CD 003825

Blood pressure lowering efficacy of loop diuretics for primary
hypertension (Review)
Musini VM, Wright JM, Bassett K, Jauca CD
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2009, Issue 4
http://www.thecochranelibrary.com
Blood pressure lowering efficacy of loop diuretics for primary hypertension (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Analysis 1.1. Comparison 1 Loop diuretics vs placebo, Outcome 1 SBP. . . . . . . . . . . . . . . . . 38
Analysis 1.2. Comparison 1 Loop diuretics vs placebo, Outcome 2 DBP. . . . . . . . . . . . . . . . . 40
Analysis 1.3. Comparison 1 Loop diuretics vs placebo, Outcome 3 Withdrawals due to adverse events. . . . . . 42
Analysis 1.4. Comparison 1 Loop diuretics vs placebo, Outcome 4 Serum potassium. . . . . . . . . . . . 43
Analysis 1.5. Comparison 1 Loop diuretics vs placebo, Outcome 5 Serum uric acid. . . . . . . . . . . . . 44
Analysis 1.6. Comparison 1 Loop diuretics vs placebo, Outcome 6 Serum creatinine. . . . . . . . . . . . 45
Analysis 1.7. Comparison 1 Loop diuretics vs placebo, Outcome 7 Blood glucose. . . . . . . . . . . . . 46
Analysis 1.8. Comparison 1 Loop diuretics vs placebo, Outcome 8 serum cholesterol. . . . . . . . . . . . 47
Analysis 1.9. Comparison 1 Loop diuretics vs placebo, Outcome 9 Serum triglyceride. . . . . . . . . . . . 48
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 50
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Blood pressure lowering efficacy of loop diuretics for primary hypertension (Review) i
[Intervention Review]
Blood pressure lowering efficacy of loop diuretics for primary

hypertension
Vijaya M Musini1 , James M Wright1 , Ken Bassett1 , Ciprian D Jauca1

1 Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
Contact address: Vijaya M Musini, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia,
2176 Health Science Mall, Vancouver, BC, V6T 1Z3, Canada. vijaya@ti.ubc.ca.
Editorial group: Cochrane Hypertension Group.

Publication status and date: New, published in Issue 4, 2009.
Review content assessed as up-to-date: 11 August 2009.
Citation: Musini VM, Wright JM, Bassett K, Jauca CD. Blood pressure lowering efficacy of loop diuretics for primary hypertension.
Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD003825. DOI: 10.1002/14651858.CD003825.pub2.
ABSTRACT
Background
Antihypertensive drugs from the thiazide diuretic drug class have been shown to reduce mortality and cardiovascular morbidity. Loop
diuretics are indicated and used as antihypertensive drugs but a systematic review of their blood pressure lowering efficacy or effectiveness
in terms of reducing cardiovascular mortality or morbidity from randomized controlled trial evidence has not been conducted.
Objectives
To determine the dose related decrease in systolic and/or diastolic blood pressure as well as adverse events leading to patient withdrawal
and adverse biochemical effects (serum potassium, uric acid, creatinine, glucose and lipids profile) due to loop diuretics versus placebo
control in the treatment of patients with primary hypertension.
Search strategy
Medline (Jan.1966-March-2009), EMBASE (Jan.1988-March-2009), CENTRAL (issue 1, 2009) and bibliographic citations were
searched.
Selection criteria
Double blind randomized placebo controlled trials of at least 3 weeks duration comparing loop diuretic with a placebo or no treatment
in patients with primary hypertension defined as BP >140/90 mmHg at baseline were included.
Data collection and analysis
Two authors independently assessed the risk of bias and extracted data. Weighted mean difference and a fixed effects model were used
to combine continuous outcome data. The drop outs due to adverse effects was analysed using relative risk ratio.
Main results
Nine trials evaluated the dose-related blood pressure lowering efficacy of five drugs within the loop diuretics class (furosemide 40 to
60mg, cicletanine 100 to 150 mg, piretanide 3 to 6 mg, indacrinone enantiomer -2.5 to -10.0/+80 mg and etozolin 200 mg) in 460
patients with baseline blood pressure of 162/103 mmHg for a mean duration of 8.8 weeks. The best estimate of SBP/DBP lowering
efficacy of loop diuretics was -7.9 (-10.5, -5.4) mmHg/ -4.4 (-5.6, -2.8) mmHg . Withdrawals due to adverse effects and serum
biochemical changes did not show a significant difference.
Blood pressure lowering efficacy of loop diuretics for primary hypertension (Review) 1
Authors’ conclusions
Based on the limited number of published RCTs, the SBP/DBP lowering effect of loop diuretics is modest -8/-4 mmHg and is likely
an overestimate due to the high risk of bias in the included studies. There is no clinically meaningful BP lowering differences between
different drugs within the loop diuretic class. The dose ranging effects of loop diuretics could not be evaluated.The review did not
provide a good estimate of the incidence of harms associated because of the short duration of the trials and the lack of reporting of
adverse effects in many of the trials.
PLAIN LANGUAGE SUMMARY
Loop diuretics cause modest blood pressure lowering
Loop diuretics are more commonly used to reduce water retention, but are also indicated to lower elevated blood pressure. We asked
how much this class of drugs lowers blood pressure and whether there is a difference between individual drugs within the class. The
available scientific literature was searched to find all the trials that had assessed this question. We found only 9 trials studying the blood
pressure lowering ability of 5 different loop diuretics (furosemide, cicletanine, piretanide, indacrinone and etozolin) in 460 participants.
The blood pressure lowering effect was modest; lowering systolic pressure by 8 mmHg and the diastolic pressure by 4 mmHg. No loop
diuretic drug appears to be any better or worse than others in terms of blood pressure lowering ability. Due to lack of reporting and
the short duration of these trials, this review could not provide an estimate of the harms associated with this class of drugs.
BACKGROUND The bioavailability of loop diuretics differ with that of azosemide

Loop diuretics are indicated as pharmacological agents for the being 10%, bumetanide and torsemide being 80 to 100%, and
treatment of hypertension. They are the most powerful of all furosemide being 40 to 60%, and the half life of these drugs are
known diuretics, capable of causing 15-25% of filtered sodium to similar 1-2 hours. Muzolimine, xipamide and ozolinone (the active
be excreted. They include drugs such as furosemide, bumetanide, metabolite of etozolin) have longer half lives of 6 to 15 hours and
torsemide, piretanide, azosemide, ethacrynic acid, indacrinone, elimination is unchanged in patients with renal insufficiency or
muzolimine, ozolinone, xipamide and tienilic acid. congestive heart failure. The route of elimination differ. About half
of intravenous furosemide is eliminated unchanged in the urine
The first loop diuretics were mercurial agents, which are of historic and most of the remainder is glucuronidated in the kidney itself.
interest only. Furosemide was synthesized by chemists in 1959. In contrast, non-renal elimination of bumetanide and torsemide
It was active orally and soon became the loop diuretic of choice. is in the liver.
Additional loop diuretics have since been developed and the dif-
ference among them is in their pharmacokinetics.
Loop diuretics act primarily on the thick ascending limb of the
Loop diuretics act from the lumen side of the nephron hence uri- loop of Henle, inhibiting the transport of sodium chloride out
nary rather than serum amounts are the major determinants of of the tubule into the interstitial tissue by inhibiting the Na+/
response. Since they are extensively bound to serum protein albu- K+/2Cl- cotransporter on the apical membrane. Furosemide and
min, they cannot enter the tubular lumen by glomerular filtration bumetanide have a direct inhibiting effect on the carrier, acting
and reach this site by active secretion by the organic acid transport on the chloride binding site while ethacrynic acid forms a com-
pump at the straight segment of the loop of Henle. These drugs are plex with cysteine, the complex being active form of the drug (
rapidly absorbed with peak serum concentration attained within Materson 1983). They lower blood pressure acutely because of
0.5-2 hours. The onset of action of furosemide after oral dosing their potent natriuretic effect and consequently fall in circulating
is slower than of other loop diuretics due to its rate of absorption blood volume. However, when used alone loop diuretics may not
is slower than the rate of elimination (Seldin 1997). have useful long term antihypertensive effect.
Another group of diuretics, the thiazides, inhibit Na+ Cl- reab- Primary objective
sorption in the early part of distal tubule. This class of thiazide and
To determine the dose related decrease in systolic and/or diastolic
thiazide related drugs include hydrochlorothiazide, bendroflume-
blood pressure due to loop diuretics versus placebo control in the
thiazide, chlorothiazide, methyclothiazide, trichlormethiazide, cy-
treatment of patients with primary hypertension.
clothiazide and chlorthalidone.
It is presently unknown whether the blood pressure lowering ef-
ficacy of either thiazide or loop diuretics is due solely to their di-
Secondary objectives
uretic effect. Diuretics were originally prescribed in starting doses
that exceed the average prescribed dose that is used now. To determine the dose related adverse events leading to patient
withdrawal and adverse biochemical effects including serum potas-
Although the aim of antihypertensive drug therapy is to reduce
sium, uric acid, creatinine, glucose and lipids profile.
systolic as well as diastolic blood pressure, the ultimate clinical
goal is to lower the risk of cardiovascular related mortality and
morbidity. Based on 19 randomized controlled trials in 39,713
patients, a systematic review of thiazides have shown proven ben-
efit in terms of reduced mortality (RR 0.89, 95% CI 0.83, 0.96), METHODS
stroke (RR 0.63, 95% CI 0.57, 0.71), coronary heart disease (RR
0.84, 95% CI 0.75, 0.95) and cardiovascular morbidity (RR 0.70,
95% CI 0.66, 0.76). Low-dose thiazides reduced coronary heart
Criteria for considering studies for this review
disease (RR 0.72, 95% CI 0.61, 0.84), but high-dose thiazides (11
RCTs) did not (RR 1.01, 95% CI 0.85, 1.20) (Wright 2009). In
the same systematic review first-line low-dose thiazide decreased
blood pressure by 13 mmHg (99% CI 12 to 14)/ 5 (99% CI 4 Types of studies
to 6) as compared to placebo or no treatment, and first-line high- Study design must meet the following criteria: double blind
dose thiazide decreased blood pressure by 14 mmHg (99% CI 13 placebo controlled trials; random allocation to loop diuretic group
to 15)/7 (99% CI 6 to 8) (Wright 2009). and parallel placebo group; duration of follow-up of at least
No systematic review of loop diuretics has been identified that three weeks; blood pressure measurement at baseline (following
measured either the blood pressure lowering efficacy or effective- washout) and at one or more time points between 3 to 12 weeks
ness in terms of lowering cardiovascular mortality or morbidity after starting treatment.
in the treatment of primary hypertension. It is also important to
establish whether loop diuretics lower blood pressure to the same
degree as thiazide diuretics and other classes of antihypertensive Types of participants
drugs, and to know the blood pressure lowering dose response re- Participants must have a baseline systolic blood pressure of at least
lationship in relation to other effects of loop diuretics such as the 140mmHg and/or diastolic blood pressure of at least 90mmHg,
metabolic adverse effects. The individual drugs within the diuretic measured in a standard way. Patients with significant renal insuf-
drug class might have differing dose-related blood pressure lower- ficiency and a documented serum creatinine level > 1.5 times the
ing efficacy and adverse effects. normal values will be excluded from analysis. Participants will not
be restricted by age, gender, baseline risk or any other co-morbid
The aims of this systematic review are:
conditions.
1. to determine the lowest dose with the maximum blood
pressure lowering efficacy for each drug within the loop diuretic
class. Types of interventions
Monotherapy with any loop diuretic, including: furosemide,
2. to establish dose equivalencies of different drugs within the
bumetanide, piretanide, torsemide, azosemide, ethacrynic acid,
loop diuretic family.
ticrynafen, tripamide, phenoxybenzoic acid, muzolimine, in-
The information derived from this review should facilitate future dacrinone, etozolin, ozolinone, cicletanine, tienilic acid and
reviews of head-to-head comparisons with other drugs classes and tizolemide.
assist clinicians in when to choose a loop diuretic and what dose Data from trials in which titration to a higher dose is based on
to use. blood pressure response are not eligible. Stepped up therapy given
only to non-responders will bias the results and will not be in-
cluded in the analysis. Potassium supplementation will be allowed
OBJECTIVES in patients with low serum potassium levels.
Types of outcome measures Searching other resources
1. Reference lists of all papers and relevant reviews were
identified.
Primary outcomes
2. Authors of trials reporting incomplete information were
Change in systolic and diastolic blood pressure compared to contacted to provide the missing information.
placebo. If blood pressure measurements were available at more
than one time during the 24-hour period the trough measurement
was used. Peak level is defined as blood pressure measurement
within 12 hours of the dose and trough level is defined as blood Data collection and analysis
pressure measurements between 12 and 24 hours. If blood pressure
measurements were available at more than one week within the 3-
12 week window, the weighted means of blood pressure measure- Selection of studies
ment was calculated and used as the best estimate of the treatment
effect. Two reviewers (VM and CJ) independently screened the titles
and the abstracts resulting from the search strategies. Articles were
rejected on initial screen if we were able to determine from the title
Secondary outcomes or the abstract that the article was not a report of a randomized
1. The number of patient withdrawals due to adverse events placebo controlled trial or did not meet the inclusion criteria.
compared to placebo. The full text of the remaining articles was then retrieved. The
2. Change in the levels of serum potassium, uric acid, bibliographies of pertinent articles, reviews and texts were searched
creatinine, glucose and lipids compared to placebo. If for additional citations. Two independent reviewers assessed the
measurements are available at more than one time within the eligibility of the trials using a trial selection form. A third reviewer
acceptable window, then the weighted mean data was calculated (JMW and KB) resolved any discrepancies.
and used as the best estimate of the treatment effect.
Data extraction and management

