Blood pressure lowering effect of hydrochlorothiazide compared to other diuretics for hypertension

Objectives

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

This review aims to assess the short‐term (3 to 12 weeks) blood pressure lowering efficacy of hydrochlorothiazide in comparison with other diuretics for primary hypertension in adults, and will build upon the other Cochrane Reviews studying the blood pressure lowering effect of diuretics (Chen 2009; Musini 2009; Musini 2014). The main outcomes of this review will be change in blood pressure, heart rate, and withdrawals due to adverse effects three to 12 weeks after starting the medication.

Background

Primary hypertension is an important medical condition characterized by an abnormally elevated blood pressure (BP) that is not caused by another medical condition. Hypertension is an important medical condition to manage and is associated with an increased incidence of angina, myocardial infarction, peripheral arterial disease, and overall cardiovascular disease (Rapsomaniki 2014). Hydrochlorothiazide is the thiazide diuretic of choice for the management of elevated blood pressure around the world. We have extensive evidence of the blood pressure lowering effect of hydrochlorothiazide as compared to placebo (Musini 2014). However, it is not known whether the blood pressure lowering effect of different diuretics is the same.  This review is designed to answer that using head‐to‐head double‐blind randomized controlled trials designed to measure the blood pressure lowering effect. 

Description of the condition

Elevated blood pressure (hypertension) is a common condition commonly defined as blood pressure greater than 140/90 mmHg, and a potentially serious risk factor. It is one of the risk factors for stroke, coronary heart disease, heart failure, kidney disease and early death that can most easily be reduced by treatment. Studies show a correlation between elevation of systolic or diastolic blood pressure and increased risk of stroke, heart failure, renal disease, and coronary heart disease. There is considerable evidence that antihypertensive drugs reduce death, stroke, and heart disease when given to people with moderate to severe hypertension (Musini 2017; Musini 2019; Wright 2018; Wright 1999). The magnitude of blood pressure reduction is an important surrogate or indicator of the likelihood that people will benefit from drug treatment

Description of the intervention

Thiazide diuretics were developed during the 1950s, when chemists and physiologists tested derivatives of sulfonamide‐based carbonic anhydrase inhibitors, with the goal of discovering drugs that enhance the excretion of sodium with chloride rather than sodium bicarbonate.  The members of this drug class are derived from benzothiadiazine. Hydrochlorothiazide has become the most widely used thiazide for hypertension worldwide. We are interested in the blood pressure lowering effect of hydrochlorothiazide compared to other diuretics. These include other thiazides: chlorothiazide, buthiazide, bendroflumethiazide, hydroflumethiazide, trichlormethiazide, methyclothiazide, polythiazide, cyclothiazide and cyclopenthiazide, as well as drugs with a similar pharmacologic action on the kidney that do not have the thiazide chemical structure, such as indapamide, chlorthalidone, metolazone, quinethazone, fenquizone, clorexolone, clopamide, diapamide, isodapamide, mefruside and xipamide. The latter, commonly termed 'thiazide‐like diuretics' act on the same co‐transporter in the kidney as thiazides (Edwin 2006). We are also interested in other diuretics such as loop diuretics: furosemide, and aldosterone antagonists: Thiazide diuretics were originally marketed and prescribed in starting doses much higher than the average starting and maximum doses that are currently used for the treatment of hypertension (Edwin 2006). Currently, thiazide diuretics are recommended at lower doses that are the equivalent of 25 mg to 50 mg of hydrochlorothiazide or 12.5 mg to 25 mg of chlorthalidone, the latter of which has been reported to be more potent than hydrochlorothiazide (Chobanian 2003; Wright 2018). Given the difference in potency between the different thiazides and thiazide‐like diuretics, this review will be conducted to ensure that the differences in blood pressure lowering are interpreted in terms of the potency of the different drugs.

