Bisoprolol

What it is

Bisoprolol is a synthetic small molecule given as the fumarate salt in tablets. It is a beta1-selective (so-called cardioselective) beta-adrenoceptor blocking drug with no intrinsic sympathomimetic activity and no significant membrane-stabilising activity at usual doses. Its selectivity is relative rather than absolute: at doses of 20 mg and above it also blocks beta2 receptors in the airways and blood vessels. About 80% of an oral dose reaches the circulation, food does not change absorption, and it is cleared about equally by the kidneys and the liver.

What the research says

The strongest evidence for bisoprolol is in chronic heart failure with a reduced ejection fraction, where a single large placebo-controlled trial and a pooled individual-patient analysis of beta-blocker trials both show fewer deaths, with an absolute mortality difference of roughly 4 to 5 percentage points over about 1.3 years. For high blood pressure, which is the only indication on the US label, the drug reliably lowers blood pressure but the Cochrane review of beta blockers as first-line antihypertensives found no effect on all-cause mortality and worse stroke prevention than calcium-channel blockers or renin-angiotensin blockers. It does not improve survival in people whose heart failure coexists with atrial fibrillation. Stopping it suddenly has been linked to rebound angina and heart attacks, and it can provoke bronchospasm in people with asthma.

Evidence grade: Well established.

How it works

Drug class: Beta1-selective (cardioselective) beta-adrenoceptor blocker without intrinsic sympathomimetic activity

Bisoprolol blocks beta1-adrenergic receptors, the main receptors through which adrenaline and noradrenaline speed up and strengthen the heart. Blocking them slows the heart at rest and during exercise, lowers cardiac output, and reduces the heart's oxygen demand; the label also lists reduced renin release by the kidney among the possible contributors to its blood-pressure effect. Selectivity for beta1 over beta2 is only relative, so at higher doses it also blocks beta2 receptors in the airways and blood vessels. (Source 1)

What it is used for

• Approved indication: this is the only indication on the US FDA-approved prescribing information (DailyMed, updated June 26, 2023), and it is also an indication in the UK/EU product information (eMC Summary of Product Characteristics, Sandoz Limited, updated 21-Apr-2022). Bisoprolol does lower blood pressure in a dose-related way. But the Cochrane review of beta blockers started as first-line treatment for hypertension found no reduction in all-cause mortality versus placebo, and worse prevention of stroke and cardiovascular events than calcium-channel blockers; most of the trial data came from atenolol rather than bisoprolol. Evidence: disputed. (Source 2)
• Approved indication in the UK/EU product information (eMC Summary of Product Characteristics, Sandoz Limited, updated 21-Apr-2022) (stable chronic heart failure with reduced left ventricular systolic function). It is NOT an indication on the US FDA-approved prescribing information (DailyMed, updated June 26, 2023), which lists hypertension only, so in the US this is prescribing outside the label. CIBIS-II randomised 2647 people with NYHA class III or IV heart failure and found 11.8% died on bisoprolol versus 17.3% on placebo, and a pooled individual-patient analysis of 11 beta-blocker trials found an absolute mortality reduction of 4.3% with a number needed to treat of 23. Evidence: established. (Source 3)
• Approved indication in the UK/EU product information (eMC Summary of Product Characteristics, Sandoz Limited, updated 21-Apr-2022). It is not an indication on the US FDA-approved prescribing information (DailyMed, updated June 26, 2023), which lists hypertension only. The TIBBS trial in 330 people with stable angina showed bisoprolol cut transient ischaemic episodes on Holter monitoring from about 8 to about 3 per 48 hours, more than slow-release nifedipine. These are ischaemia measurements rather than deaths or heart attacks, so the outcome evidence is indirect. Evidence: limited. (Source 4)
• Not an approved indication with either regulator - not on the US FDA-approved prescribing information (DailyMed, updated June 26, 2023) and not in the UK/EU product information (eMC Summary of Product Characteristics, Sandoz Limited, updated 21-Apr-2022). An individual-patient data meta-analysis of ten placebo-controlled beta-blocker heart failure trials found a clear mortality reduction in people in sinus rhythm but none in the 3066 people with atrial fibrillation (hazard ratio 0.97, 95% CI 0.83-1.14), with the lack of effect consistent across every subgroup examined. Evidence: not-supported. (Source 5)
• Not an approved indication with either regulator; this is prescribing for a cardiac indication in someone who also has COPD. A Cochrane review of 22 randomised trials of cardioselective beta blockers in COPD found no change in FEV1 or respiratory symptoms compared with placebo, including in people with severe airflow obstruction, and concluded such drugs should not be routinely withheld. The trials were short (2 days to 16 weeks) and were not designed to measure exacerbations or survival. Evidence: limited. (Source 6)