Search methods for identification of studies Data was abstracted independently by two reviewers (VM and CJ)
using a standard form, and then cross-checked. If data were pre-
See: Search Strategy (Appendix 1).
sented numerically (in tables or text) and graphically (in figures),
The Database of Abstracts of Reviews of Effectiveness (DARE)
the numeric data were preferred because of possible measurement
and the Cochrane Database of Systematic Reviews were searched
error when estimating from graphs. All numeric calculations and
for related reviews.
extractions from graphs or figures were confirmed by a second re-
The following electronic databases were searched for primary stud-
viewer. Any discrepancies were resolved by consensus.
ies:
1. The Cochrane Central Register of Controlled Trials
(CENTRAL) Issue 1, 2009
2. English language databases, including MEDLINE (1966- Assessment of risk of bias in included studies
March 2009) and EMBASE (1988-March 2009) Two reviewers (VM and CJ) checked the methodological qual-
Electronic databases were searched using a strategy combining a ity of the included studies according to the Cochrane Collabo-
variation of the Cochrane Highly Sensitive Search Strategy for ration recommended tool. The risk of bias within each included
identifying randomized trials in MEDLINE: sensitivity-maximiz- study were based on the six domains - sequence generation, allo-
ing version (2008 revision) with selected MeSH terms and free text cation concealment, blinding, incomplete outcome data and se-
terms relating to loop diuretics and hypertension. No language lective outcome reporting with ratings of ’Yes’ (low risk of bias);
restrictions were used. The MEDLINE search strategy was trans- ’No’ (high risk of bias) and ’Unclear’ (uncertain risk of bias). Refer
lated into the other databases using the appropriate controlled vo- to ‘Risk of bias’ table for each study. Also see Figure 1 and Figure
cabulary as applicable. 2.
Figure 1. Methodological quality graph: review authors’ judgements about each methodological quality
item presented as percentages across all included studies.
Figure 2. Methodological quality summary: review authors’ judgements about each methodological quality
item for each included study.
and 8.3 mmHg for DBP in the treatment group and 8.8 mmHg
Measures of treatment effect for the placebo group.
The position of the patient during blood pressure measurement
may affect the blood pressure lowering effect. However, in order Data synthesis
not to lose valuable data if only one position was reported data from Data were processed in accordance with the Cochrane Handbook
that position was included. When blood pressure measurement 2008 for Systematic Reviews of Interventions. Data synthesis and
data was available in more than one position, sitting blood pressure analyses were done using Review Manager 5.0 software. Data for
was the first preference. If standing and supine blood pressure changes in blood pressure as well as serum levels of potassium, uric
measurements were available, standing blood pressure was used. acid, creatinine, glucose, and lipids profile was were expressed as
Unit of analysis issues the mean (±SD) change from baseline to follow-up and combined
using a weighted mean difference method. Withdrawals due to
Each trial is a unit in the systematic review analysis. For each trial adverse effects (dichotomous outcome) for each comparison were
the patients allocated to placebo control group or the loop diuretic expressed as relative risks with 95% confidence intervals (CI). If
therapy group was compared to each other only within that trial there was a statistically significant relative risk difference, the as-
and not with patients in any other trial. sociated number needed to treat/harm was also calculated
Dealing with missing data
In case of missing information in the included studies, investiga- Subgroup analysis and investigation of heterogeneity
tors were contacted using email, letter and/or Fax to obtain the Sub group analyses according to age, gender, race, co-morbid con-
missing information. In case missing information was not avail- ditions, and baseline severity of hypertension (mild moderate or
able, the best estimate was included based on the information in severe) was planned but was not possible due to insufficient data.
the same trial or from other trials using the same dose. Test for heterogeneity of treatment effect between the trials was
In case of missing standard deviation of the change in blood pres- made using a standard chi-square statistic for heterogeneity as
sure, the standard deviation was imputed based on the informa- mentioned in Revman 5. The fixed effects model was applied to
tion in the same trial or from other trials using the same dose. The obtain summary statistics of pooled trials, unless significant be-
following hierarchy (listed from high to low preference) was used tween study heterogeneity was present, in which case the random
to impute standard deviation values: effects model was used.
1. standard deviation of change in blood pressure from a The funnel plot was used to examine publication bias.
different position than that of the blood pressure data used.
2. standard deviation of blood pressure at the end of
Sensitivity analysis
treatment.
3. standard deviation of blood pressure at the end of treatment Although the robustness of the results was to be tested using several
measured from a different position than that of the blood sensitivity analyses including:
pressure data used. 1. Trials of high quality versus poor quality
4. standard deviation of blood pressure at baseline, except if 2. Fixed versus random effect model
this measure was used for entry criteria (Musini 2009). 3. Trials with blood pressure data measured in sitting position
5. mean standard deviation of change in blood pressure from versus other measurements
other trials using the same drug and dose. 4. Trials with peak blood pressure measurements versus trials
6. mean weighted standard deviation of change available from with trough blood pressure measurements
all other trials meeting the inclusion criteria. 5. Trials with published standard deviations of blood pressure
Most trials reported end of treatment SD, which was imputed as change versus imputed standard deviations
SD of change from baseline for SBP as well as DBP. For the 2 6. Trials that are industry sponsored versus non-industry
piretanide trials (Homuth 1993, Verho 1986) since the end of sponsored
treatment SD was not reported the baseline SD of the SBP or due to lack of sufficient data it was not possible to do sensitivity
DBP could be used if it was not the entry criteria for inclusion in analyses.
the study. Homuth 1993 did not report the criteria for inclusion
(states as hypertensive patients) and Verho 1986 included patients
based on DBP but did not report the baseline SD values for both
SBP as well as DBP. Therefore, we calculated the mean weighted RESULTS
standard deviation at the end of treatment across all trials and
imputed it as SD of change. It was calculated as 13.7 mmHg for Description of studies
SBP in the treatment group and 15.9 mmHg for the placebo group
See: Characteristics of included studies; Characteristics of excluded
studies.
The search strategy (Appendix 1) led to 380 citations of which
264 (69.5%) were excluded on reading the abstract since they
did not meet the minimum inclusion criteria. Of the remaining
116 citations, 74 (25.6%) were excluded after retrieving the trials
and reading the detailed methodology. 42 (11.0%) potentially
appropriate studies were included of which 33 studies had to be
excluded (see Characteristics of excluded studies).
9 (2.4%) double blind randomized controlled trials out of the 380
citations met the inclusion criteria. 460 patients with mean age of
54.4 years were included in these trials (see Description of studies).
A complete account of the studies identified is presented in the
QUOROM Diagram (Figure 3).
Figure 3. QUOROM Diagram
Placebo control was compared to cicletanine 100 mg in one characteristics.

trial (Gotzen 1994) and 150 mg in one trial (Bodak 1989); to The earliest study evaluating the antihypertensive efficacy of loop
furosemide 40 mg in two trials (Perola 1985, Wertheimer 1973) diuretic monotherapy using office blood pressure measurements
and to furosemide 60 mg in one trial (Vadasz 1982); to piretanide was published in 1973. The other 8 studies were published during
3 mg in 1 trial (Homuth 1993) and to piretanide 6 mg in two the 1980s and 90s. No further studies have been published since
trials (Homuth 1993, Verho 1986); to indacrinone at doses of - 1994. Of the 9 included studies seven were published in English,
2.5/+ 80 mg, -5.0/+ 80 mg, or -10/+ 80 mg in 1 trial (Jain 1984) one in German (Gotzen 1994) and one in French (Bodak 1989).
and to etozolin in 1 trial (Licata 1989). One of the included studies was industry-sponsored (Jain 1984)
Refer to Characteristics of included studies for details on baseline while the remaining 8 studies did not report the source of funding.
Since the number of trials meeting the inclusion criteria was very
limited, in order to maximize data inclusion, data in the Bodak
1989 trial was included at the end of 6 months although data be-
tween 3 to 12 weeks was not reported in the publication. All other
trials ranged from 4 to 12 weeks duration. The mean weighted
duration of treatment across all trials was 8.8 weeks. Including or
excluding this trial from analysis showed no significant difference
in SBP or DBP WMD. The mean weighted baseline SBP/DBP
across all 9 trials was 162.3/103.4 mmHg.
Risk of bias in included studies
Refer to Figure 1 and Figure 2 for the overall risk of bias assessment.
Adequate sequence generation and allocation concealment were
reported only in one trial each (Wertheimer 1973 and Gotzen
1994, respectively) . Five of the 9 trials (55% of included studies)
reported blinding adequately. In four of the nine trials (44%) there
was incomplete outcome data reported and only 2 of the 9 trials
(22%) reported all outcome data. 4 of the 9 trials (44%) had high
risk of other bias and in the remaining 5 trials it was unclear if
other risk was present. In summary, the effect size of this review is
an overestimate due to the potential for high risk of bias.
Another source of bias that is likely to have a significant impact
on this review is the selective publication of trials. This review was
evaluated for the existence of publication bias since it only included
and appraised published trial evidence. In the absence of bias, the
funnel plot should resemble a symmetrical inverted funnel. The
most common way to investigate whether or not a review is subject
to publication bias is to examine for funnel plot asymmetry as
smaller studies with null results remained unpublished. Refer to
Figure 4, Figure 5 and Figure 6, which indicate that publication
bias was present.
Figure 4. Funnel plot of comparison: 1 Loop diuretics vs placebo, outcome: 1.1 SBP.
Figure 5. Funnel plot of comparison: 1 Loop diuretics vs placebo, outcome: 1.2 DBP.
Figure 6. Funnel plot of comparison: 1 Loop diuretics vs placebo, outcome: 1.3 Withdrawals due to adverse
effects.
Effects of interventions
Systolic blood pressure

