Регуляторное
Melinta Therapeutics, LLC; AstraZeneca AB. TOPROL-XL (metoprolol succinate) extended-release tablets, for oral use: full prescribing information US Food and Drug Administration-approved prescribing information, initial US approval 1992; DailyMed structured product labelling version 7, published 6 March 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=496ddfaa-7c9c-4888-b747-a210249b367a
Финансирование и результат
- Финансирование
- not stated; FDA-approved labelling carries no funding statement. The labeller submits the text and the Food and Drug Administration approves it; TOPROL-XL is a trademark of the AstraZeneca group of companies and the tablets are manufactured by AstraZeneca AB.
- Результат
- Indications: hypertension, long-term treatment of angina pectoris, and heart failure, to reduce the risk of cardiovascular mortality and heart-failure hospitalisation. Starting doses are 25 to 100 mg daily for hypertension, 100 mg daily for angina and 12.5 or 25 mg daily for heart failure, doubled every two weeks to the highest tolerated dose or 200 mg. Mechanism: a beta1-selective (cardioselective) adrenergic receptor blocking agent without intrinsic sympathomimetic activity; the preferential effect is not absolute and at higher plasma concentrations metoprolol also inhibits beta2 adrenoceptors, chiefly in bronchial and vascular musculature; relative beta1-selectivity diminishes and beta2 blockade increases above a plasma concentration of 300 nmol/l. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases atrioventricular nodal conduction; beta1-blocking effects of 30% to 80% of maximum, an 8% to 23% reduction in exercise heart rate, correspond to plasma concentrations of 30 to 540 nmol/l. The mechanism of the antihypertensive effect has not been elucidated, and the precise mechanism of benefit in heart failure has not been elucidated. Pharmacokinetics: average bioavailability of the extended-release tablet 77% relative to conventional metoprolol across 50 to 400 mg once daily; peak plasma levels after conventional tablets approximate 50% of those after intravenous administration, indicating about 50% first-pass metabolism; about 12% is bound to serum albumin; metoprolol is a racemic mixture primarily metabolised by CYP2D6 with stereoselective metabolism dependent on oxidation phenotype; plasma half-life ranges from about 3 to 7 hours and less than 5% of an oral dose is recovered unchanged in the urine, the rest as metabolites with no beta-blocking activity. Pharmacogenomics: CYP2D6 is absent in about 8% of Caucasians (poor metabolisers) and about 2% of most other populations, and poor metabolisers have several-fold higher metoprolol blood levels, decreasing cardioselectivity; quinidine 100 mg with immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the elimination half-life in extensive metabolisers, and propafenone 150 mg three times daily raised steady-state metoprolol 2- to 5-fold. Warnings: following abrupt cessation of certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred, so the dosage is reduced gradually over 1 to 2 weeks with monitoring, treatment is promptly reinstated if angina markedly worsens, and abrupt discontinuation is avoided even in patients treated only for hypertension; bradycardia including sinus pause, heart block and cardiac arrest have occurred; beta-blockers may prevent early warning signs of hypoglycaemia such as tachycardia and increase the risk for severe or prolonged hypoglycaemia, especially in diabetes, children and patients who are fasting; beta-adrenergic blockade may mask signs of hyperthyroidism and abrupt withdrawal may precipitate thyroid storm; patients with bronchospastic disease should in general not receive beta-blockers. In the MERIT-HF study, 10.3% of patients on this product and 12.2% on placebo discontinued for adverse reactions, with dizziness or vertigo in 1.8% against 1.0% and bradycardia in 1.5% against 0.4%; in a randomised trial of 8351 patients undergoing non-cardiac surgery, 100 mg started 2 to 4 hours before surgery and continued at 200 mg daily for 30 days raised bradycardia (6.6% against 2.4%), hypotension (15% against 9.7%), stroke (1.0% against 0.5%) and death (3.1% against 2.3%).
Регуляторное
Waylis Therapeutics LLC. COREG (carvedilol) tablets, for oral use: full prescribing information US Food and Drug Administration-approved labelling (NDA020297), initial US approval 1995, published in DailyMed; structured product labelling version 3, published 3 August 2026, label revised 10/2023, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=07c619c6-4a0c-445e-94fa-664a54f68a39
Финансирование и результат
- Финансирование
- not stated; FDA-approved labelling carries no funding statement. The labeller submits the text and the Food and Drug Administration approves it.
- Результат
- An alpha- and beta-adrenergic blocker indicated for chronic heart failure, left ventricular dysfunction after myocardial infarction and hypertension. No boxed warning. Bradycardia occurred in about 2% of hypertensive subjects, 9% of heart failure subjects and 6.5% of subjects with left ventricular dysfunction after infarction. In mild-to-moderate heart failure trials, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% on carvedilol against 3.6% and 2.5% on placebo, highest in the first 30 days of up-titration; in COPERNICUS (severe heart failure) 15.1% and 2.9% against 8.7% and 2.3%; in CAPRICORN (after infarction) hypotension or postural hypotension 20.2% against 12.6% and syncope 3.9% against 1.9%, causing discontinuation in 2.5% against 0.2%. Worsening heart failure or fluid retention may occur during up-titration. In heart failure, deterioration of renal function has occurred rarely, in patients with low blood pressure, ischaemic or diffuse vascular disease or renal insufficiency, returning to baseline when carvedilol was stopped. In heart failure with diabetes, carvedilol may worsen hyperglycaemia; beta-blockers may mask hypoglycaemia and increase the risk of severe or prolonged hypoglycaemia. Other warnings: angina, infarction and ventricular arrhythmias after abrupt cessation, so discontinuation over 1 to 2 weeks; bronchospasm; aggravated arterial insufficiency in peripheral vascular disease; masked hyperthyroidism and thyroid storm on withdrawal; phaeochromocytoma; Prinzmetal's angina; reduced response to adrenaline in anaphylaxis; intraoperative floppy iris syndrome during cataract surgery.
Регуляторное
Legacy Pharma USA, Inc. BETAPACE and BETAPACE AF (sotalol hydrochloride) tablets, for oral use: full prescribing information US Food and Drug Administration-approved labelling (NDA019865), published in DailyMed; structured product labelling version 2, published 20 December 2024, label revised 6/2023, 2024.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a6a7702f-36c9-45db-b640-453dc324baee
Финансирование и результат
- Финансирование
- not stated; FDA-approved labelling carries no funding statement. The labeller submits the text and the Food and Drug Administration approves it.
- Результат
- Sotalol combines beta blockade (class II) with prolongation of the cardiac action potential (class III). Boxed warning, life-threatening proarrhythmia: sotalol can cause life-threatening ventricular tachycardia associated with QT prolongation; initiate or reinitiate it in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring, hospitalise for at least 3 days, and reduce the dose, lengthen the interval or stop if QT reaches 500 ms or more; the dosing interval depends on creatinine clearance. Torsade de pointes risk rises with reduced creatinine clearance, female sex, higher doses, reduced heart rate and a history of sustained ventricular tachycardia, fibrillation or heart failure, and the QT effect and torsade risk are dose related. Sinus bradycardia below 50 beats per minute occurred in 13% of patients in trials and led to discontinuation in about 3%; sinus pause, arrest or node dysfunction in under 1%; second- or third-degree AV block in about 1%. It has not been shown to enhance survival in life-threatening ventricular arrhythmias. In four placebo-controlled trials in atrial fibrillation or flutter, fatigue occurred in 20% and 19% at 160 to 240 and above 240 to 320 mg daily against 9% on placebo and bradycardia in 13% and 12% against 3%; 17% discontinued for adverse events, 10% within two weeks, including proarrhythmia in 2.2%. Other warnings: abrupt discontinuation, bronchospasm, masked hypoglycaemia, thyroid abnormalities, anaphylaxis and major surgery.
Регуляторное
Upsher-Smith Laboratories, LLC. TENORMIN (atenolol) tablets: prescribing information US Food and Drug Administration-approved labelling (NDA018240), published in DailyMed; structured product labelling version 2, published 1 May 2026, label information updated 18 September 2025, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6e850b1e-28a4-4ff8-8ed7-bb0b29faa28a
Финансирование и результат
- Финансирование
- not stated; FDA-approved labelling carries no funding statement. The labeller submits the text and the Food and Drug Administration approves it.
