Morley-Senkler Et Al-2022-Cochrane Database of Systematic Reviews

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Cochrane Database of Systematic Reviews

Blood pressure lowering effect of hydrochlorothiazide compared to
other diuretics for hypertension (Protocol)
Morley-Senkler V, Jobin P, Wright JM
Morley-Senkler V, Jobin P, Wright JM.

Blood pressure lowering effect of hydrochlorothiazide compared to other diuretics for hypertension (Protocol).
Cochrane Database of Systematic Reviews 2022, Issue 11. Art. No.: CD015250.
DOI: 10.1002/14651858.CD015250.
www.cochranelibrary.com

Blood pressure lowering effect of hydrochlorothiazide compared to other diuretics for hypertension (Protocol)
Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.

Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
ABSTRACT..................................................................................................................................................................................................... 1
BACKGROUND.............................................................................................................................................................................................. 2
OBJECTIVES.................................................................................................................................................................................................. 2
METHODS..................................................................................................................................................................................................... 3
ACKNOWLEDGEMENTS................................................................................................................................................................................ 5
REFERENCES................................................................................................................................................................................................ 7
APPENDICES................................................................................................................................................................................................. 8
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 10
DECLARATIONS OF INTEREST..................................................................................................................................................................... 10
SOURCES OF SUPPORT............................................................................................................................................................................... 10
Blood pressure lowering effect of hydrochlorothiazide compared to other diuretics for hypertension (Protocol) i
Informed decisions.

[Intervention Protocol]
Blood pressure lowering effect of hydrochlorothiazide compared to

other diuretics for hypertension
Vivian Morley-Senkler1, Parker Jobin2, James M Wright3
1Faculty of Medicine, University of British Columbia, Kelowna, Canada. 2Faculty of Medicine, University of British Columbia, Vancouver,
Canada. 3Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
Contact: Vivian Morley-Senkler, vmsenkle@student.ubc.ca.
Editorial group: Cochrane Hypertension Group.

Publication status and date: New, published in Issue 11, 2022.
Citation: Morley-Senkler V, Jobin P, Wright JM. Blood pressure lowering effect of hydrochlorothiazide compared to other diuretics for
hypertension (Protocol). Cochrane Database of Systematic Reviews 2022, Issue 11. Art. No.: CD015250. DOI: 10.1002/14651858.CD015250.
ABSTRACT
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.
Blood pressure lowering effect of hydrochlorothiazide compared to other diuretics for hypertension (Protocol) 1
Informed decisions.