Hydrochlorothiazide is not metabolized, and has a half‐life of 6 to 15 hours. Hydrochlorothiazide may interact with: norepinephrine, alcohol, barbiturates, narcotics, amphotericin B, antidiabetic agents, antihypertensive drugs, antineoplastic drugs, cyclophosphamide, methotrexate, bile acid sequestrants, calcium supplements, vitamin D supplements, carbamazepine, corticosteroids, adrenocorticotropic hormone, digoxin, anti‐cholinergic agents, drugs that alter gastrointestinal (GI) motility, gout medications, lithium,e nonsteroidal anti‐inflammatory drugs NSAIDs), selective serotonin reuptake inhibitors (SSRIs), skeletal muscle relaxants of the curare family, and topiramate (PHARMASCIENCE INC. 2014). 

How the intervention might work

Hydrochlorothiazide inhibits the sodium chloride co‐transporter in the distal convoluted tubule. This inhibits the re‐uptake of sodium and water potentially leading to a decrease in blood pressure.  Physiological studies in people show that the early effect of diuretic therapy is to decrease the extracellular volume, plasma volume and cardiac output with relatively unchanged peripheral resistance (Edwin 2006). After several weeks of therapy cardiac output returns to normal and total peripheral resistance decreases.  

Why it is important to do this review

We cannot assume that all diuretics will have the same efficacy in reducing blood pressure. The different classes of diuretics and individual drugs within each class might have differing efficacy and adverse effects. It is important to know whether the blood pressure‐lowering effect of hydrochlorothiazide is different from other thiazides and other classes of diuretics.  It is also important to know whether withdrawals due to adverse effects are different between hydrochlorothiazide and other diuretics.  

This review will further investigate the blood pressure lowering effects of diuretics and will build upon other existing Cochrane Reviews studying the blood pressure lowering effects of diuretics (Chen 2009; Musini 2009; Musini 2014). This review will also extend the work by Wright and colleagues (Wright 2018), which investigated the long‐term morbidity and mortality outcomes of first‐line drugs for the treatment of hypertension, by exploring the more immediate effects of thiazides and other classes of diuretics. A parallel protocol has also been written which will build upon this protocol by comparing thiazides and thiazide‐like diuretics to other antihypertensive drug classes that are not considered diuretics and will not be investigated in this review. 

Objectives

This review aims to assess the short‐term (3 to 12 weeks) blood pressure lowering efficacy of hydrochlorothiazide in comparison with other diuretics for primary hypertension in adults, and will build upon the other Cochrane Reviews studying the blood pressure lowering effect of diuretics (Chen 2009; Musini 2009; Musini 2014). The main outcomes of this review will be change in blood pressure, heart rate, and withdrawals due to adverse effects three to 12 weeks after starting the medication.

Methods

Criteria for considering studies for this review

Types of studies

Only double‐blind (blinding of study participants and personnel) in randomized controlled trials (RCTs)will be included in this review. The studies must also follow a parallel design with random allocation into treatment groups, and include a washout period of at least two weeks before randomization. The trial must report change from baseline or end of treatment blood pressure at one or more time points three to 12 weeks after starting treatment. Only studies with complete trial reports will be included. 

Non‐randomized trials, single‐blind, cross‐over, or open‐label trials will be excluded. Studies that are limited to an abstract will also be excluded unless sufficient data can be obtained from the authors.  Cross‐over trials will be excluded as some of the medications considered in this trial may have treatment effects that may carry over and alter the effect of subsequent treatments. 

Types of participants

Only adult participants, who are at least 18 years of age, with a baseline blood pressure of at least 140 mmHg / 90 mmHg will be included. Because diuretics work on the kidney and are excreted by the kidney, participants with renal failure or a serum creatinine of 1.5 times the normal range will be excluded. Trials where participants are allowed to take other  types of antihypertensive drugs will also be excluded. Pregnant participants will also be excluded. Participants will not be excluded based on other comorbid conditions, age, or sex. If a trial reports data from a subset of relevant participants separately, we will also include it.  

Types of interventions

This review plans on including monotherapy with oral daily hydrochlorothiazide in comparison to the administration of other oral diuretics: e.g. other thiazides, thiazide‐like drugs, loop diuretics, and other diuretics,except for triamterene and amiloride. Only trials with a fixed dose will be accepted. Trials with other drugs given in combination with hydrochlorothiazide will not be included except for in combination with triamterene or amiloride, as a prior Cochrane Review found insufficient evidence indicating their blood pressure lowering effect (Heran 2012). We will further investigate the effect of adding triamterene or amiloride on blood pressure by subgroup analysis (Subgroup analysis and investigation of heterogeneity).