- Результат
- A beta1-selective blocker without membrane-stabilising or intrinsic sympathomimetic activity; selectivity is not absolute and higher doses inhibit beta2 adrenoceptors in bronchial and vascular muscle. About 50% of an oral dose is absorbed, it undergoes little or no hepatic metabolism and is eliminated mainly by the kidney, half-life about 6 to 7 hours, with significant accumulation below a creatinine clearance of 35 ml/min/1.73 m2; elderly patients have about 50% lower clearance. No boxed warning. Warnings: beta blockade can depress myocardial contractility and precipitate cardiac failure, including in patients without previous failure; severe exacerbation of angina, myocardial infarction and ventricular arrhythmias after abrupt discontinuation in angina, possibly without preceding angina, so abrupt cessation is avoided even in hypertension; bradycardia and heart block with verapamil or diltiazem; bronchospastic disease; masking of hypoglycaemia and risk of severe or prolonged hypoglycaemia, especially in diabetes, children and fasting patients; masking of hyperthyroidism and possible thyroid storm on withdrawal; untreated phaeochromocytoma; fetal harm: atenolol from the second trimester has been associated with infants small for gestational age, and neonates exposed at parturition or through breastfeeding may develop hypoglycaemia and bradycardia; peripheral arterial circulatory disorders may be aggravated; patients with previous anaphylaxis may react more severely and be unresponsive to usual adrenaline doses. In controlled hypertension studies with elicited reports (399 on atenolol, 407 on placebo): tiredness 26% against 13%, cold extremities 12% against 5%, dizziness 13% against 6%, depression 12% against 9%, dreaming 3% against 1%, dyspnoea 6% against 4%. Postmarketing reports include impotence, Peyronie's disease, psychoses, hallucinations, exacerbation of psoriasis, antinuclear antibodies, lupus syndrome and Raynaud's phenomenon. In ISIS-1 (16,027 patients with suspected infarction), vascular mortality in days 0 to 7 was 3.89% (313 deaths) on atenolol against 4.57% (365), and dosing was reduced or stopped for cardiogenic shock in 4 intravenous and 35 oral cases and for heart block above first degree in 5 and 143.
Регуляторное
European Medicines Agency, Committee for Medicinal Products for Human Use. Hemangiol (propranolol) oral solution: summary of product characteristics, EPAR product information European Medicines Agency; marketing authorisation EU/1/14/919/001, first authorised 23 April 2014, renewed 15 January 2019; product information document of 12 June 2026, 2026.
https://www.ema.europa.eu/en/documents/product-information/hemangiol-epar-product-information_en.pdf
Финансирование и результат
- Финансирование
- not stated; EU product information carries no funding statement.
- Результат
- Propranolol for proliferating infantile haemangioma requiring systemic therapy, initiated in infants aged 5 weeks to 5 months and given for 6 months. Contraindicated in asthma or history of bronchospasm, second- or third-degree AV block, sinus node disease, bradycardia or hypotension below age-specific limits, cardiogenic shock, uncontrolled heart failure, Prinzmetal's angina, severe peripheral arterial disturbance including Raynaud's phenomenon, infants prone to hypoglycaemia and phaeochromocytoma. Propranolol prevents the catecholamine response that corrects hypoglycaemia and masks its adrenergic signs; it can aggravate hypoglycaemia in children during fasting, infection or vomiting, and episodes may present as seizures or coma; the risk remains throughout treatment, and corticosteroids may increase it. Lower respiratory infection with wheeze requires temporary stopping, and isolated bronchospasm permanent stopping. In three clinical studies of 435 infants, very common adverse reactions were sleep disorders (16.7%), aggravated respiratory tract infections such as bronchitis and bronchiolitis, diarrhoea (16.5%) and vomiting (11.5%); hypoglycaemic seizure, hypotension, Raynaud's phenomenon, agranulocytosis and hyperkalaemia in large ulcerated haemangioma are listed from compassionate use and the literature. Overdose may cause bradycardia, hypotension, AV block, heart failure, bronchospasm, hypoglycaemia and, because propranolol crosses the blood-brain barrier, seizures.
Независимое
Bateman BT, Patorno E, Desai RJ, Seely EW, Mogun H, Maeda A, et al. Late Pregnancy beta Blocker Exposure and Risks of Neonatal Hypoglycemia and Bradycardia Pediatrics, 2016.
doi:10.1542/peds.2016-0731PubMed 27577580
Финансирование и результат
- Участники
- 2 292 116
- Наблюдение
- infant records from birth to day 30
- Финансирование
- Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K08HD075831), the National Heart Lung and Blood Institute (K24HL096141) and the National Institute of Mental Health (K01MH099141); the Medicaid Analytic eXtract pregnancy cohort was supported by Agency for Healthcare Research and Quality grant R01HS018533.
- Результат
- Neonatal hypoglycaemia occurred in 4.3% of exposed against 1.2% of unexposed neonates and neonatal bradycardia in 1.6% against 0.5%. After propensity-score matching (10,561 exposed, 31,683 unexposed), adjusted odds ratios were 1.68 (95% CI 1.50 to 1.89) for hypoglycaemia and 1.29 (1.07 to 1.55) for bradycardia. Hypoglycaemia odds ratios by drug: labetalol 1.78 (1.55 to 2.04), metoprolol 1.64 (1.15 to 2.33), atenolol 1.54 (0.99 to 2.40).
Независимое
Morales DR, Dreischulte T, Lipworth BJ, Donnan PT, Jackson C, Guthrie B. Respiratory effect of beta-blocker eye drops in asthma: population-based study and meta-analysis of clinical trials British Journal of Clinical Pharmacology, 2016.
doi:10.1111/bcp.13006PubMed 27161880
Финансирование и результат
- Финансирование
- The role of one author was funded by a Scottish Government Chief Scientist Office Clinical Academic Fellowship (CAF1107). No funding bodies had any role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
- Результат
- Prescribing of non-selective beta-blocker eye drops to people with asthma and ocular hypertension fell from 23.0% to 13.4% between 2000 and 2012, and of selective ones from 10.5% to 0.9%. Acute exposure to non-selective beta-blocker eye drops raised the relative incidence of moderate asthma exacerbations (incidence rate ratio 4.83, 95% CI 1.56 to 14.94); chronic exposure did not. In the meta-analysis, acute non-selective eye drops lowered FEV1 by a mean 10.9% (-14.9 to -6.9), with falls of 20% or more in one in three; selective eye drops in people sensitive to non-selective ones lowered FEV1 by 6.3% (-11.7 to -0.8).
Независимое
Dransfield MT, Voelker H, Bhatt SP, Brenner K, Casaburi R, Come CE, et al.; BLOCK COPD Trial Group. Metoprolol for the Prevention of Acute Exacerbations of COPD New England Journal of Medicine, 2019.
doi:10.1056/NEJMoa1908142PubMed 31633896
Финансирование и результат
- Регистрация
- NCT02587351
- Участники
- 532
- Наблюдение
- treatment period 336 to 350 days; stopped early for futility and safety concerns
- Финансирование
- Funded by the Department of Defense. The paper states that the Department of Defense funded the trial but had no role in its design, in the accrual or analysis of the data, or in the preparation of the manuscript, and that no commercial entity was involved in the trial.
- Результат
- Extended-release metoprolol (n = 268) against placebo (n = 264). Median time to first exacerbation 202 against 222 days, hazard ratio 1.05 (95% CI 0.84 to 1.32). Exacerbation leading to hospitalisation (severe or very severe): hazard ratio 1.91 (1.29 to 2.83), adjusted 2.08 (1.37 to 3.14); rate ratio 3.71 (1.10 to 16.98) for very severe exacerbation. Hospitalisation for any cause 0.66 against 0.42 per person-year. During treatment 11 patients died on metoprolol and 5 on placebo (hazard ratio 2.18, 0.76 to 6.29), 7 against 1 of the deaths attributed to COPD. FEV1, 6-minute walk distance and St George's Respiratory Questionnaire score did not differ.
Независимое
Bouri S, Shun-Shin MJ, Cole GD, Mayet J, Francis DP. Meta-analysis of secure randomised controlled trials of beta-blockade to prevent perioperative death in non-cardiac surgery Heart, 2014.
doi:10.1136/heartjnl-2013-304262PubMed 23904357
Финансирование и результат
- Участники
- 10 529
- Наблюдение
- 30 days or to hospital discharge
- Финансирование
- One author is supported by the British Heart Foundation (FS/10/038).
- Результат
- In the nine secure trials, 162 of 5264 patients randomised to beta-blockers and 129 of 5265 randomised to placebo died: relative risk 1.27 (95% CI 1.01 to 1.60), p = 0.04, without heterogeneity (I2 0%). Beta-blockade reduced non-fatal myocardial infarction (relative risk 0.73, p = 0.001) and increased stroke (1.73, p = 0.05) and hypotension (1.51, p < 0.00001); one large trial dominated these results. The two DECREASE trials gave a mortality relative risk of 0.42 (0.15 to 1.23), diverging from the secure trials (p = 0.05). The authors ask guideline bodies to retract recommendations based on these data and estimate that refraining from the European Society of Cardiology recommendation could prevent up to 10,000 deaths a year in the United Kingdom.
