Withdrawal of antihypertensive drugs in older people

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To investigate whether withdrawal of antihypertensive medicines is feasible, and evaluate the effects of withdrawal of antihypertensive medicines on mortality, cardiovascular outcomes, hypertension and quality of life in older people.

Background

Description of the condition

Hypertension or high blood pressure (BP) is recognised by the World Health Organization (WHO) to pose a significant impact on the global disease burden, accounting for 7% of all disability adjusted life years in 2010 (Ikeda 2014). Hypertension is a critical risk factor for subsequent cardiovascular events including ischaemic and haemorrhagic stroke, myocardial infarction, heart failure, chronic kidney disease, cognitive decline and premature death (NICE 2011). In older adults, antihypertensive medicines have proven clinical efficacy and tolerability and are utilised globally to manage high BP (Ekbom 1994). The use of antihypertensive medicines has led to reduction in overall cardiovascular disease, morbidity rates and mortality rates in people with high BP (Ikeda 2014).

Antihypertensive medicines may be broadly classified into four categories as per their mode of action: diuretics, sympathetic inhibiting medicines, vasodilators, and angiotensin II receptor antagonists and angiotensin‐converting enzyme (ACE) inhibitors (Gerber 1980). These medicines each have distinct sites of action. Diuretics act to lower BP by depleting plasma and extracellular fluid volume (Gerber 1980). Sympathetic inhibiting medicines cause adrenergic blockade at various levels within the sympathetic nervous system. Vasodilators cause relaxation of smooth muscle in blood vessels, causing the vessels to dilate. Vasodilators affect this process by causing a decrease in cytoplasmic calcium, an increase in nitric oxide or through inhibiting myosin light chain kinase (Taira 1979). Angiotensin II receptor antagonists and ACE inhibitors inhibit the renin‐angiotensin system, control sympathetic nervous system activity and accelerate prostaglandin synthesis to treat hypertension (Gerber 1980).

Ensuring appropriate use of antihypertensive drugs can be challenging, especially in older people. Internationally, guidelines recommend 'step down' or withdrawal of antihypertensive medications in people who have well‐controlled hypertension (Espeland 1999). Reasons for this recommendation include the risk of adverse drug reactions (ADRs); the undesired metabolic effects such as hypokalaemia, hyperkalaemia, hyperglycaemia or hyperuricaemia; the potential for paradoxically increasing the risk of clinical cardiovascular events and coronary heart disease (CHD) (Espeland 1999; Schobel 1992); and the desire to reduce medication costs. The use of antihypertensive drugs in older people, especially people with diminished cerebral autoregulation, may compromise cerebral blood flow (CBF) and result in hypoperfusion which can result in cognitive decline (Moonen 2015).

Polypharmacy or the use of multiple medicines simultaneously in an individual patient has been widely documented as a risk factor for ADRs, drug‐disease and drug‐drug interactions as well as increased morbidity and mortality (Reeve 2014). Reducing the number of medications taken including antihypertensive medications by deprescribing (i.e. withdrawing medications that are inappropriate), may therefore lead to reduced adverse effects and improved quality of life (QoL) (Gnjidic 2014; Reeve 2014; Scott 2015).

Description of the intervention

Withdrawal of antihypertensive medications, defined as pharmaceutical medicines utilised to reduce high BP (Ikeda 2014), can either be complete (immediate) withdrawal of medications or dose reduction with or without intermittent therapy reduction strategies, also known as tapered withdrawal (gradual withdrawal according to a predefined dosing schedule or following clinical response) (Ekbom 1994: Reeve 2014). In the context of this review, we will include and evaluate randomised controlled trials (RCTs) that look to assist older people in withdrawing from antihypertensive medications, either by immediate withdrawal or by tapering interventions.

How the intervention might work

Withdrawal of antihypertensive drugs in older people, prescribed one or more antihypertensive medications for hypertension or primary prevention of cardiovascular disease, may theoretically cause a reduction in undesired metabolic effects and reduce medication errors, drug‐drug and drug‐disease interactions, and the number of ADRs as a result of continued use of antihypertensive medications. Additional possible positive effects of antihypertensive drug withdrawal may include a reduction in the risk of falls, reduction in compromised CBF and hypoperfusion (Froom 1997; Moonen 2015). However, withdrawal of antihypertensive medications may also cause an increase in BP and may increase the risk of cardiovascular outcomes or mortality (Ekbom 1994; Ikeda 2014; NICE 2011).

