hypertension: HCTZ vs chlorthalidone

 A recent large pragmatic trial from the VA found that there was no difference between chlorthalidone vs hydrochlorothiazide (HCTZ) in terms of actual clinical outcomes (see htn chlorthal vs hctz no diff nejm2022 in dropbox, or  DOI: 10.1056/NEJMoa2212270)

 

Details:

-- a multicenter study (72 VA systems involving 537 locations) with 4128 primary care providers and 13,092 patients at least 65yo, from June 2016-November 2021

    -- open-label study (ie patients and clinicians knew what they were taking) of people on HCTZ 25-50mg who were then randomized to continuing the HCTZ vs switching to chlorthalidone (at ½ the HCTZ dose)

    -- this was a pragmatic study, recruiting primary care providers and patients in a point-of-care study, with recruitment and results based on an ongoing review of the electronic medical record (ie, an easy study and potentially replicable type of study for many other interventions)

-- mean age 72, 97% male, 77% white/15% Black, 93% non-Latinx

-- BMI 32, diabetes 44%, heart failure 8%, stroke 8%, prior MI and stroke 11%

-- eGFR <60 in 23%, current smoker 23%

-- baseline HCTZ dose was 25mg in 94% (ie very few on 50mg), systolic BP 139mmHg

-- number of BP meds prescribed: mean of 2.6

 

-- primary outcome: composite of nonfatal MI, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death; safety was also assessed (including electrolyte abnormalities, hospitalizations, and acute kidney injury)

-- secondary outcomes: individual components of the primary outcome, within pre-specified subgroups

-- mean follow-up: 2.4 years

 

Results:

-- primary composite outcome:

    -- chlorthalidone: 702 events (10.4%), annual rate of 4.5%

    -- HCTZ: 6875 events (10.0%), annual rate of 4.3%

        -- HR 1.04 (0.94-1.16), p=0.45, nonsignificant difference

 

-- secondary outcomes (individual components, etc):

    -- MI:

        -- chlorthalidone: 142 events (2.1%)

        -- HCTZ: 140 events (2.1%)

    -- Stroke:

        -- chlorthalidone: 83 events (1.2%)

        -- HCTZ: 83 events (1.2%)

    -- heart failure hospitalization:

        -- chlorthalidone: 242 events (3.6%)

        -- HCTZ: 232 events (3.4%)

    --unstable angina with urgent coronary revascularization:

        -- chlorthalidone: 20 events (0.3%)

        -- HCTZ: 13 events (0.2%)

    -- deaths from any cause:

        -- chlorthalidone: 446 events (6.6%)

        -- HCTZ: 448 events (6.6%)

    -- expected adverse reactions:

        -- new allergic or adverse reactions:

            -- chlorthalidone: 109 events (1.6%)

            -- HCTZ: 21 events (0.3%)

                -- HR 5.23 (3.28-8.35)

        -- hypokalemia:

            -- chlorthalidone: 335 events (5.0%)

            -- HCTZ: 243 events (3.6%)

                -- HR 1.39 (1.18-1.64)

 

-- those with history of MI or stroke:

    -- chlorthalidone: 105 events in 733 patients (14.3%)

    -- HCTZ: 140 events in 722 patients (19.4%)

        --HR 0.73 (0.57-0.94), statistically favoring chlorthalidone

-- those without history of MI or stroke:

    -- chlorthalidone:  597 events in 6023 patients (9.9%)

    -- HCTZ: 535 events in 6045 patients (8.9%)

        --HR 1.12 (1.00-1.26), statistically favoring HCTZ

            -- so, chlorthalidone was associated with 27% decrease in events in those with history of MI or stroke, but 12% increase in those without (this was a pre-specified subgroup analysis)

 

-- adherence to study meds:

    -- chlorthalidone: 1039 patients (15.4%) switched back to HCTZ

    -- HCTZ: 260 patients (3.8%) switched to chlorthalidone

    -- overall mean medications possession ratio (sum of days that a patient was supplied with filled prescription of assigned drug): 79.5% in those on chlorthalidone and 79.1% on HCTZ

-- mean daily dose of meds taken:

    -- chlorthalidone:  12.3 mg

    -- HCTZ: 23 mg

 

 Commentary:

-- HCTZ remains by far the most popular initial antihypertensive in the US, despite it being NOT recommended in more recent guidelines (see http://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html )

-- though early studies found that chlorthalidone was significantly better than HCTZ, this has not been found in some other studies

    -- and chlorthalidone is about twice as strong as HCTZ and is associated with more hyperkalemia (as found in this study)

    -- Medicare D expenditures have found that in 2020 there were 11.5 million prescriptions for HCTZ vs 1.5 million for chlorthalidone (again, despite US recommendations to preferentially use chlorthalidone)

--There is a pretty strong argument that chlorthalidone is superior to HCTZ:

    -- many studies have confirmed that 24-hour ambulatory BP monitoring (ABPM) is the gold standard for predicting clinical cardiovascular outcomes, leading the USPSTF to recommend ABPM as the best means documenting hypertension, see http://gmodestmedblogs.blogspot.com/2015/01/uspstf-recs-on-ambulatory-blood.html and https://www.uspreventiveservicestaskforce.org/uspstf/document/final-evidence-summary/hypertension-in-adults-screening

