Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2015-010534 on 15 June 2016. Downloaded from Effectiveness of β-blockers in physically active patients with hypertension: protocol of a systematic review Dagmar Tučková,1,2 Miloslav Klugar,1,2 Eliška Sovová,3 Markéta Sovová,4 Lenka Štégnerová3 To cite: Tucková̌ D, ABSTRACT cardiovascular diseases.1 In 2013, the et al Klugar M, Sovová E, . Introduction: Based on more than 5 decades of European Society of Cardiology and the Effectiveness of β-blockers in epidemiological studies, it is now widely accepted that European Society of Hypertension set out physically active patients with higher physical activity patterns and levels of hypertension: protocol of a new guidelines for the management of arter- cardiorespiratory fitness are associated with better systematic review. BMJ Open ial hypertension. health outcomes. Therefore, it is necessary to consider 2016;6:e010534. Appropriate lifestyle changes are the how treatment methods affect these two components. doi:10.1136/bmjopen-2015- cornerstone for the prevention and cure of 010534 Clinically, one very important question concerns the influence of aerobic performance on patients being hypertension. The recommended lifestyle treated for hypertension. The administration of β- measures that have been shown to be effective ▸ Prepublication history and — in reducing BP are salt restriction, moder- additional material is blockers can significantly reduce maximal and — available. To view please visit especially submaximal aerobic exercise capacity. The ation of alcohol consumption, change of diet, the journal (http://dx.doi.org/ objective of this review is to determine, by comparison weight reduction and regular physical activity 10.1136/bmjopen-2015- of existing mono and combination therapy, which β- such as moderate aerobic exercise 5–7 days – 010534). blockers are less physically limiting for patients with per week.2 4 hypertension who are physically active. The second part of the therapy is pharma- Methods: A three-step strategy will be adopted in the fi Received 12 November 2015 cological. Current guidelines recon rm that review, following the methods used by the Joanna diuretics, β-blockers, calcium antagonists, Revised 7 March 2016 Briggs Institute ( JBI). The initial search will be Accepted 16 March 2016 ACE inhibitors and angiotensin receptor conducted using the MEDLINE and EMBASE databases. The second search will involve the listed blockers are all suitable for the initiation and databases for the published literature (MEDLINE, maintenance of antihypertensive treatment. http://bmjopen.bmj.com/ β Biomedica Czechoslovaca, Tripdatabase, Pedro, -Blockers are among the most commonly EMBASE, the Cochrane Central Register of Controlled used medications in the treatment of hyper- Trials, Cinahl, WoS) and the unpublished literature tension, especially with regard to the devel- (Open Grey, Current Controlled Trials, MedNar, opment of cardiovascular complications5 ClinicalTrials.gov, Cos Conference Papers Index, the such as angina, myocardial infarction, International Clinical Trials Registry Platform of the various types of arrhythmias, control of atrial WHO). Following the JBI methodology, analysis of title/ fibrillation rate,6 chronic heart failure, hyper- abstracts and full texts, critical appraisal and data adrenergic states such as a thyrotoxicosis, on September 29, 2021 by guest. Protected copyright. extraction will be carried out on selected studies using migraines,7 or as a form of cardioprotection the JBI tool, MAStARI. This will be performed by two independent reviewers. If possible, statistical meta- in patients with anthracycline-induced cardi- 8 β analysis will be pooled. Statistical heterogeneity will be otoxicity. -Blockers can also improve endo- 9 assessed. Subgroup analysis will be used for different thelial dysfunction. age and gender characteristics. Funnel plots, Begg’s β-Blockers have different pharmacological rank correlation and Egger’s regression test will be properties, such as β-1 selectivity, intrinsic used to detect or correct publication bias. sympathomimetic activity, and vasodilatory Ethics and dissemination: The results will be effects with α adrenergic blocking properties disseminated by publishing in a peer-reviewed journal. and the production of nitric oxide. They may Ethical assessment is not needed—we will search/ also have hydrophilic and lipophilic proper- evaluate the existing sources of literature. ties. This class is in fact a very diverse group Trial registration number: CRD42015026914. of medications with a wide range of properties.5 For numbered affiliations see fi end of article. Based on more than ve decades of epi- demiological studies, it is now widely accepted Correspondence