Why it is important to do this review

A Cochrane Review on the safety and benefits of withdrawing antihypertensive drugs in older people may provide valuable clinical insights on the effect of ceasing or deprescribing these medicines in the form of mortality rates, non‐fatal clinical events or morbidities, patient‐reported outcomes, QoL and ADRs, and a reduction in potentially unnecessary financial costs. There is substantial evidence that the use of antihypertensive drugs within the context of polypharmacy and multi‐morbidity can lead to increased risk of harm in older people (Woolcott 2009). To inform the appropriateness of withdrawing antihypertensive drugs in older people, we thus propose to critically evaluate the evidence in relation to the safety and efficacy of stopping antihypertensive drugs to inform clinical decisions and future research. Previous systematic reviews and meta‐analyses included multiple medication classes without a primary focus on antihypertensive withdrawal interventions (Iyer 2008), were conducted in the 1990s (Froom 1997), or primarily focused on the effect of medication withdrawal interventions upon falls in older people (Leipzig 1999; Smeeth 2006; Woolcott 2009). Thus, this review will update the evidence and investigate all aspects involved in strategies of antihypertensive withdrawal in older people.

Objectives

To investigate whether withdrawal of antihypertensive medicines is feasible, and evaluate the effects of withdrawal of antihypertensive medicines on mortality, cardiovascular outcomes, hypertension and quality of life in older people.

Methods

Criteria for considering studies for this review

Types of studies

We will include RCTs. RCTs are the gold standard for research to inform medication efficacy and for systematic reviews as they use the most systematic and rigorous design possible.

Types of participants

Older adults prescribed one or more antihypertensive drug for hypertension or primary prevention of cardiovascular disease living in the community, residential aged care facilities or in hospital settings. Older adults are defined as adults aged 50 years and over. We will include a study with some adults under 50 years if the majority of participants are over the age of 50 years or if data on adults aged over 50 years are reported separately (Leipzig 1999).

Types of interventions

Withdrawal of antihypertensive medications in older adults prescribed for hypertension or primary prevention of cardiovascular disease. The intervention can be directed to the person, healthcare professional, organisation or higher level, as long as individual participant use of antihypertensive drugs is captured. We will only include studies where an antihypertensive withdrawal intervention strategy is present. Withdrawal of medications may be through a deprescribing strategy including complete withdrawal or dose reduction.

The control intervention will be no withdrawal of antihypertensive medications.

Antihypertensive agents will include:

• diuretics which act primarily by blocking reabsorption of sodium at four major sites in the nephron. Different classes of diuretics act at different sites. Loop diuretics (e.g. furosemide, torsemide) act in the thick ascending limb of the loop of Henle. Thiazide‐type diuretics (e.g. hydrochlorothiazide, chlorthalidone, indapamide) act in the distal tubule and connecting segment. Potassium‐sparing diuretics (e.g. amiloride, triamterene) increase diuresis, but without causing potassium to be lost from the body. Aldosterone receptor antagonists (e.g. spironolactone, eplerenone) stop the entry of aldosterone into the principle cells of the collecting duct and late distal tubule of the nephron, which prevents sodium and water retention;

• beta‐blockers (e.g. atenolol, carvedilol) block the effects of catecholamines at receptor sites in the heart, peripheral vasculature, bronchi, pancreas, uterus, kidney, brain and liver. Beta‐blockers reduce BP by blocking the effects of catecholamine on the heart and blood vessels;

• ACE inhibitors (e.g. captopril, enalapril) act by blocking the renin‐angiotensin system, specifically they block conversion of angiotensin I to angiotensin II and bradykinin. ACE inhibitors reduce the effects of angiotensin II‐induced vasoconstriction, sodium retention and aldosterone release.

