Journal 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 • • • • • 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 8000 7000 6000 5000 4000 3000 2000 1000 0 Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 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 8000 8000 7000 7000 6000 6000 5000 5000 4000 4000 3000 3000 2000 2000 1000 1000 0 0 Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Secondary outcomes 8000 8000 7000 7000 6000 6000 5000 5000 4000 4000 3000 3000 2000 2000 1000 1000 0 0 Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 “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 Simple PowerPoint Presentation Simple PowerPoint Presentation Simple PowerPoint Presentation “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