Furosemide 40 mg did not show a significant reduction in SBP
-5.00 (-12.9, 1.4) mmHg. Furosemide at 60 mg dose showed a
significant reduction in SBP -10.0 (-15.8, -4.2), see Analysis 1.1.
Combined doses of furosemide 40 and 60 mg showed a significant
reduction of -8.3 (-12.8, -3.9) mmHg.
Cicletanine 100 mg did not show a significant reduction in SBP
-7.00 (-16.2, 2.2). Cicletanine 150 mg showed a significant re-
duction in SBP -9.1 (-15.5, -2.7) mmHg, see Analysis 1.1. Com-
bined doses of cicletanine 100 and 150 mg showed a significant
reduction of -8.4 (-13.7, -3.1) mmHg.
Piretanide 3 mg as well as 6 mg did not show a significant reduc-
tion in SBP -2.2 (-9.9, 5.6) mmHg and -4.2 (-10.0, 1.5) mmHg,
see Analysis 1.1. Combined doses of piretanide 3 and 6 mg did
not achieve statistical significance -3.5 (-8.1, 1.2) mmHg.
Indacrinone enantiomers -2.5 /+ 80 mg as well as -5.0/+ 80 mg
did not show a significant reduction in SBP -14.9 (-31.2, 1.4)
mmHg and -11.7 (-25.4, 1.9) mmHg respectively. Indacrinone
-10.0/+ 80 mg showed a significant reduction in SBP -19.1 (-
35.9, -2.25) mmHg, see Analysis 1.1. Combined doses of the
indacrinone enantiomers showed significant reduction -14.7 (-
23.6, 5.8) mmHg.
Etozolin 200 mg reduced SBP -14.3 (-23.1, -5.6) mmHg, see
Analysis 1.1.
The 95% CI of SBP reduction across all individual drugs within
loop diuretics as well as doses were wide and overlapped with each
other, see Figure 7.
Figure 7. Forest plot of comparison: 2 loop diuretics vs placebo, outcome: 2.1 SBP.
The best estimate of systolic blood pressure lowering efficacy
of all 9 trials comparing loop diuretics to placebo control is -7.9 (-
10.5, -5.4) mmHg for a mean duration of 8.8 weeks, see Analysis
1.1.
Diastolic blood pressure

Furosemide 40 mg as well as 60 mg did not show a significant
reduction in DBP -3.5 (-7.2, 0.2) mmHg and -3.0 (-7.3, 1.3)
mmHg respectively, see Analysis 1.2. Combined doses of 40 and
60 mg showed a significant decrease -3.3 (-6.1, -0.5) mmHg.
Cicletanine 100 mg did not show a significant reduction in DBP
-3.3 (-9.5, 2.9) mmHg. Cicletanine 150 mg showed a significant
reduction in DBP -11.3 (-15.3, -7.3) mmHg, see Analysis 1.2.
Combined doses of cicletanine 100 and 150 mg showed a signifi-
cant reduction of -8.9 (-12.3, -5.6) mmHg.
Piretanide 3 mg as well as 6 mg did not show a significant reduc-
tion in DBP -0.8 (-5.4, 3.8) mmHg and -2.3 (-5.5, 0.8) mmHg,
see Analysis 1.2. Combined doses of piretanide 3 and 6 mg did
not achieve statistical significance -2.3 (-5.5, 0.8) mmHg.
Indacrinone enantiomers -2.5 /+ 80 mg as well as -5.0/+ 80 mg
and -10.0/+ 80 mg did not show a significant reduction in DBP -
7.1 (-15.2, 0.9) mmHg, -3.4 (-11.2, 4.4) mmHg and -3.4 (-11.6,
4.8) mmHg respectively, see Analysis 1.2. Combined doses of the
indacrinone enantiomers also did not show a significant reduction
in DBP -4.6 (-9.3, 0.01) mmHg.
Etozolin 200 mg did not show a reduction in DBP -7.3 (-13.2,
1.4) mmHg, see Analysis 1.2.
The 95% CI of DBP reduction across all individual drugs within
loop diuretics as well as doses were wide and overlapped with each
other, see Figure 8.
Figure 8. Forest plot of comparison: 2 loop diuretics vs placebo, outcome: 2.2 DBP.
The best estimate of diastolic blood pressure lowering efficacy
of all 9 trials comparing loop diuretics to placebo control is -4.4
(-5.6, -2.8) mmHg for a mean duration of 8.8 weeks, see Analysis
1.2.
Withdrawals due to adverse effects

Withdrawals due to adverse effects were reported in 6 of the 9
trials in 331 patients and was not statistically significant, RR with
95% CI using fixed effect model was 1.9 (0.3, 10.8), see Figure 9.
Figure 9. Forest plot of comparison: 2 loop diuretics vs placebo, outcome: 2.3 Withdrawals due to adverse
events.
ported data on 460 participants (242 treated with loop diuretics

Biochemical changes
and 198 with placebo) with a weighted mean age of 54.4 years
Data for changes in serum levels of potassium, uric acid, creati- and a weighted mean baseline blood pressure of 162/103 mm Hg.
nine, blood glucose, serum cholesterol and triglycerides as com- The best estimate at this time of the overall SBP and DBP low-
pared to placebo control was reported in 2 of the 9 trials (Bodak ering efficacy of this class of drugs is 8/4 mmHg as compared to
1989, Perola 1985). Based on available data in 88 patients for a placebo control, based on double blind randomized controlled tri-
mean duration of 20 weeks there was no statistically significant als. However, this result is based on too few patients and the 95%
difference in any parameter, see Analysis 1.4, Analysis 1.5, Analysis confidence intervals range from 5 to 11 mmHg systolic. With the
1.6, Analysis 1.7, Analysis 1.8 and Analysis 1.9. presently available data it is not possible to say whether the effect
is greater or lower than other classes of antihypertensive drugs (
Heran 2008a, Heran 2008b, Musini 2008).
Due to the limited number of published studies, there is insuffi-
DISCUSSION
cient evidence for the various loop diuretics to generate dose-re-
It is surprising and shocking to note the paucity of data available sponse curves for systolic and diastolic BP reduction. At any given
in the public domain to evaluate the dose ranging effects of loop dose of loop diuretics there were only 1 or 2 studies contributing
diuretics in the treatment of primary hypertension. We suspect BP data.
that there are trials meeting our inclusion criteria that have not
Given the limited data available, it is impossible with this anal-
been published and we hope that as a result of this review authors
ysis to be certain that there are any BP lowering differences be-
will contact us and provide us with more data. The results of this
tween one or more of the drugs. It would require head-to-head
review emphasize the need for all studies, regardless of the findings,
trials of different loop diuretics to assess whether or not there are
to be published and accessible for secondary analysis.
differences between different drugs and evaluate the dose equiva-
Only 9 trials with a mean duration of 8.8 weeks at a fixed dose lence between drugs within the loop diuretic class. However, at the
of loop diuretics met the pre-specified inclusion criteria and re- present time, given that all the drugs within the loop diuretic class
are working by the same mechanism of action and the overlapping Implications for research
of the 95% CI in the blood pressure lowering effect, it is most
Data from unpublished trials of the effect of loop diuretics on
likely that the BP lowering effect of the different loop diuretics at
blood pressure needs to be made available. More RCTs are needed
equivalent doses is the same.
assessing the blood pressure lowering effect of loop diuretics as
compared to placebo and as compared to other classes of drugs
where the blood pressure lowering effect has been established. The
AUTHORS’ CONCLUSIONS benefit of loop diuretics in the setting of renal insufficiency, the
Implications for practice patient population where loop diuretics are often used for their
antihypertensive effect, needs to be assessed.
Based on the limited number of published RCTs, the SBP/DBP
lowering effect of loop diuretics is modest -8/-4 mm Hg and is
likely an overestimate due to the high risk of bias in the available
studies and the likelihood of publication bias. There are no clini-
ACKNOWLEDGEMENTS
cally meaningful BP lowering differences between different drugs
within the loop diuretic class. No conclusions could be drawn re- The authors would like to acknowledge the help provided by the
garding the dose related decrease in systolic and diastolic blood Cochrane Hypertension Group. We would specially like to thank
pressure of loop diuretics in the treatment of primary hyperten- Stephen Adams who sorted search findings in Reference Manager
sion. The review did not provide a good estimate of the incidence and retrieved articles to complete this review. We would also like
of harms associated because of the short duration of the trials and to thank Dr. Balraj Heran for extracting data from the graph of
the lack of reporting of adverse effects in many of the trials. the Homuth 1993 trial.
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Bodak A, Gavardin Th, Salom M, Tarrade Th, Forette F, Jungers P.
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Jain 1984 {published data only} Bonaduce 1981 {published data only}
Jain AK, Michael R, Ryan JR, McMahon FG. Antihypertensive and Bonaduce D, Ferrara N, Petretta M, Canonico V, Romango E,
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1984;4:278–283. chlorthalidone: a double blind randomized cross over trial. Current
Medical reserach and Opinion 1981;7(4):247–252.
Licata 1989 {published data only}
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Ganguzza A, Merlino G. Clinical and hemodynamic effects of Buckert C, Muhlhausier W, Fratzer U, verho M. A double blind
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Current Therapeutic Research 1989;45(2):263–267. with essentail hypertension. J Int Med Res 1984;12:81–86.
Campbell 1998 {published data only} Kopp 1978 {published data only}
Campbell N, Brant R, Stalts H, Stone J, Mahallati H. Fluctuations Kopp VH. The antihypertensive effect of etozolin [Zur
in blood lipid levels during furosemide therapy. Archives of Internal antihypertensiven wirkung des diuretikums etozolin]. Fortschr.
medicine 1998;158:1461–1463. Med.96.jg. 1978;22:1194–1198.
Charansonney 1997 {published data only} Krogsgaard 1976 {published data only}
Charossoney SL, Lievre, Laville M, Lion L et al. Eurieve Study Krogsgaard AR, Trap-Jensen J, Hartling O, Svendsen TL. Clinical
Group. The Eurieve study: contrasting effect of pirentanide and and hemodynamic effects of high doses of slow release furosemide
thiazides in mild to moderate hypertension. Therapie 1997;52: in arterial hypertension. A double blind cross over study with
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Efficacy and tolerance of cicletanine added to a previous beta Kumar S, Pandi p, Wahi PL, Sharma PL. A randomized double
blocking tehrapy in essential hypertensive patients [Evaluation de blind clinical trial of Xipamid and hydrochlorthiazide in essential
l’efficacite et de la tolerance du cicletanine chez des patients hypertension. International Journal of Clinical Pharmacology 1984;
hypertendus traites par beta–bloquants]. Arch Mal Coeur 1989;82: 22(10):349–331.
1293–1297. Kuramoto 1985 {published data only}
Di Somma 1990 {published data only} Kuramoto K, Masuyama Y. Comparison of clinical usefullness of
Di Somma S, Liguori V, Petitto M, Galletti P, De Divitis O. The diuretics in elderly and younger essentila hypertension - Double
hemodynamic effect of etozolin in teh treatment of hypertension. blind trial using tripamide. Jpn J Geriat 1985;22:346–353.
Current therapeutic Research 1990;48(6):1044–1052.
Magrini 1988 {published data only}
Fried 1979 {published data only} Magrini F, Reggiani P, Roberts N, Meazza R, Ciulla M, Zanchetti
Fried ED. Tienilic acid in the treatment fo hypertension. Double A. Effects of angiotensin and angiotensin blockade on coronary
blind assessment of tienilic acid in essential hypertension. circulation and coronary reserve. The American Journal of medicine
Postgraduate Medical Journal 1979;55(Suppl 3):92–97. 1988;84(suppl 3A):55–60.
Galleti 1991 {published data only} Miziara 1982 {published data only}
Galleti F, Strazzullo P, Barba G, Cappuccio P, Iacone R, Mancici R. Miziara LJ, Goncalves JGF, Feres F. Comparative double blind trial
Diuretic therapy for mild hypertension: A comparison of the with long acting furosemide and chlorthalidone in the treatment of
meatbolic effects of etozoline and chlorthalidone during long term essential hypertension [Ensaio comparativo duplo–cego com
treatment. Current Therapeutic Research 1991;50(2):159–166. furosemide de acao prolongada e chortalidona no tratamento da
hipertensao essencial]. Farmacologica Clinica 1982;85(4):773–778.
Gupta 1981 {published data only}
Gupta PS, Dave ML. Pirenbtanide (HOE118): A new diuretic in Nami 1991 {published data only}
essential hypertension. Current therapeutic reaserch 1981;30(4): Nami R. Acute antihypertensive, diuretic and metabolic effect of
468–476. etozolin and chlorthalidone. Pamnivera Med 1991;33:157–163.
Heijden 1998 {published data only} Obel 1984 {published data only}
van der Heijden M, Donders SH, Cleophas TJ, Niemeyer MG, van Obel A, Griffin L, Were J. Comparison of slow release frusemide
der Meulen J, Bernink PJ, de Planque B, van der Wall EE. A and bendrofluazide in teh treatment of moderater hypertension in
randomized placebo controlled study of loop diuretics in patients Kenyan Negroes.. Clinical Trials Journal 1984;21(6):443–450.
with essential hypertension: teh Bumetanide and furosemide on Okun 1978 {published data only}
lipid profile (BUFUL) clinical study report. Journal of Clinical Okun R, Beg Mirza. Tricynafen and hydrochlorthiazide in
Pharmacology 1998;38:630–635. hypertension. Clin Pharmacol, Ther June 1978;23(6):703–711.
Holland 1979 {published data only} Okun 1979 {published data only}
Holland B, Gomez-Sanchez C, Fairchild C, Kaplan NM. Role of Okun R, Beg MA. A double-blind study of tienilic acid with two
renin classification for diuretic treatment of black hypertensive year follow-up of patients with mild to moderate essential
patients. Arch Internal medicine 1979;139:1365–1370. hypertension. Postgrad Med J 1979;55(Suppl 3):103–9.
Jungers 1989 {published data only} [PUBMED: PMID: 388395]
Jungers P, Gavardin T, Salom M, Tarrade T, Berthet P. Dosage study Oli 1983 {published data only}
of ciclretanine in elderly hypertensive patients: comparison of 50 vs Oli JM, Ikeakor IP. Sustained release frusemide and blood glucose
100mg daily dose [Etude comparative de deux posologies d’ un levels in diabetics. Cuurent Therapeutic Research 1983;34(3):
nouvel antihypertenseur, le cicletanine chez le sujet age’]. Arch Mal 537–541.
Coeur 1989;82(IV):125–129. Olshan 1981 {published data only}
Knoben 1982 {published data only} Olshan AR, O’Connor DT, Preston RA, Frigon RP, Stone RA.
Knobem JM, Chada DR. Clinical experience with a fixed dose Involvement of Kallikrein in the Antihypertensive Response to
combination of penbutolol and furosemide in hypertension. Furosemide in Essential Hypertension. Journal of Cardiovascular
Current Therapeutic Research 1982;31(3):281–292. Pharmacology 1981;3(1):161–8.
Pearson 1979 {published data only} treatment of mild to moderate hypertension: a double blind study
Pearson RM, Bulpitt CJ, Havard CWH. Biochemical and against placebo. Curr. Med. Res. Opi. 1987;10(6):397–406.
haematological changes induced by tienilic acid combined with Yasky J, Verho M, Rangoonwala B. Efficacy of a low dose fixed
propranolol in essential hypertension. The Lancet 1979 March 31;1 combination of penbutolol and pirentanide in teh treatment of
(8118):697–9. [PUBMED: PMID: 85937] mild to moderate hypertension: a double blind study against
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Potter 1987 {published data only}
Heran 2008a
Potter JF, Beevers DG. Atenolol improves blood pressure control in
Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure
patients taking captopril and frusemide. Journal of Human
lowering efficacy of angiotensin converting enzyme (ACE)
Hypertension 1987;1:127–130.
inhibitors for primary hypertension. Cochrane Database of
Reyes 1990 {published data only} Systematic Reviews 2008, Issue 4. [DOI: CD003823. DOI:
Reyes AJ, Chiesa PD, Santucci MR, Batista LB, Olhaberry JV, 10.1002/14651858.CD003823.pub2]
Mosler AL, Mignone AM, Leary WP, Queiruga G. Heran 2008b
Hydrochlorthiazide versus a non-diuretic dose of torasemide as Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure
once daily antihypertensive monopharmacotharapy in elderly lowering efficacy of angiotensin receptor blockers for primary
patients. A randomized douible blind study.. Progress in hypertension. Cochrane Database of Systematic Reviews 2008, Issue
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14651858.CD003822.pub2]
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Ronchi E, Posca M, Sassi S, Agostara F, Palumbo G. Adding Materson BJ. Insights into intrarenal sites and mechanism of action
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Musini 2008
Rutledge 1988 {published data only} Musini VM, Fortin PM, Bassett K, Wright JM. Blood pressure
Rutledge J, Ayers C, Davidson R, DiPette D, Guthrie G, Fisher M, lowering efficacy of renin inhibitors for primary hypertension.
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of Cardiology 1988;62:1062–1067. Musini 2009
Musini VM, Wright JM. Factors affecting blood pressure
Valmin 1980 {published data only} variability: Lessons learned from two systematic reviews of
Valmin K, Hansen T, Ronsted P. Treatment of benign essential randomized controlled trials . PLOS ONE 22 May 2009;4(5):
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Webster J, Petrie JC, Robb OJ, Witte K, Lovell HG. Atenolol or physiology and pharmacology. San Diego, California: Academic
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and frusemide. Journal of Human Hypertension 1987;1:121–126. Wright 2009
Wright JM, Musini VM. First line treatment of hypertension.
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combination of 40mg penbutolol with 6 mg pirentanide in the ∗
Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Bodak 1989
Methods Double blind prospective randomised placebo controlled study
Participants 132 patients aged more than 60 years with diastolic arterial pressure over 95mmHg and
systolic over 160mmHg.
62.9% patients were aged over 75 years.
Mean age was 73.6 years; Male 32/60 (53.3%);
Baseline SBP/DBP with SD
Placebo = 173.2 + 14.7/104.7 + 6.9 mm Hg
Cicletanine 150mg = 176.3 + 10.7/ 103.2 + 7.6 mmHg
Heart rate : placebo = 75.8 + 6.7 and cicletanine = 76.9 + 9
Interventions Study A: Cicletanine 150mg per day and placebo for a duration of 180 days
Cicletanine 150mg = 30 and Placebo = 30
Study B: Cicletanine 50mg and Cicletanine 100mg with no parallel placebo arm so this
study was excluded from the review
Outcomes Systolic blood pressure, diastolic blood pressure