• calcium channel blockers (e.g. amlodipine, felodipine) act by blocking inward current of calcium via L‐type calcium channels. Calcium channel blockers lower BP by blocking the effects of calcium on blood vessels;

• angiotensin II receptor antagonists (e.g. candesartan, irbesartan) act by blocking binding of angiotensin II to type 1 angiotensin (AT₁) receptors. This leads to reduction in angiotensin II‐induced vasoconstriction, sodium reabsorption and aldosterone release, blood vessels dilate leading to reduction in BP.

• renin inhibitors (e.g. aliskiren) prevent the conversion of angiotensinogen to angiotensin I by binding to the S3^bp binding site of renin.

Types of outcome measures

Primary outcomes

• Survival rates (mortality rates ‐ all‐cause mortality, cardiovascular mortality).

• Myocardial infarction (fatal and non‐fatal).

• Adverse drug reactions (ARD) including withdrawal due to adverse effects.

Secondary outcomes

• Blood pressure (BP). Includes systolic and diastolic BPs, before and after withdrawal of antihypertensive drugs and mean arterial pressure.

• Hospitalisation (all‐cause, cardiovascular hospitalisation, heart failure hospitalisation).

• Stroke (fatal and non‐fatal, ischaemic and haemorrhagic, transient ischaemic attack).

• Success (rate) of withdrawal from antihypertensive drugs over the short term (12 months or less) and long term (greater than 12 months). Success (rate) will be defined as the ability of the participant to complete the study having experienced withdrawal from antihypertensive medications and resisted restarting existing treatment given before withdrawal.

• Quality of life (QoL) of participants, carers, families or a combination, compared between people continuing on antihypertensive drugs as normal versus people withdrawn from antihypertensive drugs measured with standard QoL instruments (i.e. EQ‐5D (EuroQol five dimensions questionnaire)/Short Form ‐ six dimensions (SF‐6D).

• Incidence of falls in the included populations. Generally measured through risk ratios or odds ratios between participants in the intervention group and participants in the control group.

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist will search the following databases from date of inception for published, unpublished and ongoing studies:

• the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS Web);

• the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS Web);

• MEDLINE Ovid (from 1946), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations;

• Embase Ovid (from 1974);

• ClinicalTrials.gov (www.clinicaltrials.gov);

• WHO International Clinical Trials Registry Platform (www.who.it.trialsearch).

We will model the subject strategies for databases on the search strategy designed for MEDLINE (see Appendix 1). Where appropriate, we will combine these with subject strategy adaptations of the sensitivity and precision‐maximising search strategy designed by Cochrane for identifying RCTs (as described in Box 6.4.d of the Cochrane Handbook for Systematic Reviews of Interventions; Higgins 2011).

Searching other resources

The Cochrane Hypertension Information Specialist will search the Hypertension Specialised Register segment (which includes searches of MEDLINE and Embase) for systematic reviews and Epistemonikos to retrieve published systematic reviews related to this review title, so that we can scan their reference lists to identify additional relevant trials.

We will check the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.

We will contact experts/organisations in the field to obtain additional information on relevant trials.

We may contact trial authors for clarification and further data if trial reports are unclear.

The Cochrane Hypertension Information Specialist will search the Hypertension Specialised Register segment for information of adverse effects relevant to this review.

Data collection and analysis

Selection of studies

Two review authors (TG and ZB) will independently search and screen identified studies for relevance and adherence to inclusion criteria. If studies do not meet the inclusion criteria, we will exclude them and record reasons for exclusion in a 'Characteristics of excluded studies' table. We will resolve disagreements through consultation with a third review author. We will present the selection process using a Prisma diagram (Moher 2009). We will utilise GRADE to determine the strength of studies and thus additional reasoning for inclusion or exclusion of potential studies.

Data extraction and management

Two review authors (TG and ZB) will independently extract data. We will utilise a data extraction form and that will be piloted on two studies. We will resolve disagreements by consultation with an external expert (Ms Joanna Stewart, biostatistician).

The summary statistics required for each trial and outcome for continuous data will be the mean change from baseline (or control group), the standard deviation and the number of participants for each group (treatment and control). The baseline assessment will be defined as the latest available assessment between the treatment and control group, or from baseline. For binary outcomes (i.e. success rate), we will require the number/percentage in (each) treatment group compared to baseline or control groups at each time point.

