Chlorthalidone Versus Hydrochlorothiazide – A Comparison

Chlorthalidone and hydrochlorothiazide (podcast) are both thiazide diuretics. They are primarily used in the management of hypertension and occasionally for the management of edema. Hypokalemia, frequent urination, and risk for dehydration are all common adverse effects of both of these agents. The drug interaction profiles’ (like this one with lithium) are very similar as well. When comparing chlorthalidone versus hydrochlorothiazide, is there really a difference? If so, which one should you use?

Let’s dig a little deeper into this comparison. The guidelines from 2017 prefer chlorthalidone due to the longer half-life of the drug as well as the proven reduction of cardiovascular events (CVE). Where did this come from? In 2011, there was a trial done by Dorsch et al that demonstrated a reduction in CVE. Quoting the 2017 ACC/AHA guidelines: “Chlorthalidone is preferred based on prolonged half-life and proven trial reduction of CVD.” In addition, the ALLHAT trial used chlorthalidone and found a reduction in all cardiovascular events.

The half-life of hydrochlorothiazide ranges from 6-to 15 hours while the half-life for chlorthalidone ranges from 40-to 60 hours. Both are typically used once daily for hypertension but on rare occasions, I have seen hydrochlorothiazide dosed twice daily in practice. The biggest concern of using hydrochlorothiazide twice daily is patient inconvenience. In my experience, these patients are more likely to experience bothersome frequent urination at night if we dose hydrochlorothiazide twice daily.

What advantage does hydrochlorothiazide have versus chlorthalidone? Prior to the newer evidence discussed below, the two most common advantages of hydrochlorothiazide that I have heard cited are prescriber comfort and cost. These aren’t incredibly convincing arguments as the cost difference is not dramatic and prescriber comfort shouldn’t really be a reasonable defense in using hydrochlorothiazide. Another potential benefit of hydrochlorothiazide is that it comes in more drug combinations than chlorthalidone. This can improve adherence which can obviously be a good thing for our patients.

Chlorthalidone Versus Hydrochlorothiazide – New Evidence

Chlorthalidone is better. The guidelines tell us that. This is an open and shut case, correct? The debate of whether to use chlorthalidone versus hydrochlorothiazide rages on with evidence following the release of a clinical trial in 2020. Hripcsak et al performed a cohort study of over 700,000 individuals and no cardiovascular benefit was noted with chlorthalidone compared to hydrochlorothiazide.

Is that all? No, it’s not. Hripcsak et al also found that chlorthalidone had a higher incidence of adverse effects compared to hydrochlorothiazide. Hypokalemia, hyponatremia, and acute renal failure were all higher in the chlorthalidone group.

Comparing Chlorthalidone to HCTZ – What Do I Think?

Prior to this newer evidence, I have never been a strong believer in transitioning patients from hydrochlorothiazide to chlorthalidone if blood pressure was well managed and the patient was tolerating hydrochlorothiazide. Prior to this new evidence, if I was given a new patient, it was reasonable to utilize chlorthalidone over hydrochlorothiazide based on the guidelines and supporting evidence.

After this newer evidence, I’m definitely comfortable with recommending hydrochlorothiazide. I don’t like adding additional risks for adverse effects in many of the geriatric patients I work with so I will probably steer clear of chlorthalidone in most situations. As always, you need to look at the entire clinical situation of the patient prior to making a decision. Will I recommend switching patients off of chlorthalidone in favor of hydrochlorothiazide? That’s probably unlikely unless they are not tolerating chlorthalidone or there is a greater risk for acute renal failure or electrolyte imbalances.

Please feel free to comment below if you have an opinion on chlorthalidone versus hydrochlorothiazide!

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Written By Eric Christianson

May 15, 2022

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