Независимое
Boal AH, Smith DJ, McCallum L, Muir S, Touyz RM, Dominiczak AF, et al. Monotherapy with major antihypertensive drug classes and risk of hospital admissions for mood disorders Hypertension, 2016.
doi:10.1161/HYPERTENSIONAHA.116.08188PubMed 27733585
Финансирование и результат
- Участники
- 144 066
- Наблюдение
- up to 5 years; 641,685 person-years
- Финансирование
- S. Padmanabhan is funded by the Medical Research Council (MR/M016560/1 and The AIM-HY Study) and the British Heart Foundation (PG/12/85/29925 and CS/16/1/31878); D.J. Smith by a Lister Institute Prize Fellowship; L. McCallum by a BHF fellowship (FS/14/52/30901); A.F. Dominiczak has funding from the Scottish Ecosystem for Precision Medicine.
- Результат
- 299 hospital admissions with a mood disorder, median time 847 days. Against ACE inhibitors or angiotensin receptor blockers, which had the lowest risk, calcium antagonists had a hazard ratio of 2.28 (95% CI 1.13 to 4.58) and beta blockers 2.11 (1.12 to 3.98); no antihypertensive 1.63 (0.94 to 2.82) and thiazides 1.56 (0.65 to 3.73). The authors describe the findings as exploratory.
Независимое
Nazarzadeh M, Bidel Z, Canoy D, Copland E, Wamil M, Majert J, et al.; on behalf of the Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis Lancet, 2021.
doi:10.1016/S0140-6736(21)01920-6PubMed 34774144
Финансирование и результат
- Участники
- 145 939
- Наблюдение
- median 4.5 years (IQR 2.0)
- Финансирование
- British Heart Foundation (MN, grant FS/19/36/34346; KR and DC, grant PG/18/65/33872), the National Institute for Health Research Oxford Biomedical Research Centre, the Oxford Martin School and the UKRI Global Challenge Research Fund (ES/P011055/1). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
- Результат
- Of 145,939 participants followed for a median 4.5 years, 9883 were diagnosed with new-onset type 2 diabetes; the incidence per 1000 person-years was 16.44 (95% CI 16.01 to 16.87) in the comparator group and 15.94 (15.47 to 16.42) in the intervention group. A 5 mm Hg reduction in systolic blood pressure reduced the risk of type 2 diabetes by 11% (hazard ratio 0.89, 95% CI 0.84 to 0.95). In a network meta-analysis of 22 trials, compared with placebo, calcium channel blockers had no material effect (relative risk 1.02, 95% CI 0.92 to 1.13, 11% direct evidence), angiotensin-converting enzyme inhibitors (0.84, 0.76 to 0.93) and angiotensin II receptor blockers (0.84, 0.76 to 0.92) reduced the risk, and beta blockers (1.48, 1.27 to 1.72) and thiazide diuretics (1.20, 1.07 to 1.35) raised it. In a complementary mendelian randomisation analysis, each 5 mm Hg genetically influenced lower systolic blood pressure was associated with a 12% lower risk of type 2 diabetes (0.88, 0.84 to 0.92), and the pattern across drug classes was reproduced except for thiazide diuretics, for which the genetic evidence lacked power.
Независимое
MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results BMJ, 1992.
doi:10.1136/bmj.304.6824.405PubMed 1445513
Финансирование и результат
- Участники
- 4 396
- Наблюдение
- mean 5.8 years; 25,355 patient-years
- Финансирование
- The report carries no separate funding section. It is issued by the Medical Research Council Working Party, the trial ran within the MRC general practice research framework, and data were reviewed and analysed by its coordinating centre staff. The acknowledgements thank Merck Sharp and Dohme for supplying Moduret and placebo, Imperial Chemical Industries for supplies of Tenormin and placebo, and Bayer for supplies of Adalat.
- Поддержка в натуральной форме
- Merck Sharp and Dohme supplied hydrochlorothiazide-amiloride (Moduret) and placebo; Imperial Chemical Industries supplied atenolol (Tenormin) and placebo; Bayer supplied nifedipine (Adalat).
- Результат
- Single-blind randomisation to atenolol 50 mg daily (1102 patients), hydrochlorothiazide 25 or 50 mg with amiloride 2.5 or 5 mg (1081) or placebo (2213). Randomised treatment accounted for 55% of patient-years in the atenolol group, supplemented by the diuretic for 16%, and for 69% in the diuretic group. Event rates per 1000 patient-years with atenolol (6330 patient-years), diuretic (6290) and placebo (12,735): strokes 56 (9.0), 45 (7.3) and 134 (10.8); coronary events 80 (12.8), 48 (7.7) and 159 (12.7); all cardiovascular events 151 (24.6), 107 (17.4) and 309 (25.2); deaths from all causes 167 (26.4), 134 (21.3) and 315 (24.7). After adjustment the diuretic reduced stroke by 31% (95% CI 3% to 51%), coronary events by 44% (21% to 60%) and all cardiovascular events by 35% (17% to 49%) against placebo; the beta-blocker group showed no significant reduction in these end points, and coronary and all cardiovascular event rates were significantly lower with the diuretic than with the beta-blocker (p = 0.006 and p = 0.007). Withdrawals per 1000 patient-years were higher with atenolol than placebo for impaired glucose tolerance (5.8 against 2.7), Raynaud's phenomenon (11.3 against 0.3), dyspnoea (22.9 against 1.1), lethargy (19.1 against 2.0) and low pulse rate (28.0 against 0.0). Over five years 333 atenolol patients were withdrawn for suspected major side effects against 160 on the diuretic and 82 on placebo; about 25% were lost to follow-up, and 63% of the atenolol group, 48% of the diuretic group and 53% of the placebo group stopped their randomised treatment.
Регуляторное
ANI Pharmaceuticals, Inc. INDERAL LA (propranolol hydrochloride) extended-release capsules: prescribing information US Food and Drug Administration-approved labelling (NDA018553), published in DailyMed; structured product labelling version 11, published 31 August 2026, label information updated 24 August 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=35d28979-36b1-4630-b85e-a44e0a443734
Финансирование и результат
- Финансирование
- not stated; FDA-approved labelling carries no funding statement. The labeller submits the text and the Food and Drug Administration approves it.
- Результат
- A non-selective beta-adrenergic blocker; at doses above those required for beta blockade it exerts a quinidine-like membrane action. It crosses the blood-brain barrier and the placenta and enters breast milk. Possible antihypertensive mechanisms include decreased cardiac output, inhibition of renin release by the kidneys and diminished tonic sympathetic outflow from brain vasomotor centres. No boxed warning. Warnings: exacerbation of angina and myocardial infarction after abrupt discontinuance, so the dose is reduced over at least a few weeks; hypersensitivity including anaphylactic reactions, and Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme; precipitation of more severe heart failure; bronchospasm, since it blocks catecholamine-mediated bronchodilation; masking of hypoglycaemia and risk of severe or prolonged hypoglycaemia, also reported after prolonged physical exertion and in renal insufficiency; masking of hyperthyroidism, with thyroid storm after abrupt withdrawal, and changes in thyroid tests (T4 and reverse T3 up, T3 down); severe bradycardia needing a pacemaker in Wolff-Parkinson-White syndrome; patients with previous anaphylaxis may be unresponsive to usual adrenaline doses, and adrenaline given during long-term propranolol may cause uncontrolled hypertension from unopposed alpha stimulation. Reported adverse reactions include bradycardia, heart failure, intensified AV block, Raynaud-type arterial insufficiency, mental depression with insomnia, lassitude and fatigue, catatonia, hallucinations, vivid dreams, an acute reversible syndrome of disorientation and short-term memory loss, mesenteric arterial thrombosis, ischaemic colitis, agranulocytosis, systemic lupus erythematosus, male impotence and Peyronie's disease; fatigue, lethargy and vivid dreams appear dose related with immediate-release forms. In pregnancy, intrauterine growth retardation, small placentas and congenital abnormalities have been reported, and neonates exposed at parturition have shown bradycardia, hypoglycaemia and respiratory depression. In hypertension, propranolol has been associated with raised serum potassium, transaminases and alkaline phosphatase.
Независимое
Williams H, Jagpal P, Sandilands E, Morrison E, Gray L, Thanacoody HKR, et al. The problem of propranolol poisoning British Journal of Clinical Pharmacology, 2025.
doi:10.1002/bcp.70147PubMed 40611599
Финансирование и результат
- Участники
- 359
- Наблюдение
- enquiries 1 January 2022 to 31 December 2023
- Финансирование
- The authors state that they received no remuneration from any manufacturer or other company in connection with this study; no funder is named.
- Результат
- 444 enquiries concerned 363 intentional propranolol overdoses in 359 patients, 248 (69%) women, median age 32 years (interquartile range 22 to 45), 52 (14%) under 18. The indication was known in 121 cases and was anxiety in 111. In 43 of 61 cases with a co-prescribed antidepressant, both were taken. Outcome was confirmed in 159 exposures (44%): 110 recovered completely, 13 had ongoing features, one had permanent sequelae and 35 died. The authors advise primary care prescribers that propranolol for anxiety can be dangerous.
