chlorthalidone vs hctz

Another study came out with a bit of fanfare in the medical community, comparing the cardiovascular and safety outcomes in people on chlorthalidone vs hydrochlorothiazide (HCTZ) for hypertension, though I don’t think that this is a very useful study (see htn chlorthal vs hctz no diff jamaintmed2020 in dropbox, or doi:10.1001/jamainternmed.2019.7454)

Details:
-- a large network of databases of observational comparative cohort studies (LEGEND: Large-Scale Evidence Generation and Evaluation in a Network of Databases), using large-scale propensity score stratification, accessed data from 2001-2019
-- they compared the outcomes for those patients newly put on chlorthalidone vs hydrochlorothiazide:
    -- excluding those who had any known prior exposure to any hypertensive therapy, or had initiated another antihypertensive within 7 days after starting one of these diuretics
    -- including those initiating another antihypertensive after 7 days
-- primary outcomes assessed were: acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite of cardiovascular disease outcomes including these + cardiac death. Also 51 safety outcomes were measured
-- 730,225 individuals qualified for the analysis: 693,337 were prescribed hydrochlorothiazide; 36,918 were prescribed chlorthalidone
    -- overall 450,100 women (62%), mean age 51.5 years
    -- hyperlipidemia 26%, obesity 11%, osteoarthritis 11%, heart disease 7%, heart failure 0.3%, renal impairment 1%, depression 8%. [Overall quite a healthy and happy group]

Results:
-- hydrochlorothiazide: 3089 composite cardiovascular events
-- chlorthalidone: 149 composite cardivascular events
    -- no significant difference was found for MI, hospitalization for heart failure, or stroke. And this was independent of baseline blood pressure values
-- but, chlorthalidone was associated with significantly higher risk of:
    -- hypokalemia, almost 3 times the risk, HR 2.72 (2.38-3.12)
    -- hyponatremia, 31% increased risk, HR 1.31 (1.16-1.47)
    -- acute renal failure, 37% increased risk, HR 1.37 (1.15-1.63)
    -- chronic kidney disease, 24% increased risk, HR 1.24 (1.09-1.42)
    -- diabetes, 21% increased risk, HR 1.21 (1.12-1.30) [this increased rate of diabetes may be related to the hypokalemia, which impairs insulin release]
    -- but 37% lower risk of abnormal weight gain, HR 0.73 (0.61-0.86)

Commentary:
--international guidelines (including the US) over the past several years have promoted chlorthalidone over HCTZ (see below)
--one general concern with chlorthalidone is the well-documented hypokalemia. Small studies have suggested that it is not much different from HCTZ, on a milligrams per milligram basis, but larger studies have suggested that half the dose of chlorthalidone has a similar effect to full dose HCTZ. The current study found more hypokalemia even with half dose chlorthalidone

--there were several issues in this study that undercut its real utility:
    -- we do not know what the achieved blood pressure was in the different groups of patients, which could certainly have a large effect on cardiovascular outcomes.
    -- we do not know anything about other blood pressure medications added to the diuretics as soon as 7 days after the diuretic was initiated. We know neither which ones, their dosages, nor how many different medications were added, or the resulting blood pressure over time
    -- as an observational study, there was no consistency of prescribing patterns among different clinicians. And, there may have been big differences. For example, several studies evaluating diuretics evolved during the study period when this study was done, leading to the strong recommendation by NICE in the UK in 2011 to avoid using hydrochlorothiazide, but preferentially use chlorthalidone. So, for example, clinicians who were more attuned to the evolving medical literature may have preferentially used more chlorthalidone, and also perhaps a different selection of antihypertensives that the literature supported more (e.g. amlodipine). So, there may have been very different prescribing patterns for diuretics based on clinicians’ academic orientation (and how up-to-date they were), leading to a non-randomized approach and potential biases in treating patients overall
    -- many clinicians are prescribing the lower dose HCTZ of 12.5mg. this was not evaluated in this study: in the largest database included in this study, they restricted the analysis to HCTZ 25 mg and compared that to chlorthalidone 12.5 mg. though the blogs noted below do suggest that HCTZ 12.5mg is far inferior to chlorthalidone in terms of cardiovascular events, older studies suggest that higher doses of HCTZ may be more clinically effective (the lower dose of HCTZ may be okay in combo with other meds, such as ACE/ARB, but seems to be inferior as a single agent)
    -- and, unfortunatetly in the US, chlorthalidone is only available as 25mg tabs, and they are small. i have asked patients to cut them in 1/2, but this was difficult. But, when i sent out the blog below making this point about chlorthalidone, a physician reader responded to me that he had no problem cutting the pill in quarters and his blood pressure was just fine on 6.25mg/d....

http://gmodestmedblogs.blogspot.com/2016/04/chlorthalidone-is-better-than-hctz-for.html a study showing that chlorthalidone 6.25 mg per day has about twice the blood pressure lowering as compared to hydrochlorothiazide 12.5 mg. This blog also references other studies noting benefit of chlorthalidone. One major point is that clinic-based blood pressures tend to look good on hydrochlorothiazide 12.5mg, so the patient and clinician are happy with the med, but the 24 hour efficacy (the evaluation with the best correlation with future cardiovascular events) is far inferior to that of chlorthalidone. E.g. see http://gmodestmedblogs.blogspot.com/2018/04/ambulatory-blood-pressure-monitoring.html ; and

http://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html has the AHA hypertension guidelines, which prefer chlorthalidone as the thiazide-like diuretic, and that if using hydrochlorothiazide, it should be at least in the 25-50 mg dose.

-- limitations of study:
     -- this is an observational study of a large number of people, though they were quite healthy with very few relevant comorbidities, which limit the generalizability to sicker patients
     -- there can be concerns about the quality of the propensity match scoring (e.g. see http://gmodestmedblogs.blogspot.com/2020/03/tramadol-fo-oa-inc-mortalityprobs-with.html), but in this case there really was not much difference before and after stratification (both groups were equally healthy and happy)
     -- this study combined data from multiple large databases, which can be problematic if the databases contain different information, or the information is quantified differently
  
So, I don’t really think this article adds much useful clinical information. There is apparently an ongoing head-to-head randomized controlled trial comparing chlorthalidone to HCTZ that really should give insight. My concerns overall are as follows:
-- HCTZ is the most widely prescribed antihypertensive in the US
-- at least the lower dose HCTZ (e.g. 12.5 mg, and often the one that is prescribed) seems to be a significantly inferior choice as a solo agent (it might be fine in combination with other agents)
-- hypokalemia is certainly an issue with chlorthalidone, though i suppose it might be useful in those who are hyperkalemic...
-- I personally have been using amlodipine as my 1^st choice antihypertensive, as suggested by several guidelines including the UK NICE guidelines. As per prior blogs, it does have the longest duration of action, it has the least blood pressure by variability (see http://gmodestmedblogs.blogspot.com/2016/09/blood-pressure-variability-increases.html ), it is usually well-tolerated (and, even the edema from it is dose-dependent and often decreases with lower doses) and it is highly effective.
-- So patients with well-controlled clinic blood pressure on HCTZ 12.5 mg alone probably should be changed to a more effective antihypertensive, which could include chlorthalidone or potentially high-dose HCTZ (though hypokalemia may still be a problem with that), or from a different medication class

geoff​

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