Effectiveness of Β-Blockers in Physically Active Patients with Hypertension: Protocol of a Systematic Review

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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 epidemiological 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, population (both genders, 18 years and older) with any and found that metoprolol led to a greater increase in type of hypertension. maximal exercise capacity. Nodari et al22 compared the effect of atenolol versus nebivolol in a group of patients Types of interventions with diastolic heart failure and arterial hypertension. This review will consider studies that evaluate pharmaco- Nebivolol was associated with greater haemodynamic logical treatment using a β-blocker (monotherapy or improvement than atenolol. combination therapy); for example, propranolol, meti- Exercise testing is used widely for the detection of cor- pranolol, sotalol, pindolol, bopindolol, bisoprolol, betax- onary artery disease, prediction of cardiovascular events, olol, atenolol, nebovolol, talinolol, esmolol, acebutol, evaluation of physical capacity and effort tolerance, celiprolol, metoprolol, nadolol, α carvedilol. evaluation of exercise-related symptoms, assessment of chronotropic competence and arrhythmias, response to Types of comparison implanted device therapy and assessment of the This review will consider studies that evaluate pharmaco- response to medical interventions.23 Current clinical logical treatment using another β-blocker (monotherapy exercise testing procedures involve a predominant or combination therapy); for example, propranolol,

2 Tucková̌ D, et al. BMJ Open 2016;6:e010534. doi:10.1136/bmjopen-2015-010534 Open Access BMJ Open: first published as 10.1136/bmjopen-2015-010534 on 15 June 2016. Downloaded from metipranolol, sotalol, pindolol, bopindolol, bisoprolol, 3. β blocker* OR β-adrenergic blocking agent* OR betaxolol, atenolol, nebovolol, talinolol, esmolol, acebu- β-adrenergic antagonists OR propranolol OR meti- tol, celiprolol, metoprolol, nadolol, α carvedilol. pranolol OR nadolol OR sotalol OR pindolol OR bopindolol OR betaxolol OR atenolol OR metoprolol Types of outcomes OR bisoprolol OR nebovolol OR talinolol OR This review will consider studies that include the follow- esmolol OR acebutolol OR celiprolol OR α carvedilol ing outcome measures: pharmacological treatment by 4. physical activity* OR physical exercise OR physical β-blockers with the most positive influence on physical movement activity performance as measured by a maximal or sub- 5. maximal stress test OR cardiac stress test OR VO2 maximal exercise stress test, or by both a maximal and max test OR submaximal stress test. submaximal test. The search strategy for the MEDLINE–EMBASE inter- The review is primarily focused on patients with hyper- face is attached in online supplementary appendix I. tension. However, hypertension is often followed by other comorbidities. Other comorbidities with hyperten- STUDY RECORDS sion will be evaluated by a subgroup analysis according The literature search results will be uploaded to to the type and severity of the comorbidity. EndNote X7, and shared by all authors of the review. This will enable a collaboration among reviewers during Types of studies the process of study selection. Two reviewers (DT and This review will consider primarily experimental study MK) will independently screen and select studies for designs, including parallel and crossover RCTs and possible inclusion in the study in two phases. In the first quasi-experimental studies. If non-experimental study phase, titles and abstracts will be analysed. In the second designs are found, the review will also consider epi- phase, all possible relevant full texts will be analysed. demiological study designs for inclusion, including pro- Any disagreements will be resolved by discussion and a spective and retrospective cohort studies, case–control third reviewer (ES). studies and analytical cross-sectional studies. RISK OF BIAS IN INDIVIDUAL STUDIES SEARCH STRATEGY Papers selected for retrieval will be assessed by two inde- A search strategy will be developed using medical pendent reviewers (DT and MK) for methodological subject headings (eg, MeSH for MEDLINE) and quality prior to inclusion in the review, using standardised adopted for each database included in the review. Text critical appraisal instruments from the JBI Meta Analysis fi

words related to the issue will also be identi ed. The of Statistics Assessment and Review Instrument http://bmjopen.bmj.com/ search strategy aims to ﬁnd both, published and unpub- ( JBI-MAStARI) (see online supplementary appendix II).27 lished studies. A three-step search strategy will be utilised Any disagreements that arise between the reviewers will be in this review. An initial limited search of MEDLINE and resolved by discussion and a third reviewer (ES). EMBASE will be undertaken followed by analysis of the text words contained in the title and abstract, and also DATA COLLECTION PROCESS of the index terms used to describe an article. A second Data will be extracted independently by reviewers (DT search using all identiﬁed keywords and index terms will and MK) from papers included in the review, using the

