hypertension: chlorthalidone vs hctz

a population-based cohort study published this week in the annals of internal medicine compared treatment with chlorthalidone and hydrochlorothiazide for htn in older adults (see htn chlorthal vs hctz elderly aim 2013 in dropbox).  canadian study of 30K patients, assessing death or hosp for chf, stroke or MI. the 30K patients were from a database of 1.1M pts on either of these drugs (ie, this study was data-mining from prescriptions written, hospitalizations, and a few demographics).  mean age and median followup of about 1 year. mean dose of chlorthal was 27.3mg and hctz was 18.3.  results:

-no diff in primary outcome (3.2 vs 3.4/100 person-yrs) for chlorthal vs hctz

-hosp for hypokalemia (hazard ratio of 3) or hyponatremia (HR 1.7)

-when compare hospitalizations for hypokalemia and compare similar doses of chlorthal and hctz, only achieves significance with the 25mg dose (HR 2.2) and the 50mg dose (HR 5.5).  the 12.5 mg dose had a trend with chlorthal doing better. [in this country, there is no 12.5mg dosage form of chlorthal]

so, their conclusions: no benefit from chlorthal over httz and more serious side-effects

BUT, there are are lot of issues with this study.

-the prior articles i sent out suggesting that chlorthal is superior were when used as a single agent (see see htn hctz metaanal meserli am j cardiol 2011 in dropbox, and the natl institute for clinical excellence (NICE) in UK guidelines --  htn nice recs 2011 and htn nice recs summary 2011 in dropbox).  in the above cohort study, 65% were on other antihypertensives

-in terms of the primary outcomes in the cohort study, no real difference over 3 years (sl trend to dec in primary outcome with chlorthal), but we do not know the baseline BP (and, as per other recent study i sent out, don't see many events for several years in those with only slightly high BPs. as a reference point, the HYVET trial in the elderly on a different diuretic, indapamide, did find decrease in cardivasc deaths but only after about 2 years, with BP initially 173/91.  don't know the bp in above cohort study). a meta-anal of 9 studies comparing chlorthal to hctz (see htn chlorthal vs hctz metaanal hypertension 2012 in dropbox), in pts with mean age around 70, found that those on chlorthal had a highly significant 18% decrease in cardiovasc events compared with hctz, with equivalent systolic blood pressures.  this was a funny study, though, since there are minimal head-to-head comparisons, so they looked at studies with hctz and those with chlorthal and modeled the attributable benefit for each.  as with the meserli article above, they thought the benefit of chlorthal might be its longer duration of action (messerli also noted that the office based systolic blood pressures were equiv in hctz and chlorthal, but the nighttime pressures were different on 24-hour ambulatory monitoring and higher with hctz.)

-there were perhaps significant other differences in the groups on hctz and chlorthal.  turns out that as other meds for htn were used in the cohort study, chlorthal had much higher use of b-blockers (38 vs 22%) and lower use of ACE-I (34 vs 46%). hard to interpret exactly, but there are pretty impressive data that b-blockers are less effective agents in decreasing cardiovasc events (eg htn atenolol lancet 2004 in dropbox, and there was a general analysis of b-blockers in another lancet with similar results), which may be attributable to some data suggesting that the measured blood pressure in the arm is 5mm lower than the central blood pressure with b-blockers but not other meds), so the chlorthal arm may not have as good cardiovasc results because more b-blockers used.  alternatively, perhaps b-blockers were preferentially used in patients who had chf, where b-blockers are an important therapy. if so,  the patients in the two groups were clinically dissimilar, making it hard to comment on the validity of the outcomes.

-although this paper suggests found more hypokalemia in the chlorthal group and cites a study suggesting it is more common with chlorthal, there were older studies finding the opposite. one large study (MRFIT) had the hctz arm stopped because of excessive probable arrhythmic deaths vs the chlorthalidone arm. many clinicians (myself included) concluded chlorthal was safer and, with older studies showing less metabolic madness with chlorthal compared with high doses of hctz, there might have been a bias to prescribing chlorthal in patients who had lower potassium to begin with.  we are unaware in this cohort study what the pre-medication potassium was.

so, lots of caveats.  not sure this study adds much to the debate. i still like the NICE recommendations, which suggest using a calc channel blocker for all over 55 years old and all patients of afro-caribbean origin, and ACE-i in white patients under 55 years old.  they also recommend using chlorthal over hctz if one wants to use a diuretic.