Interactions

• Other beta-blocking agents (label): The US label's first drug-interaction instruction is that bisoprolol should not be combined with another beta blocker at all - including beta-blocker eye drops such as timolol, which are absorbed systemically. (Source 7)
• Verapamil and diltiazem (and other drugs that slow AV conduction) (label): Adding bisoprolol to these calcium-channel blockers compounds the slowing of the heart's electrical conduction and the weakening of its contraction; intravenous verapamil in someone on a beta blocker can cause severe low blood pressure and AV block. (Source 7)
• Digoxin and other digitalis glycosides (label): Both slow conduction through the AV node and slow the heart rate, so taking them together raises the chance of an excessively slow heartbeat. (Source 7)
• Rifampin (rifampicin) (pharmacokinetic study): Rifampin speeds up the liver enzymes that clear bisoprolol, shortening how long it stays in the body. The label states that an initial dose change is generally not needed. (Source 7)
• Warfarin (pharmacokinetic study): No interaction was found: bisoprolol did not change prothrombin time in people on stable warfarin doses. This is a documented absence of an interaction, not a caution. (Source 7)
• Clonidine (label): If both are being stopped, the order matters: withdrawing clonidine while a beta blocker is still on board can trigger rebound high blood pressure, so the product information advises stopping the beta blocker several days first. (Source 7)
• Non-steroidal anti-inflammatory drugs (ibuprofen, naproxen, diclofenac) (label): NSAIDs blunt the blood-pressure-lowering effect of bisoprolol. (Source 8)
• Beta-blocker eye drops for glaucoma (for example timolol, including timolol combined with dorzolamide) (label): Eye drops are absorbed into the bloodstream, so a topical beta blocker can add to the systemic beta-blocking effect of bisoprolol - relevant for anyone on both a heart drug and glaucoma drops. (Source 8)
• Insulin and oral diabetes medicines (label): Beta blockade can mask the warning signs of low blood sugar, particularly a racing pulse, and the blood-sugar-lowering effect may be increased. (Source 8)
• Mefloquine (antimalarial) and monoamine oxidase inhibitors (label): Mefloquine adds to the risk of a slow heart rate; MAO inhibitors other than MAO-B inhibitors can both deepen the blood-pressure fall and, conversely, carry a risk of hypertensive crisis. (Source 9)
• Alcohol (label): No pharmacokinetic interaction is documented. The product information notes that impaired ability to drive or use machines should be considered particularly at the start of treatment, on a change of medicine, or together with alcohol. (Source 10)
• Food (meals in general) (pharmacokinetic study): Food does not change how much bisoprolol is absorbed, so it can be taken with or without a meal. No specific food - including grapefruit - has a documented pharmacokinetic interaction, because bisoprolol is not a CYP2D6 substrate and is cleared about half unchanged by the kidney. (Source 11)

Stopping it

• Both the US label and the European product information warn against stopping abruptly: in people with coronary artery disease, sudden cessation of a beta blocker has been followed by worsening angina and, in some cases, heart attack or ventricular arrhythmia. The label suggests tapering over roughly a week even in people without known coronary disease, and restarting the drug at least temporarily if withdrawal symptoms appear. (Source 12)
• The strongest observational signal comes from a case-control study of treated hypertensive patients with no prior coronary disease, in which people identified from pharmacy records as recent stoppers had about a fourfold higher relative risk of a first coronary event; the association was specific to beta blockers and not seen with diuretics. The confidence interval was very wide (1.1 to 18.5), so the size of the risk is uncertain. (Source 13)
• A larger population-based cohort of older people found NO overall increase in heart attacks after stopping any beta blocker. Only when the drugs were split by type did stopping a beta1-selective agent - the class bisoprolol belongs to - show an association with raised risk in the first 30 days and again between 30 and 180 days. No increased risk was found in the non-selective or other subgroups, and the subgroup confidence intervals only just exclude 1. (Source 14)
• The UK/EU product information is more prescriptive than the US label about how to come off it: treatment must not be stopped abruptly, and the dose should be reduced slowly by halving it each week. It also treats heart failure as a case where the dose is reached, and left, through a formal titration phase supervised by a clinician experienced in heart failure. (Source 15)

What goes wrong

In people with chronic heart failure taking a beta blocker, bradycardia is very common and worsening of pre-existing heart failure is common. (Source 16)

