Resistant hypertension increases the risk for cardiovascular events and end-stage kidney disease.1 Yet few therapies exist for people with CKD. In a double-blind randomized controlled trial, Chlorthalidone in Chronic Kidney Disease (CLICK, NCT02841280), we demonstrated that chlorthalidone substantially reduced BP in stage 4 CKD2. Here, we examined the drug’s safety and efficacy in people with resistant hypertension and stage 4 CKD with or without a loop diuretic, and whether chlorthalidone reduces albuminuria.
After approval by an institutional review committee and obtaining informed consent, patients with stage 4 CKD were randomly assigned to either placebo or chlorthalidone 12.5 mg daily in a 1:1 ratio stratified by prior loop diuretic use. The primary endpoint was the change in 24-hour systolic ambulatory blood pressure (BP) from baseline to 12 weeks. Of the 160 randomized patients, 113 (71%) had resistant hypertension, defined as having poorly controlled 24-hour ambulatory BP monitoring receiving ≥3 antihypertensive medications. Among the 90 subjects (80%) on loop diuretics, 42 (78%) were in the placebo group and 49 (83%) in the chlorthalidone group. Patients on average took 4.1 antihypertensive agents (SD=1.1). K-sparing diuretics were used in 14 (12%) patients (spironolactone 13, amiloride 1), of which 9 (17%) were assigned placebo and 5 (8%) chlorthalidone. Mean 24-hour ambulatory BP at randomization was 140.7 (8.4)/71.8(9.8) mmHg in the placebo group and 142.7 (7.9)/73.3 (10.5) mmHg in the chlorthalidone group. The statistical approach used in the current analysis mirrored that of the main analysis of the CLICK trial. All supporting data are available within the article and the original publication.2
The adjusted change from baseline to 12 weeks in 24-hour systolic BP was 1.3 mmHg (95% CI: [−2.3, 5.0]) in the placebo group (n=54) and −12.6 mmHg (95% CI: [−16.4, −8.8]) in the chlorthalidone group (n=59). The between-group difference was −13.9 mmHg (95% CI, [−19.4, −8.4]; p<0.0001) (Table 1). Improvement in clinic blood pressure occurred rapidly within 4 weeks and was sustained over the 12 weeks of the trial. Seated clinic systolic BP was reduced by 13.2, 14.5, and 16.2 mmHg with chlorthalidone in 4, 8, and 12 weeks. Thus, 81% of the treatment effect was evident with the lowest dose of chlorthalidone (12.5 mg per day) in 4 weeks. Two weeks after stopping the drug, 76% of the treatment effect persisted, suggesting that the treatment effect is long-acting. Prior diuretic use did not modify the primary endpoint (change from baseline −14.4 mmHg (95% CI: [−25.5, −3.3]) in non-loop diuretic users (n=23) vs −14.0 mmHg (95%CI: [−19.6, −8.3]) in loop diuretic users (n=90).
Table 1:
Ambulatory blood pressure at randomization and at 12 weeks (end of assigned regimen)
| Variable | Placebo (n=54) | Chlorthalidone (n = 59) | Treatment Effect (95% CI) |
|---|---|---|---|
| Systolic BP (mmHg) | |||
| 24-hour BP (mmHg) | |||
| At randomization--mean (SD) | 140.7 (8.4) | 142.7 (7.9) | |
| Adjusted change at 12 wk (95% CI) | 1.3 (−2.3 to 5.0) | −12.6 (−16.4 to −8.8) | −13.9 (−19.4 to −8.4) |
| Daytime BP --mmHg | |||
| At randomization--mean (SD) | 142.9 (8.9) | 145 (8.4) | |
| Adjusted change at 12 wk (95% CI) | 1.4 (−2.4 to 5.3) | −13.1 (−17.1 to −9.1) | −14.5 (−20.3 to −8.8) |
| Nighttime BP --mmHg | |||
| At randomization--mean (SD) | 136.4 (10.7) | 138.7 (9.8) | |
| Adjusted change at 12 wk (95% CI) | 1.5 (−2.8 to 5.8) | −10.4 (−14.5 to −6.3) | −11.9 (−17.7 to −6.1) |
| Diastolic Blood Pressure | |||
| 24-hour BP (mmHg) | |||
| At randomization--mean (SD) | 71.8 (9.8) | 73.3 (10.5) | |
| Adjusted change at 12 wk (95% CI) | 0.4 (−1.8 to 2.6) | −5.4 (−7.7 to −3.2) | −5.8 (−9.0 to −2.6) |
| Daytime BP --mmHg | |||
| At randomization--mean (SD) | 73.6 (9.6) | 75.8 (10.9) | |
| Adjusted change at 12 wk (95% CI) | 0.5 (−1.9 to 2.8) | −6.2 (−8.6 to −3.9) | −6.7 (−10.2 to −3.2) |
| Nighttime BP --mmHg | |||
| At randomization--mean (SD) | 68.2 (11.1) | 69.1 (11) | |
| Adjusted change at 12 wk (95% CI) | −0.1 (−2.7 to 2.5) | −3.7 (−6.2 to −1.3) | −3.7 (−7.2 to −0.1) |
| Patients with a nocturnal dip in systolic BP | |||
| At randomization -- no./total no. (%) | 13/54 (24%) | 10/58 (17%) | |
| At 12 wk -- no./total no. (%) | 11/49 (22%) | 10/48 (21%) | 0.64 (0.22 to 1.86) |
Data at randomization are means and (SD). Data on final 24h and daytime ambulatory BP were imputed for 13 patients (4 placebo, 9 chlorthalidone) who had missing values for ambulatory BP. Data on nighttime BP was missing in 18 patients (6 placebo, 12 chlorthalidone) of which 17 were imputed because 1 was missing nighttime BP at baseline. The treatment effect is expressed as the mean difference with a 95% CI for all the variables except nocturnal dip in systolic BP for which the effect is expressed as an odds ratio with a 95% CI. A nocturnal dip in systolic BP indicates a decrease of more than 10% from the daytime value.