Финансировано индустрией
Chen ZM, Pan HC, Chen YP, Peto R, Collins R, Jiang LX, et al.; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial Lancet, 2005.
doi:10.1016/S0140-6736(05)67661-1PubMed 16271643
Финансирование и результат
- Регистрация
- NCT00222573
- Участники
- 45 852
- Наблюдение
- scheduled treatment until discharge or up to 4 weeks in hospital; mean 15 days in survivors
- Финансирование
- The funding statement of the trial report could not be read: the publisher page requires a subscription. Registry NCT00222573 names the University of Oxford as lead sponsor and Sanofi and AstraZeneca as collaborators. Industry collaboration sets the class to industry.
- Результат
- Metoprolol up to 15 mg intravenously then 200 mg orally daily (n = 22,929) against placebo (n = 22,923). Neither co-primary outcome was reduced: death, reinfarction or cardiac arrest 2166 (9.4%) against 2261 (9.9%), odds ratio 0.96 (95% CI 0.90 to 1.01); death 1774 (7.7%) against 1797 (7.8%), odds ratio 0.99 (0.92 to 1.05). Per 1000 treated, metoprolol prevented five reinfarctions (464, 2.0%, against 568, 2.5%; odds ratio 0.82, 0.72 to 0.92) and five episodes of ventricular fibrillation (581, 2.5%, against 698, 3.0%; 0.83, 0.75 to 0.93) and caused 11 more cases of cardiogenic shock (1141, 5.0%, against 885, 3.9%; 1.30, 1.19 to 1.41). The excess of shock arose mainly on days 0 to 1, when the overall effect on death, reinfarction, arrest or shock was adverse; net hazard was substantial in haemodynamically unstable patients and net benefit moderate in relatively stable patients after days 0 to 1.
Справочное издание
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010PubMed 39552041
Финансирование и результат
- Финансирование
- National Human Genome Research Institute [HG002273]; Office of the Director, NIH OD [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; Biotechnology and Biological Sciences Research Council [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; State Secretariat for Education, Research and Innovation; EMBL Australia. Funding for open access charge: National Institutes of Health.
- Результат
- Reviewed human UniProtKB entries read on 2026-10-22 through rest.uniprot.org, annotation update 2026-09-02. ADRB1 (P08588, entry version 234): G-protein-coupled catecholamine receptor coupling to G(s) to activate adenylate cyclase and the cAMP pathway; binds adrenaline and noradrenaline with approximately equal affinity; stimulates cardiomyocyte contraction; involved in the regulation of sleep and wake behaviour, and ADRB1 variants are associated with inter-individual variation in resting heart rate and with familial natural short sleep 2. ADRB2 (P07550, version 260): couples to both G(s) and G(i); binds adrenaline with about 30-fold greater affinity than noradrenaline; in the heart (annotated by similarity) G(s) signalling regulates contraction rate and G(i)/PI3K/Akt signalling exerts cardioprotective effects under hypoxia and oxidative stress; regulates cellular pH through the Na+/H+ exchanger SLC9A3 independently of PKA; phosphorylated by PKA and GRK2 after agonist binding, which mediates homologous desensitisation; the Gly-16 allele is overrepresented in nocturnal asthma. ADRB3 (P13945, version 234): couples to G(s) and G(i); potency noradrenaline greater than adrenaline; expressed mainly in adipose tissue; involved in thermogenesis and lipolysis in brown and white adipose tissue through G(s) and the cAMP-PKA axis, annotated by similarity to the mouse protein (P25962); activates lipolysis through G(i) and the ERK1/2 MAP kinase cascade (experimental, PubMed:10207024, a study in mouse 3T3-F442A adipocytes and HEK-293 cells expressing the human receptor); participates in relaxation of blood vessels and of the urinary bladder (experimental, PubMed:10188996, a study of isolated human detrusor muscle); mediates negative inotropic effects in cardiomyocytes through nitric oxide synthase and cGMP; the Arg-64 variant is associated with weight gain and susceptibility to type 2 diabetes.
Независимое
Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic hyperglycemia in insulin-dependent diabetes mellitus Journal of Clinical Investigation, 1982.
doi:10.1172/jci110455PubMed 6120181
Финансирование и результат
- Участники
- 15
- Наблюдение
- two study days per subject
- Финансирование
- This study was supported by U.S. Public Health Service grants AM 27085, RR 00036 and AM 20579.
- Результат
- After intravenous regular insulin 0.075 U/kg, glucose recovery from hypoglycaemia during propranolol infusion was compared with saline. In non-diabetic controls beta-adrenergic blockade left glucose counterregulation unaffected. In patients with insulin-dependent diabetes, whose glucagon responses to hypoglycaemia were markedly diminished, glucose recovery was significantly impaired during blockade, and posthypoglycaemic hyperglycaemia was prevented; the dependence on adrenaline-mediated beta-adrenergic mechanisms varied inversely with residual glucagon secretion.
Независимое
Pollare T, Lithell H, Selinus I, Berne C. Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients BMJ, 1989.
doi:10.1136/bmj.298.6681.1152PubMed 2500169
Финансирование и результат
- Участники
- 60
- Наблюдение
- placebo run-in of 4 to 6 weeks, then two 16-week crossover treatment periods
- Финансирование
- Supported by grants from the Swedish Medical Research Council, the Swedish Diabetes Association, the Ernfors Family Fund, the King Gustaf V Fund, the Heart and Lung Fund and the Forenade Liv Mutual Life Insurance Corporation.
- Результат
- Double-blind, double-dummy crossover of metoprolol 100 mg twice daily and atenolol 25 mg twice daily. Insulin-mediated glucose uptake during a euglycaemic hyperinsulinaemic clamp fell from 5.6 to 4.5 mg/kg/min on metoprolol and from 5.6 to 4.9 on atenolol; fasting insulin, glucose and glycated haemoglobin rose slightly, and the small insulin response to intravenous glucose suggested inhibited insulin release. Against placebo (total triglycerides 2.04 mmol/l, HDL cholesterol 1.03 mmol/l), total serum triglycerides rose by 0.59 mmol/l on metoprolol and 0.43 on atenolol and HDL cholesterol fell by 0.06 and 0.08 mmol/l; LDL cholesterol did not rise. Difficulty in concentrating and vivid dreams were more pronounced on metoprolol.
Независимое
Choi HK, Soriano LC, Zhang Y, Rodríguez LA. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study BMJ, 2012.
doi:10.1136/bmj.d8190PubMed 22240117
Финансирование и результат
- Участники
- 74 768
- Наблюдение
- UK general practice records, 2000 to 2007
- Финансирование
- This work was supported in part by grants from the National Institutes of Health (AR056291 and P60AR047785). The Spanish Centre for Pharmacoepidemiological Research has received an unrestricted research grant from Novartis to work on other projects related to gout. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication.
- Результат
- Among people with hypertension, multivariable relative risks of incident gout with current use were 0.81 (95% CI 0.70 to 0.94) for losartan, 1.29 (1.16 to 1.43) for other angiotensin receptor blockers, 1.24 (1.17 to 1.32) for ACE inhibitors, 0.87 (0.82 to 0.93) for calcium channel blockers, 2.36 (2.21 to 2.52) for diuretics and 1.48 (1.40 to 1.57) for beta blockers. With losartan the relative risk fell from 0.98 below one year of use to 0.87 at 1 to 1.9 years and 0.71 at two years or more (P<0.05 for trend).
Финансирование не установлено
Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction JAMA, 2002.
doi:10.1001/jama.288.3.351PubMed 12117400
Финансирование и результат
- Наблюдение
- trials of at least 6 months
- Финансирование
- not read: the publisher page refused access and the archived copy holds no article text.
- Результат
- In trials involving more than 35,000 subjects, beta-blockers did not significantly raise the annual risk of reported depressive symptoms (6 per 1000 patients, 95% CI -7 to 19). They raised reported fatigue by 18 per 1000 patients a year (5 to 30), one additional report per 57 patients treated for a year, and reported sexual dysfunction by 5 per 1000 a year (2 to 8), one per 199. Risks did not differ by lipid solubility; fatigue was significantly more frequent with early-generation than late-generation beta-blockers (P = 0.04). Adverse events were abstracted from trial reports.
Справочное издание
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010PubMed 39552041
Финансирование и результат
- Финансирование
- National Human Genome Research Institute [HG002273]; Office of the Director, NIH OD [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; Biotechnology and Biological Sciences Research Council [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; State Secretariat for Education, Research and Innovation; EMBL Australia. Funding for open access charge: National Institutes of Health.