BACKGROUND the latter of which has been reported to be more potent than
hydrochlorothiazide (Chobanian 2003; Wright 2018). Given the
Primary hypertension is an important medical condition difference in potency between the different thiazides and thiazide-
characterized by an abnormally elevated blood pressure (BP) that like diuretics, this review will be conducted to ensure that the
is not caused by another medical condition. Hypertension is an differences in blood pressure lowering are interpreted in terms of
important medical condition to manage and is associated with an the potency of the different drugs.
increased incidence of angina, myocardial infarction, peripheral
arterial disease, and overall cardiovascular disease (Rapsomaniki Hydrochlorothiazide is not metabolized, and has a half-life
2014). Hydrochlorothiazide is the thiazide diuretic of choice for of 6 to 15 hours. Hydrochlorothiazide may interact with:
the management of elevated blood pressure around the world. norepinephrine, alcohol, barbiturates, narcotics, amphotericin
We have extensive evidence of the blood pressure lowering effect B, antidiabetic agents, antihypertensive drugs, antineoplastic
of hydrochlorothiazide as compared to placebo (Musini 2014). drugs, cyclophosphamide, methotrexate, bile acid sequestrants,
However, it is not known whether the blood pressure lowering calcium supplements, vitamin D supplements, carbamazepine,
effect of different diuretics is the same. This review is designed corticosteroids, adrenocorticotropic hormone, digoxin, anti-
to answer that using head-to-head double-blind randomized cholinergic agents, drugs that alter gastrointestinal (GI) motility,
controlled trials designed to measure the blood pressure lowering gout medications, lithium,e nonsteroidal anti-inflammatory
effect. drugs NSAIDs), selective serotonin reuptake inhibitors (SSRIs),
skeletal muscle relaxants of the curare family, and topiramate
Description of the condition (PHARMASCIENCE INC. 2014).
Elevated blood pressure (hypertension) is a common condition How the intervention might work
commonly defined as blood pressure greater than 140/90 mmHg,
and a potentially serious risk factor. It is one of the risk factors Hydrochlorothiazide inhibits the sodium chloride co-transporter
for stroke, coronary heart disease, heart failure, kidney disease in the distal convoluted tubule. This inhibits the re-uptake of
and early death that can most easily be reduced by treatment. sodium and water potentially leading to a decrease in blood
Studies show a correlation between elevation of systolic or pressure. Physiological studies in people show that the early
diastolic blood pressure and increased risk of stroke, heart failure, effect of diuretic therapy is to decrease the extracellular volume,
renal disease, and coronary heart disease. There is considerable plasma volume and cardiac output with relatively unchanged
evidence that antihypertensive drugs reduce death, stroke, and peripheral resistance (Edwin 2006). After several weeks of therapy
heart disease when given to people with moderate to severe cardiac output returns to normal and total peripheral resistance
hypertension (Musini 2017; Musini 2019; Wright 2018; Wright 1999). decreases.
The magnitude of blood pressure reduction is an important
surrogate or indicator of the likelihood that people will benefit from Why it is important to do this review
drug treatment We cannot assume that all diuretics will have the same efficacy
in reducing blood pressure. The different classes of diuretics and
Description of the intervention individual drugs within each class might have differing efficacy
Thiazide diuretics were developed during the 1950s, when chemists and adverse effects. It is important to know whether the blood
and physiologists tested derivatives of sulfonamide-based carbonic pressure-lowering effect of hydrochlorothiazide is different from
anhydrase inhibitors, with the goal of discovering drugs that other thiazides and other classes of diuretics. It is also important
enhance the excretion of sodium with chloride rather than to know whether withdrawals due to adverse effects are different
sodium bicarbonate. The members of this drug class are between hydrochlorothiazide and other diuretics.
derived from benzothiadiazine. Hydrochlorothiazide has become
the most widely used thiazide for hypertension worldwide. This review will further investigate the blood pressure lowering
We are interested in the blood pressure lowering effect of effects of diuretics and will build upon other existing Cochrane
hydrochlorothiazide compared to other diuretics. These include Reviews studying the blood pressure lowering effects of diuretics
other thiazides: chlorothiazide, buthiazide, bendroflumethiazide, (Chen 2009; Musini 2009; Musini 2014). This review will also
hydroflumethiazide, trichlormethiazide, methyclothiazide, extend the work by Wright and colleagues (Wright 2018), which
polythiazide, cyclothiazide and cyclopenthiazide, as well as investigated the long-term morbidity and mortality outcomes of
drugs with a similar pharmacologic action on the kidney first-line drugs for the treatment of hypertension, by exploring the
that do not have the thiazide chemical structure, such more immediate effects of thiazides and other classes of diuretics.
as indapamide, chlorthalidone, metolazone, quinethazone, A parallel protocol has also been written which will build upon this
fenquizone, clorexolone, clopamide, diapamide, isodapamide, protocol by comparing thiazides and thiazide-like diuretics to other
mefruside and xipamide. The latter, commonly termed 'thiazide- antihypertensive drug classes that are not considered diuretics and
like diuretics' act on the same co-transporter in the kidney will not be investigated in this review.
as thiazides (Edwin 2006). We are also interested in other
diuretics such as loop diuretics: furosemide, and aldosterone
OBJECTIVES
antagonists: Thiazide diuretics were originally marketed and This review aims to assess the short-term (3 to 12 weeks) blood
prescribed in starting doses much higher than the average starting pressure lowering efficacy of hydrochlorothiazide in comparison
and maximum doses that are currently used for the treatment with other diuretics for primary hypertension in adults, and
of hypertension (Edwin 2006). Currently, thiazide diuretics are will build upon the other Cochrane Reviews studying the blood
recommended at lower doses that are the equivalent of 25 mg to 50 pressure lowering effect of diuretics (Chen 2009; Musini 2009;
mg of hydrochlorothiazide or 12.5 mg to 25 mg of chlorthalidone, Musini 2014). The main outcomes of this review will be change in
Informed decisions.