We will extract the following data from the studies and present them in a table:

• author, year of publication, type of intervention, design of study, number of participants, country;

• inclusion, exclusion and matching criteria;

• sex of participant;

• age of participant by age groups (50 to 65 years, over 65 to 80 years, over 80 years);

• withdrawal method (immediate or tapered);

• mortality status (from baseline);

• treatment effect on outcomes;

• fatal and non‐fatal cardiovascular events (i.e. myocardial infarction, stroke);

• adverse drug reactions;

• BP;

• QoL score (at baseline, from baseline);

For each outcome measure, we will seek data on each assessed participant using an intention‐to‐treat method. We will include per‐protocol analyses if available.

Assessment of risk of bias in included studies

Two review authors (TG, ZB) will independently assess the risk of bias in the included studies utilising the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011; Sterne 2014). The risk of bias will be assessed in terms of internal validity criteria for RCTs including random sequence generation (randomisation), allocation concealment, participant and study personnel blinding, blinding of outcome assessors, level of incomplete outcome data, selective reporting and other risks of bias that may be relevant (Higgins 2011; Sterne 2014). We will resolve disagreements through consultation with two additional review authors (ER, DG).

Measures of treatment effect

Studies may or may not utilise similar rating scales in outcome assessment. For this reason, for continuous outcomes, we will use the mean difference when the collective studies utilise identical scales of rating or tests. However, when dissimilar scales of rates or tests are utilised, we will use the standardised mean difference. In the case of binary outcomes such as mortality, we will use a Peto odds ratios to measure the treatment effect. We will calculate 95% confidence intervals (Cl).

Unit of analysis issues

If there are any cluster RCTs, we will determine if the risk of unit of analysis error was dealt with appropriately. Where the analysis was carried out correctly taking into account the clustering design, we will consider the studies for meta‐analysis and use the reported effect sizes and standard errors. Where the analysis was incorrect (i.e. not taking the clustering design into account), we will apply an interclass correlation (Higgins 2011).

Dealing with missing data

We will contact the corresponding author of included studies in the event of missing data that will compromise the ability of the review authors to examine the data and eligibility for study exclusion/inclusion in the final analysis.

Assessment of heterogeneity

The review authors will analyse and present each study separately. We will only perform meta‐analysis where studies are satisfactorily homogenous in terms of interventions, outcomes and participants. In the evaluation of heterogeneity, we will determine clinical heterogeneity by review author opinion and use an I² test to determine statistical heterogeneity. An I² value higher than 50% is considered as evidence for the presence of heterogeneity of the studies. If heterogeneity is present, we will not add these studies to any meta‐analyses undertaken and present them separately, with an investigation into the reasons for the presence of heterogeneity. Due to the nature of the intervention of interest, it is anticipated that a level of heterogeneity between studies will be present. Therefore, we will utilise a random‐effects model to incorporate and address this issue.

Assessment of reporting biases

Two review authors (TG, ZB) will independently assess the risk of reporting bias in the included studies utilising the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve disagreements through consultation with two additional review authors (ER, DG).

Data synthesis

We will synthesise data for each study separately using Review Manager 5 (RevMan 2014), and undertake meta‐analyses if we find data from multiple studies.

We will compare outcome measures for binary data utilising risk ratios and 95% CI. If there is heterogeneity, we will use a random‐effects model. For continuous variables or data, we will utilise mean differences and 95% CI.

Subgroup analysis and investigation of heterogeneity

Where there are sufficient data from two or more studies, we will perform subgroup analysis of medications within antihypertensive drug classes (e.g. ACE inhibitors and diuretics) if sufficient and meaningful data are available. Where studies are conducted for a period of 12 months or less, we will analyse these studies separately from longer‐term studies that are conducted for more than 12 months of follow‐up. This is due to the possible large disparity in outcomes due to the time period. Additionally, we will include subgroups for age group (50 to 65 years, over 65 to 80 years, over 80 years) and gender (men and women).