Compared to placebo, the urine albumin-to-creatinine ratio in the chlorthalidone group at 12 weeks was −54% lower (95% CI: [−65%, −40%]). Two weeks after the assigned regimen was discontinued, the percent change in urinary albumin-to-creatinine ratio remained at −33% in the chlorthalidone group and −9% in the placebo group (between-group difference, −33% points; 95% CI: [−51%, −8%]).
Following randomization, hypokalemia (13.6% vs 0%), reversible increases in serum creatinine (51.8% vs 14.8%), hyperglycemia (18.6% vs 5.6%), dizziness (27.1% vs 20.4%), orthostatic hypotension (11.9% vs 3.7%), and hyperuricemia (23.7% vs 11.1%) occurred more frequently in the chlorthalidone group. From the time of randomization to the end of the trial, increases in the serum creatinine level greater than 25% from baseline were strongly influenced by baseline loop diuretic use. The odds ratio associated with a 25% or greater increase in creatinine was 1.1 (95% CI: [0.1, 18.3]) among patients not on loop diuretics at baseline as compared to 8.5 (95% CI: [2.7, 29.2]) among those that were. But the difference did not reach the nominal level of statistical significance (p=0.078 for the treatment×loop interaction).
In the general population, spironolactone is the standard of care for treating resistant hypertension.3 However, in a meta-analysis, spironolactone doubled the risk of hyperkalemia and quintupled the risk of gynecomastia compared to ACEi or ARB (or both).4 In a randomized trial of patients with resistant hypertension and eGFR between 25 and ≤45 mL/min/1.73m2, patiromer, a potassium binding polymer, enabled the use of spironolactone.5 But even with patiromer, approximately 1/3 of patients administered spironolactone had experienced hyperkalemia (K ≥5.5 mEq/L) over 12 weeks. Given the difficulty of using spironolactone, we believe that chlorthalidone is an attractive alternative to treat resistant hypertension in advanced CKD. An important advantage of chlorthalidone over spironolactone is that the risk of hyperkalemia is essentially nonexistent. However, hypokalemia becomes a concern. Serum creatinine, blood pressure, blood glucose, and serum sodium would require careful monitoring.
In summary, data from patients with resistant hypertension in CLICK demonstrated that chlorthalidone effectively reduced both systolic and diastolic 24h ambulatory BP with stage 4 CKD, independent of loop diuretic use. Chlorthalidone represents an attractive option for managing resistant hypertension in patients with advanced CKD.
Disclosures
RA reports personal fees and nonfinancial support from Bayer Healthcare Pharmaceuticals Inc. Akebia Therapeutics, Boehringer Ingelheim, Eli Lilly, Vifor Pharma; he has received personal fees from Lexicon, and Reata; he is a member of data safety monitoring committees for Vertex and Chinook; a member of steering committees of randomized trials for Akebia Therapeutics, Bayer, and Relypsa; and a member of adjudication committees for Bayer; he has served as Associate Editor of the American Journal of Nephrology and Nephrology Dialysis and Transplantation, and has been an author for UpToDate; and he has received research grants from the NIH and the U.S. Veterans Administration.
ADS is an endpoint adjudication consultant for George Clinical.
WT has nothing to disclose.
Funding sources:
Supported by National Heart Lung and Blood Institute: R01 HL126903 and Indiana Institute for Medical Research.
References
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