to BACKGROUND that higher levels of physical activity and car- Dr Miloslav Klugar; High-blood pressure (BP) is one of the most diorespiratory fitness are associated with [email protected] important risk factors in the development of better health outcomes.10 Clinically, one very Tucková̌ D, et al. BMJ Open 2016;6:e010534. doi:10.1136/bmjopen-2015-010534 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2015-010534 on 15 June 2016. Downloaded from important question concerns how the treatment of hyper- dynamic aerobic component. Tread mill and cycle erg- tension influences aerobic performance.2 The adminis- ometers are the most commonly used dynamic exercise tration of β-blockers can significantly reduce maximal, testing devices. Ventilatory expired gas analysis allows 11 and especially submaximal, aerobic exercise capacity. the measurement of minute ventilation, VO2 and VCO2, Impaired chronotropic response to exercise stress testing and the combination with ergometers is commonly is a predictor of mortality.12 β-Blockers can cause a reduc- known as cardiopulmonary exercise testing. The 6 min tion in resting metabolic rate.13 Both findings raise the walk test is a functional test that can be used to evaluate question as to whether treating hypertension using submaximal exercise capacity. This assessment is fre- β-blockers is always appropriate, and which drug, in quently used in patients with chronic disease, such as which form, least affects cardiorespiratory fitness. heart failure or chronic obstructive pulmonary disease.24 β Many trials have evaluated the effects of -blockers in VO2 max is the peak oxygen uptake achieved during patients with hypertension, with the endpoints being all- exercise performance and is considered the best measure cause mortality, morbidity and cardiovascular events;514 of cardiovascular fitness and exercise capacity.25 Exercise however, few studies have evaluated the influence of capacity is the most powerful predictor of survival.23 β-blocker therapy on patients’ cardiorespiratory fitness This systematic review with its extensive search strategy and exercise capacity. Billeh et al15 studied the effect of may clarify this issue and influence practice by inform- administering 50 mg metoprolol versus 25 mg carvedilol ing recommendations aimed at physicians and patients to 12 healthy participants. The O2 peak consumption with hypertension who want to be physically active. was significantly reduced by metoprolol but not by carve- The preliminary search was conducted using dilol. Koshucharova et al16 compared the effect of carve- MEDLINE, Prospero, and the JBI Library and Cochrane dilol and bisoprolol on healthy participants but found databases, to establish whether any systematic reviews on no statistically significant difference in the influence on this topic had been conducted. The search was per- heart rate during exercise. Herman et al17 investigated formed in October 2015. Neither systematic reviews nor the different effects of carvedilol and atenolol on guidelines related to this issue were found. plasma norepinephrine during exercise in a group of 12 healthy volunteers, and found that carvedilol blunted OBJECTIVE the increase in plasma norepinephrine. Nebivolol is a third-generation β-blocker with vasodilator properties.18 The objective of this review is to determine, by compari- 19 son of existing mono and combination therapy, which Van Bortel and van Baak, in another study, compared β exercise tolerance in healthy volunteers administered -blockers are less physically limiting for patients with with nebivolol 5 mg versus atenolol 100 mg daily; both hypertension who are physically active. drugs reduced blood pressure to a similar degree, http://bmjopen.bmj.com/ although atenolol reduced peak exercise heart rate METHODS more than nebivolol. Atenolol also reduced peak exer- The protocol was developed according to the Preferred cise and endurance, whereas nebivolol was not asso- Reporting Items for Systematic Reviews and ciated with any change in peak exercise, endurance, or Meta-Analysis Protocols (PRISMA-P).26 This protocol is 19 perceived exercise effort. registered with the PROSPERO prospective register of β fl When comparing different -blockers and their in u- systematic reviews: CRD42015026914. ence on patients with cardiovascular disease, different 20 et al21 effects were found. Marazzi compared the effect on September 29, 2021 by guest. Protected copyright. of nebivolol and carvedilol in hypertensive heart failure STUDY ELIGIBILITY patients and found no difference between these two Types of participants drugs. Metra et al20 conducted a prospective randomised This review will consider studies that include the adult double-blind comparison of metoprolol and carvedilol,