Normalization of blood pressure
Serum sodium, potassium, glucose, uric acid, creatinine, cholesterol and triglycerides
Notes Article in French translated by Ciprian Jauca.

End of treatment SBP/DBP + SD were reported in table III page 104.
Withdrawal due to adverse events reported in Study A. 2 patients left in placebo group
due to serious adverse events.
Biochemical parameters at baseline and end of treatment with SD were reported in table
V page 105.
Change from baseline to end point in SBP, DBP and biochemical values was calculated
and SD at end of treatment was imputed for meta-analysis.
Risk of bias
Item Authors’ judgement Description
Adequate sequence generation? Unclear Not described in the publication.
Allocation concealment? Unclear Not described in the publication.
Blinding? Unclear Not described in the publication.

All outcomes
Incomplete outcome data addressed? Yes “14 patients left the study early”, 12 from
All outcomes the excluded Study B and 2 from the in-
cluded Study A (both from the placebo
Bodak 1989 (Continued)
group, both due to serious adverse events).
Free of selective reporting? Yes All outcome measures were reported.
Free of other bias? Unclear Sponsorship or funding of this study and

conflict of interest were not declared by the
authors in the publication.
Gotzen 1994
Participants 39 patients with mild to moderate hypertension

Mean age = 60 years; Male (53.3%);
Baseline SBP was 143.9 + 10.3 mmHg and DBP was 85.5 + 8.9 mmHg in placebo
group
Baseline SBP was 149.9 + 15.5 mmHg and DBP was 91.1 + 13.8 mmHg in Cicletanine
100mg group
Interventions Cicletanine 100mg per day or placebo for 8 weeks duration

Cicletanine 100mg = 20 and Placebo =19
Outcomes Systolic blood pressure, diastolic blood pressure at end of treatment

Also Day time (6.00am to 22.00pm) and night time (22.00pm to 6.00am) measurements
Notes Article in German translated by Ciprian Jauca.

Table II :
End of treatment week 8 SBP in Cicletanine 100mg was 139.3 + 13.5 mmHg and DBP
was 85.0 + 9.9 mmHg
End of treatment week 8 SBP in placebo group was 140.3 + 15.6 mmHg and DBP was
82.7 + 9.8 mmHg
All 39 patients completed the study (no withdrawals).
Biochemical para metres were either not measured or not reported.
Risk of bias
Allocation concealment? Yes “optically identical placebo was adminis-

tered double-blind at 8:00 AM”.

All outcomes
Incomplete outcome data addressed? Yes All patients completed the study and their
All outcomes blood pressure measurements are reported.
Gotzen 1994 (Continued)
Free of selective reporting? No Adverse events and biochemical markers

are not reported.

Homuth 1993
Participants Participants were from 20 outpatient clinics in Germany ages between 21 and 65 years
(mean age = 52.5 years).
482 patients were recruited and 480 were randomized to 12 groups in a multifactorial
design. (Table II page 668)
Mean duration of high BP 9 to 10 years; 25/120 (20.8%) patients were smokers; 5/120
(4.2%) patients with congestive heart failure; 6/120 (5%) patients with diabetes; 10/120
(8.3%) with uricemia and 21/120 (17.5%) patients with hyperlipidaemia. (Table III
page 668)
Baseline SBP was 161.0 + 17.0 mmHg and DBP was 109 + 5.0mmHg in placebo group
Baseline SBP was 160.0 + 13.0 mmHg and DBP was 108.8 + 6.0 mmHg in Pirentanide
3mg group
Baseline SBP was 165.0 + 17.0 mmHg and DBP was 108.0 + 7.0 mmHg in Pirentanide
6mg group
Interventions Placebo; ramipril 2.5, 5.0 and 10mg; and piretanide 3.0 or 6.0mg; or combination of
ramipril doses with the 2 piretanide doses for a treatment duration of 6 weeks given as
a single daily morning dose
Relevant treatment groups for this review are the following three groups (N = 120)
Pirentanide 3 mg = 40; Pirentanide 6mg = 40= Placebo = 40
Outcomes Systolic blood pressure, diastolic blood pressure in supine, sitting and standing position
at baseline and weekly during week 1 to week 6.
BP was measured by specially trained personnel with mercury column sphygmomanome-
ters. The fifth Korotkoff sound was accepted as diastolic blood pressure after 3 minutes
of rest. There after patient assumed the sitting position, followed by standing position
for > 3 minutes after which BP was recorded again.
Adverse events were assessed by means of questionnaire that was given at each patient
visit.
Notes Analysis was performed on an intention-to treat basis.

Data was abstracted from the response surface contour plot on page 669 which was based
on a bi quadratic regression model and was decided to be included in the meta-analysis.
The data abstracted is as follows:
Change in SBP from baseline in placebo = -5.5 mmHg; Piretanide 3 mg = -7.7 mmHg
and piretanide 6mg = -12.8 mmHg
Change in DBP from baseline in placebo = -4.9 mmHg, Piretanide 3 mg = --5.7 mmHg
and piretanide 6mg = --8.0 mmHg
Homuth 1993 (Continued)
Withdrawal due to adverse events were reported placebo = 1 and piretanide = 1 (3 or 6

mg group is not reported)
Biochemical parameters were not reported.
Risk of bias
Blinding? Yes “The regimens had identical appearance

All outcomes and the Physician, nurses and patient-care
personnel, as well as patients were unaware
of the regimens”.
Incomplete outcome data addressed? Yes Total withdrawal in the three relevant treat-
All outcomes ment groups included in this review was
7/40 (17.5%) patients in placebo group
and 2/80 (2.5%) patients in piretanide
group.
Analysis was an intention-to-treat analysis
which included randomized patients with
any post-randomization data available dur-
ing double blind phase were included.
Free of selective reporting? No All mentioned outcome measures in the

methods section were reported.
However, the absolute values of SBP, DBP
at end of treatment as measured by the
sphygmomanometer was not reported . In-
stead a graph of the response was presented
as a surface contour plot which was based
on a bi quadratic regression model.