    -- it is clear that HCTZ does NOT provide even close to 24-hour coverage, though in-clinic blood pressures seem to be okay (and therefore may mislead us into thinking that HCTZ works well): see http://gmodestmedblogs.blogspot.com/2016/04/chlorthalidone-is-better-than-hctz-for.html: these studies have found that the ABPM for HCTZ was ½ the blood pressure lowering of other BP meds tested, including chlorthalidone. there are data suggesting that HCTZ 50mg may have a prolonged effect, but we are now mostly using 12.5mg, or up to 25mg

    -- combination pills including HCTZ may work better than HCTZ by itself:

        -- the combination of lisinopril and HCTZ does seem to maintain 24-hour effectiveness (https://pubmed.ncbi.nlm.nih.gov/8117053/), although this does not seem to be as true with the combination of losartan and HCTZ (https://pubmed.ncbi.nlm.nih.gov/16372579/)

    -- which all means to me: if one decides to use a diuretic as first-line antihypertensive therapy, chlorthalidone is likely the best choice (assuming renal function permits). There is a much higher incidence of hypokalemia (so potassium should be followed). And it is a small pill, so not so easy to decrease to less than the 25mg dose (though, when I wrote a prior blog on chlorthalidone, a physician reader responded that he cut the 25mg tablet in quarters, no mean feat, and did very well with that)

    -- my bias as per prior blogs is still to use amlodipine as my first line BP med for almost everyone (except those with significant proteinuria), since it has great 24-hour effectiveness, has the least blood pressure variability (and BP variability is a marker for adverse cardiovascular outcomes), is often very effective at low dose (eg 2.5mg/d), has less renal toxicity than ACE/ARBs, and several studies have found that ACEs or ARBs are associated with more strokes than amlodipine (eg see https://www.ahajournals.org/doi/10.1161/hypertensionaha.107.089763 ). this stroke issue is likely related to the wearing off of ACE/ARB blood pressure control in the early AM when the cortisol surge happens and strokes are more common

 

Another issue is that chlorthalidone may have additional pleiotropic effects over thiazides. For example, chlorthalidone may decrease platelet aggregation and vascular permeability and promote angiogenesis, significantly different from the thiazide bendroflumethiazide (and, presumably, other thiazides) in this study: https://pubmed.ncbi.nlm.nih.gov/20625077/. But there are some conflicting reports on this (see https://pubmed.ncbi.nlm.nih.gov/36067089/ )

 

Limitations:

-- as a VA study, this was predominantly older white males (all >65yo, 97% male, 77% white), limiting generalization to others

-- patients were on multiple BP meds (mean of 2.6 meds, only 13% were on HCTZ alone), making the direct comparison of HCTZ and chlorthalidone a bit murky (and, per above, HCTZ may provide more 24-hour coverage when combined with other meds: the results of this study should not be translated into clinical effectiveness in those on one of these diuretics as a single agent)

-- there was a real selection bias: these participants were already on HCTZ and presumably tolerating it well. The switch for ½ of them to chlorthalidone is therefore not an unbiased comparison: there is likely a nocebo effect of starting a new med. And this might have led to a higher number of participants switching back to HCTZ (which occurred in 15% vs 4% the other way); those switched from HCTZ to chlorthalidone were more likely to suspect the new med vs just continuing the HCTZ that they had tolerated for perhaps many years (hence the likely nocebo effect with more reported adverse reactions).

    -- also, the much more substantial numbers of people changing from chlorthalidone back to HCTZ would likely understate the potential chlorthalidone benefit

-- there was also “contamination” of the results: likely many participants were on long-term HCTZ prior to the study and may have suffered significant cardiovascular disease before beginning the study, perhaps related to less cardiovascular protection (with 11% having known MI or stroke, and likely the vast majority of the others having significant but less symptomatic cardiovascular disease). So, how much of the results above were from the long-term legacy of being on the less-than-optimal HCTZ but only on chlorthalidone for 2.4 years??  ie, was the horse already out of the barn, the die was cast, or some other aphorism...

 

So, a few comments:

 

--This study had the advantage of being pragmatic (real-world), easily done if the electronic medical record is extensive and will allow such a study to be embedded in the record system, and involving a large network of providers and patients who can easily be recruited.

-- based on the above comments, I do not think that HCTZ in the 12.5 or 25 mg dosages provide the important 24-hour protection and should not be used as a single agent

-- if a diuretic is chosen as a single agent, I think that the data so far (and the national and international recommendations support) the use of chlorthalidone. I would start with 12.5 mg (or even 6.125 in those dexterous enough to split the pill into quarters), pending the unlikely event that pills <25 mg become available

-- I still would continue with the 2011 NICE guidelines from the UK (referenced in the above-mentioned prior blogs) suggesting that for most people, amlodipine is the best first med. (they do strongly support chlorthalidone as the diuretic of choice if a diuretic is selected as a first agent, and they basically trash HCTZ)

-- and the limitations, I think it is hard to make the case based on this study that HCTZ is as clinically effective as chlorthalidone as a single agent....

geoff

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