blood pressure, heart rate, and withdrawals due to adverse effects Primary outcomes
three to 12 weeks after starting the medication.
Change from baseline or end-of-treatment systolic and diastolic
METHODS blood pressure (office blood pressure, defined as blood pressure
readings measured in office settings rather than ambulatory
Criteria for considering studies for this review readings) three to 12 weeks after starting the medication. The
duration of three to 12 weeks has been chosen as it takes three
Types of studies weeks for the maximal effect to occur and trials of 12 weeks or
Only double-blind (blinding of study participants and personnel) less reduce the number of participants who drop out. If more
in randomized controlled trials (RCTs)will be included in this than one blood pressure measurement is reported during the
review. The studies must also follow a parallel design with random treatment period three to 12 weeks) the weighted mean of the
allocation into treatment groups, and include a washout period blood pressure measurements will be used to optimize use of the
of at least two weeks before randomization. The trial must report available data. The weighted mean will assess the change from
change from baseline or end of treatment blood pressure at one or baseline versus placebo and end of treatment versus placebo may
more time points three to 12 weeks after starting treatment. Only be used to calculate the pooled difference. The preferred positions
studies with complete trial reports will be included. for measuring office blood pressure in order of preference are
sitting, standing, and supine.
Non-randomized trials, single-blind, cross-over, or open-label trials
will be excluded. Studies that are limited to an abstract will also be Secondary outcomes
excluded unless sufficient data can be obtained from the authors. 1. Change from baseline or end-of-treatment heart rate three to 12
Cross-over trials will be excluded as some of the medications weeks after starting the medication.
considered in this trial may have treatment effects that may carry 2. Withdrawals due to adverse effects.
over and alter the effect of subsequent treatments.
Search methods for identification of studies
Types of participants
Electronic searches
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 The Cochrane Hypertension Information Specialist (CIS) will search
included. Because diuretics work on the kidney and are excreted the following databases without language, publication year or
by the kidney, participants with renal failure or a serum creatinine publication status restrictions:
of 1.5 times the normal range will be excluded. Trials where
participants are allowed to take other types of antihypertensive • Cochrane Hypertension Specialised Register via the Cochrane
drugs will also be excluded. Pregnant participants will also Register of Studies;
be excluded. Participants will not be excluded based on other • Cochrane Central Register of Controlled Trials (CENTRAL) via the
comorbid conditions, age, or sex. If a trial reports data from a subset Cochrane Register of Studies;
of relevant participants separately, we will also include it. • Ovid MEDLINE(R) ALL;
Types of interventions • Ovid Embase;
• US National Institutes of Health Ongoing Trials Register
This review plans on including monotherapy with oral daily ClinicalTrials.gov (www.clinicaltrials.gov);
hydrochlorothiazide in comparison to the administration of other
• World Health Organisation International Clinical Trials Registry
oral diuretics: e.g. other thiazides, thiazide-like drugs, loop
Platform (www.who.it.trialsearch).
diuretics, and other diuretics,except for triamterene and amiloride.
Only trials with a fixed dose will be accepted. Trials with other drugs The Information Specialist will model the subject strategies for
given in combination with hydrochlorothiazide will not be included databases on the search strategy designed for MEDLINE. Where
except for in combination with triamterene or amiloride, as a prior appropriate, the CIS will combine the subject strategy adaptations
Cochrane Review found insufficient evidence indicating their blood of the highly sensitive search strategy designed by Cochrane
pressure lowering effect (Heran 2012). We will further investigate for identifying randomised controlled trials (as described in the
the effect of adding triamterene or amiloride on blood pressure Cochrane Handbook for Systematic Reviews of Interventions Version
by subgroup analysis (Subgroup analysis and investigation of 6.2 (Higgins 2021). We present the MEDLINE search strategy
heterogeneity). in Appendix 1.
Types of outcome measures Searching other resources
This review is designed to measure the surrogate outcomes of The CIS will search the Hypertension Specialised Register segment
blood pressure and heart rate and not the "hard" outcomes of (which includes searches of MEDLINE and Embase for systematic
mortality, stroke, etc., which are the outcomes of other reviews. reviews) to retrieve published systematic reviews related to this
Hydrochlorothiazide and other diuretics are not currently known to review title, so that we can scan their reference lists to identify
affect heart rate; however, several other classes of antihypertensive additional relevant trials.
medications including calcium channel blockers and beta blockers
have been found to influence heart rate (Wright 2018), and thus we We will check the bibliographies of included studies and any
intend to further explore this outcome in this upcoming Cochrane relevant systematic reviews identified for further references to
Review. relevant trials.
Informed decisions.

