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Twelve weeks of treatment with the thiazide diuretic chlorthalidone led to about an average 10 mmHg cut in systolic blood pressure in patients with treatment-resistant hypertension and advanced stage 4 chronic kidney disease in a randomized study with 160 patients.

Results from the CLICK trial have disproved conventional wisdom that thiazide diuretics are ineffective in patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2.

The findings also appear to cement a role for chlorthalidone as a new option for reducing systolic blood pressure in patients with stage 4 chronic kidney disease (CKD) (eGFR 15-29 mL/min/1.73m2) who remain hypertensive despite treatment with several antihypertensive agents.

“We were fooled that thiazide diuretics don’t work in patients with advanced CKD, but chlorthalidone is very good at lowering blood pressure on top of three or four other medications. It lowered systolic blood pressure by an average of about 10 mmHg, a very good result,” said Rajiv Agarwal, MD, who presented the results during virtual Kidney Week 2021, sponsored by the American Society of Nephrology.

The results were simultaneously published in The New England Journal of Medicine.

“Treatment of refractory hypertension in patients with CKD is very challenging. I think chlorthalidone will be adopted into practice based on these data,” commented F. Perry Wilson, MD, prescription drugs fluoxetine a nephrologist at Yale University in New Haven, Connecticut.

“You don’t always need a phase 3 study to start to change practice,” Wilson said, noting that the CLICK trial randomized just 160 patients and used surrogate endpoints such as systolic blood pressure reduction and impact on urinary albumin to creatinine ratio (UACR) to assess efficacy.

Agarwal agreed that the CLICK trial is probably akin to a phase 2 study, but also highlighted chlorthalidone’s highly practical status. 

Treatment Costs About 5 Cents a Day

“The real promise is that you can treat patients for about 5 cents a day,” said Agarwal, a nephrologist and professor at Indiana University in Indianapolis.

This bargain price is a function of chlorthalidone’s long-standing generic status since it first received US regulatory approval about six decades ago. That also means clinicians are “very comfortable” prescribing chlorthalidone, said Wilson.

Tejas Desai, MD, a nephrologist with the US Department of Veterans Affairs, Charlotte, North Carolina, agrees. “Because chlorthalidone is cheap, easily available, and both the incidence and prevalence of CKD stage 4 are high, the outcomes of this trial will have broad and immediate applicability, he told Medscape Medical News.  

Paul K. Whelton, MD, professor at Tulane University in New Orleans, Louisiana, and chair of the panel that wrote the 2017 American College of Cardiology/American Heart Association hypertension-treatment guideline, concurred: “Chlorthalidone is a good drug, and the best documented of any diuretic for lowering blood pressure.”

“An 11-mmHg reduction in blood pressure is very impressive” in patients who are “a classic group with resistant hypertension,” Whelton said in an interview.

Whelton cautioned that the evidence did come from a short, 12-week study, but “it’s better than any other evidence we have” for efficacy of an added antihypertensive drug in the types of patients studied.

CLICK enrolled patients already on an average of 3.4 blood pressure medications a day, and despite that, they had an average systolic blood pressure of about 140 mmHg, roughly 10 mmHg above their goal.

Halving Proteinuria Compared With Controls Is the Big Finding

Another facet of chlorthalidone’s benefit was that 12 weeks of treatment cut average UACR by 50 percentage points among the 81 chlorthalidone-treated patients compared with the 79 patients randomized to placebo.

This effect led Agarwal and colleagues to suggest that treatment with chlorthalidone might produce kidney and cardiovascular protection, a hypothesis that Wilson called “plausible.”

Chlorthalidone’s effect on proteinuria “is the big finding,” Wilson said in an interview.

A 50% reduction “is really important” because proteinuria is a major risk factor for progressive CKD.

Not an Agent to Prescribe and Forget, but Few Safety Surprises

Chlorthalidone’s safety profile in CLICK also “seems acceptable” and was “not surprising,” said Wilson, while Whelton called the adverse events of treatment “nothing dramatic.”

Agarwal acknowledged that some clinicians may be hesitant about prescribing chlorthalidone, but he encouraged them to embrace it, albeit with caution.

Chlorthalidone “is not an agent to prescribe and forget. It’s a very potent drug and you need to monitor patients for complications,” especially patients already on a loop diuretic, Agarwal said during a Kidney Week virtual press briefing.

The biggest concerns center on fluctuations in serum levels of some electrolytes and other components.  

In CLICK, 10% of patients on chlorthalidone developed hypokalemia compared with no cases among controls; 23% developed hypermagnesemia compared with 16% of controls; and 20% of those on chlorthalidone developed hyperuricemia compared with 9% of controls.

CLICK ran at three medical centers in Indianapolis in 2016-2021. Of the 160 randomized patients, 140 (88%) completed the 12-week treatment course. The study protocol called for gradual up-titration of chlorthalidone as needed during the treatment phase with a starting dose of 12.5-mg once daily. The average dose patients received at 12 weeks was 23 mg once daily.

CLICK received no commercial funding. Agarwal has reported being a consultant for several drug companies. Wilson and Desai are contributors to Medscape and reported no other relevant financial relationships. Whelton has reported no relevant financial relationships.

N Engl J Med. Published online November 5, 2021. Abstract

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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