Types of outcome measures

This review is designed to measure the surrogate outcomes of blood pressure and heart rate and not the "hard" outcomes of mortality, stroke, etc., which are the outcomes of other reviews. Hydrochlorothiazide and other diuretics are not currently known to affect heart rate; however, several other classes of antihypertensive medications including calcium channel blockers and beta blockers have been found to influence heart rate (Wright 2018), and thus we intend to further explore this outcome in this upcoming Cochrane Review.

Primary outcomes

Change from baseline or end‐of‐treatment systolic and diastolic blood pressure (office blood pressure, defined as blood pressure readings measured in office settings rather than ambulatory readings) three to 12 weeks after starting the medication. The duration of three to 12 weeks has been chosen as it takes three weeks for the maximal effect to occur and trials of 12 weeks or less reduce the number of participants who drop out. If more than one blood pressure measurement is reported during the treatment period three to 12 weeks) the weighted mean of the blood pressure measurements will be used to optimize use of the available data.  The weighted mean will assess the change from baseline versus placebo and end of treatment versus placebo may be used to calculate the pooled difference. The preferred positions for measuring office blood pressure in order of preference are sitting, standing, and supine. 

Secondary outcomes

1. Change from baseline or end‐of‐treatment heart rate three to 12 weeks after starting the medication. 

2. Withdrawals due to adverse effects.  

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist (CIS) will search the following databases without language, publication year or publication status restrictions: 

• Cochrane Hypertension Specialised Register via the Cochrane Register of Studies;

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

• Ovid MEDLINE(R) ALL;

• Ovid Embase;

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov);

• World Health Organisation International Clinical Trials Registry Platform (www.who.it.trialsearch).

The Information Specialist will model the subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, the CIS will combine the subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (Higgins 2021). We present the MEDLINE search strategy in Appendix 1. 

Searching other resources

The CIS will search the Hypertension Specialised Register segment (which includes searches of MEDLINE and Embase for systematic reviews) 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 check the included studies for retractions and errata via PubMed (www.pubmed.ncbi.nlm.nih.gov) and the Retraction Watch Database (www.retractiondatabase.org [https://We will check the included studies for retractions and errata via PubMed (www.ncbi.nlm.gov/pubmed) and the Retraction Watch Database (http://retractiondatabase.org) and report the search dates in the review.]), and report the search dates in the review.

We will search Epistemonikos (www.epistemonikos.org) for related systematic reviews.

Where necessary, we will contact experts/organizations in the field of antihypertensive pharmacology to obtain additional information on relevant trials.

We may contact original authors or funding of included studies for clarification and further data if trial reports are unclear.

Data collection and analysis

Selection of studies

The results of the search will be managed in Covidence. Studies that satisfy the: types of study criteria, types of participants criteria, types of intervention criteria, and types of outcome measures will be included as long as they do not meet any of the exclusion criteria. All studies will be reviewed independently by two review authors (VMS and PJ) using a standardised form. Any discrepancies will be resolved by the third review author. The unit of interest for this review is the study and multiple reports and papers related to a single study will be grouped under a single reference ID. The selection process will be completed with sufficient detail to complete a PRISMA flow diagram (Page 2020) and 'Characteristics of excluded studies' table.

Data extraction and management

The data will be transferred to RevMan Web 2022. We will pilot‐test a data collection form using a random sample of five studies before commencing the full data extraction. The data will be extracted independently by two review authors (VMS, and PJ) for all critical and secondary outcomes using a standardised form. The data will then be cross‐checked. All calculations and statistical analyses will be checked by the second review author. Data will be extracted for: (1) change from baseline systolic and diastolic blood pressure or (2) systolic and diastolic blood pressure measurements taken three to12 weeks after the onset of treatment. (3) change or end of treatment heart rate three to 12 weeks after starting treatment, (4) the number of participant withdrawals due to adverse effects, (5) the number of participants: randomized, lost to follow‐up, withdrawn, analysed, (6) the participants: mean age, age range, gender, (7) funding for the trial and other notable conflicts of interest of the trial author, (8) information needed to assess bias, (10) study design, (11) setting, (12) method of participant recruitment, (13) disease severity, (14) eligibility criteria, (15) details of the interventions, and (16) information needed to assess GRADE. 

