β-adrenoceptor blockers valuable but higher doses not necessary

Abstract

β-adrenoceptor blockers have an important role in the treatment of heart disease and are useful as an adjunct in systemic hypertension. They are often prescribed at unnecessarily high doses, near the top of the dose−response curve. Higher doses are associated with more adverse events, have not been shown to improve clinical outcomes in cardiac failure and may worsen outcome in hypertension. β-adrenoceptor blockers can be very effective in lower doses, guided by close monitoring of heart rate and blood pressure and, when used in combination with low dose vasodilators and diuretics, give a better risk benefit profile.

Introduction

β-adrenoceptor blockers are thought to be essential in cardiac failure [1] and are often useful in coronary disease [1,2], atrial fibrillation [3] and hypertension [4]. Guidelines recommend dosages [5] at the upper end of the dose−response curve, without published evidence that this improves outcomes. Higher doses may merely increase adverse events, without any therapeutic gain, as shown in a recent Cochrane systematic review of non-selective β-adrenoceptor blockers in hypertension [6]. Clinicians may increase dose seeking greater benefits and to help the patient avoid a second antihypertensive drug. However, combining lower dose pharmacotherapy, for example, β-adrenoceptor blocker, vasodilator and diuretic, has the dual merit of additive efficacy and mostly non-additive side effects [7].

Recent guidelines for the treatment of hypertension [8,9] implying that β-adrenoceptor blockers might be less effective than other antihypertensive agents are at variance with systematic reviews that do not favour one class of antihypertensive over another [10,11]. β-adrenoceptor blockers blunt the effects of catecholamines, which explains their beneficial effects in angina [1,2] and arrhythmia [3] and their greater effectiveness compared with other antihypertensive drugs in lowering exercise [12] and stress [13] related elevations in blood pressure.

Lower dose reduces side effects

In practice, β-adrenoceptor blockers are prescribed at half or less of the doses recommended by manufacturers [14]. Contrary to the implication by commentators that this is under-prescribing, lower doses of some drugs can improve outcomes [15], in part because of less adverse effects. Given the variety of effects of β-adrenoceptor blockade, increasing dose may cause unintended effects and significant morbidity, in particular hypotension and bradycardia, without increasing benefits. Dosing should also take into account patient size, along with liver and renal function. Unfortunately, whilst drug blood concentrations have utility in toxicology, they have not proved to be a useful guide to efficacy.

Reliable information about β-adrenoceptor blocker adverse effects is surprisingly limited. Most clinical trials recruit uncomplicated patients and are powered for major efficacy endpoints. Adverse events are usually only noted incidentally. Potential participants with any history of relevant adverse drug effects are excluded. In one study of β-adrenoceptor blockers in cardiac failure, the number needed to be treated annually to cause harm was estimated at 17 (dizziness), 91 (hypotension) and 26 (bradycardia) [16].

Increased dose does not reduce mortality

When β-adrenoceptor blockers are used in cardiac failure, heart rate reduction has proven a better predictor of favourable outcome than dose [17]. Improved left ventricular function seen with β-adrenoceptor blockers may be due to greater ventricular filling with the slower heart rate. However, when β-adrenoceptor blockers are used in hypertension, a slower heart rate appears to be associated with increased cardiovascular events and mortality [18]. This may be because with the relatively normal left ventricular function, the greater ventricular filling and stroke volume at slower heart rates increases pulse pressure and thereby systolic blood pressure [19].

In cardiac failure, β-adrenoceptor blockers are often started at low dose because of the risk of hypotension. Contrary to popular belief, there is no evidence that higher doses confer any additional clinical benefit [17]. In a carefully conducted study, haemodynamics improved in patients randomized to 25 mg twice daily of carvedilol, compared with 12.5 and 6.25 mg, yet there was no difference in re-hospitalization rates [20]. In larger studies, in which patients were randomized to placebo or maximum tolerated dose, the reduced mortality with bisoprolol in CIBIS II [21] and metoprolol in MERIT-HF [22] was little different between the highest (41%, 38%, respectively) and lowest (34%, 38%) doses. Hospitalization rates were similar at different doses [21,22]. In the former study, mortality was statistically lower with the two higher doses compared with the lowest dose, but participants were not randomized by dose. Dosage was increased as tolerated and participants who managed higher doses proved to have higher blood pressure and less arrhythmia at baseline [21], presumably because they had less severe heart disease, which would account for their better outcome. Systematic review of clinical trials of β-adrenoceptor blockers in cardiac failure confirms that higher doses do not improve outcomes [17]. The flat dose−response, with similar benefits over the four-fold range of β-adrenoceptor blocker dose, suggests that even the lower doses used in published clinical trials are near the top of the dose−response curve with respect to outcomes. β-adrenoceptor blockers clearly differ in their individual properties and not all have been equally evaluated in different indications but the available evidence provides a fairly consistent message.

The incidence and severity of adverse drug effects are often dose related [15]. In larger studies of the newer anti-angiotensin agents in cardiac failure, lisinopril [23] and losartan [24], randomization to high (33 mg, 150 mg, respectively) compared with low (4 mg, 50 mg) dose reduced hospitalization by a modest 20% (lisinopril) and 14% (losartan) but did not reduce mortality and increased hypotension, hyperkalaemia and renal failure by over 30%. These findings attest to superior risk benefit profile with lower doses, provided sufficient efficacy is confirmed by appropriate clinical monitoring.

Conclusion

Cardiovascular disorders still account for over one third of community mortality [25] and much morbidity and β-adrenoceptor blockers can benefit many patients. Unfortunately, dosing has been neglected in studies to date. Pharmacokinetics, body size, liver and renal function and disease severity are clearly relevant and vary widely between patients. Higher doses of β-adrenoceptor blockers lower heart rate but do not appear to lower mortality [17] or re-hospitalization [21,22]. Patients should be closely clinically monitored and the dose increased as necessary to manage symptoms. The well substantiated increase in cardiovascular events as heart rate increases above 60 beats min⁻¹ [26] and evidence of worse outcomes in cardiac failure above 80 beats min⁻¹ [27] can guide dose titration of β-adrenoceptor blockers in individual patients. β-adrenoceptor blockers have an important place in the treatment of cardiac disease and hypertension and are best used at the lowest effective dose.

Competing Interests

The authors have completed the Unified Competing Interest form at http://www.icmje.org.coi_discolosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.