• Official position, Moderate certainty.
• Size: Post-marketing and trial frequency categories in the UK/EU product information.
• Who: People taking bisoprolol for hypertension, angina or chronic heart failure.
• How long: Not applicable (cumulative labelling data)
• Result: Very common (>=1/10): bradycardia in chronic heart failure. Common (>=1/100 to <1/10): worsening of pre-existing heart failure in chronic heart failure, dizziness, headache, cold or numb extremities, hypotension, fatigue, gastrointestinal complaints. Uncommon (>=1/1,000 to <1/100): bronchospasm in people with asthma or obstructive airways disease, AV conduction disturbance, sleep disorders, depression.
• Funding: Manufacturer product information (a regulatory position, not a trial)

Very common: bradycardia in patients with chronic heart failure Common: worsening of pre-existing heart failure in patients with chronic heart failure Uncommon: AV-conduction disturbances. Worsening of pre-existing heart failure (in patients with hypertension or angina pectoris); bradycardia (in patients with hypertension or angina pectoris)

A single dose of a cardioselective beta blocker reduced FEV1 by about 7.5% in people with reversible airway disease, although continued dosing for 3 to 28 days produced no measurable change. (Source 17)

• Systematic review, Moderate certainty.
• Size: 19 single-dose studies and 10 continued-treatment studies.
• Who: People with asthma or COPD with a reversible obstructive component.
• How long: Single dose, or continued treatment for 3 to 28 days.
• Result: Single-dose cardioselective beta-blocker produced a 7.46% (95% confidence interval (CI) 5.59 to 9.32) reduction in forced expiratory volume in one second (FEV1), but with a 4.63% (95% CI 2.47 to 6.78) increase in FEV1 with beta2-agonist, compared to placebo.
• Funding: Cochrane review (Salpeter, Ormiston, Salpeter); no industry funding stated.

Single-dose cardioselective beta-blocker produced a 7.46% (95% confidence interval (CI) 5.59 to 9.32) reduction in forced expiratory volume in one second (FEV1), but with a 4.63% (95% CI 2.47 to 6.78) increase in FEV1 with beta2-agonist, compared to placebo. Treatment lasting three to 28 days produced no change in FEV1 (mean difference (MD) -0.42% change from baseline; 95% CI -3.74 to 2.91), symptoms or inhaler use

Compared with renin-angiotensin system inhibitors, people starting a beta blocker for hypertension were more likely to stop treatment because of adverse events. (Source 18)

• Systematic review, Moderate certainty.
• Size: 9,951 participants in 2 studies for the adverse-event comparison.
• Who: Adults with primary hypertension starting first-line treatment.
• How long: Trials of at least 12 months.
• Result: Adverse events versus renin-angiotensin system inhibitors RR 1.41 (95% CI 1.29 to 1.54), moderate-certainty evidence; versus diuretics RR 1.69 (0.95 to 3.00) and versus calcium-channel blockers RR 1.20 (0.71 to 2.04), both low certainty.
• Funding: Cochrane review summarised by its own authors; competing interests declared as none.

there is low-certainty evidence that hypertensive patients on beta-blockers are more likely to discontinue medications due to adverse events than patients on renin–angiotensin system inhibitors. Nonetheless, there is little or no difference in adverse events between beta-blockers and diuretics or calcium-channel blockers.

Recently stopping a beta blocker was associated with a transient fourfold increase in the relative risk of a first coronary heart disease event in treated hypertensive patients. (Source 13)

• Case-control study, Low certainty.
• Size: 248 cases of new coronary heart disease and 737 controls.
• Who: Health maintenance organisation patients with medication-treated high blood pressure and no prior coronary heart disease, 1982-1984.
• How long: Exposure window defined by pharmacy refill compliance below 80%.
• Result: After adjustment for potential confounding factors, subjects who had recently stopped using beta-blockers had a transient fourfold increase in the relative risk of coronary heart disease (relative risk, 4.5; 95% confidence interval, 1.1 to 18.5). The association was specific to beta-blockers but not diuretics.
• Funding: Not stated in the abstract; a population-based study in a US health maintenance organisation.

subjects who had recently stopped using beta-blockers had a transient fourfold increase in the relative risk of coronary heart disease (relative risk, 4.5; 95% confidence interval, 1.1 to 18.5).

In a population-based cohort of older people the headline result was null - stopping a beta blocker was not associated with more heart attacks overall - and only a subgroup analysis of selective beta blockers showed a raised risk, roughly 2.4 to 2.7 times, in the following 180 days. (Source 14)

• Cohort study, Low certainty.
• Size: 2,588 beta-blocker users within the Rotterdam Study, of whom 148 had an incident myocardial infarction.
• Who: Community-dwelling adults aged 55 and over treated with a beta blocker for at least 30 days, 1991-2002.
• How long: Up to 11 years of follow-up; exposure windows of <30 days, 30-180 days and >180 days after cessation.
• Result: Analyses within subgroups showed that discontinuation of selective beta-blockers was associated with an increased risk of myocardial infarction compared with current use of any beta-blocker within the first 30 days (relative risk [RR] 2.70; 95% CI 1.06, 6.89) and also between 30 and 180 days after discontinuation (RR 2.44; 95% CI 1.07, 5.59). No increased risk was demonstrated in the other beta-blocker subgroups.
• Funding: Not stated in the abstract; an academic pharmacoepidemiology analysis of the Rotterdam Study.