We plan to synthesize the characteristics of all the studies that will contribute to each comparison described above, and present these in the 'Characteristics of included studies' table in our full review. We will convert data found in studies to a format appropriate for meta‐analysis following the methods described in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). 

Assessment of risk of bias in included studies

Two independent review authors (VMS and PJ) will assess the risk of bias of included studies and a third review author (JW) will arbitrate in case of disagreements. Each study will be examined for bias using the Cochrane Collaboration's tool for assessing risk of bias (RoB 1) for the following domains (Higgins 2019): random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, industry sponsorship, and other sources of bias. This risk assessment will inform GRADE and the summary of findings table. Any discrepancies between the review authors will be resolved by discussion with a third review author (JW). The risk of bias judgement will be summarised for each outcome across different studies for each of the domains listed, where the overall risk of bias for the result is the least favourable assessment across the domains of bias. We will include a risk of bias graph and a risk of bias summary to illustrate risk of bias, and where possible we will add this information to figures showing the meta‐analysis. If there are sufficient data then sensitivity analyses will be used to assess the robustness of data with regard to: high versus low risk of bias in included studies, and industry versus non‐industry sponsored trials (Sensitivity analysis). GRADE criteria will be used to assess the certainty of evidence as in Higgins 2019. 

Measures of treatment effect

The mean differences (MDs) and the corresponding 95% confidence intervals (CIs) will be calculated to compare the effects of different treatments on blood pressure, and heart rate. Withdrawals due to adverse effects will be assessed using relative risk, risk difference, and number need to harm. We will ensure that all scales are measuring their effect in the same direction, and we will convert any that run counter to others. We do not expect that it will be necessary to use standardized mean differences (SMDs) and their 95% CIs. If data are not reported in a randomized controlled trial (RCT) in a format that we can enter directly into a meta‐analysis, we will convert them to the required format using the information in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). 

Unit of analysis issues

No unit of analysis issues are expected as no cross‐over trials will be included in this study. If multi‐arm studies are included, we will analyse multiple intervention groups in an appropriate way that avoids arbitrary omission of relevant groups and double‐counting of participants.

Dealing with missing data

In the event that data is not reported (including missing outcome data for participants) we will contact the study authors in order to obtain the missing data. The only missing data that we will impute is SD by using the average of this value from other studies (Higgins 2021). Selective outcome reporting will also be considered in the risk of bias assessment using RoB1. Trial registers may be used to identify any initiated, ongoing or completed (but not necessarily published) studies that meet the eligibility criteria to reduce the risk of bias due to missing results.

Assessment of heterogeneity

Statistical heterogeneity will be assessed using the standard Chi² test and I² statistic available in RevMan Web 2022. We plan to assess statistical heterogeneity by visual inspection of forest plots to consider the direction and magnitude of effects and the degree of overlap between CIs. If we identify substantial heterogeneity (an I² of greater than 50%) (Higgins 2019), we will report it and explore possible causes by prespecified subgroup analysis. Data for clinical and methodological variability will be covered in the Characteristics of included studies table. 

Assessment of reporting biases

Each study will be assessed using the Cochrane Collaboration's recommended tool (RoB 1) which assesses selective outcome reporting. 

If there are more than 10 trials, a thorough assessment of selective non‐reporting or under‐reporting of results will be conducted to assess the risk of bias due to missing results. Funnel plots will be used to assess for reporting biases if we have sufficient studies (10 or more) included in our meta‐analysis. We will also note that funnel plot asymmetry may arise because of small‐study effects and not just non‐reporting bias. 

