impact of blood pressure lowering drugs on central aortic pressure and

clinicaL outcomes CAFÉ study . CIRCULATION 113:1213,2006

CENTRAL AORTIC PRESSURE

Beta-blockers are not a preferred initial therapy for uncomplicated hypertension.

Beta-blockers may be considered in 1. Angina pectoris2. Post-myocardial infarction3. Heart failure 4. Supraventricular tachycardia5. Glaucoma6. Pregnancy7. with evidence of increased sympathetic drive.

Beta blockers increase the incidence of diabetes through a decrease in insulin sensitivity secondary to reduce skeletal muscle perfusion from peripheral vasoconstriction

If therapy is initiated with a beta-blocker and a second drug is required, add a calcium-channel blocker rather than a thiazide-like diuretic to reduce the person’s risk of developing diabetes.

BETA BLOCKERS IN HEART FALIURE

Beta blockers have been one of the mainstays of treatment because of their ability to reverse the neurohumoral effects of the sustained sympathetic nervous system activation with prognostic and symptomatic benefits

Although there are potential benefits of blocking all three adrenergic receptors ,most of the deleterious effects are mediated by beta1 receptors

Beta blockers are indicated in symptomatic and asymptomatic HF and a depressed EF<40%

Three beta blockers have been shown to be effective in reducing the risk of death in patients with chronic HF bisoprolol, sustained release metoprolol succinate and carvedilol

Beta blockers reduces mortality from both SCD and progressive pump faliure in both ischemic and non ischemic patients

Carvedilol is superior to metoprolol in maintaining a favorable glycemic profile in patients with diabetes, improved insulin sensitivity, and decreased progression to microalbuminuria, all of which have been shown to have cardioprotective effects

Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli F, Phillips RA, et al, for the GEMINI Investigators. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA 2004;292:2227-36

The first trial that showed mortality benefit of beta blockers was MERIT-HF trial

In this trial metoprolol succinate provided a significant 34% reduction in mortality in subjects with moderate to severe systolic dysfunction

Subsequently CBIS trial with bisoprolol established beta blockers in heart failure

CBIS 3 trial found that initial treatment strategy using the beta blocker was non inferior to using ACE inhibitor first in newly diagnosed mild to moderate heart failure

COPERNICUS study of carvedilol enroll more advanced heart failure patients with EF<25% when compared with placebo carvedilol reduced the mortality risk at 12 month by 38% and the relative risk of death or heart failure hospitalization by 31%

In a recent meta analysis of 8,680 patients with HF, and 1,677 of them had AF (19%; mean 68 years of age; 30% women); there were 842 patients treated with beta-blocker, and 835 with placebo.

In AF patients, beta blockade did not reduce mortality (odds ratio [OR]: 0.86 [95% confidence interval (CI): 0.66 to 1.13]; p ¼ 0.28)

While in sinus rhythm patients, there was a significant reduction (OR: 0.63 [95% CI: 0.54 to 0.73]; p < 0.0001).

BETA BLOCKERS IN HEART FAILURE WITH ATRIAL FIBBRILATION

In patients with sinus rhythm with HF lower heart rate is associated with a better outcome and reduction of HR plays an important role in the beneficial effect of these drugs

In patients with AF with or without HF, lower heart rate, however, is not associated with a better outcome

Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363–73

Loss of the atrial kick and irregularity in ventricular response during AF patients with AF may need a higher heart rate to maintain a similar cardiac output

Low heart rate in patients with AF may be an expression of an underlying conduction disorder, which may be associated with impaired outcome Itself

AF in patients with HF may be a marker of a poorer clinical condition leading to a worse outcome, less modifiable by beta-blocker treatment

How can these different effects of beta-blockers betweenHF patients with AF and sinus rhythm be explained?

During sinus rhythm beta-blockers exert their heart rate lowering effect by targeting the sinus node, whereas during AF their main site of action is the AV node.

Heart rates were measured only at rest. HR reduction during exercise may have been different between AF and sinus rhythm patients

Other drugs for HF ACE inhibitors, ARB and mineralocorticoid antagonists have been shown to be as effective in patients with AF as they are in patients with sinus rhythm

Swedberg K, Olsson LG, Charlesworth A, et al. Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET. Eur Heart J 2005; 26:1303–8

BETA BLOCKERS IN POST MYOCARDIAL INFACTION

Meta analysis of trials from prethrombolytic era involving more than 24000 patients who received beta blockers in doses sufficient to blunt the heart rate response to stress or exercise after STEMI have shown a 23% reduction in long term mortality

Much of the impact of beta blockers in preventing mortality occurs in the first weeks so treatment should be started early

The latest ECS guidelines, however, have downgraded the recommendation to class Iia for all patients with ST-segment elevation MI with normal LV function and no heart failure

ESC guidelines for the management of acute myocardial infarction in patients presenting with ST‑segment elevation: the Task Force on the Management of ST‑Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology (ESC). Eur. Heart J. 33, 2569–2619 (2012)

In French national reimbursement database on a population of 11,604 patients hospitalized for MI in 2006, and who were alive after 6 months. Long-term adherence to their treatment in patients who had been prescribed β‑blockers at discharge was not associated with a reduced risk of death or readmission for acute coronary syndromes at 30 months

Tuppin, P. et al. Evidence-based pharmacotherapy after myocardial infarction in France: adherence-associated factors and relationship with 30-month mortality and rehospitalization. Arch. Cardiovasc. Dis. 103, 363–375 (2010).

FAST‑MI 2005 registry cohort of patients with ST-segment elevation MI who were given β‑blockers at discharge from hospital, 5‑year survival was similar whether β‑blocker treatment was stopped or on‑going at 1 year

FAST-MI REGISTRY

AHA association recommends 3 year course of beta blockers after STEMI