We will check the included studies for retractions and errata Assessment of risk of bias in included studies
via PubMed (www.pubmed.ncbi.nlm.nih.gov) and the Retraction
Two independent review authors (VMS and PJ) will assess the risk of
Watch Database (www.retractiondatabase.org [https://We will
bias of included studies and a third review author (JW) will arbitrate
check the included studies for retractions and errata via PubMed
in case of disagreements. Each study will be examined for bias
(www.ncbi.nlm.gov/pubmed) and the Retraction Watch Database
using the Cochrane Collaboration's tool for assessing risk of bias
(http://retractiondatabase.org) and report the search dates in the
(RoB 1) for the following domains (Higgins 2019): random sequence
review.]), and report the search dates in the review.
generation, allocation concealment, blinding, incomplete outcome
We will search Epistemonikos (www.epistemonikos.org) for related data, selective outcome reporting, industry sponsorship, and other
systematic reviews. sources of bias. This risk assessment will inform GRADE and the
summary of findings table. Any discrepancies between the review
Where necessary, we will contact experts/organizations in the field authors will be resolved by discussion with a third review author
of antihypertensive pharmacology to obtain additional information (JW). The risk of bias judgement will be summarised for each
on relevant trials. outcome across different studies for each of the domains listed,
where the overall risk of bias for the result is the least favourable
We may contact original authors or funding of included studies for assessment across the domains of bias. We will include a risk of bias
clarification and further data if trial reports are unclear. 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-
Data collection and analysis analysis. If there are sufficient data then sensitivity analyses will be
Selection of studies used to assess the robustness of data with regard to: high versus low
risk of bias in included studies, and industry versus non-industry
The results of the search will be managed in Covidence. Studies sponsored trials (Sensitivity analysis). GRADE criteria will be used
that satisfy the: types of study criteria, types of participants criteria, to assess the certainty of evidence as in Higgins 2019.
types of intervention criteria, and types of outcome measures will
be included as long as they do not meet any of the exclusion criteria. Measures of treatment effect
All studies will be reviewed independently by two review authors
The mean differences (MDs) and the corresponding 95% confidence
(VMS and PJ) using a standardised form. Any discrepancies will
intervals (CIs) will be calculated to compare the effects of different
be resolved by the third review author. The unit of interest for
treatments on blood pressure, and heart rate. Withdrawals due to
this review is the study and multiple reports and papers related
adverse effects will be assessed using relative risk, risk difference,
to a single study will be grouped under a single reference ID.
and number need to harm. We will ensure that all scales are
The selection process will be completed with sufficient detail to
measuring their effect in the same direction, and we will convert
complete a PRISMA flow diagram (Page 2020) and 'Characteristics
any that run counter to others. We do not expect that it will be
of excluded studies' table.
necessary to use standardized mean differences (SMDs) and their
Data extraction and management 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,
The data will be transferred to RevMan Web 2022. We will pilot-test we will convert them to the required format using the information
a data collection form using a random sample of five studies before in Chapter 6 of the Cochrane Handbook for Systematic Reviews of
commencing the full data extraction. The data will be extracted Interventions (Higgins 2019).
independently by two review authors (VMS, and PJ) for all critical
and secondary outcomes using a standardised form. The data will Unit of analysis issues
then be cross-checked. All calculations and statistical analyses will
No unit of analysis issues are expected as no cross-over trials will
be checked by the second review author. Data will be extracted
be included in this study. If multi-arm studies are included, we will
for: (1) change from baseline systolic and diastolic blood pressure
analyse multiple intervention groups in an appropriate way that
or (2) systolic and diastolic blood pressure measurements taken
avoids arbitrary omission of relevant groups and double-counting
three to12 weeks after the onset of treatment. (3) change or end
of participants.
of treatment heart rate three to 12 weeks after starting treatment,
(4) the number of participant withdrawals due to adverse effects, Dealing with missing data
(5) the number of participants: randomized, lost to follow-up,
withdrawn, analysed, (6) the participants: mean age, age range, In the event that data is not reported (including missing outcome
gender, (7) funding for the trial and other notable conflicts of data for participants) we will contact the study authors in order to
interest of the trial author, (8) information needed to assess obtain the missing data. The only missing data that we will impute
bias, (10) study design, (11) setting, (12) method of participant is SD by using the average of this value from other studies (Higgins
recruitment, (13) disease severity, (14) eligibility criteria, (15) details 2021). Selective outcome reporting will also be considered in the
of the interventions, and (16) information needed to assess GRADE. risk of bias assessment using RoB1. Trial registers may be used to
identify any initiated, ongoing or completed (but not necessarily
We plan to synthesize the characteristics of all the studies that will published) studies that meet the eligibility criteria to reduce the risk
contribute to each comparison described above, and present these of bias due to missing results.
in the 'Characteristics of included studies' table in our full review.
We will convert data found in studies to a format appropriate for Assessment of heterogeneity
meta-analysis following the methods described in Chapter 6 of the
Statistical heterogeneity will be assessed using the standard Chi2
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
test and I2 statistic available in RevMan Web 2022. We plan to
2019).
assess statistical heterogeneity by visual inspection of forest plots
Informed decisions.