Data synthesis

Data synthesis and analysis will be done using RevMan Web 2022. A P value of less than 0.05 will be considered statistically significant. The fixed‐effect model will be used to obtain summary statistics from pooled trials unless there is significant heterogeneity in: intervention, population characteristics, and methodological differences that could lead to different intervention effects being estimated. If significant heterogeneity is present in these characteristics, then the random‐effects model will be used. Our choice of fixed‐effect or random‐effects model will not be determined by I². Hydrochlorothiazide's effect on heart rate and blood pressure will be compared to each of the other diuretics. Withdrawals due to adverse events with hydrochlorothiazide will also be compared to each of the other diuretics. The outcome of interest is the difference from placebo. Change from baseline versus placebo and end of treatment versus placebo will be entered into RevMan Web 2022 to calculate the pooled difference. A narrative synthesis will be considered should numerical (meta) analysis be deemed impossible due to heterogeneity or limited evidence (Higgins 2021), for example by following the nine‐item Synthesis Without Meta‐analysis (SWiM) guideline (Campbell 2020).

Subgroup analysis and investigation of heterogeneity

The sex of study participants, co‐administration of triampterene or amiloride,  different doses of hydrochlorothiazide, and high versus low risk of bias in included studies will be assessed in subgroup analyses using the statistical test for subgroup differences available in RevMan Web 2022. We have previously investigated the dose‐related effects of hydrochlorothiazide in our previous review and the review findings will guide our interpretation of differences in blood pressure effects (Musini 2014). We will also assess ethnicity using subgroup analysis as long as there is sufficient data to allow for it. Heterogeneity will be assessed using the standard Chi² test, and I² available in RevMan Web 2022 (Assessment of heterogeneity). We are aware of the limitations of subgroup analyses that require consideration when interpreting results, including their observational nature. 

Sensitivity analysis

If we identify sufficient data then sensitivity analysis will be used to assess the robustness of data with regard to the position of blood pressure measurement, fixed‐effect versus random‐effects model, trough versus peak blood pressure measurement, and industry versus non‐industry sponsored trials. Body positioning has been shown to have a significant effect on blood pressure (Privšek 2018) and may have an effect on our overall effect estimates. The trough‐to‐peak ratio refers to the extent by which antihypertensive medications exert their effects over a standard dosing interval (Myers 1996), which is also a potential modifier of our effect estimates. 

Summary of findings and assessment of the certainty of the evidence

Our summary of findings table will compare oral daily hydrochlorothiazide with each of the other oral diuretics (other thiazides, thiazide‐like drugs, loop diuretics, and other diuretics except for triamterene and amiloride) in each of our outcomes. The critical outcome to be included in the summary of findings table is 'Change from baseline or end‐of‐treatment systolic and diastolic blood pressure' three to 12 weeks after starting the medication. The two secondary outcomes 'Change or end of treatment heart rate three to 12 weeks after starting the medication' and 'Withdrawals due to adverse effects' will also be included. A separate summary of findings table will be prepared for each comparison. GRADE criteria will be used to assess the certainty of a body of evidence as it relates to the studies that contribute data to the meta‐analyses for the specified outcomes. Our consideration includes within‐study risk of bias, directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias. We will rate the certainty of evidence as high, moderate, low, or very low, and will justify all decisions to downgrade the certainty of the evidence using footnotes and make comments to aid reader’s understanding of the review where necessary. The GRADE assessment will be carried out by review authors VMS and PJ. Any disputes will be resolved by a third review author JW.  The findings of each outcome investigated will be shown graphically and in the text. 