Limit of this finding: The study's overall result was no increase in heart attacks after stopping a beta blocker. The raised risk appears only when the drugs are split into subgroups, in the selective beta-blocker subgroup, on small numbers with confidence intervals that only just exclude 1 (RR 2.70, 95% CI 1.06-6.89 and RR 2.44, 95% CI 1.07-5.59). A subgroup finding like that is a hypothesis, not a demonstrated effect, and it does not support a general claim that stopping any beta blocker raises the risk of a heart attack.

Discontinuation of any beta-blocker was not associated with an increased risk of myocardial infarction compared with current use of a beta-blocker. Analyses within subgroups showed that discontinuation of selective beta-blockers was associated with an increased risk of myocardial infarction compared with current use of any beta-blocker within the first 30 days (relative risk [RR] 2.70; 95% CI 1.06, 6.89) and also between 30 and 180 days after discontinuation (RR 2.44; 95% CI 1.07, 5.59).

What the evidence supports

In people with NYHA class III-IV heart failure and an ejection fraction of 35% or less, bisoprolol reduced all-cause death from 17.3% to 11.8% over a mean 1.3 years. (Source 3)

• Randomized trial, High certainty.
• Size: 2,647 patients (1,327 bisoprolol, 1,320 placebo)
• Who: Symptomatic chronic heart failure, NYHA class III or IV, LVEF <=35%, already on diuretics and an ACE inhibitor, in European centres.
• How long: Mean follow-up 1.3 years; trial stopped early at the second interim analysis.
• Result: All-cause mortality was significantly lower with bisoprolol than on placebo (156 [11.8%] vs 228 [17.3%] deaths with a hazard ratio of 0.66 (95% CI 0.54-0.81, p<0.0001). There were significantly fewer sudden deaths among patients on bisoprolol than in those on placebo (48 [3.6%] vs 83 [6.3%] deaths), with a hazard ratio of 0.56 (0.39-0.80, p=0.0011).
• Funding: Not stated in the abstract; CIBIS-II was a manufacturer-supported multicentre European trial (Merck KGaA)

All-cause mortality was significantly lower with bisoprolol than on placebo (156 [11.8%] vs 228 [17.3%] deaths with a hazard ratio of 0.66 (95% CI 0.54-0.81, p<0.0001).

Pooling individual data from 11 placebo-controlled beta-blocker heart failure trials, the absolute mortality reduction was 4.3% over a median 1.3 years, a number needed to treat of 23, with no significant interaction with age. (Source 19)

• Meta-analysis, High certainty.
• Size: 13,833 patients with HFrEF in sinus rhythm across 11 randomised trials.
• Who: Adults aged 40-85 in sinus rhythm with LVEF <0.45; median age 64; 24% women.
• How long: Median follow-up 1.3 years.
• Result: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23).
• Funding: Investigator-initiated; an unrestricted administrative grant from Menarini and data extraction support from GlaxoSmithKline, with four manufacturers supporting the collaboration.

There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23).

In stable angina, 10 mg of bisoprolol daily cut transient ischaemic episodes on 48-hour Holter monitoring by more than slow-release nifedipine. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 330 patients (161 bisoprolol, 169 nifedipine slow release) at 30 centres in seven European countries.
• Who: Stable angina pectoris with a positive exercise test and more than two transient ischaemic episodes on 48-hour Holter monitoring.
• How long: Two 4-week treatment phases.
• Result: In phase 1 of the trial, 4 weeks of bisoprolol therapy (10 mg daily) reduced the mean [+/- SD] number of transient ischemic episodes from 8.1 +/- 0.6 to 3.2 +/- 0.4/48 h. Nifedipine (2 x 20 mg) reduced transient ischemic episodes from 8.3 +/- 0.5 to 5.9 +/- 0.4/48 h. Total duration of ischemia was reduced from 99.3 +/- 10.1 to 31.9 +/- 5.5 min/48 h with bisoprolol and from 101 +/- 9.1 to 72.6 +/- 8.1 min/48 h with nifedipine. Reductions were statistically significant for both drugs; the difference between bisoprolol and nifedipine was also significant (p < 0.0001).
• Funding: Not stated in the abstract; conducted by the TIBBS Investigators with manufacturer involvement.