Jain 1984
Participants 40 patients were recruited of which 2 were lost to follow up early in the study and 1 did
not receive DB medication because of marginally increased SGOT and SGPT levels.
37 patients with sitting DBP between 90 and 104 mmHg after 4 weeks of subject blind
placebo washout period were randomized to 4 treatment groups for a duration of 12
Jain 1984 (Continued)
weeks. Through out the study patients were instructed to follow a no salt added diet.
Except for the occasional use of a laxative or a non-narcotic anlagesic, no concurrent
medications were allowed. If the potassium level was decreased below 3.0 mEq/L on two
consecutive visits, a potassium supplement was permitted.
The population was mainly black females 27/37 (73%), except for the placebo group,
which had 5 males and 4 females.
Mean age ranged from 53 to 56 years; and duration of hypertension ranged from 7.3 to
14.7 years.
Baseline sitting SBP was 157.0 + 18.0 mmHg and DBP was 96 + 3.0mmHg for -2.5/ +
80 mg group.
Baseline sitting SBP was 149.0 + 8.0 mmHg and DBP was 95 + 4.0 mmHg for -5.0/ +
80 mg group.
Baseline sitting SBP was 156.0 + 20.0 mmHg and DBP was 95 + 4.0 mmHg for -10.0/
+ 80 mg group.
Baseline sitting SBP was 150.0 + 8.0 mmHg and DBP was 95 + 4.0mmHg for placebo
group.
Interventions one of the ratios of 1 enantiomers of indacrinone namely

-2.5/ + 80 mg, -5.0/ + 80 mg, -10.0/ + 80 mg or placebo for duration of 12 weeks once
daily
-2.5/ + 80 mg =9 , -5.0/ + 80 mg = 9, -10.0/ + 80 mg = 10 or
placebo = 9
Outcomes Systolic blood pressure, diastolic blood pressure (sitting and standing)
BP was measured in duplicate after 5 minutes of sitting and 2 minutes of standing by a
standard mercury sphygmomanometers by the same observer at approximately 24 hours
after the previous day dosing. The fifth Korotkoff sound was accepted as diastolic blood
pressure.
Heart rate, ECG
Laboratory data - serum uric acid, potassium, chloride, sodium, glucose , creatinine,
BUN
Body weight
Notes Mean weighted SBP and DBP with mean weighted standard deviation was calculated.
Withdrawal due to adverse events none.
Biochemical parameters absolute data is not reported. No comparison data is presented
comparing treatment groups to placebo.
Authors report “ No significant changes observed in mean serum sodium, chloride, glu-
cose, creatinine, BUN and body weight during treatment with indacrinone enantiomers
-2.5 and -5.0 and placebo when baseline data was compared to data at week 16. With
Indacrinone -10mg significant changes were seen in serum chloride from 104 to 99.5
mEq/L, serum glucose from 110 to 128mg/dl. Lipid changes were not monitored”.
Risk of bias
Jain 1984 (Continued)

All outcomes
Incomplete outcome data addressed? Yes Of the 40 patients 2 were lost to follow up
All outcomes early in the study and 1 did not receive dou-
ble blind medication because of marginal
increase in SGOT and SGPT levels. Data
was reported in the remaining 37 patients
completing the trial.
Free of selective reporting? No “During the DB phase, if the DBP was

greater than 104 mmHg on two consecu-
tive visits, the patient was dropped as ther-
apeutic failure”. (Pg 280)
Absolute values of serum biochemical
changes are not reported.
Free of other bias? No Industry funded study.
Licata 1989
Methods Double blind prospective randomised placebo controlled parallel group study
Participants 28 patients with essential hypertension (WHO stage I-II) after 15 days wash out period
with placebo were randomized.
Mean age 54 + 10 years; men 16/28 (57%); 18/28 (64.3%) with mild hypertension and
10/28 (35.7%) with moderate hypertension
Baseline sitting SBP was 171.4 + 10.6 mmHg and DBP was 102.4 + 5.4 mmHg for
etozolin group.
Baseline sitting SBP was 169.7 + 10.2 mmHg and DBP was 103.7 + 6.1 mmHg for
placebo group.
Interventions Etozolin 200mg once a day or placebo for 30 days

15 day wash-out period on placebo
All patients received 150 to 200 mEq sodium daily.
Etozolin = 14 and placebo = 14
Outcomes Resting systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate
(ECG tracing) and first pass radionuclide angiocardiography.
BP was measured with a mercury sphygmomanometers after a 5 minute rest at the first
and fifth Korotkoff phase as the mean of three recordings 24 hours after the last dose.
Daily urine volume, serum sodium, potassium. calcium, blood glucose, blood urea ni-
trogen, cholesterol and uric acid were measured.
Licata 1989 (Continued)
Notes Total withdrawals and withdrawal due to adverse effects were not reported.
Change from baseline for biochemical paratmeters were reported in the publication for
the etozolin group but not reported for the placebo group.
Authors state “ No significant modifications emerged in hematological and metabolic
picture” page 265.
Risk of bias

All outcomes
Incomplete outcome data addressed? Unclear Total withdrawals were not reported.
All outcomes
Free of selective reporting? No Change from baseline for all outcomes were
reported in the publication for the etozolin
group but biochemical parameters were not
reported in the placebo group.

Perola 1985
Methods Double blind prospective randomised placebo cross over study
Participants 15 mildly hypertensive patients classified as WHO I (12 patients) or WHO II (3 patients)
. Age ranged from 27 to 65 years (mean age is 48.3 years).
Supine SBP 159.7 + 17.0 and DBP 101.1 + 8.1 mmHg in all patients
Standing SBP 158.5 + 17.9 and DBP 107.7 + 7.2 mmHg in all patients
Interventions Furosemide 40mg + triameterene 50mg; Furosemide 40mg; triameterene 50mg; or

placebo for a treatment duration of 4 weeks each
Relevant treatment groups for this review are the following two groups : Furosemide
40mg or placebo (N = 15 since cross over study)
No mention of washout period between treatments.
Outcomes Systolic blood pressure, diastolic blood pressure, serum sodium, potassium, calcium,
magnesium, creatinine, urate, transaminase, cholesterol, HDL-cholesterol, triglyceride,
glucose, plasma renin activity, plasma insulin and C peptide.
Perola 1985 (Continued)
Blood pressure was measured in the supine position as well as in the standing position
(3 measurements) by a nurse on the right arm of each patient with accuracy of paired 2
mmHg.
Notes The standing SBP and DBP were used in analysis.

No data has been reported during the parallel placebo arm period in the first 4 week
phase.
Mean of 2 and 4 weeks data has been reported in each treatment group at end of 4 weeks.
In order to maximize inclusion of data, since blood pressure was taken at end of 4 weeks
of each treatment period we assume there was no carry over effect and include data from
furosemide vs placebo group at end of 4 weeks in all 15 randomized patients. Table 2
page 547
Withdrawal due to adverse events were not reported.
Biochemical parameters are reported in table III and IV page 549 and 550.
Risk of bias
Blinding? Yes “Corresponding placebo tablets made the

All outcomes medication uniform for all patients, who
received every morning a total of three
tablets”. (Page 546)
Incomplete outcome data addressed? No Number of patient withdrawals was not

All outcomes mentioned in the publication.
Free of selective reporting? Yes Table 1,2, 3 and 4 in the publication pro-
vide data for all outcomes.
Free of other bias? Unclear Since it is a cross over trial we would pre-
fer using the parallel group data which was
not available. The authors have not stated
if order of treatment significantly affected
results.
Sponsorship or funding of this study and
Vadasz 1982
Participants 36 patients with mild to moderate hypertension with DBP between 95 and 120 mmHg
were enrolled. 26 completed the study.
7/18 patients in placebo group and none in the furosemide group had to withdraw
because of deterioration in their hypertension. 2 of the three drop outs in frusemide
group occurred in the second part of the trial when dose was doubled after 4 weeks in
some patients.
The DBP at baseline was 108 + 7 mmHg in frusemide group and 98 + 4 mmHg in
placebo group. “The same pattern was seen for standing DBP, and supine SBP and DBP”.
(Page 201)
Median age is 51 in frusemide group and 45 in placebo group.
Interventions Frusemide slow release formulation 60mg or placebo given for 8 weeks
The 1st weeks is fixed dose in all randomized patients after which the dose was increased
“in patients failing to achieve a clinically meaningful fall in blood pressure”. Page 200
Therefore data at 4 weeks duration will be included for this review.
Furosemide = 15 and Placebo = 11
Patients were advised to maintain a low-salt-diet. Potassium supplements were not pre-
scribed.
Outcomes Systolic blood pressure, diastolic blood pressure, plasma electrolytes (sodium, potassium,
chloride, and bicarbonate), blood glucose, blood urea nitrogen, plasma uric acid, serum
creatinine, haemoglobin, hematocrit, red cell count, white cell count and blood film
examination.
Blood pressure was measured by a standardized technique using a random zero (Hawsk-
ley) sphygmomanometer. This was applied to the same arm generally by the same in-
vestigator at about the same time of the day. The patient rested for 10 to 15 minutes
before supine pressure was recorded and stood for at least 2 minutes for the standing
blood pressure reading. The DBP was taken as the fifth Korotkoff phase.
Notes “Two randomized groups were broadly comparable except for age since there were many
older patients in the frusemide group”.
“The baseline supine diastolic was higher in frusemide group 108mmHg + 7 as compared
to 98 + 4 mmHg in placebo group. The same pattern was seen in erect diastolic, supine
systolic and erect systolic blood pressure”.
Total withdrawals = 10/26 in the trial. Withdrawal due to adverse effects 3/15 in
frusemide group and 0/11 in placebo.
Absolute value of biochemical changes were not reported. “ None of the laboratory
tests revealed any clinically meaningful changes. In particular no patients developed
hypokalaemia, although there was one patient with relatively low serum potassium (<
3.2 mmol/L) at the end of treatment in the frusemide group”.
Risk of bias
Vadasz 1982 (Continued)
Blinding? Yes Stated as double blind and “matching

All outcomes placebo” was was administered
Incomplete outcome data addressed? No It is not known how the data in the10 pa-
All outcomes tients who were lost and did not complete
the trial was accounted for.
Free of selective reporting? No SBP and DBP is reported but other labo-
ratory parameters are reported as “ None
of the laboratory tests revealed any clini-
cally meaningful changes”. Absolute values
at baseline or end of treatment are not pro-
vided.
Free of other bias? No The two groups diffred in their age pat-
tern, baseline level of blood pressure and
response to low-salt-diet during wash-out
run-in period.
The pattern of individual responses dif-
fered in the group. Despite the protocol the
3 patients achieving normal BP at week 4
in frusemide group dose was doubled in all
15 patients.
The authors state that “despite the lack of
comparability of the two groups firm clin-
ical inferences could be drawn from the
study”.
Verho 1986
Methods Double blind prospective randomised placebo controlled parallel group study
Participants Sixty patients with DBP between 95 and 120mmHg were randomised. No drop outs
during the study. Age range from 37 to 65 years (mean age 52.5 years).
Any existing hypertensive medication was discontinued and after 2 - 3 week placebo
run-in period patients were randomized to pirentanide 6mg or placebo for 6 weeks.
After 6 weeks dose was doubled from one tablet daily to one tablet twice a day in patients
who had an inadequate blood pressure lowering effect (supine DBP of > 95 mmHg)
therefore data at 6 weeks is included in this review.
Baseline supine blood pressure : Piretanide group = 163.8/101.4 mm Hg and placebo
group = 157.9/99.1 mmHg
Interventions Pirentanide 6 mg = 30 or placebo = 30 for 12 weeks
Verho 1986 (Continued)
Outcomes Systolic blood pressure, diastolic blood pressure, biochemical values

Blood pressure was measured at rest after 10 minutes in recumbent position and 2
minutes after standing. The mean of three measurements was recorded each time.
Standing SBP and DBP data cannot be used since it is reported in a subset of randomized
patients - 17 in piretanide group and 10 in the placebo group. Supine blood pressure
measurements in all randomized patients are used for analysis.
Notes Withdrawal due to adverse events = none.