Appendices

Appendix 1. MEDLINE search strategy

1 hydrochlorothiazide/ 
2 (hydrochlorothiazid* or apo‐hydro or aquarius or aquazide or bisalunil or bpzide or bremil or chlorosulthiadil or chlorsulfonamidodihydrobenzothiadiazine or cidrex or clothia or dehydratin or diaqua or dichlorosal or dichlothiazide or dichlotride or dichlozid or diclotride or didralin or dihydrochlorothiazide or dihydrodiuril or direma or disaluril or disothiazide or dithiazide or diu melusin or diumelusin or diurace or diurex or esidrex or esidrix or fluvin or hctz or hidrenox or hidril or hidroronol or hidrosaluretil or hudorex or hychlozide or hydrex‐semi or hydril or hydro aquil or hydrochlor or hydrochloro thiazide or hydrochlorothiamide or hydrochlorothiazid or hydrochlorothiazine or hydrochlorzide or hydrochlothiazide or hydro diuril or hydrodiuril or hydromal or hydrororonol or hydro saluric or hydrosaluric or hydrothide or hydro tonuron or hydrozide or hypothiazid or hypothiazide or ivaugan or maschitt or microzide or mictrin or nefrix or neoflumen or newtolide or niagar or oretic or pantemon or ridaq or sectrazide or tandiur or thiadril or thiaretic or thiuretic or urodiazin or urodiazine or urozide or vetidrex).mp. 
3 or/1‐2 
4 exp thiazides/ 
5 diuretics/ 
6 exp sodium chloride symporter inhibitors/ 
7 exp sodium potassium chloride symporter inhibitors/ 
8 exp mineralocorticoid receptor antagonists/ 
9 thiazide*.mp. 
10 diuretic*.ti,kf. 
11 ((sodium chloride adj2 cotransporter inhibit*) or (sodium chloride adj2 co‐transporter inhibit*) or (sodium chloride adj2 symporter inhibit*)).mp. 
12 ((ceiling adj2 diuretic?) or (loop adj2 diuretic?) or (potassium‐depleting adj2 diuretic?)).mp.
13 ((aldosterone or mineralocorticoid) adj2 antagonist*).mp. 
14 (altizide or althiazide or altizida or altizidum).mp.
15 amiloride/ or (amilorid* or amiclaran or amidal or amiduret trom or amikal or amiloberag or amilorid or amiloridehydrochlorhydrate or amiloridine or amipramidine or amyloride or arumil or berkamil or colectril or guanamprazine or kaluril or medamor or midamor or midoride or modamide or nirulid or pandiuren).mp. 
16 (azosemide or azosemid or luret).mp. 
17 bendroflumethiazide/ or (bendroflumethiazid* or aprinox or bendrofluazide or bendroflumethiazide or benzhydroflumethiazide or benzydroflumethiazide or benzyl hydroflumethiazide or benzylhydroflumethiazide or benzide or berkozide or bristuron or centonuron or centyl or esberizid or naturetin or naturine or neo naclex or neonaclex or naturetin or naturine or neonadex or pluryl or pluryle or repicin or salures or sinesalin or urizid).mp. 
18 exp benzothiadiazines/ 
19 bumetanide/ or (bumetanid* or budema or bumedyl or bumelex or bumet or bumetamide or bumethanide or bumetidine or bumex or burinax or burinex or busix or butinat or butinon or bymex or cambiex or drenural or farmadiuril or fontego or fordiuran or lixil or lunetoron or miccil or primex).mp. 
20 (butizid* or buthiazide or eunephran or eunepran or isobutylhydrochlorothiazide or modenol or saltucin or thiabulazid or thiabutazide or thiobulazid or tiabutazide).mp. 
21 chlorothiazide/ or (chlorothiazid* or chlorosal or chlorothiazid or chlorothiazidum or chlorothiazine or chlorthiazide or chlotride or diachlor or diuril or diurilix or diuriwas wassermann milano or flumen or lyovac or saluric or warduzuide).mp. 
22 chlorthalidone/ or (chlorthalidon* or aquadon or chlorphthalidolone or chlortalidon or chlortalidone or clortalidone or chlorthalidine or chlorthalidon or chlorthialidone or clortalil or edemdal or hidronal or higroton or higrotona or hygroton or hylidone or hypertol or hythalton or igrolina or igroton or isoren or natriuran or oxodolin or oxodoline or phthalamidine or phthalamodine or phthalamudine or renon or servidone or thalitone or urandil or urofinil or zambesil).mp. 