- Результат
- Reviewed human UniProtKB entries read on 2026-10-21 through rest.uniprot.org. ADRB1 (P08588, entry version 234): G-protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and the cAMP-dependent pathway; binds adrenaline and noradrenaline with approximately equal affinity; as part of the sympathetic nervous system it stimulates cardiomyocyte contraction; located in the cell membrane. ADCY5 (O95622, version 207): adenylate cyclase type 5, EC 4.6.1.1, catalysing ATP to 3',5'-cyclic AMP plus diphosphate with Mg2+ or Mn2+ as cofactor; activated by the G(s) alpha protein GNAS and mediating signalling downstream of ADRB1. PRKACA (P17612, version 260): cAMP-dependent protein kinase catalytic subunit alpha, EC 2.7.11.11, phosphorylating protein seryl and threonyl residues with ATP; activated by cAMP, which dissociates the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free catalytic subunits; RYR2 is among its substrates. PLN (P26678, version 222): phospholamban, expressed in heart muscle, reversibly inhibits ATP2A2/SERCA2 in the cardiac sarcoplasmic reticulum by lowering the pump's apparent affinity for Ca2+ and modulates calcium re-uptake during muscle relaxation; the inhibition is alleviated by phosphorylation, Ser16 being phosphorylated by PKA and DMPK and Thr17 by CaMK2. ATP2A2 (P16615, version 263): sarcoplasmic/endoplasmic reticulum calcium ATPase 2, EC 7.2.2.10, a magnesium-dependent pump hydrolysing ATP while translocating calcium from the cytosol into the sarcoplasmic reticulum lumen and regulating the contraction-relaxation cycle; isoforms 2 and 3 are highly expressed in the heart. RYR2 (Q92736, version 246): ryanodine receptor 2, a cytosolic calcium-activated calcium channel that releases Ca2+ from the sarcoplasmic reticulum and triggers cardiac muscle contraction, activated in cardiac myocytes by the rise in cytosolic Ca2+ that follows activation of the L-type channel CACNA1C; Ser2031 is phosphorylated by PKA and Ser2808 by CaMK2D and PKA, and the channel is identified in a complex with FKBP1B, the PKA catalytic subunit, PRKAR2A, AKAP6 and the phosphatases PP1 and PP2A. TNNI3 (P19429, version 230): cardiac troponin I, the inhibitory subunit of troponin, the thin-filament regulatory complex that confers calcium sensitivity to striated muscle actomyosin ATPase; Ser23 and Ser24 are phosphorylated by PKA and PKD/PRKD1. HCN4 (Q9Y3Q4, version 204): hyperpolarisation-activated channel permeable to Na+ and K+ with very slow activation that contributes to the native pacemaker current of the heart, If, which regulates the rhythm of the heart beat; activated by cAMP, whose binding removes a tonic inhibition conferred by the cyclic nucleotide-binding domain and leads to assembly of an active tetramer and channel opening; inhibited by extracellular Cs+; highly expressed in heart. CYP2D6 (P10635, version 245): cytochrome P450 monooxygenase that inserts one oxygen atom into a substrate and reduces the second to water with two electrons provided by NADPH through cytochrome P450 reductase, and is involved in the oxidative metabolism of drugs including antiarrhythmics and adrenoceptor antagonists.
Регуляторное
Sun Pharmaceutical Industries, Inc.; Harman Finochem Ltd. Bisoprolol fumarate tablets, USP: full prescribing information US Food and Drug Administration-approved prescribing information, published in DailyMed; structured product labelling version 4, published 19 October 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7556f457-c4d3-49d6-b383-0ade6d489091
Финансирование и результат
- Финансирование
- not stated; FDA-approved labelling carries no funding statement. The labeller submits the text and the Food and Drug Administration approves it.
- Результат
- Indicated in the management of hypertension, alone or with other antihypertensive agents; the usual starting dose is 5 mg once daily, 2.5 mg in some patients, increased to 10 mg and if necessary 20 mg. A beta1-selective (cardioselective) adrenoceptor blocking agent without significant membrane-stabilising or intrinsic sympathomimetic activity in its therapeutic dosage range; cardioselectivity is not absolute and at doses of 20 mg or more bisoprolol also inhibits beta2 adrenoceptors, chiefly in bronchial and vascular musculature, so the lowest effective dose is important. It is a racemic mixture and the S(-) enantiomer carries most of the beta-blocking activity. Absolute bioavailability after 10 mg is about 80%, first-pass metabolism about 20%, serum protein binding about 30%, peak concentrations at 2 to 4 hours, plasma elimination half-life 9 to 12 hours and steady state within 5 days of once-daily dosing. Bisoprolol is eliminated equally by renal and non-renal pathways, with about 50% of the dose appearing unchanged in the urine and the remainder as inactive metabolites, and it is not metabolised by cytochrome P450 II D6 (debrisoquin hydroxylase). With creatinine clearance below 40 ml/min the plasma half-life is increased about threefold, and in cirrhosis the half-life ranges from 8.3 to 21.7 hours. The most prominent effect is negative chronotropy, reducing resting and exercise heart rate, with a fall in cardiac output and little change in stroke volume; electrophysiology studies in man show that bisoprolol significantly decreases heart rate, increases sinus node recovery time, prolongs atrioventricular node refractory periods and prolongs atrioventricular nodal conduction during rapid atrial stimulation. The mechanism of the antihypertensive effect has not been completely established; decreased cardiac output, inhibition of renin release by the kidneys and diminished tonic sympathetic outflow may be involved. In placebo-controlled US trials of mild-to-moderate hypertension, placebo-subtracted falls in sitting pressure after 3 to 4 weeks were 5.0/4.8 mm Hg at 5 mg, 5.8/7.7 at 10 mg and 7.4/8.7 at 20 mg, with placebo-subtracted heart-rate reductions of 6.7, 8.2 and 10.8 beats per minute; blood pressure returned to baseline when bisoprolol was tapered over two weeks in a long-term study. Pulmonary function studies in healthy volunteers, asthmatics and patients with chronic obstructive pulmonary disease found slight asymptomatic increases in airways resistance and decreases in forced expiratory volume at 20 mg and higher, similar to other cardioselective beta-blockers and reversed by bronchodilator therapy. Warnings: exacerbation of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia have been observed in patients with coronary artery disease after abrupt cessation of beta-blocker therapy, so patients are cautioned against interruption without medical advice, therapy is tapered over approximately one week under careful observation even without overt coronary artery disease, and treatment is reinstituted at least temporarily if withdrawal symptoms occur; beta-blockers may mask some manifestations of hypoglycaemia, particularly tachycardia, and non-selective beta-blockers may potentiate insulin-induced hypoglycaemia and delay recovery of serum glucose, which is less likely with a beta1-selective agent; beta-adrenergic blockade may mask clinical signs of hyperthyroidism and abrupt withdrawal may precipitate thyroid storm. Contraindicated in cardiogenic shock, overt cardiac failure, second- or third-degree atrioventricular block and marked sinus bradycardia. In two US placebo-controlled studies, withdrawal for adverse events occurred in 3.3% of patients receiving bisoprolol and 6.8% receiving placebo, and bradycardia, diarrhoea, asthenia, fatigue and sinusitis appeared dose related.
Независимое
Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-blockers for hypertension Cochrane Database of Systematic Reviews, 2017.
doi:10.1002/14651858.CD002003.pub5PubMed 28107561
Финансирование и результат
- Участники
- 91 561
- Наблюдение
- randomised trials of at least one year
- Финансирование
- Internal sources: South African Medical Research Council; Stellenbosch University; University of the Western Cape; University of Cape Town. External sources: no sources of support supplied.
- Результат
- Against placebo: all-cause mortality 51 against 52 per 1000 (RR 0.99, 95% CI 0.88 to 1.11; moderate certainty), total cardiovascular disease 57 against 64 per 1000 (RR 0.88, 0.79 to 0.97; low certainty), stroke 18 against 23 per 1000 (RR 0.80, 0.66 to 0.96; low certainty) and coronary heart disease 34 against 37 per 1000 (RR 0.93, 0.81 to 1.07; moderate certainty). Against calcium channel blockers: mortality 78 against 73 per 1000 (RR 1.07, 1.00 to 1.14), total cardiovascular disease 96 against 81 per 1000 (RR 1.18, 1.08 to 1.29) and stroke 29 against 23 per 1000 (RR 1.24, 1.11 to 1.40), moderate certainty. Against renin-angiotensin system inhibitors: stroke RR 1.30 (1.11 to 1.53) and discontinuation for adverse events RR 1.41 (1.29 to 1.54), moderate certainty. In the single trial in people aged 65 or older, atenolol carried more coronary heart disease than a diuretic (RR 1.63, 1.15 to 2.32). No outcome trial of a vasodilating beta-blocker such as nebivolol was found, and most trials carried a high risk of bias. The authors conclude that initiating treatment with beta-blockers leads to modest reductions in cardiovascular disease and little or no effect on mortality, inferior to those of other antihypertensive drugs.