Since SD data at baseline, end of treatment or change in blood pressure is not reported
in this trial the mean weighted SD will be calculated from the other trials and imputed
in the analysis.
Change in biochemical parameters were not reported at week 6 as required for this
systematic review. Data at 12 weeks is reported.
Risk of bias
Blinding? Yes Stated as double blind. “The tablets were

All outcomes identical in appearance and each patient
took the tablets as a single dose at break-
fast”. (Page 386)
Incomplete outcome data addressed? No “No drop outs during the study”. This is
All outcomes true only for supine blood pressure data
in all randomized patients. However, the
standing blood pressure data are reported
in a small subset of patients 27/60 (45%)
in figures.
Free of selective reporting? No Biochemical values at 6 weeks are not re-

ported.
Free of other bias? No Baseline supine blood pressure in pire-

tanide group were significantly higher than
in placebo group (163.8/101.4 mmHg ver-
sus 157.9/99.1 mmHg)
Wertheimer 1973
Methods Double blind prospective randomised placebo cross over study
Participants 60 patients from three different hospital clinics by investigators following the same
protocol. Patients with DBP > 90 mm Hg during 3 to 6 week control period in which
no antihypertensive medication was given.
Men 28/60 (46.6%); Black 26/60 (43.3%) and Caucasian 34/60 (56.6%); mean age
58.6 years.
Baseline standing SBP 177 + 21.9 and DBP 107 + 10.4 mm Hg (range 91 to 131 mmHg)
for both groups
Group 1 placebo followed by furosemide = 30
Group 2 furosemide followed by placebo = 30
Interventions Furosemide 40mg or placebo for (5 to 14 weeks, mean duration of 7.9 weeks)
Group 1 placebo followed by furosemide 40mg = 30
Group 2 furosemide 40mg followed by placebo = 30
No wash out period and then cross over
Data after first parallel group phase can be used.
Outcomes Systolic blood pressure, diastolic blood pressure, laboratory measures (hematocrit, com-
plete blood cell count, urinanalysis, serum potassium, blood urea nitrogen and fasting
blood glucose)
Blood pressure was measured once or twice weekly with patients in standing , sitting or
supine position.
Notes BP data in the 1st period between furosemide and parallel placebo group is useful for
this systematic review.
Authors report“ the order in which treatment was administered influenced the results”
page 935
Blood pressure values are provide for Group 1 vs. Group 2 in 1st phase that can be used
at the end of 4 weeks.
Also difference between placebo and frusemide group is given in placebo and frusemide
treatment arms at end of 4 weeks. Page 936
Biochemical parameter absolute values are not provided at the end of the first phase of
the study. End of treatment data is provided.
Withdrawal due to adverse effects during 1st phase has not been reported.
Risk of bias
Adequate sequence generation? Yes “Patients were assigned treatment accord-

ing to randomized scheme”. (page 934)
Blinding? Yes “Medication supplied as tablets in bottles

All outcomes with coded labels so that neither patient
nor investigator knew which preparation
was being given at any time. The placebo
Wertheimer 1973 (Continued)
tablets were identical in appearance to those

containing active ingredients”. (Page 934)
Incomplete outcome data addressed? No Separate data has not been provided at end
All outcomes of first period for biochemical changes as
well as total withdrawals.
Free of selective reporting? Yes All outcomes at end of the study were re-
ported in the publication
Free of other bias? No Authors report“ the order in which treat-

ment was administered influenced the re-
sults” page 935
Characteristics of excluded studies [ordered by study ID]
Bonaduce 1981 This DB cross over study after placebo washout randomized patients to xipamide or chorthalidone. There is
no parallel placebo control arm in this study.
Buckert 1984 This DB randomized study compared piretanide to two doses of HCTZ and had no parallel placebo arm.
Campbell 1998 This DB randomized placebo controlled cross over study is a single dose study and does not meet minimum
treatment duration of 3 weeks for inclusion.
Charansonney 1997 This DB RCT after 3 weeks placebo washout randomized patients to Pirentanide, HCTZ or combination of
both drugs. There is no parallel placebo control arm in this study.
Clerson 1989 This DB randomized trial in 120 patients with essential hypertension uncontrolled on beta blocking therapy
were randomized to placebo, cicletanine 50mg/day and cicletanine 100mg/day in addition to beta blocker
therapy. There is no monotherapy arm so does not meet our inclusion criteria.
Di Somma 1990 There is no parallel placebo control arm in this study.
Fried 1979 This DB randomized trial compared tienilic acid to HCTZ. There is no parallel placebo arm in this study.
Galleti 1991 There is no parallel placebo control arm in this study.
Gupta 1981 This double blind controlled study after 2 weeks placebo run in period randomized patients to three doses of
piretanide. There is no parallel placebo control arm in this study.
(Continued)
Heijden 1998 This double blind placebo controlled randomized cross over trial in 27 patients with essential hypertension
was excluded since during the first 6 week period placebo was administered in single blind fashion followed
by second 6 week period in which furosemide or bumetanide was administered in double blind fashion. In
the third 6 week period placebo was again administered in single blind fashion followed by fourth 6 week
period of double blind alternative active medication. There is no parallel placebo arm during active treatment
in these randomized patients.
Holland 1979 There is no parallel placebo control arm in this study.
Jungers 1989 This DB RCT included 72 patients with mild to moderate hypertension and after 2 weeks single blind placebo
run in period randomised patients to 50 mg or 100mg/day cicletanine. There is no parallel placebo control
arm in this study.
Knoben 1982 There is no parallel placebo control arm in this study.
Kopp 1978 This DB randomized trial in 100 patients was carried out over 22 days with 5 days without medication, 12
days therapy and 5 days follow up and does not meet the criteria of minimum 3 weeks of treatment with
etozolin or placebo.
Krogsgaard 1976 There is no parallel placebo control arm in this DB randomized cross over study.
Kumar 1984 This DB RCT included 17 patients who had 2 weeks placebo run in and randomized to xipamid or HCTZ.
There is no parallel placebo control arm in this study.
Kuramoto 1985 This DB comparative method study in 33 elderly patients with essential hypertension compared 60 years or
more to those 59 years or younger and had no parallel placebo control group.
Magrini 1988 Single blind cross over study . Short- term administration of 25 mg of captopril.
Miziara 1982 This DB randomized trial randomized patients to chorthalidone and furosemide after a 15 day placebo period.
There is no parallel placebo treatment arm.
Nami 1991 This DB placebo controlled study randomized patients to single dose of etozolin (200, 400 and 600 mg),
chlorthalidone (25, 50 and 75mg) and placebo. Therefore this study does not meet the criteria of minimum
3 weeks of treatment.
Obel 1984 This DB randomized cross over study in included 50 patients with hypertension compared furosemide to
bendrofluazide. There is no parallel placebo arm in the study.
Okun 1978 Double blind prospective randomised placebo controlled study. 30 male patients ranging in age from 28 to 60
years with mild to moderate hypertension were randomized to ticrynafen 250mg, hydrochlorothiazide 50mg
or placebo for 6 weeks. However, after 2 weeks of DB treatment , dosage could be increased from one to
two tablets in any patient who had not had a 10mmHg decrease in DBP and who had not experienced any
serious adverse event. Dosage was increased in 8 of the 9 placebo patients, 4 of the 9 patients in ticrynafen
and 5 of the 10 patients on HCTZ. Since fixed dose monotherapy or increase in dose all randomized patients
irrespective of response is not used, this trial was excluded.
(Continued)
Okun 1979 This DB study in 30 patients to six weeks regimen of either tienilic acid, HCTZ or placebo was excluded
since after first two weeks of DB treatment dosage was increased in any patient who had not had a 10mmHg
decrease in diastolic blood pressure.
Oli 1983 This study in 22 non-insulin Nigerian diabetics compared frusemide to placebo for a period of 9 weeks but
was not a randomized trial.
Olshan 1981 This trial in 12 white men with essential hypertension randomized patients to placebo or furosemide and
entry criteria is based on mean arterial pressure of 105mmHg and end of treatment data is also reported as
mean arterial pressure.
Pearson 1979 Tienilic acid or ticrynafen (USAN) is a diuretic drug with uric acid-lowering (uricosuric) action, formerly
marketed for the treatment of hypertension. It was withdrawn in 1982, shortly after its introduction to the
market, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.
This double blind placebo controlled cross over trial was excluded as there was no wash out period prior to
randomization of patients.
Potter 1987 This randomized double blind study compared atenolol with matching placebo in patients already receiving
fixed dose of captopril and frusemide. There is no monotherapy arm in this study.
Reyes 1990 There is no parallel placebo control arm in this study.
Ronchi 1990 This DB RCT in which diuretic was added to nifedipine. There is no diuretic monotherapy treatment arm.
Rutledge 1988 This randomized double blind study compared intravenous enalapril to placebo in 42 moderate hypertensive
patients and to intravenous furosemide in 23 severe hypertensive patients for 2 days.
Valmin 1980 This DB randomized cross over study in 26 hypertensive patients to 4 week of placebo followed by 6 weeks
of different doses of frusemide and intervening placebo of 4 weeks. There is no parallel placebo control arm
in this study.
Webster 1987 This DB randomized trial in 18 patients compared atenolol, propanolol or placebo in patients not controlled
on captopril 50mg b.i.d. and frusemide 40mg b.i.d. There is no parallel loop diuretic monotherapy arm.
Yasky 1987 This DB randomized cross over study in 20 patients with mild to moderate hypertension had a parallel placebo
arm but piretanide was not given as monotherapy.
DATA AND ANALYSES
Comparison 1. Loop diuretics vs placebo
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 SBP 9 440 Mean Difference (IV, Fixed, 95% CI) -7.94 [-10.45, -5.42]
1.1 Furosemide 40mg versus 2 90 Mean Difference (IV, Fixed, 95% CI) -5.80 [-12.96, 1.36]
placebo
1.2 Furosemide 60mg versus 1 26 Mean Difference (IV, Fixed, 95% CI) -10.0 [-15.77, -4.23]
placebo
1.3 Cicletanine 100mg versus 1 39 Mean Difference (IV, Fixed, 95% CI) -7.0 [-16.18, 2.18]
placebo
1.4 Cicletanine 150mg versus 1 60 Mean Difference (IV, Fixed, 95% CI) -9.10 [-15.54, -2.66]
placebo
1.5 Pretanide 3mg versus 1 60 Mean Difference (IV, Fixed, 95% CI) -2.2 [-9.97, 5.57]
placebo
1.6 Piretanide 6mg versus 2 100 Mean Difference (IV, Fixed, 95% CI) -4.23 [-10.00, 1.53]
placebo
1.7 Indacrinone enantiomer - 1 12 Mean Difference (IV, Fixed, 95% CI) -14.90 [-31.15,
2.5 /+ 80mg versus placebo 1.35]
1.8 Indacrinone -5.0 /+ 1 12 Mean Difference (IV, Fixed, 95% CI) -11.70 [-25.37,
80mgversus placebo 1.97]
1.9 Indacrinone -10.0 /+ 80 1 13 Mean Difference (IV, Fixed, 95% CI) -19.1 [-35.95, -2.25]
mg versus placebo
1.10 Etozolin 200mg versus 1 28 Mean Difference (IV, Fixed, 95% CI) -14.30 [-23.05, -
placebo 5.55]
2 DBP 9 460 Mean Difference (IV, Fixed, 95% CI) -4.36 [-5.87, -2.84]
placebo
placebo
2.3 Cicletanine 100mg versus 1 39 Mean Difference (IV, Fixed, 95% CI) -3.30 [-9.48, 2.88]
placebo
2.4 Cicletanine 150mg versus 1 60 Mean Difference (IV, Fixed, 95% CI) -11.3 [-15.30, -7.30]
placebo
2.5 Pretanide 3mg versus 1 60 Mean Difference (IV, Fixed, 95% CI) -0.80 [-5.44, 3.84]
placebo
2.6 Piretanide 6mg versus 2 120 Mean Difference (IV, Fixed, 95% CI) -2.32 [-5.48, 0.84]
placebo
2.7 Indacrinone enantiomer - 1 12 Mean Difference (IV, Fixed, 95% CI) -7.1 [-15.16, 0.96]
2.5 /+ 80mg versus placebo
2.8 Indacrinone -5.0 /+ 1 12 Mean Difference (IV, Fixed, 95% CI) -3.40 [-11.24, 4.44]
80mgversus placebo
2.9 Indacrinone -10.0 /+ 80 1 13 Mean Difference (IV, Fixed, 95% CI) -3.40 [-11.61, 4.81]
mg versus placebo
2.10 Etozolin 200mg versus 1 28 Mean Difference (IV, Fixed, 95% CI) -7.30 [-13.22, -1.38]
placebo
3 Withdrawals due to adverse 6 331 Risk Ratio (M-H, Fixed, 95% CI) 1.93 [0.34, 10.81]
events
4 Serum potassium 2 88 Mean Difference (IV, Fixed, 95% CI) -0.12 [-0.36, 0.12]
4.1 Cicletanine 150mg 1 58 Mean Difference (IV, Fixed, 95% CI) -0.12 [-0.36, 0.12]
4.2 Furosemide 40mg 1 30 Mean Difference (IV, Fixed, 95% CI) Not estimable
5 Serum uric acid 2 88 Mean Difference (IV, Fixed, 95% CI) 10.52 [-17.88,
38.92]
5.2 Furosemide 40mg 1 30 Mean Difference (IV, Fixed, 95% CI) 53.00 [0.44, 105.56]
6 Serum creatinine 2 88 Mean Difference (IV, Fixed, 95% CI) 0.93 [-5.74, 7.61]
6.2 Furosemide 40 mg 1 30 Mean Difference (IV, Fixed, 95% CI) 3.0 [-7.05, 13.05]
7 Blood glucose 2 88 Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.19, 0.31]
7.2 Furosemide 40mg 1 30 Mean Difference (IV, Fixed, 95% CI) 0.1 [-0.22, 0.42]
8 serum cholesterol 2 88 Mean Difference (IV, Fixed, 95% CI) 0.31 [-0.17, 0.80]
8.1 Cicletanine 150mg 1 58 Mean Difference (IV, Fixed, 95% CI) 0.17 [-0.51, 0.85]
9 Serum triglyceride 2 88 Mean Difference (IV, Fixed, 95% CI) -0.02 [-0.35, 0.31]
Analysis 1.1. Comparison 1 Loop diuretics vs placebo, Outcome 1 SBP.
Review: Blood pressure lowering efficacy of loop diuretics for primary hypertension
Comparison: 1 Loop diuretics vs placebo
Outcome: 1 SBP
Study or subgroup Experimental Control Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Furosemide 40mg versus placebo

