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club
Chlorthalidone for Hypertension in Advanced CKD
Warakorn ChiaoAkasayan, 6th yr Pharm.D Mahasarakham university
2021 Impact factor
N Engl J Med
2021;385:2507-19.
DOI: 10.1056/NEJMoa211073
91.25
From the Division of Nephrology, De- partment of Medicine (R.A., A.D.S., A.E.C., M.B.-F.,
J.H.D.), and the Depart- ment of Biostatistics and Health Data Science, Richard M. Fairbanks
School of Public Health (F.O., W.T.), Indiana Uni- versity School of Medicine, Richard L.
Roudebush Veterans Affairs Medical Center (R.A., A.D.S., A.E.C., M.B.-F., J.H.D.), and Indiana
University Center for Aging Research, Regenstrief Institute (W.T.) — all in Indianapolis. Dr.
Agarwal can be contacted at ragarwal@iu.edu or at Richard L. Roudebush Veterans Affairs
Medical Center, 1481 W. 10th St., 111N, Indianapolis, IN 46202. This article was published on
November 5, 2021, and last updated on December 30, 2021, at NEJM.org.
N ENGL
J MED 385;27
NEJM.ORG
DEC 30, 2021
Introduction
Hypertension is often poorly controlled in CKD.
Chlorthalidone reduces vascular morbidity & mortality
Efficacy and safety among advanced CKD
remain poorly understood.
Chlorthalidone would decrease the 24- hour
ambulatory systolic blood pressure
Chlorthalidone would reduce the degree of
albuminuria over 12 weeks
Methods
S T U D Y
D E S I G N
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The study was approved by
the Institutional Review Board
of Indiana University
and the Research and
Development Committee
Single-institution
Multicenter
Placebo-controlled
Double-blind
Randomized control trial
Portfolio Designed
The study is designed to test the hypothesis that CTD, when
added to the current regimen of antihypertensive drugs,
improves BP in patients with stage 4 CKD and uncontrolled
hypertension.
Participants
Inclusion
AGE
≥ 18 year
GFR
<30 mL/min/1.73 m2
but
≥15 mL/min/1.73 m2
Antihypertensives
Least 1 either for 12 wk
ACEis or ARBs
Or
Beta blockers
if these are contraindicated
Blood pressure
either ≥130 mm Hg systolic
≥80 mm Hg diastolic
by 24-h ABP monitoring
Exclusion criteria
procedures
Assessments
PRIMARY
OUTCOME
24-hour ABP
from baseline
to 12 weeks
Secondary outcomes
Albumin to creatinine ratio
Plasma renin & aldosterone
NT-proBNP
Total body volume
All analyses were based on ITT
Mixed model: one-way, two-way and three-way
Two-sided t-test at 0.05 significance was used
to estimate that least 80% power to detect
6 mmHg change in BP
Sensitivity imputation analyses were
performed to validate the trial findings
Statistical
analysis
RESULTS
Primary outcome
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At 4 weeks after the initiation of the assigned regimen,
the chlorthalidone group had a decrease in the seated
clinic systolic blood pressure of 9.2 mm Hg, and the
placebo group had an increase of 2.7 mm Hg (betweengroup difference, −11.9 mm Hg; 95% CI, −17.1 to −6.7).
The change from baseline was −10.6 mm Hg in the
chlorthalidone group and 5.1 mm Hg in the placebo
group at 8 weeks (between-group difference, −15.7 mm
Hg; 95% CI, −21.0 to −10.5) and −12.6 mm Hg and 2.4
mm Hg, respectively, at 12 weeks (between- group
difference, −15.1 mm Hg; 95% CI, −19.4 to −10.7). Two
weeks after the assigned regimen was discontinued,
the change from baseline in the seated clinic systolic
blood pressure was −7.0 mm Hg in the chlorthalidone
group and 5.3 mm Hg in the placebo group (betweengroup difference, −12.3 mm Hg; 95% CI, −17.5 to −7.2).
Similar changes in blood pressure were observed in the
home blood-pressure recordings
Treatment effect by pre-specified
subgroups. For each subgroup,
there was a reduction in systolic
24h ambulatory blood pressure.
Data reported are those for
complete case analysis.
Secondary outcomes
“The reduction in the degree of albuminuria in the chlorthalidone may be explained by a hemodynamic effect
or a diuretic-induced potentiation of antialbuminuric effects of renin–angiotensin system”
Secondary outcomes
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Secondary outcomes
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“Reductions in body weight, body volume, and NT-proBNP levels and increases in plasma renin and
aldosterone suggest that the mechanism of blood pressure reduction is consistent with the changes in
effective arterial blood volume over time”
Adverse outcomes
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“The reversible changes in the estimated GFR that occurred in the chlorthalidone group were
probably due to better blood pressure control, but the estimated GFR returned to approximately
the baseline value, which suggests the additional involvement of tubuloglomerular feedback.”
Follow-up
Observational follow-up study
Over the course of the observational
follow-up period of up to 3 years, which started
2 weeks after the assigned regimen was
discontinued, 49 had a decrease in the
estimated GFR to below 10 ml per minute per
1.73 m2, underwent long-term dialysis,
or died. The hazard ratio for a decrease in the
estimated GFR to below 10 ml per minute per
1.73 m2, long-term dialysis, or death, with
adjustment for use of loop diuretics at baseline,
was 0.63 (95% CI, 0.36 to 1.12)
DISCUSSION
Limitations
36 / 160
Asian
Hispanic
Female
22.5%
2%
1%
N = 160
CKD stage IV
Strengths
RCT
Double blinded in 2021
High percentage 24-h
ABPM completed
01
University hospital
General hospital
05
02
04
03
3 distinct practices
Health administration hospital
Conclusion
Among patients with advanced chronic
kidney disease and poorly controlled
hyper-tension, chlorthalidone therapy
improved blood-pressure control at 12
weeks as compared with placebo
Funded by the National Heart, Lung, and Blood Institute
and the Indiana Institute of Medical Research; CLICK ClinicalTrials.gov number, NCT02841280.
Literature
EVALUATION
1 Did the trial address a clearly focused issue?
( / ) Yes ( ) No ( ) Can’t tell
2 Was the assignment of patients to treatments randomized?
( / ) Yes ( ) No ( ) Can’t tell
3 Were all of the patients who entered the trial properly
accounted for at its conclusion?
( / ) Yes ( ) No ( ) Can’t tell
4 Were patients, health workers and study personnel
‘blind’ to treatment?
( / ) Yes ( ) No ( ) Can’t tell
5 Were the groups similar at the start of the trial?
( ) Yes ( / ) No ( ) Can’t tell
6 Aside from the experimental intervention
were the groups treated equally?
( ) Yes ( / ) No ( ) Can’t tell
How large was the treatment effect?
( / ) Yes ( ) No ( ) Can’t tell
How precise was the estimate of the treatment effect?
( / ) Yes ( ) No ( ) Can’t tell
Can the results be applied to the local population, or in
your context?
( / ) Yes ( ) No ( ) Can’t tell
Were all clinically important outcomes considered?
( / ) Yes ( ) No ( ) Can’t tell
Are the benefits worth the harms and costs?
( / ) Yes ( ) No ( ) Can’t tell
What are the
result ?
Will the
result help
locally ?
Natural
Thank You
AW E S O M E
PRESENTATION
Appendix