134. COVID19, Dexamethasone, Chlorthalidone vs Hydrochlorothiazide

Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report

(RECOVERY) trial is a randomized, controlled, open-label,

comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone.
2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care.

The primary outcome was 28-day mortality

(21.6%) patients allocated dexamethasone vs (24.6%) patients in usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001).

No oxygen then dexamethasone did not reduce mortality at 28 17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14).
patients receiving oxygen without invasive mechanical ventilation dexamethasone did reduce mortality at 28days (21.5% vs. 25.0%,-- a number needed to treat around 30.
And if you were intubated then dex 6mg for for to 10 days really was a show stopper with a nnt of 9 for mortality at 28days.

Last case bias.
but things I dont like about this
open label- obviously not ideal but I do believe doctors are better than open label
enrolled if confirmed or clinically expected covid-- not quite the same thing
-the good news is almost every vented pt. had criteria for acute resp destress syndrome or ARDS and would have met criteria for every ARDS trial performed to date. and this is similar to numbers we saw with what is now standard of care- like the 8% benefit we saw low title volume and 16% benefit we saw with proning. It is totally possible these results are real. and if they arent then who cares!!
examethasone has little mineralocorticoid activity, which is potentially beneficial for a few reasons. Mineralocorticoid stimulation may promote fluid retention and hypernatremia (which are especially undesirable in patients with ARDS).

6mg oral or IV once a day!

now

Comparison of Cardiovascular and Safety Outcomes of Chlorthalidone vs Hydrochlorothiazide to Treat Hypertension

JAMA Intern Med. 2020;180(4):542-551. doi:10.1001/jamainternmed.2019.7454


To compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide for first time antihypertensive drug users

730 225 individuals retrospective, observational, comparative cohort design- 2001-2018 large cohort and had to have taken the medication for a year prior to having any event occur.


The primary outcomes were acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease outcome including the first 3 outcomes and sudden cardiac death. Fifty-one safety outcomes were measured.

That’s a total of 55 outcomes

“To address multiplicity concerns, we indicate which estimates remain statistically significant after a Bonferroni correction for 55 hypotheses”
“
IN THE END
No significant difference was found in the associated risk of myocardial infarction, hospitalized heart failure, or stroke

Chlorthalidone was associated with a significantly higher risk of hypokalemia (hazard ratio [HR], 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30).


No difference in cardiovascular diseaes- but these are first time hypertesnive patients. They are not honda—did we expect sick???



Chlorthalidone was associated with a significantly higher risk of hypokalemia (hazard ratio [HR], 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30).

chlorthalidone was associated with an increased risk of hypomagnesemia, hyperkalemia, vomiting, syncope, gout, impotence, and anaphylactoid reaction and associated with a decreased risk of anemia, depression, dementia, and anxiety. BUT
many of these did not pass the bonferroni threshold

Bonferroni

If multiple hypotheses are tested, the chance of observing a rare event increases, and therefore, the likelihood of incorrectly rejecting a null hypothesis (i.e., making a Type I error) increases.--- example
If you test one negative person for covid your of that one test being positive are low but if you test 55 negative people for covid for odds of having one test turn positive is much higher. The Bonferroni correction accounts for this and says well you are running all these test so you now need to see a statistical number that looks like XYZ in order for it to be significant.

So even after calculation and the Bonferroni chlorthalidone

Chlorthalidone was associated with a significantly higher risk of hypokalemia (hazard ratio [HR], 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30).


And many will say well yes but chlorthalidone is STRONGER than hctz it is more potent so clearly you cant compare apples to apples or at least not the same bushel basket of apples to the same bushel basket.

The subgroup receiving 12.5 mg of chlorthalidone vs 25 mg of hydrochlorothiazide had an uncalibrated HR for hypokalemia of 1.71 (95% CI, 1.37-2.11) and calibrated HR of 1.57 (95% CI, 1.25-2.01), passing the Bonferroni threshold (eTables 1-2 in the Supplement). No other outcomes passed the threshold.


I think in the end the real thing we call care about are cardiovascular events- and many of us care about the surrogate marker of blood pressure. In the end just control the blood pressure, use one drug and your more than one drug but if you have the choice you should like choose drugs with fewer sides effets as a standard rule of thumb and I think we can say HCTZ for sure has fewer side effects than chlorthalidone so it is probably what you should be writing for.