Независимое
Kristensen AMD, Rossello X, Atar D, Yndigegn T, Kimura T, Latini R, et al.; Beta-Blocker Trialists' Collaboration Study Group. Beta-blockers after myocardial infarction with normal ejection fraction New England Journal of Medicine, 2026.
doi:10.1056/NEJMoa2512686PubMed 41211954
Финансирование и результат
- Регистрация
- PROSPERO CRD420251119176
- Участники
- 17 801
- Наблюдение
- median 3.6 years (interquartile range 2.3 to 4.6)
- Финансирование
- Supported by the Centro Nacional de Investigaciones Cardiovasculares Carlos III (the REBOOT trial); the Swedish Research Council, the Swedish Heart and Lung Association and the Region of Stockholm (the REDUCE-AMI trial); the South-Eastern Norway Regional Health Authority and the Research Council of Norway (the BETAMI trial); the Danish Heart Foundation and the Novo Nordisk Foundation (the DANBLOCK trial); and the Research Institute for Production Development, Kyoto, Japan (the CAPITAL-RCT trial). No company is named among the funders.
- Результат
- One-stage fixed-effects Cox proportional-hazards analysis of individual-patient data. Of 17,801 patients, 8831 (49.6%) were assigned a beta-blocker and 8970 (50.4%) none. Death from any cause, myocardial infarction or heart failure occurred in 717 patients (8.1%) against 748 (8.3%), hazard ratio 0.97 (95% CI 0.87 to 1.07), P = 0.54, over a median 3.6 years. Death from any cause occurred in 335 against 326 patients (hazard ratio 1.04, 0.89 to 1.21), myocardial infarction in 360 against 407 (0.89, 0.77 to 1.03) and heart failure in 75 against 87 (0.87, 0.64 to 1.19).
Финансировано индустрией
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet, 1999.
doi:10.1016/S0140-6736(99)04440-2PubMed 10376614
Финансирование и результат
- Участники
- 3 991
- Наблюдение
- mean 1 year; stopped early at the second interim analysis
- Финансирование
- The funding statement of the trial report could not be read: the publisher page is behind a subscription, the archived copy stops at the abstract and the article is absent from PubMed Central; the archived full text of the companion report in JAMA (doi 10.1001/jama.283.10.1295) contains no funding section. The design paper of the Beta-Blockers in Heart Failure Collaborative Group, which lists this trial among those proposed for pooling, states that of those trials only BEST was principally sponsored by public bodies and that all the others were funded by pharmaceutical companies. Metoprolol CR/XL is marketed as TOPROL-XL, a trademark of the AstraZeneca group of companies.
- Результат
- Double-blind randomisation, after a 2-week single-blind placebo run-in, to metoprolol CR/XL 12.5 mg once daily in class III or IV or 25 mg in class II (n = 1990), titrated over 8 weeks towards 200 mg, or placebo (n = 2001); the mean daily dose reached was 159 mg. All-cause mortality, the primary endpoint, occurred in 145 patients against 217 (7.2% against 11.0% per patient-year of follow-up; relative risk 0.66, 95% CI 0.53 to 0.81; p = 0.00009, p = 0.0062 adjusted for interim analyses): 7.3% against 10.8% of those randomised, an absolute difference of 3.6 percentage points over a mean 1 year, so 28 patients treated for a year avoid one death. Sudden death occurred in 79 against 132 patients (0.59, 0.45 to 0.78; p = 0.0002) and death from worsening heart failure in 30 against 58 (0.51, 0.33 to 0.79; p = 0.0023). In the companion report, all-cause mortality or all-cause hospitalisation occurred in 641 against 767 patients (risk reduction 19%, 95% CI 10% to 27%).
Финансировано индустрией
CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial Lancet, 1999.
doi:10.1016/S0140-6736(98)11181-9PubMed 10023943
Финансирование и результат
- Участники
- 2 647
- Наблюдение
- mean 1.3 years; stopped early at the second interim analysis
- Финансирование
- The funding statement of the trial report could not be read: the publisher page is behind a subscription, the archived copy stops at the abstract and the article is absent from PubMed Central. The design paper of the Beta-Blockers in Heart Failure Collaborative Group, which lists this trial among those proposed for pooling, states that of those trials only BEST was principally sponsored by public bodies and that all the others were funded by pharmaceutical companies.
- Результат
- Double-blind randomisation to bisoprolol 1.25 mg daily, increased progressively to a maximum of 10 mg (n = 1327), or placebo (n = 1320), analysed by intention to treat. All-cause mortality, the primary endpoint, occurred in 156 patients (11.8%) against 228 (17.3%), hazard ratio 0.66 (95% CI 0.54 to 0.81; p below 0.0001): an absolute difference of 5.5 percentage points over a mean 1.3 years, so 18 patients treated avoid one death. Sudden death occurred in 48 patients (3.6%) against 83 (6.3%), hazard ratio 0.56 (0.39 to 0.80; p = 0.0011). Treatment effects were independent of the severity or cause of heart failure, and the authors caution that the results should not be extrapolated to patients with severe class IV symptoms and recent instability, in whom safety and efficacy were not established.
Финансировано индустрией
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al.; U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure New England Journal of Medicine, 1996.
doi:10.1056/NEJM199605233342101PubMed 8614419
Финансирование и результат
- Участники
- 1 094
- Наблюдение
- 6 months (12 months in mild heart failure); median 6.5 months of therapy; stopped early
- Финансирование
- Supported by grants from SmithKline Beecham Pharmaceuticals and Boehringer-Mannheim Therapeutics.
- Результат
- All 1197 patients entering the programme first took open-label carvedilol 6.25 mg twice daily for two weeks; 5.6% failed to complete this run-in because of adverse events, including worsening heart failure in 1.4% and death in 0.6%, and 3.0% for protocol or administrative reasons; dizziness affected 5.9% during the run-in. The 1094 who tolerated it were randomised to placebo (398) or carvedilol (696). Mortality was 7.8% on placebo against 3.2% on carvedilol, a 65% risk reduction (95% CI 39% to 80%); hospitalisation for cardiovascular causes 19.6% against 14.1%; hospitalisation or death 24.6% against 15.8%. The authors state that deaths during the open-label period cannot be assigned to either group and that the study allows no conclusion about safety without rigorous supervision or in bedridden patients with advanced heart failure. No formal stopping rules were adopted before enrolment.
Финансировано индустрией
Beta-Blocker Evaluation of Survival Trial Investigators; Eichhorn EJ, Domanski MJ, Krause-Steinrauf H, Bristow MR, Lavori PW. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure New England Journal of Medicine, 2001.
doi:10.1056/NEJM200105313442202PubMed 11386264
Финансирование и результат
- Участники
- 2 708
- Наблюдение
- average 2.0 years; stopped after the seventh interim analysis
- Финансирование
- Supported by the Division of Epidemiology and Clinical Applications of the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs Cooperative Studies Program, through an interagency agreement. Additional support was provided by Incara Pharmaceuticals, which supplied bucindolol and placebo. The steering committee and the monitoring committee each included D. Ward of Incara Pharmaceuticals, and the monitoring committee also included M. Schleman of Astra-Merck. An industry role in the conduct of the trial sets the class to industry.
- Поддержка в натуральной форме
- Incara Pharmaceuticals supplied bucindolol and placebo.
- Результат
- Double-blind randomisation to bucindolol (1354) or placebo (1354). Deaths from any cause, the primary end point, numbered 411 (30%) against 449 (33%), hazard ratio 0.90 (95% CI 0.78 to 1.02), unadjusted P = 0.10, adjusted P = 0.13, an annual mortality of 15% against 17%. Death from cardiovascular causes was lower with bucindolol (hazard ratio 0.86, 0.74 to 0.99). A nominally significant interaction with race (P = 0.02) reflected no benefit in Black patients (hazard ratio 1.17, 0.89 to 1.53) and benefit in non-Black patients (0.82, 0.70 to 0.96); the authors note that with any reasonable adjustment for multiple comparisons this could be due to chance. Annual placebo mortality in class III was 16%, against 12% in CIBIS-II and 13% in MERIT-HF.
Финансировано индустрией
Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al.; Beta-blockers in Heart Failure Collaborative Group. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials European Heart Journal, 2018.
doi:10.1093/eurheartj/ehx564PubMed 29040525
Финансирование и результат
- Регистрация
- NCT0083244; PROSPERO CRD42014010012
- Участники
- 17 312
- Наблюдение
- median 1.3 years
- Финансирование
- Menarini Farmaceutica Internazionale provided an unrestricted research grant for administrative costs; GlaxoSmithKline provided data extraction support; IRCCS San Raffaele provided a collaborative research grant. One author is funded through a National Institute for Health Research Career Development Fellowship (CDF-2015-08-074) that also supports a second author. The acknowledgements thank AstraZeneca, GlaxoSmithKline, Menarini Farmaceutica and Merck Serono for full access to trial data, and BEST data came through the NHLBI BioLINCC programme.