23 (cicletanine or cicletanide or cycletanide or justar or tenstaten or tenstatin).mp. 
24 clopamide/ or (clopamid* or adurix or aquez or brinaldix or brinaldrix or brinedine or chlosudimeprimylum clopamid or clopamidum or clopamine).mp. 
25 clorexolone/ or (clorexolon* or anhydron or clorexone or chlorexolone or cyclothiazide or doburil or flonatril or fluidil or klorex or nefrolan or valmiran).mp. 
26 cyclopenthiazide/ or (cyclopenthiazid* or cyclomethiazide or cyclopenthiazine or cyclopentiazide or navidex or navidrex or navidrix or salimid or tsiklometiazid).mp. 
27 (cyclothiazid* or anhydron or doburil or fluidil or valmiran).mp. 
28 (epitizide or epithiazide or epitizid or flurese or thiaver).mp.
29 (fenquizone or idrolone).mp. 
30 furosemide/ or (furosemid* or aldic or aluzine or anfuramaide or aquarid or arasemide or cetasix or desal or diamazon or dirine or discoid or diumide or diural or diuresal or diurin or diurix or diurolasa or diusemide or diuspec or dryptal or durafurid or edenol or errolon or eutensin or eutensine or flurosemide or franyl or fretic or frumid or frusedan or frusehexal or frusema or frusemidor frusemide or frusid or fruzex or fumarenid or fumide or furanthril or furantral or furantril or furanturil or furasemide or furesin or furesis or furetic or furix or furmid or furo puren or furo‐basan or furo‐puren or furobasan or furomen or furomex or furomide or furomin or furopuren or furorese or furosamide or furoscan or furose or furosemid or furosemix or furosimide or furosix or furovite or fursemide or fusid or fusimex or hissuflux or hydro rapid or impugan or jufurix or kofuzon or kutrix or lasiletten or lasilix or lasix or laxis or laxur or luramide or marsemide or mirfat or odemase or odemex or oedemase or oedemex or pharmix or promedes or radisemide or rasitol or retep or salinex or seguril or selectofur or sigasalur or uremide or uresix or urex‐m or vesix or zafurida).mp. 
31 (errolon or frusemid or frusemide or furanthril or furantral or furosemide or fursemide or fusid or lasix).mp. 
32 hydroflumethiazide/ or (hydroflumethiazid* or bristab or di ademil or diademil or dihydroflumethiazide or diraudixin or diucardin or hiserpin or hydrenox or leodrin or leodrine or metflorylthiadiazine or naclex or rontyl or saluron or sisuril or trifluoromethylhydrothiazide).mp. 
33 indapamide/ or (indapamid* or agelan or apadex or arifon or damide or dapamax or diflerix or dixamid or extur or fludex or fluidema or frumeron or indahexal or indalix or indamol or indapam or indapress or indicontin or indoline or indopamide or inpamide or insig or ipamix or lorvas or loxide or lozol or metindamide or millibar or naplin or natrilix or natrix or noranat or pamid or pressural or pretanix or rinalix or sicco or tandix or tertensif or veroxil).mp. 
34 isodapamide.mp.
35 (mebutizide or neoniagar).mp.
36 mefruside/ or (mefruside or bay caron or baycaron or baycarone or mefrusid).mp. 
37 methyclothiazide/ or (methylclothiazide or aquatensen or enduron or enduron‐m or enduronum or methyclothiazide or methylchlorothiazide or thiazidil).mp. 
38 metolazone/ or (metolazone or barolyn or diulo or metalazone or metenix or metolazon or miclox or microx or mykrox or normelan or xuret or zaroxolyn).mp.
39 polythiazide/ or (polythiazid* or drenusil or nephril or renese).mp. 
40 (quinethazone or aquamox or chinethazon or chinethazone or guinethazone or hydromox or kinetazone or quinethazon).mp. 