Total duration of ischemia was reduced from 99.3 +/- 10.1 to 31.9 +/- 5.5 min/48 h with bisoprolol and from 101 +/- 9.1 to 72.6 +/- 8.1 min/48 h with nifedipine. Reductions were statistically significant for both drugs; the difference between bisoprolol and nifedipine was also significant (p < 0.0001).

What the evidence does not support

Started as first-line treatment for hypertension, beta blockers had little or no effect on all-cause mortality and were inferior to calcium-channel blockers for preventing stroke and cardiovascular events. (Source 18)

• Systematic review, Moderate certainty.
• Size: Up to 44,825 participants across comparisons; 13 studies in total.
• Who: Adults with primary hypertension randomised to a beta blocker versus placebo, diuretics, calcium-channel blockers or renin-angiotensin system inhibitors.
• How long: Trials of at least 12 months.
• Result: Versus calcium-channel blockers: all-cause mortality RR 1.07 (1.0 to 1.14), cardiovascular events RR 1.18 (1.08 to 1.29), stroke RR 1.24 (1.11 to 1.4). Versus renin-angiotensin system inhibitors: stroke RR 1.30 (1.11 to 1.53)
• Funding: Cochrane review summarised by its own authors; competing interests declared as none.

there is moderate-certainty evidence that beta-blockers have little or no effect on all-cause mortality when used as initial treatment for hypertension. This effect of beta-blockers on mortality is identical to that of diuretics and renin–angiotensin system inhibitors, but it is inferior to that of calcium-channel blockers.

In a meta-analysis of 105,951 people in hypertension trials, beta blockers carried a 16% higher relative risk of stroke than other antihypertensive drugs. (Source 20)

• Meta-analysis, Moderate certainty.
• Size: 105,951 participants in 13 randomised trials versus other drugs; 27,433 in 7 trials versus placebo or no treatment.
• Who: Adults with primary hypertension.
• How long: Long-term outcome trials.
• Result: The relative risk of stroke was 16% higher for beta blockers (95% CI 4-30%) than for other drugs. There was no difference for myocardial infarction. When the effect of beta blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta blockers (7-29%), about half that expected from previous hypertension trials. There was no difference for myocardial infarction or mortality.
• Funding: Not stated in the abstract; the authors are academic hypertension researchers.

In comparison with other antihypertensive drugs, the effect of beta blockers is less than optimum, with a raised risk of stroke. Hence, we believe that beta blockers should not remain first choice in the treatment of primary hypertension and should not be used as reference drugs in future randomised controlled trials of hypertension.

Beta blockers did not reduce death in people who had both heart failure and atrial fibrillation, in contrast to a clear benefit in sinus rhythm. (Source 5)

• Meta-analysis, High certainty.
• Size: 18,254 patients assessed from ten randomised placebo-controlled trials; 3,066 with atrial fibrillation.
• Who: Adults with heart failure and reduced ejection fraction, split by baseline rhythm on electrocardiograph.
• How long: Mean follow-up 1.5 years (SD 1.1)
• Result: β-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67-0·80; p<0·001), but not in patients with atrial fibrillation (0·97, 0·83-1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002).
• Funding: Menarini Farmaceutica Internazionale (administrative support grant)

The lack of efficacy for the primary outcome was noted in all subgroups of atrial fibrillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy. Interpretation: Based on our findings, β blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation.

In the manufacturer's placebo-controlled hypertension trials, several commonly feared side effects were no more frequent on bisoprolol than on placebo, and more people withdrew from placebo than from bisoprolol. (Source 21)

• Randomized trial, Moderate certainty.
• Size: 273 patients on 5-20 mg, 404 on 2.5-40 mg, 132 on placebo (two US placebo-controlled studies)
• Who: Adults with hypertension in two US placebo-controlled studies of 4 and 12 weeks.
• How long: 4 weeks (Study A) and 12 weeks (Study B)
• Result: Withdrawal for adverse events 3.3% on bisoprolol versus 6.8% on placebo; headache 8.8% on 5-20 mg versus 11.4% on placebo; dizziness 2.9% versus 3.8%; bronchospasm 0% in all groups.
• Funding: Manufacturer-conducted registration trials reported in the FDA label.

Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8% for patients on placebo. Withdrawals were less than 1% for either bradycardia or fatigue/lack of energy.