Sensitivity analysis

We will undertake a sensitivity analysis and consider how the results of any meta‐analyses undertaken change under different assumptions, related to the reasons for these effects. More specifically, we will conduct a sensitivity analysis on the choice of utilising a random‐effects model. Since many issues pertaining to sensitivity analysis are only identified in the review process as a result of the characteristics of the studies, we will undertake suitable sensitivity analyses in the relevant context (Higgins 2011).

Data presentation ‐ ’Summary of findings’ tables

We will use the GRADE approach to assess the quality of the supporting evidence behind each estimate of treatment effect (Schünemann 2011a; Schünemann 2011b). We will present key findings of the review, including a summary of the amount of data, the magnitude of the effect size and the overall quality of the evidence, in a ’Summary of findings’ table. We have preselected the following outcomes for inclusion in the 'Summary of findings' table: mortality, myocardial infarction, adverse drug reactions, blood pressure, hospitalization, stroke and incidence of falls.

Appendices

Appendix 1. MEDLINE search strategy

Database: Ovid MEDLINE(R) 1946 to Present with Daily Update Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 exp aged/ (2916801)

2 middle aged/ (4105496)

3 (advanced years or ageing or aging or elder$ or elderly or frail or geriatric? or gerontolog$ or later life or middle aged or midlife or nursing care or nursing home? or old age or oldest old or pensioner? or post‐menopausal or postmenopausal or senior or seniors).mp. (4638106)

4 (old$ adj3 (adult? or female? or male? or men or people or person or women)).tw. (248898)

5 ((over or older) adj2 ("49" or "50" or "51" or "52" or "53" or "54" or "55" or "56" or "57" or "58" or "59" or "60" or "61" or "62" or "63" or "64" or "65" or "66" or "67" or "68" or "69" or "70" or "71" or "72" or "73" or "74" or "75" or "76" or "77" or "78" or "79" or "80" or "81" or "82" or "83" or "84" or "85" or "86" or "87" or "88" or "89" or "90" or "91" or "92" or "93" or "94" or "95" or "96" or "97" or "98" or "99" or "100") adj years).tw. (35828)

6 (aged or aging or ageing or elder$ or geriatric$ or gerontolog$).jw,nw. (135639)

7 or/1‐6 (5225833)

8 hypertension/ (236571)

9 (antihypertens$ or hypertens$).tw. (388311)

10 ((elevat$ or high$ or raised) adj2 (bp or blood pressure)).tw. (35231)

11 or/8‐10 (454663)

12 exp antihypertensive agents/ (258006)

13 exp thiazides/ (15913)

14 exp sodium chloride symporter inhibitors/ (14603)

15 exp sodium potassium chloride symporter inhibitors/ (14205)

16 ((ceiling or loop) adj diuretic?).tw. (2564)

17 (amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or hydrochlorothiazide or hydroflumethiazide or methyclothiazide or metolazone or polythiazide or trichlormethiazide or veratide or thiazide?).tw. (34947)

18 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide).tw. (2353)

19 or/13‐18 [THZ] (50922)

20 exp angiotensin‐converting enzyme inhibitors/ (44001)

21 angiotensin converting enzyme inhibit$.tw. (18514)

22 (ace adj2 inhibit$).tw. (18317)

23 acei.tw. (2857)

24 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$ or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril).tw. (27226)

25 or/20‐24 [ACEI] (59725)

26 exp Angiotensin Receptor Antagonists/ (22055)

27 (angiotensin adj3 (receptor antagon$ or receptor block$)).tw. (11889)

28 arb?.tw. (5159)

29 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or Teveten).tw. (15972)

30 or/26‐29 [ARB] (31152)

31 exp calcium channel blockers/ (83029)

32 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM).tw. (62158)

33 (calcium adj2 (antagonist? or block$ or inhibit$)).tw. (39065)

34 or/31‐33 [CCB] (111557)

35 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin or hydopa or methyldihydroxyphenylalanine or methyl dopa or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa).mp. (16154)

36 (reserpine or serpentina or rauwolfia or serpasil).mp. (20757)