- Результат
- In sinus rhythm, all-cause mortality hazard ratios with beta-blockers against placebo were 0.70 (95% CI 0.60 to 0.83) at ejection fraction below 20% (623 deaths among 2531), 0.76 (0.65 to 0.89) at 20% to 25%, 0.75 (0.64 to 0.88) at 26% to 34%, 0.67 (0.50 to 0.90) at 35% to 39%, 0.59 (0.34 to 1.03) at 40% to 49% (21 of 292 against 35 of 283 died; cardiovascular death 13 of 292 against 26 of 283, hazard ratio 0.48, 0.24 to 0.97) and 1.79 (0.78 to 4.10) at 50% or more (24 deaths among 241). In atrial fibrillation, beta-blockers raised ejection fraction when below 50% but did not improve prognosis: all-cause mortality hazard ratios 1.23 (0.88 to 1.74) below 20%, 0.74 (0.54 to 1.02) at 20% to 25%, 0.98 (0.74 to 1.29) at 26% to 34%, 0.92 (0.53 to 1.58) at 35% to 39% and 1.30 (0.63 to 2.67) at 40% to 49%.
Независимое
Dibben G, de Vries FB, Faulkner J, Oldridge N, Rees K, Stens NA, et al. Exercise-based cardiac rehabilitation for coronary heart disease Cochrane Database of Systematic Reviews, 2026.
doi:10.1002/14651858.CD001800.pub5PubMed 42754260
Финансирование и результат
- Участники
- 26 886
- Наблюдение
- short term 6 to 12 months; medium term above 12 to 36 months; long term above 36 months
- Финансирование
- Internal sources: University of Glasgow (time of two authors); Radboud University Medical Centre (time of three authors). External sources: past NIHR Cochrane Infrastructure funding to Cochrane Heart.
- Результат
- At 6 to 12 months, exercise-based rehabilitation likely reduced all-cause mortality (RR 0.86, 95% CI 0.74 to 1.00; 30 trials, 10,391 participants; number needed to treat 125; moderate certainty), may reduce cardiovascular mortality (RR 0.87, 0.68 to 1.11; moderate certainty), reduced myocardial infarction (RR 0.72, 0.54 to 0.95; 25 trials, 8584 participants; number needed to treat 71; high certainty) and likely reduced all-cause hospital admissions (RR 0.65, 0.51 to 0.82; number needed to treat 17; moderate certainty), with little or no difference in CABG or PCI. Beyond 12 months it was associated with reduced cardiovascular mortality and myocardial infarction. About a quarter of trials predate contemporary optimal medical therapy.
Независимое
Neal B, Wu Y, Feng X, Zhang R, Zhang Y, Shi J, et al. Effect of salt substitution on cardiovascular events and death New England Journal of Medicine, 2021.
doi:10.1056/NEJMoa2105675PubMed 34459569
Финансирование и результат
- Регистрация
- NCT02092090
- Участники
- 20 995
- Наблюдение
- mean 4.74 years, median 5.12 years
- Финансирование
- Supported by research grants (APP1164206 and APP1049417) and an investigator grant (APP1197709, to Dr. Neal) from the National Health and Medical Research Council of Australia. The trial was sponsored by the George Institute for Global Health, where the analyses were performed; the first author wrote the first draft and all authors took the decision to submit. Registry lead sponsor: The George Institute; collaborators were universities and the Chinese Center for Disease Control and Prevention.
- Поддержка в натуральной форме
- The salt substitute (75% sodium chloride, 25% potassium chloride) was purchased by the investigators from local manufacturers in each province for years 1, 2 and 5 and donated by Jiangsu Sinokone Technology for years 3 to 4.
- Результат
- Stroke 29.14 versus 33.65 events per 1000 person-years with salt substitute versus regular salt (rate ratio 0.86, 95% CI 0.77 to 0.96); fatal stroke 6.78 versus 8.79 (0.77, 0.65 to 0.91); haemorrhagic 4.37 versus 6.30 (0.69, 0.56 to 0.85); ischaemic 21.36 versus 22.90 (0.93, 0.82 to 1.05); major adverse cardiovascular events 49.09 versus 56.29 (0.87, 0.80 to 0.94); death 39.28 versus 44.61 (0.88, 0.82 to 0.95); serious adverse events attributed to hyperkalaemia 3.35 versus 3.30 (1.04, 0.80 to 1.37). Mean differences: 24-hour urinary sodium -350 mg, potassium +803 mg, systolic blood pressure -3.34 mm Hg. Exclusions: potassium-sparing diuretic, potassium supplement or known serious kidney disease in the household; no routine kidney function or serum potassium measurement; 22.8% used an ACE inhibitor or angiotensin-receptor blocker.
Консенсус
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8) JAMA, 2014.
doi:10.1001/jama.2013.284427PubMed 24352797
Финансирование и результат
- Финансирование
- The evidence review for this project was funded by the National Heart, Lung, and Blood Institute (NHLBI).
- Результат
- In the general population aged 60 or older, start drug treatment at systolic 150 mm Hg or diastolic 90 mm Hg or higher and treat to below 150/90 (strong recommendation, grade A). Below age 60, start at diastolic 90 or higher (grade A for ages 30 to 59, expert opinion for 18 to 29) and at systolic 140 or higher (expert opinion), with goals below 90 and 140. With chronic kidney disease or diabetes, start at 140/90 and treat to below 140/90 (expert opinion). Initial drugs in the non-black population: thiazide-type diuretic, calcium channel blocker, ACE inhibitor or angiotensin receptor blocker; in the black population a thiazide-type diuretic or calcium channel blocker. The panel was unable to reach unanimity on the systolic goal below 150 mm Hg; some members recommended continuing the JNC 7 goal below 140 mm Hg for people older than 60.
Консенсус
McEvoy JW, McCarthy CP, Bruno RM, Brouwers S, Canavan MD, Ceconi C, et al.; ESC Scientific Document Group. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension European Heart Journal, 2024.
doi:10.1093/eurheartj/ehae178PubMed 39210715
Финансирование и результат
- Финансирование
- Funding for the development of ESC Guidelines is derived entirely from the ESC with no involvement of the healthcare industry.
- Результат
- Office blood pressure categories: non-elevated below 120/70 mm Hg; elevated 120 to 139 systolic or 70 to 89 diastolic; hypertension 140 or above systolic or 90 or above diastolic, unchanged as a definition. In elevated blood pressure, a 10-year predicted cardiovascular risk of 10% or more is considered sufficiently high to warrant lowering by lifestyle or drug treatment, with lifestyle measures for 3 months first and drugs recommended for confirmed pressure of 130/80 mm Hg or more; confirmed hypertension is recommended for treatment without further risk stratification. Adults receiving blood-pressure-lowering drugs should pursue a systolic target of 120 to 129 mm Hg if well tolerated, with more lenient targets for some patients and out-of-office confirmation. ACE inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers and diuretics are recommended as first-line options; beta-blockers can be added preferentially for angina, heart failure, after myocardial infarction or for heart-rate control, are less effective at preventing stroke, have a higher discontinuation rate due to side effects, are associated with new-onset diabetes in predisposed patients, especially with diuretics, and should be avoided in isolated systolic hypertension or arterial stiffness; in resistant hypertension a beta-blocker, preferably vasodilating, is an alternative to a mineralocorticoid receptor antagonist as fourth-line treatment.
Консенсус
National Institute for Health and Care Excellence. Hypertension in adults: diagnosis and management. NICE guideline NG136 National Institute for Health and Care Excellence, published 28 August 2019, last updated 26 February 2026, 2026.
https://www.nice.org.uk/guidance/ng136/chapter/recommendations
Финансирование и результат
- Финансирование
- not stated
- Результат
- Step 1 treatment, recommendations marked 2019: offer a calcium channel blocker to adults starting step 1 antihypertensive treatment who are aged 55 or over and do not have type 2 diabetes, or who are of Black African or African-Caribbean family origin and do not have type 2 diabetes, of any age (1.4.35); if a calcium channel blocker is not tolerated, for example because of oedema, offer a thiazide-like diuretic (1.4.36); if there is evidence of heart failure, offer a thiazide-like diuretic (1.4.37). Step 2: if hypertension is not controlled on a calcium channel blocker, offer the choice of an ACE inhibitor, an angiotensin receptor blocker or a thiazide-like diuretic in addition (1.4.42); if it is not controlled on an ACE inhibitor or angiotensin receptor blocker, offer the choice of a calcium channel blocker or a thiazide-like diuretic in addition (1.4.41). Step 3: offer an ACE inhibitor or angiotensin receptor blocker with a calcium channel blocker and a thiazide-like diuretic (1.4.45). Step 4: patients whose hypertension is not controlled on optimal tolerated doses of those three drugs are regarded as having resistant hypertension (1.4.46).