to consider the direction and magnitude of effects and the degree Sensitivity analysis
of overlap between CIs. If we identify substantial heterogeneity
If we identify sufficient data then sensitivity analysis will be used to
(an I2 of greater than 50%) (Higgins 2019), we will report it and
assess the robustness of data with regard to the position of blood
explore possible causes by prespecified subgroup analysis. Data
pressure measurement, fixed-effect versus random-effects model,
for clinical and methodological variability will be covered in the
trough versus peak blood pressure measurement, and industry
Characteristics of included studies table.
versus non-industry sponsored trials. Body positioning has been
Assessment of reporting biases shown to have a significant effect on blood pressure (Privšek
2018) and may have an effect on our overall effect estimates. The
Each study will be assessed using the Cochrane Collaboration's trough-to-peak ratio refers to the extent by which antihypertensive
recommended tool (RoB 1) which assesses selective outcome medications exert their effects over a standard dosing interval
reporting. (Myers 1996), which is also a potential modifier of our effect
estimates.
If there are more than 10 trials, a thorough assessment of selective
non-reporting or under-reporting of results will be conducted to Summary of findings and assessment of the certainty of the
assess the risk of bias due to missing results. Funnel plots will be evidence
used to assess for reporting biases if we have sufficient studies
(10 or more) included in our meta-analysis. We will also note that Our summary of findings table will compare oral daily
funnel plot asymmetry may arise because of small-study effects hydrochlorothiazide with each of the other oral diuretics (other
and not just non-reporting bias. thiazides, thiazide-like drugs, loop diuretics, and other diuretics
except for triamterene and amiloride) in each of our outcomes. The
Data synthesis critical outcome to be included in the summary of findings table
is 'Change from baseline or end-of-treatment systolic and diastolic
Data synthesis and analysis will be done using RevMan Web blood pressure' three to 12 weeks after starting the medication. The
2022. A P value of less than 0.05 will be considered statistically two secondary outcomes 'Change or end of treatment heart rate
significant. The fixed-effect model will be used to obtain summary three to 12 weeks after starting the medication' and 'Withdrawals
statistics from pooled trials unless there is significant heterogeneity due to adverse effects' will also be included. A separate summary of
in: intervention, population characteristics, and methodological findings table will be prepared for each comparison. GRADE criteria
differences that could lead to different intervention effects will be used to assess the certainty of a body of evidence as it relates
being estimated. If significant heterogeneity is present in these to the studies that contribute data to the meta-analyses for the
characteristics, then the random-effects model will be used. specified outcomes. Our consideration includes within-study risk
Our choice of fixed-effect or random-effects model will not be of bias, directness of evidence, heterogeneity, precision of effect
determined by I2. Hydrochlorothiazide's effect on heart rate and estimates and risk of publication bias. We will rate the certainty
blood pressure will be compared to each of the other diuretics. of evidence as high, moderate, low, or very low, and will justify
Withdrawals due to adverse events with hydrochlorothiazide will all decisions to downgrade the certainty of the evidence using
also be compared to each of the other diuretics. The outcome footnotes and make comments to aid reader’s understanding of the
of interest is the difference from placebo. Change from baseline review where necessary. The GRADE assessment will be carried out