41 spironolactone/ or (spironolacton* or abbolactone or acelat or adultmin or alaton or alatone or aldace or aldactone or aldopur or aldospirone or almatol or aquareduct or berlactone or crl635 or diram or duraspiron or dyta urese or dytaurese or espironolactona or flumach or frumikal or hypazon or idrolattone or jenaspiron or merabis or novospiroton or osiren or osyrol or pirolacton or pondactone or practon or resacton or sas1060 or sc9420 or spiractin or spiridon or spirix or spiro or spiroctan or spirobeta or spirogamma or spirolacton or spirolactone or spirolang or spiron or spirone or spironex or spirono or spironol or spironone or spirospare or spirothiobarbiturate or spirotone or supra puren or suprapuren or uractone or veroshpiron or verospiron or verospirone or xenalon or youlactone).mp. 
42 (tiamizide or diapamide or thiamizide).mp. 
43 tizolemide.mp. 
44 torsemide/ or (torsemide* or demadex or dilutol or diuremid or isemid or isodiur or luprac or presaril or sutril or toradiur or torem or torrem or torasemide or unat or upcard).mp. 
45 trichloromethiazide/ or (trichloromethiazid* or aquazide or dichloromethylhydrochlorothiazide or diurese or esmarin or eurinol or fluitran or flutra or gangesol or hydrotrichlorothiazide or metahydrin or methahydrin or naqua or naquasone or salurin or triazide or trichlordiuride or trichlorex or trichlormethazide or trichlormethiazide or trichlormas or trichloromethylhydrochlorothiazide or triflumen or wadel).mp. 
46 (tripamide or normonal).mp. 
47 xipamide/ or (xipamid* or aquaforil or aquaphor or aquaphoril or aquavor or diurexan or lumitens or xipamid or xypamide or zipix).mp. 
48 or/4‐47 
49 hypertension/ 
50 essential hypertension/ 
51 hypertens*.tw,kf.
52 ((chang* adj2 blood pressur*) or (effect* adj2 blood pressur*) or (elevat* adj2 blood pressur*) or (lower* adj2 blood pressur*) or (high* adj2 blood pressur*) or (rais* adj2 blood pressur*) or (reduc* adj2 blood pressur*)).tw,kf. 
53 ((chang* adj2 bloodpressur*) or (effect* adj2 bloodpressur*) or (elevat* adj2 bloodpressur*) or (lower* adj2 bloodpressur*) or (high* adj2 bloodpressur*) or (rais* adj2 bloodpressur*) or (reduc* adj2 bloodpressur*)).tw,kf. 
54 ((chang* adj2 bp) or (effect* adj2 bp) or (elevat* adj2 bp) or (lower* adj2 bp) or (high* adj2 bp) or (rais* adj2 bp) or (reduc* adj2 bp)).tw,kf.
55 ((chang* adj2 dbp) or (effect* adj2 dbp) or (elevat* adj2 dbp) or (lower* adj2 dbp) or (high* adj2 dbp) or (rais* adj2 dbp) or (reduc* adj2 dbp)).tw,kf. 
56 ((chang* adj2 mbp) or (effect* adj2 mbp) or (elevat* adj2 mbp) or (lower* adj2 mbp) or (high* adj2 mbp) or (rais* adj2 mbp) or (reduc* adj2 mbp)).tw,kf. 
57 ((chang* adj2 sbp) or (effect* adj2 sbp) or (elevat* adj2 sbp) or (lower* adj2 sbp) or (high* adj2 sbp) or (rais* adj2 sbp) or (reduc* adj2 sbp)).tw,kf. 
58 or/49‐57 
59 randomized controlled trial.pt.
60 controlled clinical trial.pt.
61 randomi*ed.ab. 
62 placebo.ab. 
63 clinical trials as topic/ 
64 randomly.ab.
65 trial.ti. 
66 or/59‐65 
67 animals/ not (humans/ and animals/)
68 66 not 67
69 3 and 48 and 58 and 68

Contributions of authors

Vivian Morley‐Senkler and James M Wright wrote and edited the protocol. Parker Jobin reviewed the protocol. All review authors approved the final version for publication.

Sources of support

Internal sources

• University of British Columbia, Canada

  Vivian Morley‐Senkler is a second year medical student attending the University of British Columbia.

External sources

• BC Ministry of Health , Canada

  infrastructure support provided in form of a grant to the Therapeutics Initiative 

Declarations of interest

Vivian Morley‐Senkler: no relevant interests; medical student at the University of British Columbia (UBC). 

Parker Jobin: none known.

James Wright: no relevant interests; Coordinating Editor for Cochrane Hypertension Group.

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