Консенсус
National Institute for Health and Care Excellence. Chronic heart failure in adults: diagnosis and management. NICE guideline NG106 National Institute for Health and Care Excellence, published 12 September 2018, last updated 3 September 2025, 2025.
https://www.nice.org.uk/guidance/ng106/chapter/Recommendations
Финансирование и результат
- Финансирование
- not stated
- Результат
- For heart failure with reduced ejection fraction, offer an angiotensin-converting enzyme inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and a sodium-glucose cotransporter-2 inhibitor (1.4.1, marked 2025); where an ACE inhibitor is not tolerated, offer an angiotensin receptor-neprilysin inhibitor with the beta-blocker, mineralocorticoid receptor antagonist and SGLT2 inhibitor (1.4.3, 2025); after angio-oedema on an ACE inhibitor, or intolerance of an ARNI, offer a beta-blocker, mineralocorticoid receptor antagonist and SGLT2 inhibitor and consider an angiotensin receptor blocker (1.4.4, 2025). For heart failure with mildly reduced ejection fraction, consider an ACE inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor (1.5.1, 2025); evidence suggested each of these medicines reduces hospitalisation for heart failure, and possibly mortality, in this group. Prescribing a beta-blocker: do not withhold treatment solely because of age or the presence of peripheral vascular disease, erectile dysfunction, diabetes, interstitial pulmonary disease or chronic obstructive pulmonary disease (1.7.9, 2010); assess heart rhythm, rate and conduction with a 12-lead electrocardiogram before deciding whether to prescribe one (1.7.10, 2025); do not offer a beta-blocker to people with second- or third-degree heart block without a pacemaker or with a heart rate below 50 beats per minute (1.7.11, 2025); assess heart rate and clinical status after each dose increment (1.7.12, 2010) and consider repeating the electrocardiogram after each increment in people with symptoms and bradycardia (1.7.13, 2025).
Консенсус
National Institute for Health and Care Excellence. Acute coronary syndromes. NICE guideline NG185 National Institute for Health and Care Excellence, published 18 November 2020, 2020.
https://www.nice.org.uk/guidance/ng185/chapter/Recommendations
Финансирование и результат
- Финансирование
- not stated
- Результат
- Recommendations on beta-blockers after myocardial infarction: offer a beta-blocker as soon as possible after a myocardial infarction, when the person is haemodynamically stable (1.4.27, marked 2013); communicate plans for titrating beta-blockers up to the maximum tolerated or target dose (1.4.28, 2013); consider continuing a beta-blocker for 12 months after a myocardial infarction for people without reduced left ventricular ejection fraction (1.4.29, 2020); discuss the potential benefits and risks of stopping or continuing beyond 12 months in such people, including the lack of evidence on the relative benefits and harms of continuing beyond 12 months and the person's experience of adverse effects (1.4.30, 2020); continue a beta-blocker indefinitely in people with reduced left ventricular ejection fraction (1.4.31, 2013); do not offer a beta-blocker to people without reduced left ventricular ejection fraction or heart failure whose myocardial infarction was more than 12 months ago, unless there is an additional clinical indication (1.4.33, 2013). Where beta-blockers are contraindicated or need to be discontinued, diltiazem or verapamil may be considered for secondary prevention in people without pulmonary congestion or reduced left ventricular ejection fraction (1.4.35, 2007). Offer all people who have had a myocardial infarction treatment with an ACE inhibitor, dual antiplatelet therapy, a beta-blocker and a statin (1.4.1, 2007, amended 2020).
Независимое
Aarons RD, Nies AS, Gal J, Hegstrand LR, Molinoff PB. Elevation of beta-adrenergic receptor density in human lymphocytes after propranolol administration Journal of Clinical Investigation, 1980.
doi:10.1172/JCI109781PubMed 6102572
Финансирование и результат
- Участники
- 12
- Наблюдение
- 8 days of treatment and about 1 week after the last dose
- Финансирование
- This work was supported by the U. S. Public Health Service (NS 13289 and RR 00051) and The Colorado and American Heart Associations. One author was a Predoctoral Fellow (HD 07072) and one a postdoctoral trainee (GM 07063) of the U. S. Public Health Service.
- Поддержка в натуральной форме
- Hydroxybenzylpindolol was a gift of Sandoz Pharmaceuticals, practolol and the propranolol stereoisomers gifts of Ayerst Laboratories, 4-methylpropranolol a gift of ICI Pharmaceutical Division and d-isoproterenol a gift of Winthrop Laboratories.
- Результат
- Propranolol 160 mg daily for 8 days produced trough plasma concentrations of about 35 ng/ml. By day 5 the density of beta-adrenergic receptors on lymphocyte membranes, measured by binding of [125I]iodohydroxybenzylpindolol, had risen 43 plus or minus 4% above pretreatment values (P below 0.01). Standing and supine heart rates fell during treatment. After the last dose propranolol disappeared from plasma within 24 hours, while receptor density returned to the pretreatment level only over several days; standing heart rate returned to control within 24 hours and supine heart rate only 4 days after discontinuation. The orthostatic change in heart rate (P below 0.05) and in the heart rate-systolic pressure product (P below 0.01) rose significantly during the first 48 hours after withdrawal, and the change in receptor density correlated with the orthostatic change in heart rate (r = 0.63, P = 0.036) and in the double product (r = 0.67, P = 0.024).
Независимое
Silvain J, Cayla G, Ferrari E, Range G, Puymirat E, Delarche N, et al.; ABYSS Investigators of the ACTION Study Group. Beta-blocker interruption or continuation after myocardial infarction New England Journal of Medicine, 2024.
doi:10.1056/NEJMoa2404204PubMed 39213187
Финансирование и результат
- Регистрация
- NCT03498066
- Участники
- 3 698
- Наблюдение
- median 3.0 years (interquartile range 2.0 to 4.0)
- Финансирование
- Supported by a grant (PHRC-2015) from the French Ministry of Health and the ACTION (Allies in Cardiovascular Trials, Initiatives, and Organized Networks) Study Group. Registry NCT03498066 names Assistance Publique - Hopitaux de Paris as lead sponsor and Groupe Hospitalier Pitie-Salpetriere as collaborator; no company is named as funder or sponsor.
- Результат
- Open-label non-inferiority trial of interrupting against continuing beta-blocker treatment; 1846 patients were assigned interruption and 1852 continuation. Death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for cardiovascular reasons occurred in 432 of 1812 patients (23.8%) after interruption against 384 of 1821 (21.1%) with continuation, a risk difference of 2.8 percentage points (95% CI below 0.1 to 5.5) and a hazard ratio of 1.16 (1.01 to 1.33); the upper confidence boundary exceeded the 3-percentage-point non-inferiority margin, so interruption was not non-inferior. Interruption did not seem to improve quality of life measured with the European Quality of Life-5 Dimensions questionnaire.
Независимое
Silvain J, Choi KH, Monguillon V, Kang D, Cayla G, Kim W, et al.; ABYSS and SMART-DECISION investigators. Discontinuation of beta-blockers in stable patients with previous myocardial infarction, preserved left ventricular ejection fraction, and no heart failure: a pooled analysis of individual patient data Lancet, 2026.
doi:10.1016/S0140-6736(26)01426-1PubMed 42669300
Финансирование и результат
- Регистрация
- PROSPERO CRD420261299839
- Участники
- 6 238
- Наблюдение
- median 3.0 years (interquartile range 2.3 to 3.8)
- Финансирование
- Funding: None, as stated in the published abstract. The pooled trials were funded by the French Ministry of Health with the ACTION Study Group (ABYSS) and by the Ministry of Health and Welfare of South Korea (SMART-DECISION).
- Результат
- One-stage mixed-effects Cox model with trial as random effect; 3092 patients assigned to discontinuation and 3146 to continuation. Death, myocardial infarction, stroke or hospitalisation for cardiovascular reasons occurred in 532 (17.2%) against 500 (15.9%), hazard ratio 1.09 (95% CI 0.97 to 1.24), non-inferior against a margin of 1.25 (P = 0.016). Death, myocardial infarction or hospitalisation for heart failure occurred in 201 (6.5%) against 201 (6.4%), hazard ratio 1.01 (0.83 to 1.23), non-inferior against a margin of 1.40 (P = 0.0006). Findings were consistent across ejection fraction; the authors state that interpretation of the primary end point is limited by its hospitalisation-heavy and trial-dependent composition.
Финансирование не установлено
Psaty BM, Koepsell TD, Wagner EH, LoGerfo JP, Inui TS. The relative risk of incident coronary heart disease associated with recently stopping the use of beta-blockers JAMA, 1990.
PubMed 1968518
Финансирование и результат
- Участники
- 985
- Наблюдение
- first coronary events 1982 to 1984
- Финансирование
- not read: the full text requires a subscription and is absent from PubMed Central.
- Результат
- After adjustment for potential confounders, recent stopping of a beta-blocker carried a transient increase in the relative risk of incident coronary heart disease (relative risk 4.5, 95% CI 1.1 to 18.5). The association was specific to beta-blockers and absent for diuretics. The authors propose a withdrawal syndrome as an acute precipitant of angina and myocardial infarction in hypertensive patients without prior coronary disease.