37 (clonidine or adesipress or arkamin or caprysin or catapres$ or catasan or chlofazolin or chlophazolin or clinidine or clofelin$ or clofenil or clomidine or clondine or clonistada or clonnirit or clophelin$ or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or m‐5041t or normopresan or paracefan or st‐155 or st 155 or tesno timelets).mp. (19858)

38 exp hydralazine/ (4964)

39 (hydralazin$ or hydrallazin$ or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1‐hydrazinophthalazine or apressin or nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat).tw. (4648)

40 or/35‐39 [CNS] (59745)

41 exp adrenergic beta‐antagonists/ (84772)

42 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).tw. (62363)

43 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw. (101145)

44 or/41‐43 [BB] (159886)

45 exp adrenergic alpha antagonists/ (51279)

46 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin).tw. (14099)

47 (adrenergic adj2 (alpha or antagonist?)).tw. (20625)

48 ((adrenergic or alpha or receptor?) adj2 block$).tw. (58854)

49 or/45‐48 [AB] (116499)

50 12 or 19 or 25 or 30 or 34 or 40 or 44 or 49 (545270)

51 withdraw$.tw. (106817)

52 (ceased or ceasing or cessation$).tw. (75554)

53 (deprescrib$ or discontinu$).tw. (100561)

54 ((reduced or reduces or reducing or reduction?) adj4 (antihypertens$ or anti‐hypertens$ or dosage? or dose or doses or drug$ or medicat$ or prescri$)).tw. (74185)

55 stop$.tw. (109061)

56 taper$.tw. (14350)

57 or/51‐56 (446297)

58 randomized controlled trial.pt. (484850)

59 controlled clinical trial.pt. (97360)

60 randomized.ab. (371359)

61 placebo.ab. (182081)

62 clinical trials as topic/ (194591)

63 randomly.ab. (255305)

64 trial.ti. (167150)

65 or/58‐64 (1091343)

66 animals/ not (humans/ and animals/) (4782114)

67 Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ (908496)

68 (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti. (14675)

69 65 not (66 or 67 or 68) (963798)

70 7 and 11 and 50 and 57 and 69 (2161)

71 remove duplicates from 70 (1963)

What's new

Last assessed as up‐to‐date: 13 December 2016.

Date	Event	Description
27 February 2017	Amended	Contact details updated.

Contributions of authors

Zaheer Babar: Guarantor of the Review, Co‐ordinating the Protocol, providing a policy perspective, designing search strategies, undertaking searches

Todd M Gammie: Designing the Protocol, Writing the Protocol, Co‐ordinating the Protocol, providing a policy perspective, designing search strategies, undertaking searches

Danijela Gnjidic: Concieving the Research Question, Writing the Protocol, providing a clinical perspective

Emily Reeve: Concieving the Research Question, Writing the Protocol, providing a clinical perspective, providing a consumer perspective

Vanessa Jordan: Providing general advice on the protocol, Providing a methodological perspective

Sarah N Hilmer: Providing a clinical perspective

Ingrid Hopper: Providing a policy perspective

Christine Y Lu: Providing a policy perspective

Sources of support

Internal sources

• Department of Pharmacy, University of Huddersfield, UK.

  Salary, office space, computer support, library resources

• Faculty of Pharmacy, University of Sydney, Sydney, Australia, Australia.

  Salary, office space, computer support, library resources

• Cognitive Decline Partnership Centre, School of Medicine, University of Sydney, St Leonards, Australia.

  Salary, office space

• Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand.

  Salary

• Department of Medicine, Royal North Shore Hospital, The University of Sydney, St Leonards, Australia.

  Salary, office space, library resources

• Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.

  Salary, office space, library resources

• Department of Population Medicine, Harvard Medical School, Boston, MA, USA.

  Salary, office space, library resources

External sources

• No sources of support supplied

Declarations of interest

Zaheer Babar: Nothing to declare

Todd M Gammie: Nothing to declare

Danijela Gnjidic: Nothing to declare

Emily Reeve: Nothing to declare

Vanessa Jordan: Nothing to declare

Sarah N Hilmer: Nothing to declare

Ingrid Hopper: Nothing to declare

Christine Y Lu: Nothing to declare

Edited (no change to conclusions)