then be undertaken across all included databases. As a on September 29, 2021 by guest. Protected copyright. standardised data extraction tools from JBI-MAStARI for third step, the reference list of all identified reports and RCTs and pseudo-randomised trials, for prospective and articles will be searched for additional studies. Studies retrospective cohort studies, for case–control studies and published in all possible languages, if they have a title for cross-sectional studies (see online supplementary and abstract in English, will be considered for inclusion appendix III).27 The data extracted will include specific in this review. Studies published with no time restriction details about the interventions, populations, study will also be considered for inclusion in this review. methods and outcomes of significance, of the review The databases to be searched include: objectives. Any disagreement will be resolved by MedLine@Ovid MEDRLINE(R), Biomedica Czechoslo- discussion. vaca, Tripdatabase, Pedro, EMBASE, Cochrane Central Register of Controlled Trials, Cinahl and Web of Science. The search for unpublished studies will include: DATA ITEMS/DEALING WITH MISSING DATA Open Grey, Current Controlled Trials, MedNar, We will extract the generic and trade names of the inter- ClinicalTrials.gov, Cos Conference Papers Index and the ventions and compare them in terms of use control, International Clinical Trials Registry Platform of the dosage, frequency and duration of treatment, pharmaco- WHO. logical drugs and patient characteristics (age, gender, Search strategy (MEDLINE–Ovid interface): given disease, physical activity and type of hypertension). 1. adult* OR adult patient* OR adult population Whenever possible, we will use the results from an 2. hypertension OR high blood pressure intention-to-treat analysis. If effect size cannot be

Tucková̌ D, et al. BMJ Open 2016;6:e010534. doi:10.1136/bmjopen-2015-010534 3 Open Access BMJ Open: first published as 10.1136/bmjopen-2015-010534 on 15 June 2016. Downloaded from calculated, we will contact the authors for additional SUBGROUP ANALYSIS data. The authors of the included studies will be con- Subgroup analysis will be used for different age and tacted, when necessary, to gather relevant information. gender characteristics. Another subgroup analysis will be used for a different level of physical activity, as measured by VO2 max. Subgroup analysis will be used for different OUTCOMES AND PRIORITISATION stress tests. The next subgroup analysis will be used for The primary outcome will be to establish which different levels of drug dosage. Subgroup analysis will β -blockers are the most effective in physically active also be used for hypertension and different comorbid- patients with hypertension, in terms of minimal limita- ities, according to their type and severity. β-blockers have tion of physical activity performance. Data relating to different pharmacodynamics and pharmacokinetic prop- the following questions will be sought: erties, so subgroup analysis will be used for hydrophil- β 1. Which -blockers enable the patients with hyperten- icity, lipophilicity, intrinsic sympathomimetic activity and sion to be physically active with no performance vasodilatory properties. We also will pay attention to limitation? another subgroup due to the category of the nature of β 2. Which -blockers help patients with hypertension to β-blockers, which are divided into non-selective, β-1 be physically active and are most effective in treating selective, α and β-blocker, and partial antagonist. hypertension? 3. Which β-blockers help patients with hypertension and comorbidities to be physically active, and which META-BIAS ASSESSMENT are most effective in treating hypertension? We plan to provide assessment of publication bias based on whether the RCT protocols were published before the research on the patients or respondents was con- DATA SYNTHESIS ducted—for published as well as unpublished studies Quantitative data will, where possible, be pooled in statis- (see ‘Search strategy’). The fixed-effect estimate versus tical meta-analyses, using JBI-MAStARI. All results will be the random-effect model will be evaluated to allow the subject to double-data entry. Effect sizes expressed as presence of bias in the published sources of literature to OR (for categorical data) and weighted mean differ- be assessed. For reporting the potential reporting bias, ences (for continuous data) and their 95% CIs will be we will use funnel plots if ≥10 studies are available. We calculated for analysis. If we retrieve homogeneous will use Begg’s rank correlation and Egger’s regression RCTs, we will not include any other study design, and we tests for detecting or correcting publication bias. will then perform fixed-effects meta-analyses to synthe- sise the data by pooling the results of included studies. If we do not retrieve homogeneous RCTs, or have to http://bmjopen.bmj.com/ CONFIDENCE IN CUMULATIVE EVIDENCE include other study designs, we will perform Based on the results and quality of evidence, the tool random-effects meta-analyses. We will pool studies with known as ‘Grading of Recommendation Assessment, similar designs, for example, the data from RCTs will not Development and Evaluation’ (GRADE)28 will be used. be pooled with data from quasi-randomised trials or The quality of evidence will be assessed across the non-randomised trials. Where statistical pooling is not domains of risk of bias, consistency, directness, precision possible, the findings will be presented in narrative fi and publication bias. Quality will be assessed as high form, including tables and gures to aid in data presen- fi