In the pooled heart failure trials, people stopped beta blockers no more often than placebo, which argues against the common assumption that these drugs are poorly tolerated. (Source 22)

• Meta-analysis, Moderate certainty.
• Size: 13,833 patients with HFrEF in sinus rhythm across 11 trials.
• Who: Adults aged 40-85 with HFrEF in sinus rhythm.
• How long: Median 1.3 years.
• Result: Small numbers of patients discontinued treatment because of hypotension (0.7-1.6%), bradycardia (0-3.5%), exacerbation of heart failure (2.0-4.9%), renal impairment (0-1.2%), and respiratory compromise (0.5-1.2%).
• Funding: Investigator-initiated with an unrestricted administrative grant from Menarini.

Overall, a numerically lower number of patients discontinued β blockers (14.4% v 15.6% in placebo). Table F in the appendix shows specific causes of β blocker discontinuation according to age and sex. Small numbers of patients discontinued treatment because of hypotension (0.7-1.6%), bradycardia (0-3.5%), exacerbation of heart failure (2.0-4.9%), renal impairment (0-1.2%), and respiratory compromise (0.5-1.2%).

Cardioselective beta blockers given to people with COPD produced no change in FEV1 or respiratory symptoms against placebo, including in severe airflow obstruction. (Source 6)

• Systematic review, Moderate certainty.
• Size: 22 randomised controlled trials (11 single-dose, 11 longer duration)
• Who: People with COPD, including those with severe chronic airways obstruction, a reversible component, or concomitant cardiovascular disease.
• How long: Single dose up to 16 weeks.
• Result: Cardioselective beta-blockers, given as a single dose or for longer duration, produced no change in FEV1 or respiratory symptoms compared to placebo, and did not affect the FEV1 treatment response to beta2-agonists. Subgroup analyses revealed no significant change in results for those participants with severe chronic airways obstruction, those with a reversible obstructive component, or those with concomitant cardiovascular disease.
• Funding: Cochrane review; no industry funding stated.

Cardioselective beta-blockers, given as a single dose or for longer duration, produced no change in FEV1 or respiratory symptoms compared to placebo, and did not affect the FEV1 treatment response to beta2-agonists.

Where the evidence is mixed

Against placebo, first-line beta blockers for hypertension reduced cardiovascular events and stroke but the evidence was rated low certainty, and coronary heart disease was not reduced. (Source 18)

• Systematic review, Low certainty.
• Size: 23,613 participants in 4 placebo-controlled studies (13 studies in the full review)
• Who: Adults with primary hypertension starting treatment, mostly in Western Europe and North America; atenolol was the beta blocker in about three-quarters of beta-blocker participants.
• How long: Trials of at least 12 months.
• Result: Versus placebo: all-cause mortality RR 0.99 (0.88 to 1.11), cardiovascular events RR 0.88 (0.79 to 0.97), stroke RR 0.80 (0.66 to 0.96), coronary heart disease RR 0.93 (0.81 to 1.07)
• Funding: Cochrane review summarised by its own authors in Heart; competing interests declared as none.

When used as initial treatment for hypertension, there is low-certainty evidence that beta-blockers may reduce the risk of cardiovascular events compared with placebo. This beneficial effect is a reflection of the substantial reduction in strokes with beta-blockers since there is little or no difference in coronary events between patients on beta-blockers and those on placebo.

Where the research disagrees

Whether beta blockers should still be offered as a first-line drug for uncomplicated high blood pressure

• Lindholm, Carlberg and Samuelsson (Lancet meta-analysis), Meta-analysis of 13 randomised trials (105,951 participants) against other antihypertensives plus 7 trials against placebo: we believe that beta blockers should not remain first choice in the treatment of primary hypertension and should not be used as reference drugs in future randomised controlled trials of hypertension. (Source 20)
• The Cochrane review authors, on the limits of their own finding, Cochrane systematic review of 13 trials, most judged at high risk of bias, with most outcomes rated low certainty: Atenolol (a second-generation or selective beta-blocker) was the beta-blocker used in three-quarters of participants in beta-blocker arms. Thus, it is not possible to say whether the suboptimal effectiveness and safety seen with beta-blockers is a property of atenolol or is a class effect of all beta-blockers. We did not find any trials that assessed the effects of vasodilatory beta-blockers in preventing mortality or cardiovascular events. (Source 23)

