Bisoprolol, a cardioselective beta-blocker is used in the treatment of hypertension and chronic heart failure. In this article, Dr Anant Patil discusses the pharmacology and indications for the use of bisoprolol in patients with hypertension and chronic heart failure.

Introduction

Beta-blockers are useful drugs in the treatment of ischaemic heart disease, hypertension, and heart failure. They are not favoured as initial drugs for the treatment of hypertension in patients without compelling indications. [1] Based on their selectivity towards the type of beta receptors, these agents are classified as non-selective beta-blockers or relatively selective beta 1 blockers (also known as cardioselective beta-blockers).

Bisoprolol pharmacology

Bisoprolol is a cardioselective beta-blocker without intrinsic sympathomimetic and membrane-stabilising activity. It is mainly used in the treatment of arterial hypertension and chronic heart failure. [2] When given in the dose of 10 mg orally, bisoprolol fumarate has an absolute bioavailability of 80%. Its absorption is not altered by the presence of food. Given at higher doses (>20 mg) it can inhibit beta 2 adrenoceptors. Therefore, in order to get the benefits of cardioselectivity, it is important to use the lowest effective dose of bisoprolol. Bisoprolol is excreted by renal and non-renal routes. About half of the dose of bisoprolol is excreted unchanged in the urine. [3]

Bisoprolol in the treatment of coronary heart disease and hypertension

1. A retrospective subgroup analysis of the BISO-CAD study (multi-centre, open-label, single-arm, phase IV) reported the effectiveness of bisoprolol in reducing resting heart rate in Asian patients with coronary artery disease with comorbid hypertension. [4] 
2. Another double-blind, randomised trial in 25 patients with stable coronary artery disease showed a reduction in ST-segment depression during exercise by 56% and 64% with bisoprolol 5 mg and 10 mg given once daily respectively. Both doses reduced heart rate, systolic and diastolic blood pressure at rest as well as during exercise.[5]
3. In a study (n=13) among patients with mild to moderate essential hypertension, the effects of bisoprolol on glucose metabolism were evaluated when given for 24 weeks. Bisoprolol administered in the dose of 5 to 10 mg once daily significantly reduced systolic, diastolic as well as mean blood pressure. Importantly, it did not result in an adverse impact on glycemic parameters i.e. blood glucose level and glycosylated haemoglobin. These glycaemic parameters did not significantly differ as compared to baseline levels. Thus, bisoprolol provided a satisfactory reduction of blood pressure without impairment of blood glucose metabolism. [6]
4. A study in 100 patients with hypertension and coronary artery disease with ineffective or irregular previous treatment, reported the effectiveness of the fixed-dose combination of bisoprolol and amlodipine. It also resulted in the reduction of the number of ischaemic episodes. Fixed-dose combination also helps to increase compliance to treatment. [7]
5. A recently published randomised, double-blind, placebo-controlled study in 16 male patients with grade I-II primary hypertension (never-treated) reported that bisoprolol treatment given in the dose of 5 mg/day reduces peripheral and central blood pressure in the supine position. It decreased heart rate in supine and upright position. However, during upright position, aortic systolic blood pressure did not decrease significantly with bisoprolol. It had a detrimental effect on central pulse pressure in an upright position; 2.7 times upright increase in the systemic vascular resistance was reported as compared to placebo. [8]

Bisoprolol in the treatment of heart failure

Beta-blockers play an important role in the treatment of chronic heart failure. Bisoprolol is a highly selective beta 1 antagonist. [9, 10] Its use in patients with chronic heart failure is associated with improvement in the left ventricular function and it also reduces heart rate. Two major clinical trials [The Cardiac Insufficiency Bisoprolol Studies i.e. CIBIS (n=641) and CIBIS-II (n=2647)] have evaluated the efficacy of bisoprolol administered with angiotensin-converting enzyme (ACE) inhibitors and diuretics in patients with stable chronic heart failure.