Perola 1985 15 -22 (10.1) 15 -15.7 (14.9) 7.6 % -6.30 [ -15.41, 2.81 ]
Wertheimer 1973 30 -17 (19.3) 30 -12 (26) 4.7 % -5.00 [ -16.59, 6.59 ]
Subtotal (95% CI) 45 45 12.4 % -5.80 [ -12.96, 1.36 ]

Heterogeneity: Chi2 = 0.03, df = 1 (P = 0.86); I2 =0.0%
Test for overall effect: Z = 1.59 (P = 0.11)
Vadasz 1982 15 -10 (9) 11 0 (6) 19.0 % -10.00 [ -15.77, -4.23 ]
Subtotal (95% CI) 15 11 19.0 % -10.00 [ -15.77, -4.23 ]

Heterogeneity: not applicable
3 Cicletanine 100mg versus placebo
-100 -50 0 50 100

Favours experimental Favours control
(Continued . . . )
(. . . Continued)
Gotzen 1994 20 -10.6 (13.5) 19 -3.6 (15.6) 7.5 % -7.00 [ -16.18, 2.18 ]
Subtotal (95% CI) 20 19 7.5 % -7.00 [ -16.18, 2.18 ]

Bodak 1989 30 -20.3 (11.8) 30 -11.2 (13.6) 15.3 % -9.10 [ -15.54, -2.66 ]
Subtotal (95% CI) 30 30 15.3 % -9.10 [ -15.54, -2.66 ]

5 Pretanide 3mg versus placebo
Homuth 1993 40 -7.7 (15.9) 20 -5.5 (13.7) 10.5 % -2.20 [ -9.97, 5.57 ]
Subtotal (95% CI) 40 20 10.5 % -2.20 [ -9.97, 5.57 ]

6 Piretanide 6mg versus placebo
Homuth 1993 20 -12.8 (15.3) 20 -5.5 (13.7) 7.8 % -7.30 [ -16.30, 1.70 ]
Verho 1986 30 -5.4 (15.9) 30 -3.3 (13.7) 11.2 % -2.10 [ -9.61, 5.41 ]
Subtotal (95% CI) 50 50 19.0 % -4.23 [ -10.00, 1.53 ]

7 Indacrinone enantiomer -2.5 /+ 80mg versus placebo
Jain 1984 9 -19.3 (16.6) 3 -4.4 (10.7) 2.4 % -14.90 [ -31.15, 1.35 ]
Subtotal (95% CI) 9 3 2.4 % -14.90 [ -31.15, 1.35 ]

8 Indacrinone -5.0 /+ 80mgversus placebo
Jain 1984 9 -16.1 (9.7) 3 -4.4 (10.7) 3.4 % -11.70 [ -25.37, 1.97 ]
Subtotal (95% CI) 9 3 3.4 % -11.70 [ -25.37, 1.97 ]

9 Indacrinone -10.0 /+ 80 mg versus placebo
Jain 1984 10 -23.5 (18.9) 3 -4.4 (10.7) 2.2 % -19.10 [ -35.95, -2.25 ]
Subtotal (95% CI) 10 3 2.2 % -19.10 [ -35.95, -2.25 ]

10 Etozolin 200mg versus placebo

Licata 1989 14 -21.7 (12.2) 14 -7.4 (11.4) 8.3 % -14.30 [ -23.05, -5.55 ]
Subtotal (95% CI) 14 14 8.3 % -14.30 [ -23.05, -5.55 ]

-100 -50 0 50 100

(Continued . . . )
(. . . Continued)
Total (95% CI) 242 198 100.0 % -7.94 [ -10.45, -5.42 ]
Test for overall effect: Z = 6.18 (P < 0.00001)
Test for subgroup differences: Chi2 = 9.39, df = 9 (P = 0.40), I2 =4%
-100 -50 0 50 100

Analysis 1.2. Comparison 1 Loop diuretics vs placebo, Outcome 2 DBP.
Outcome: 2 DBP


Perola 1985 15 -4.5 (6.5) 15 -2.6 (7) 9.8 % -1.90 [ -6.73, 2.93 ]
Wertheimer 1973 30 -10 (11) 30 -4 (12.5) 6.5 % -6.00 [ -11.96, -0.04 ]
Subtotal (95% CI) 45 45 16.3 % -3.53 [ -7.28, 0.23 ]

Heterogeneity: Chi2 = 1.10, df = 1 (P = 0.29); I2 =9%
Vadasz 1982 15 -5 (7) 11 -2 (4) 12.6 % -3.00 [ -7.26, 1.26 ]
Subtotal (95% CI) 15 11 12.6 % -3.00 [ -7.26, 1.26 ]

Gotzen 1994 20 -6.1 (9.9) 19 -2.8 (9.8) 6.0 % -3.30 [ -9.48, 2.88 ]
Subtotal (95% CI) 20 19 6.0 % -3.30 [ -9.48, 2.88 ]

Bodak 1989 30 -18 (6.9) 30 -6.7 (8.8) 14.3 % -11.30 [ -15.30, -7.30 ]
Subtotal (95% CI) 30 30 14.3 % -11.30 [ -15.30, -7.30 ]

-100 -50 0 50 100

(Continued . . . )
(. . . Continued)
5 Pretanide 3mg versus placebo
Homuth 1993 40 -5.7 (8.3) 20 -4.9 (8.8) 10.7 % -0.80 [ -5.44, 3.84 ]
Subtotal (95% CI) 40 20 10.7 % -0.80 [ -5.44, 3.84 ]

6 Piretanide 6mg versus placebo
Homuth 1993 40 -7.7 (8.3) 20 -4.9 (8.8) 10.7 % -2.80 [ -7.44, 1.84 ]
Verho 1986 30 -4.6 (8.3) 30 -2.7 (8.8) 12.2 % -1.90 [ -6.23, 2.43 ]
Subtotal (95% CI) 70 50 22.9 % -2.32 [ -5.48, 0.84 ]

7 Indacrinone enantiomer -2.5 /+ 80mg versus placebo
Jain 1984 9 -12.1 (6.9) 3 -5 (5.9) 3.5 % -7.10 [ -15.16, 0.96 ]
Subtotal (95% CI) 9 3 3.5 % -7.10 [ -15.16, 0.96 ]

8 Indacrinone -5.0 /+ 80mgversus placebo
Jain 1984 9 -8.4 (6.3) 3 -5 (5.9) 3.7 % -3.40 [ -11.24, 4.44 ]
Subtotal (95% CI) 9 3 3.7 % -3.40 [ -11.24, 4.44 ]

9 Indacrinone -10.0 /+ 80 mg versus placebo
Jain 1984 10 -8.4 (7.7) 3 -5 (5.9) 3.4 % -3.40 [ -11.61, 4.81 ]
Subtotal (95% CI) 10 3 3.4 % -3.40 [ -11.61, 4.81 ]

10 Etozolin 200mg versus placebo

Licata 1989 14 -10.3 (8.8) 14 -3 (7.1) 6.5 % -7.30 [ -13.22, -1.38 ]
Subtotal (95% CI) 14 14 6.5 % -7.30 [ -13.22, -1.38 ]

Total (95% CI) 262 198 100.0 % -4.36 [ -5.87, -2.84 ]
-100 -50 0 50 100

Analysis 1.3. Comparison 1 Loop diuretics vs placebo, Outcome 3 Withdrawals due to adverse events.
Outcome: 3 Withdrawals due to adverse events
Study or subgroup Loop diuretics Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bodak 1989 0/30 0/19 0.0 [ 0.0, 0.0 ]
Gotzen 1994 0/20 0/19 0.0 [ 0.0, 0.0 ]
Homuth 1993 1/80 1/40 0.50 [ 0.03, 7.79 ]
Jain 1984 0/28 0/9 0.0 [ 0.0, 0.0 ]
Vadasz 1982 3/15 0/11 5.25 [ 0.30, 92.33 ]
Verho 1986 0/30 0/30 0.0 [ 0.0, 0.0 ]
Total (95% CI) 203 128 1.93 [ 0.34, 10.81 ]