How much

• Reference intake: There is no reference intake for a prescription medicine; the dose is set by the prescriber. As a position, the UK/EU product information for hypertension and angina states that treatment is individually adjusted according to pulse rate and response, usually starting at 5 mg daily with a usual dose of 10 mg once daily, and that heart failure requires a separate stepwise titration. (Source 24)
• Upper limit: As a position, the UK/EU product information gives a maximum recommended dose of 20 mg once daily for hypertension and angina (the US label likewise tops out at 20 mg once daily). (Source 24)
• Studied: CIBIS-II gave bisoprolol 1.25 mg daily, progressively increased to a maximum of 10 mg per day, to 1,327 people with NYHA class III-IV heart failure already taking diuretics and an ACE inhibitor. (Source 25)
• Studied: TIBBS gave 10 mg of bisoprolol daily for four weeks and then 20 mg daily for a further four weeks to people with chronic stable angina. (Source 4)
• Studied: The two US placebo-controlled hypertension studies behind the label gave 5, 10 and 20 mg for 4 weeks (Study A) and 2.5, 10 and 40 mg for 12 weeks (Study B). (Source 21)

A common belief, and what the research shows

The belief: Beta blockers like bisoprolol make most people tired, dizzy and depressed, so they are hard to tolerate.

What the research shows: In the pooled individual-patient data from 11 placebo-controlled heart failure trials, slightly fewer people stopped the beta blocker than stopped placebo, and the review's authors wrote that apparent intolerance in practice 'could reflect false attribution to intercurrent events or preconceptions about side effects'. The manufacturer's own placebo-controlled hypertension studies show the same pattern: 'Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8% for patients on placebo.' Dizziness and headache were, if anything, reported slightly more often on placebo. That does not mean no one gets side effects - bradycardia is very common in heart failure and bronchospasm is an uncommon but real risk in asthma - but the typical fatigue attributed to these drugs is much less consistent in trials than in reputation.

Questions and answers

What is it?

Bisoprolol is a man-made prescription tablet, not a nutrient or anything found in food. It belongs to the beta-blocker family and is 'cardioselective', meaning it mostly blocks the beta1 receptors on the heart rather than the beta2 receptors in the airways. That selectivity is relative, not absolute: at doses of 20 mg and above it starts blocking airway receptors too. (Source 11)

What does it do in the body?

It blunts the effect of adrenaline on the heart. The most obvious result is a slower pulse at rest and during exercise, with a fall in the amount of blood the heart pumps per minute and little change in stroke volume. Blood pressure also falls, through mechanisms the label says are not fully established, possibly including reduced renin release from the kidney. (Source 1)

Is it good or bad for you?

It depends entirely on the setting. In heart failure with a weak left ventricle the evidence is strong and the benefit is survival: 11.8% died on bisoprolol versus 17.3% on placebo in CIBIS-II. In plain high blood pressure the same class showed no mortality benefit against placebo and was worse than calcium-channel blockers at preventing stroke. In someone with asthma it can narrow the airways. So it is good for a failing heart, mediocre as a first blood-pressure drug, and potentially harmful in brittle airway disease. (Source 3)

How do you get more of it?

Bisoprolol is available only on prescription and there is no food, supplement or behaviour that increases it. Where the dose goes is a clinical decision: for blood pressure and angina the product information describes individual adjustment by pulse rate and response, and for heart failure a formal titration phase is required before a maintenance dose is reached. This write-up reports what trials and labels used and is not a dose for any reader. (Source 24)

If it is harmful, what reduces it?

Bisoprolol clears from the body on its own with a plasma half-life of about 9 to 12 hours, so stopping it removes it within a day or two. The important point is that this speed is itself the hazard: abrupt cessation in someone with coronary artery disease has been followed by worsening angina, heart attack or ventricular arrhythmia, and the label advises tapering over roughly a week with medical supervision rather than stopping outright. (Source 12)

Why might someone be low in it or missing it?

The idea of being 'low' in bisoprolol does not apply, because it is a drug and not something the body makes or needs. What the literature does document is under-dosing: in the pooled heart failure trials people reached only about 73% of the target beta-blocker dose at the interim point, against 84% of the matching placebo dose, and discontinuation rose slightly with age. So the realistic reason someone is 'missing' it is that it was never started, or never titrated up. (Source 22)

Which whole foods contain it or feed it?

No whole food contains bisoprolol or feeds it; it is a synthetic molecule supplied as the fumarate salt in tablets. Food does matter in one narrow sense only: it does not interfere with absorption, so the tablet works the same taken with or without a meal. Tablets containing lactose are a separate issue for people with severe lactose or galactose intolerance. (Source 11)

What happens if you do not have it?

Nothing happens from lacking bisoprolol itself. What matters is the untreated condition. In CIBIS-II the people who did not get it - the placebo arm with class III-IV heart failure on diuretics and an ACE inhibitor - had a 17.3% death rate over a mean 1.3 years and more sudden deaths (6.3% versus 3.6%). For uncomplicated hypertension, by contrast, the Cochrane review found no mortality difference between beta blockers and placebo. (Source 3)

How can you test for it?