1. In the CIBIS-II trial, the primary endpoint of all-cause mortality was significantly lower with bisoprolol as compared to placebo. It was decreased with all doses of bisoprolol. In the CIBIS trial also it was decreased, but the difference was not statistically significant. The meta-analysis of these studies showed a relative reduction of 29% with bisoprolol than placebo. It is generally well tolerated by patients with chronic heart failure. Patients receiving bisoprolol are less likely to develop tachycardia. Thus, the addition of bisoprolol to ACE inhibitor and a diuretic results in significant improvement in the survival rate in patients with stable chronic heart failure. The requirement for hospital admission is also reduced. [9]
2. The CIBIS-III trial having 1010 patients reported no difference in efficacy and safety between the two strategies of treatment initiation (either enalaprol or bisoprolol) in stable chronic heart failure patients. [11, 12]
3. In the MAIN-CHF-II study, the effects of bisoprolol fumarate were compared with carvedilol in chronic heart failure. The mean maintenance dose of bisoprolol in this study was 3.3 mg/day. It was found to be well-tolerated, as effective as a mean carvedilol dose of 13.6 mg/day. The mean duration of bisoprolol was 188.2 days. Mean change from baseline to week 32 in left ventricular ejection fraction, left ventricular end-diastolic volume and left ventricular end-systolic volume with bisoprolol was 11.7%, -37.5 ml and -41.9 ml respectively. Thus bisoprolol was effective in reducing left ventricular volume as well as an increase in left ventricular ejection fraction. [13]
4. A prospective study has also reported that bisoprolol significantly improves left ventricular ejection fraction, significantly reduces heart rate and reduces QTc dispersion in patients with chronic heart failure. [14] A study examined the pharmacokinetics of bisoprolol in patients with chronic heart failure (n=46) who were followed for an average of 8 months. In this study, the mean clearance of bisoprolol in patients with chronic heart failure was 30% lesser than in healthy people. Patients with lower body weight show more fluctuations and higher maximal levels of bisoprolol concentration. [15]

Bisoprolol is effective and well-tolerated in the treatment of congestive heart failure because of systolic dysfunction. Literature review suggests that it can be the first-line beta-blockers in patients with systolic heart failure. [10]

Dose of bisoprolol in hypertension

The dose of bisoprolol in hypertension management is selected based on the requirements of the patient. Usually, it is started in the dose of 5 mg once daily. Some patients may need a 2.5 mg starting dose. In patients not achieving satisfactory antihypertensive response with 5 mg, the dose may be increased to 10 mg. If required, the dose may be increased to 20 mg once daily. In patients with hepatic impairment or renal dysfunction (CrCL< 40 mL/min), it should be started at a daily dose of 2.5 mg. Dose titration should be done carefully. [3]

Dose of bisoprolol in chronic heart failure

Chronic heart failure is treated with an ACE inhibitor or angiotensin receptor blocker in patients with intolerance to ACE inhibitors, beta-blockers, diuretic, and cardiac glycoside (if required). Treating physicians should have experience in the management of chronic heart failure. In patients with stable chronic heart failure, it is given in a slow up-titration phase and regular monitoring with an initial dose of 1.25 mg once daily. The dose is then gradually increased to 2.5, 3.75, 5, 7.5, 10 mg once daily based on the patient’s tolerability with a maximum recommended dose of 10 mg once daily. [16]

Contraindications for use of bisoprolol

Bisoprolol should not be given to patients with acute heart failure, hypotension, bradycardia before initiation of treatment, severe bronchial asthma, Raynaud’s syndrome, sick sinus syndrome, second or third-degree AV block, cardiogenic shock, heart failure decompensation or patients with prior hypersensitivity. [16]

Conclusion

Bisoprolol is a cardioselective beta-blocker used in the treatment of hypertension and chronic heart failure. Its use in patients with chronic heart failure is associated with an increase in left ventricular function. It reduces all-cause mortality in patients with chronic heart failure.

Disclaimer: This information is for educational purposes. Physicians are requested to refer to the updated approved prescribing information of bisoprolol for its indications, dose, interactions contraindications and other details. The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a Professor of Pharmacology from Mumbai.