Total events: 4 (Loop diuretics), 1 (Control)
0.01 0.1 1 10 100

Analysis 1.4. Comparison 1 Loop diuretics vs placebo, Outcome 4 Serum potassium.
Outcome: 4 Serum potassium
Study or subgroup Loop diuretic Control Mean Difference Mean Difference

1 Cicletanine 150mg
Bodak 1989 30 0 (0.49) 28 0.12 (0.45) -0.12 [ -0.36, 0.12 ]
Subtotal (95% CI) 30 28 -0.12 [ -0.36, 0.12 ]

2 Furosemide 40mg
Perola 1985 15 -0.1 (0.2) 15 0 (0) 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 15 15 0.0 [ 0.0, 0.0 ]

Total (95% CI) 45 43 -0.12 [ -0.36, 0.12 ]
-100 -50 0 50 100

Analysis 1.5. Comparison 1 Loop diuretics vs placebo, Outcome 5 Serum uric acid.
Outcome: 5 Serum uric acid
Study or subgroup Loop diuretic Control Mean Difference Weight Mean Difference
1 Cicletanine 150mg
Bodak 1989 30 -21 (71) 28 -14 (60) 70.8 % -7.00 [ -40.75, 26.75 ]
Subtotal (95% CI) 30 28 70.8 % -7.00 [ -40.75, 26.75 ]

2 Furosemide 40mg
Perola 1985 15 57 (81) 15 4 (65) 29.2 % 53.00 [ 0.44, 105.56 ]
Subtotal (95% CI) 15 15 29.2 % 53.00 [ 0.44, 105.56 ]

Total (95% CI) 45 43 100.0 % 10.52 [ -17.88, 38.92 ]
-100 -50 0 50 100

Analysis 1.6. Comparison 1 Loop diuretics vs placebo, Outcome 6 Serum creatinine.
Outcome: 6 Serum creatinine
1 Cicletanine 150mg
Bodak 1989 30 -10.4 (17.4) 28 -9.7 (17.3) 55.8 % -0.70 [ -9.63, 8.23 ]
Subtotal (95% CI) 30 28 55.8 % -0.70 [ -9.63, 8.23 ]

2 Furosemide 40 mg
Perola 1985 15 9 (15) 15 6 (13) 44.2 % 3.00 [ -7.05, 13.05 ]
Subtotal (95% CI) 15 15 44.2 % 3.00 [ -7.05, 13.05 ]

Total (95% CI) 45 43 100.0 % 0.93 [ -5.74, 7.61 ]
Test for subgroup differences: Chi2 = 0.29, df = 1 (P = 0.59), I2 =0.0%
-100 -50 0 50 100

Analysis 1.7. Comparison 1 Loop diuretics vs placebo, Outcome 7 Blood glucose.
Outcome: 7 Blood glucose
1 Cicletanine 150mg
Bodak 1989 30 0.02 (0.82) 28 0.03 (0.71) 40.3 % -0.01 [ -0.40, 0.38 ]
Subtotal (95% CI) 30 28 40.3 % -0.01 [ -0.40, 0.38 ]

2 Furosemide 40mg
Perola 1985 15 0.2 (0.4) 15 0.1 (0.5) 59.7 % 0.10 [ -0.22, 0.42 ]
Subtotal (95% CI) 15 15 59.7 % 0.10 [ -0.22, 0.42 ]

Total (95% CI) 45 43 100.0 % 0.06 [ -0.19, 0.31 ]
-100 -50 0 50 100

Analysis 1.8. Comparison 1 Loop diuretics vs placebo, Outcome 8 serum cholesterol.
Outcome: 8 serum cholesterol
1 Cicletanine 150mg
Bodak 1989 30 0.02 (1.35) 28 -0.15 (1.28) 51.1 % 0.17 [ -0.51, 0.85 ]
Subtotal (95% CI) 30 28 51.1 % 0.17 [ -0.51, 0.85 ]

2 Furosemide 40 mg
Perola 1985 15 0.18 (1.07) 15 -0.28 (0.85) 48.9 % 0.46 [ -0.23, 1.15 ]
Subtotal (95% CI) 15 15 48.9 % 0.46 [ -0.23, 1.15 ]

Total (95% CI) 45 43 100.0 % 0.31 [ -0.17, 0.80 ]
-100 -50 0 50 100

Analysis 1.9. Comparison 1 Loop diuretics vs placebo, Outcome 9 Serum triglyceride.
Outcome: 9 Serum triglyceride
1 Cicletanine 150mg
Bodak 1989 30 -0.04 (0.57) 28 0.12 (0.88) 72.6 % -0.16 [ -0.54, 0.22 ]
Subtotal (95% CI) 30 28 72.6 % -0.16 [ -0.54, 0.22 ]

2 Furosemide 40 mg
Perola 1985 15 0.3 (1.02) 15 -0.06 (0.7) 27.4 % 0.36 [ -0.27, 0.99 ]
Subtotal (95% CI) 15 15 27.4 % 0.36 [ -0.27, 0.99 ]

Total (95% CI) 45 43 100.0 % -0.02 [ -0.35, 0.31 ]
-100 -50 0 50 100

APPENDICES
Appendix 1. Search Strategy

1. randomized controlled trial$.mp
2. randomized controlled trial.pt
3. controlled clinical trial.pt
4. controlled clinical trial$.mp
5. random allocation.mp
6. exp random allocation/
7. exp double-blind method/
8. double-blind.mp
9. exp single-blind method/
10. single-blind.mp
11. or/1-10
12. (animals not human).sh
13. 11 not 12
14. clinical trial$.mp
15. clinical trial.pt
16. (clin$ adj25 trial$).mp
17. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).mp
18. random$.mp
19. exp research design/
20. research design.mp
21. or/14-20
22. 21 not 12
23. 13 or 22
24. comparative stud$.mp
25. evaluation stud$.mp
26. follow up stud$.mp
27. prospective stud$.mp
28. (control$ or prospective$ or volunteer$).mp
29. or/24-28
30. 29 not 12
31. 23 or 30
32. blood pressure.mp
33. exp hypertension/
34. hypertens$.mp
35. exp blood pressure/
36. or/32-35
37. 31 and 36
38. loop diuretics.mp. or exp Loop Diuretic Agent/
39. Furosemide Plus Triamterene/ or exp Furosemide/ or furosemide.mp
40. Bumetanide.mp. or exp Bumetanide/
41. Ethacrynic acid.mp. or exp Etacrynic Acid/
42. muzolimine.mp. or exp Muzolimine/
43. torasemide.mp. or exp Torasemide/
44. Piretanide/ or Pirentanide.mp or exp. Piretanide/
45. azosemide.mp. or exp Azosemide/
46. Ticrynafen.mp. or exp Tienilic Acid/
47. exp Tripamide/
48. Benzoic Acid Derivative/ or Phenoxybenzoic acid.mp.
49. Indacrinone.mp. or exp Indacrinone/
50. etozolin.mp. or exp Etozolin/
51. ozolinone.mp. or exp Ozolinone/
52. cicletanine.mp. or exp Cicletanine/
53. tienilic acid.mp. or exp Tienilic Acid/
54. tizolemide/ or tizolemide.mp.
55. or/38-54
56. 37 and 55
HISTORY
Protocol first published: Issue 3, 2002
Review first published: Issue 4, 2009
11 August 2008 Amended Converted to new review format.
(Continued)
11 August 2008 Amended Search strategy includes Cochrane Central database. The search has been updated in Medline, Embase
and Central until June 30th 2008.
CONTRIBUTIONS OF AUTHORS
James Wright and Vijaya Musini formulated the idea for the review and developed the basis for the protocol.
Vijaya Musini designed the search strategy, undertook the search, screened search results, collected data for the review, screened retrieved
papers against eligibility criteria, appraised the risk of bias of papers, extracted data from papers, entered data into RevMan, analysed
and interpreted data, and wrote the review.
Ciprian Jauca was the second reviewer in identifying trials meeting inclusion criteria, translating two non-English studies (one in French
and one in German), assessing risk of bias of all included studies and performing data abstraction.
James Wright and Ken Bassett confirmed accuracy of data and were the third and fourth reviewers to settle any discrepancies in inclusion
criteria or data abstraction.
DECLARATIONS OF INTEREST
None.
SOURCES OF SUPPORT
Internal sources
• Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Canada.
External sources
• Canadian Institutes of Health Research, Canada.

grant to the Hypertension Review Group.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The search was updated until March 2009. To be able to maximize data inclusion, trials that reported data after 12 weeks were also
included in the meta-analysis.
INDEX TERMS
Medical Subject Headings (MeSH)

Antihypertensive Agents [∗ administration & dosage; adverse effects]; Blood Pressure [drug effects]; Dose-Response Relationship,
Drug; Hypertension [∗ drug therapy]; Randomized Controlled Trials as Topic; Sodium Potassium Chloride Symporter Inhibitors
[∗ administration & dosage; adverse effects]
MeSH check words

Humans

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Blood pressure lowering efficacy of loop diuretics for primary

Musini VM, Wright JM, Bassett K, Jauca CD

Blood pressure lowering efficacy of loop diuretics for primary

Vijaya M Musini1 , James M Wright1 , Ken Bassett1 , Ciprian D Jauca1

Editorial group: Cochrane Hypertension Group.

PLAIN LANGUAGE SUMMARY

Loop diuretics cause modest blood pressure lowering

BACKGROUND The bioavailability of loop diuretics differ with that of azosemide

Data extraction and management

Placebo control was compared to cicletanine 100 mg in one characteristics.

Systolic blood pressure

Diastolic blood pressure

Withdrawals due to adverse effects

ported data on 460 participants (242 treated with loop diuretics

Characteristics of included studies [ordered by study ID]

Methods Double blind prospective randomised placebo controlled study

Outcomes Systolic blood pressure, diastolic blood pressure

Notes Article in French translated by Ciprian Jauca.

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described in the publication.

Allocation concealment? Unclear Not described in the publication.

Blinding? Unclear Not described in the publication.

group, both due to serious adverse events).

Free of selective reporting? Yes All outcome measures were reported.

Free of other bias? Unclear Sponsorship or funding of this study and

Methods Double blind prospective randomised placebo controlled study

Participants 39 patients with mild to moderate hypertension

Interventions Cicletanine 100mg per day or placebo for 8 weeks duration

Outcomes Systolic blood pressure, diastolic blood pressure at end of treatment

Notes Article in German translated by Ciprian Jauca.

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described in the publication.

Allocation concealment? Yes “optically identical placebo was adminis-

Blinding? Unclear Not described in the publication.

Free of selective reporting? No Adverse events and biochemical markers

Free of other bias? Unclear Sponsorship or funding of this study and

Methods Double blind prospective randomised placebo controlled study

Notes Analysis was performed on an intention-to treat basis.

Withdrawal due to adverse events were reported placebo = 1 and piretanide = 1 (3 or 6

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described in the publication.

Allocation concealment? Unclear Not described in the publication.

Blinding? Yes “The regimens had identical appearance

Free of selective reporting? No All mentioned outcome measures in the

Free of other bias? Unclear Sponsorship or funding of this study and

Methods Double blind prospective randomised placebo controlled study

Interventions one of the ratios of 1 enantiomers of indacrinone namely

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described in the publication.

Allocation concealment? Unclear Not described in the publication.

Blinding? Unclear Not described in the publication.

Free of selective reporting? No “During the DB phase, if the DBP was

Free of other bias? No Industry funded study.

Interventions Etozolin 200mg once a day or placebo for 30 days

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described in the publication.

Allocation concealment? Unclear Not described in the publication.

Blinding? Unclear Not described in the publication.

Free of other bias? Unclear Sponsorship or funding of this study and

Methods Double blind prospective randomised placebo cross over study

Interventions Furosemide 40mg + triameterene 50mg; Furosemide 40mg; triameterene 50mg; or

Notes The standing SBP and DBP were used in analysis.

Item Authors’ judgement Description