versus placebo and end of treatment versus placebo will be by review authors VMS and PJ. Any disputes will be resolved by a
entered into RevMan Web 2022 to calculate the pooled difference. third review author JW. The findings of each outcome investigated
A narrative synthesis will be considered should numerical (meta) will be shown graphically and in the text.
analysis be deemed impossible due to heterogeneity or limited
evidence (Higgins 2021), for example by following the nine-item ACKNOWLEDGEMENTS
Synthesis Without Meta-analysis (SWiM) guideline (Campbell 2020).
The review authors would like to acknowledge Douglas Salzwedel
Subgroup analysis and investigation of heterogeneity for his help in designing and carrying out the literature searches.
The sex of study participants, co-administration of triampterene or Cochrane Hypertension supported the authors in the development
amiloride, different doses of hydrochlorothiazide, and high versus of this protocol. James Wright is a member of Cochrane
low risk of bias in included studies will be assessed in subgroup Hypertension but was not involved in the editorial process or
analyses using the statistical test for subgroup differences available decision-making for this protocol. The following people conducted
in RevMan Web 2022. We have previously investigated the dose- the editorial process for this protocol.
related effects of hydrochlorothiazide in our previous review and • Sign-off Editor (final editorial decision): Michael Brown,
the review findings will guide our interpretation of differences in Michigan State University College of Human Medicine, USA.
blood pressure effects (Musini 2014). We will also assess ethnicity
using subgroup analysis as long as there is sufficient data to • Managing Editor (selected peer reviewers, collated peer-
allow for it. Heterogeneity will be assessed using the standard reviewer comments, provided editorial guidance to authors,
edited the article): Joey Kwong, Cochrane Central Editorial
Chi2 test, and I2 available in RevMan Web 2022 (Assessment
Service.
of heterogeneity). We are aware of the limitations of subgroup
analyses that require consideration when interpreting results, • Copy Editor (copy-editing and production): Heather Maxwell, c/
including their observational nature. o Cochrane Production Service.
• Peer-reviewers (provided comments and recommended an
editorial decision): Alun Hughes, Institute of Cardiovascular
Science, UCL (clinical/content review); Vitor Magnus Martins,
Division of Cardiology, Hospital de Clinicas de Porto
Informed decisions.

Alegre, Brazil (clinical/content review); Vikas Kapil, Clinical School of Hygiene and Tropical Medicine (consumer review);
Pharmacology and Cardiovascular Medicine, Barts Heart Centre Rachel Richardson, Cochrane Evidence Production & Methods
and William Harvey Research Institute, Queen Mary University Directorate (methods review); Robin Featherstone, Cochrane
of London (clinical/content review); Titilope Akinola, London Central Editorial Service (search review).
Informed decisions.

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Informed decisions.

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
Informed decisions.

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/)
Informed decisions.

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.
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.
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

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Morley-Senkler V, Jobin P, Wright JM

Morley-Senkler V, Jobin P, Wright JM.

Blood pressure lowering effect of hydrochlorothiazide compared to

Vivian Morley-Senkler1, Parker Jobin2, James M Wright3

Contact: Vivian Morley-Senkler, vmsenkle@student.ubc.ca.

Editorial group: Cochrane Hypertension Group.

Appendix 1. MEDLINE search strategy

Parker Jobin: none known.

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

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