There is no routine blood test for bisoprolol levels, and none is used clinically. Its effect is judged physiologically instead: the product information says the dose is adjusted according to pulse rate and therapeutic success, so resting heart rate and blood pressure are the practical measures. Plasma concentrations have been characterised in pharmacokinetic studies (peak at 2 to 4 hours, 16 ng/mL at 5 mg up to 70 ng/mL at 20 mg) but they are a research measure, not a monitoring test. (Source 11)

References

1. DailyMed / US FDA label. BISOPROLOL FUMARATE TABLET - prescribing information (Solco Healthcare US, LLC). 2023. Read the source
2. DailyMed / US FDA label. BISOPROLOL FUMARATE TABLET - prescribing information (Solco Healthcare US, LLC). 2023. Read the source
3. Lancet (London, England). The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. 1999. PMID 10023943. Read the source
4. Journal of the American College of Cardiology. Medical treatment to reduce total ischemic burden: total ischemic burden bisoprolol study (TIBBS), a multicenter trial comparing bisoprolol and nifedipine. The TIBBS Investigators. 1995. PMID 7798508, DOI 10.1016/0735-1097(94)00345-q. Read the source
5. Lancet (London, England). Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. 2014. PMID 25193873, DOI 10.1016/s0140-6736(14)61373-8. Read the source
6. Cochrane Database of Systematic Reviews. Cardioselective beta-blockers for chronic obstructive pulmonary disease (CD003566). 2005. DOI 10.1002/14651858.CD003566.pub2. Read the source
7. DailyMed / US FDA label. BISOPROLOL FUMARATE TABLET - prescribing information (Solco Healthcare US, LLC). 2023. Read the source
8. electronic Medicines Compendium (UK) / Sandoz Limited. Bisoprolol Fumarate 5 mg Film-coated Tablets - Summary of Product Characteristics. 2022. Read the source
9. electronic Medicines Compendium (UK) / Sandoz Limited. Bisoprolol Fumarate 5 mg Film-coated Tablets - Summary of Product Characteristics. 2022. Read the source
10. electronic Medicines Compendium (UK) / Sandoz Limited. Bisoprolol Fumarate 5 mg Film-coated Tablets - Summary of Product Characteristics. 2022. Read the source
11. DailyMed / US FDA label. BISOPROLOL FUMARATE TABLET - prescribing information (Solco Healthcare US, LLC). 2023. Read the source
12. DailyMed / US FDA label. BISOPROLOL FUMARATE TABLET - prescribing information (Solco Healthcare US, LLC). 2023. Read the source
13. JAMA. The relative risk of incident coronary heart disease associated with recently stopping the use of beta-blockers. 1990. PMID 1968518, DOI 10.1001/jama.1990.03440120075040. Read the source
14. Drug safety. Discontinuation of beta-blockers and the risk of myocardial infarction in the elderly. 2007. PMID 17536880, DOI 10.2165/00002018-200730060-00008. Read the source
15. electronic Medicines Compendium (UK) / Sandoz Limited. Bisoprolol Fumarate 5 mg Film-coated Tablets - Summary of Product Characteristics. 2022. Read the source
16. electronic Medicines Compendium (UK) / Sandoz Limited. Bisoprolol Fumarate 5 mg Film-coated Tablets - Summary of Product Characteristics. 2022. Read the source
17. Cochrane Database of Systematic Reviews. Cardioselective beta-blockers for reversible airway disease (CD002992). 2002. DOI 10.1002/14651858.CD002992. Read the source
18. Heart. Cochrane corner: beta-blockers for hypertension. 2018. PMID 28756403, DOI 10.1136/heartjnl-2017-311585. Read the source
19. BMJ. Effect of age and sex on efficacy and tolerability of beta blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis. 2016. PMID 27098105, DOI 10.1136/bmj.i1855. Read the source
20. Lancet (London, England). Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. 2005. PMID 16257341, DOI 10.1016/s0140-6736(05)67573-3. Read the source
21. DailyMed / US FDA label. BISOPROLOL FUMARATE TABLET - prescribing information (Solco Healthcare US, LLC). 2023. Read the source
22. BMJ. Effect of age and sex on efficacy and tolerability of beta blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis. 2016. PMID 27098105, DOI 10.1136/bmj.i1855. Read the source
23. Heart. Cochrane corner: beta-blockers for hypertension. 2018. PMID 28756403, DOI 10.1136/heartjnl-2017-311585. Read the source
24. electronic Medicines Compendium (UK) / Sandoz Limited. Bisoprolol Fumarate 5 mg Film-coated Tablets - Summary of Product Characteristics. 2022. Read the source
25. Lancet (London, England). The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. 1999. PMID 10023943. Read the source