Among patients with advanced chronic kidney disease and poorly controlled hypertension, can chlorthalidone therapy improve blood-pressure control?
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What’s the Evidence for the Use of Thiazide Diuretics in Patients with Advanced Chronic Kidney Disease?
Hey everybody, welcome back! We saw this paper and just couldn’t resist. We figured; some bread-and-butter primary care evidenced base medicine is something anyone can enjoy.
So, this week we’re going to discuss if thiazide diuretics could be a useful tool for the treatment of hypertension in patients with advanced chronic kidney disease. We know, we know…. historically we’ve thought that these drugs just don’t work in patients with severely impaired kidney function. But new evidence is starting to suggest differently….
So, in this double blind, randomized, placebo-controlled trial of 160 adults with stage 4 chronic kidney disease, patients were randomized to either chlorthalidone or placebo. Randomization was stratified based on previous use of loop diuretics. Before we get ahead of ourselves, let’s look at this trial population as its particularly important here….
Patients had to have a GFR between 15 to 30 and have uncontrolled hypertension, defined as 24-hour ambulatory blood pressure above 130 over 80 while on at least one blood pressure medication. Patients had to be on an ACE, ARB or a beta blocker at the time of randomization.
They excluded those on high doses of loop diuretics, defined as over 200 mg per day of furosemide or equivalent. Patients with 24-hour ambulatory blood pressure above 160 over 100 or expected to go on dialysis within 3 months were also excluded.
Sooo.. here’s how the trial worked. Prior to starting therapy, all patients had their current blood pressure regimens modified to a standardized drug from each class. For example, everyone on any ACE inhibitor would be given an equivalent dose of lisinopril to take during the trial. The same was done for all other blood pressure medications. After stabilizing on their new regimen, patients were started on 12 and a half mg of chlorthalidone or placebo daily. Blood pressure was measured by a 24-hour ambulatory monitor. If pressures were above 135 over 85 after 4 weeks, the dose could be doubled to 25 mg daily. They could titrate again after another 4 weeks to a maximum of 50 mg daily if necessary.
Before we get to the results, we want to point out on BIG thing…. 60% of patients in this trial were on loop diuretics! So let’s keep an eye out for adverse effects of this combination.
After 12 weeks of therapy, final results were assessed. The primary outcome of 24-hour ambulatory systolic blood pressure was decreased from baseline over 10 points in the chlorthalidone group compared to placebo and this was statistically significant. For reference, the baseline systolic pressures were around 140 in both groups. The diastolic pressures also went down about 4 points compared to placebo and this was also significant. Of the secondary outcomes, the most interesting was a 50% decrease from baseline compared to placebo in the urinary albumin to creatinine ratio.
Let’s also look at safety though. I don’t know about you, but I think a lot of clinicians think twice about adding a thiazide diuretic on top of a loop diuretic, especially in those with stage 4 chronic kidney disease. Given that the majority of patients in this study were already on loop diuretics, we can learn more about this combination. There was quite a bit more acute kidney injury in the chlorthalidone group….41% of patients vs only 13% with the placebo! While most of these events occurred in those taking loop diuretics, only one patient discontinued the drug due to this as most of these events were reversible. There was also more dizziness, hyperuricemia, hyperglycemia, hypomagnesemia and hyponatremia in the chlorthalidone group.
So, the question here really becomes, do the benefits of chlorthalidone outweigh the risks in this specific population? It’s a tough question, and a lot of clinicians might instead opt for hydrochlorothiazide as evidence has shown its associated with fewer metabolic abnormalities. The problem is the best evidence for thiazide diuretics decreasing cardiovascular outcomes comes from using chlorthalidone in studies such as ALLHAT. In fact, the literature for hydrochlorothiazide is somewhat disappointing. The ACCOMPLISH trial used it as part of a combination regimen, and found it was inferior to a different combo therapy in preventing cardiovascular events. Most think that chlorthalidone is better than hydrochlorothiazide at lowering blood pressure due to its longer duration of action and thus better nighttime control of blood pressure. But the tradeoff is the metabolic abnormalities.
So back to the issue at hand though… Should we start using chlorthalidone more often in those with CKD? Well, it’s a very patient specific question. Those with poorly controlled diabetes or gout might not do well with the increased glucose or uric acid levels. If already on a loop diuretic, keeping in mind the potential for kidney injury and dizziness due to increased fluid loss is also important. And don’t forget electrolyte disturbances too. All this being said, uncontrolled blood pressure is bad too. Patients in this trial were on about 3 and a half medications already for blood pressure and finally chlorthalidone seemed to help. But keep in mind, patients were only followed for 12 weeks and major outcomes like death or cardiovascular events weren’t a part of this trial, so overall it’s not a complete home run either.
But in the end, as always there are risks and benefits and it’s up to you guys to help work through those with patients to figure out what’s right for them. We just do our best to provide you with the evidence.
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Relevants sources:
Dhalla IA, Gomes T, Yao Z, Nagge J, Persaud N, Hellings C, Mamdani MM, Juurlink DN. Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: a population-based cohort study. Ann Intern Med. 2013 Mar 19;158(6):447–55.
Hripcsak G, Suchard MA, Shea S, Chen R, You SC, Pratt N, Madigan D, Krumholz HM, Ryan PB, Schuemie MJ. Comparison of Cardiovascular and Safety Outcomes of Chlorthalidone vs Hydrochlorothiazide to Treat Hypertension. JAMA Intern Med. 2020 Apr 1;180(4):542–551.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981–97. Erratum in: JAMA 2003 Jan 8;289(2):178. Erratum in: JAMA. 2004 May 12;291(18):2196.
Ernst ME, Carter BL, Basile JN. All thiazide-like diuretics are not chlorthalidone: putting the ACCOMPLISH study into perspective. J Clin Hypertens (Greenwich). 2009 Jan;11(1):5–10.