(further research is very unlikely to change our con - on September 29, 2021 by guest. Protected copyright. tation where appropriate. dence in the estimate of effect) or moderate (further research is likely to have an important impact on our ASSESSMENT OF HETEROGENEITY confidence in the estimate of effect and may change the Initially, clinical heterogeneity will be assessed by deter- estimate) or low (further research is very likely to have fi mining whether the studies are sufficiently similar to an impact on our con dence in the estimate of effect pool in terms of inclusion criteria. If they are clinically and is likely to change the estimate) or very low (very homogeneous, statistical heterogeneity will be assessed uncertain about the estimate of effect). using the standard χ2 test (significance level: 0.1) and I2 statistic, with a value of I2 ≥50% indicating significant heterogeneity. If statistical heterogeneity is found, it will ETHICS AND DISSEMINATION be assessed by sensitivity and subgroup analyses. This protocol of a systematic review was created in October 2015. Next, the systematic review development team will start to work on a planned systematic review. SENSITIVITY ANALYSIS The results will be disseminated—focusing on patients To ensure sensitivity analysis, we will exclude all studies and experts in cardiovascular practice—by publication that are appraised as having a high risk of bias. The sen- in a peer-reviewed journal. Ethical assessment is not sitivity analysis will be used to assess the robustness of needed because we will search and evaluate only existing the results to specific decisions made and methods used. sources of literature.

4 Tucková̌ D, et al. BMJ Open 2016;6:e010534. doi:10.1136/bmjopen-2015-010534 Open Access BMJ Open: first published as 10.1136/bmjopen-2015-010534 on 15 June 2016. Downloaded from

Author affiliations 6. Kotecha D, Holmes J, Krum H, et al. Efficacy of β blockers in 1Department of Social Medicine and Public Health, Faculty of Medicine and patients with heart failure plus atrial fibrillation: an individual-patient – Dentistry, Palacký University in Olomouc, Olomouc, Czech Republic data meta-analysis. Lancet 2014;384:2235 43. 7. Jackson JL, Cogbill E, Santana-Davila R, et al. A comparative 2The Czech Republic (Middle European) Centre for Evidence-Based Health effectiveness meta-analysis of drugs for the prophylaxis of migraine Care: An affiliated Centre of the Joanna Briggs Institute, Department of Social headache. PLoS ONE 2015;10:e0130733. Medicine and Public Health, Faculty of Medicine and Dentistry, Palacký 8. Yun S, Vincelette ND, Abraham I. Cardioprotective role of β-blockers University in Olomouc, Olomouc, Czech Republic and angiotensin antagonists in early-onset anthracyclines-induced 3Department of Exercise Medicine and Cardiovascular Rehabilitation, Faculty cardiotoxicity in adult patients: a systematic review and – of Medicine and Dentistry, Palacký University in Olomouc, Olomouc, Czech meta-analysis. Postgrad Med J 2015;91:627 33. 9. Peller M, Ozierański K, Balsam P, et al. Influence of beta-blockers Republic on endothelial function: a meta-analysis of randomized controlled 4 Department of Internal Medicine II – Gastroenterology and Hepatology, trials. Cardiol J 2015;22:708–16. Faculty of Medicine and Dentistry, Palacký University in Olomouc, Olomouc, 10. Myers J, McAuley P, Lavie CJ, et al. Physical activity and Czech Republic cardiorespiratory fitness as major markers of cardiovascular risk: their independent and interwoven importance to health status. 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