COVID: hydroxychloroquine works, at least this time

Another observational study on the use of hydroxychloroquine +/- azithromycin was published, this one with lots of people and earlier treatment, finding decreased mortality with the meds (see covid hydroxychloroquine detroit helped IJID2020 in dropbox, or doi.org/10.1016/j.ijid.2020.06.099). And, another pre-proof, pre-peer-reviewed article (ie, the final article might be somewhat different)

Details:

--2561 consecutive Covid-19 positive patients by nasopharyngeal PCR were admitted to 6 hospitals in the Henry Ford Health System in Detroit, and staying there at least 48 hours unless they died within 24 hours

-- study based on med records review, including data on demographics (age, gender, race, BMI), clinical characteristics (admission and discharge dates, LOS, comorbidities including CVD/ CKD/hypertension/asthma/COPD/diabetes/immunodeficiency/cancer), ICU status/ventilation use, and clinical severity (oxygen saturation, mSOFA scale (predictive value similar to SOFA but without ABGs or LFTs)): see https://www.mdcalc.com/modified-sequential-organ-failure-assessment-msofa-score for details of mSOFA score

--median age 64, 51% male, 56% African-American, 52% had BMI>30

--comorbidities: chronic lung dz 64%, cardiovasc dz 9%, CKD 43%, COPD 13%, hypertension 65%, asthma 10%, diabetes 38%, cancer 15%

--disease severity: mSOFA 3.7 (31% had mSOFA>5); ox sat mean 92%, 14% were in lowest group of 86-89%

--patients were in one of 4 groups: hydroxychloroquine, azithromycin, both, or neither

    --overall: those who were the sickest or had the worst comorbidities were in one of the med groups

--propensity score matching was used to mathematically control for differences between groups

--primary outcome: the mortality effect on those given hydroxychloroquine alone or with azithromycin

--median time to starting meds: 1 day from time of admission

--median inpatient stay 6 days, follwoup 29 days

Results:

--predictors of mortality:

    --age >65: HR 2.6 (1.9-3.3)

    --CKD: HR 1.7 (1.4-2.1)

    --white race: HR 1.7 (1.4-2.1)

    --reduced oxygen sat on admission, HR 1.5 (1.1-2.1)

    --ventilator use, HR 2.2 (1.4-3.3)

--mortality, overall: 18.1% (16.6%-19.7%); by med groupings:

    --neither drug: 108/409 patients, 26.4% 22.2%-31.0%)

    --hydroxychloroquine alone: 162/1202 patients, 13.5% (11.6%-15.5%)

    --azithromycin alone: 33/147 patients, 22.4% (16.0%-30.1%)

    --hydroxychloroquine plus azithromycin: 157/783 patients, 20.1% (17.3%-23.0%)

--by multivariate Cox regression model of mortality, vs no meds:

    --hydroxychloroquine provided 66% mortality reduction, HR 0.34 (0.25-0.46), p<0.001

    --and, combo with azithromycin provided 71% reduction, HR 0.29 (0.22-0.40), p<0.001

--mortality benefit, per their graphs, was evident within 2 days of admission (one day after starting the meds)

--by the propensity-matched scoring: hydroxychloroquine treatment led to a 51% decreased HR for mortality, p=0-009

--adjunctive corticosteroids were given to 66% and the IL-6 inhibitor tocilizumab in 4.5%

--the enhanced survival with meds persisted at the 28-day analysis

--primary cause of mortality: respiratory failure (88%). 4% had cardiac arrest (mean QTc on last EKG: 471 ms)

--torsades de pointes: no patients

Commentary:

--one advantage of this study is that it was protocol-driven and uniform in all hospitals: 

    --hydroxycholoroquine 400mg bid for 2 doses on first day, then 200mg bid for days 2-5

    --azithromycin 500mg on first day then 250mg daily for days 2-5

    --the combo was reserved for patients with severe Covid-19 and minimal cardiac risk factors, including QTc >500ms (so, severe disease patients had telemetry monitoring as well as serial QTc checks)

--the study found impressive and clinically significant mortality differences, despite the large number of older people (50% >65yo), high BMI (mean 32), and lots of comorbidity: the overall high death rate reflected these high risks

--as noted in prior blogs, there are substantial non-human data suggesting that both hydroxychloroquine and azithromycin might have significant immunomodulatory and other benefits, many of which are likely to be most beneficial if using the drugs early in Covid-19 (for more detail on purported mechanisms, see http://gmodestmedblogs.blogspot.com/2020/03/covid-19-chloroquine-and.html )

    -- however, there was the disappointing article on the use of hydroxychloroquine for post-exporure prophylaxis, which was used even much earlier after infection than in this Detroit study (see http://gmodestmedblogs.blogspot.com/2020/06/covid-hydroxychloroquine-post-exposure.html )

--their article was much larger than prior articles on hydroxychloroquine, which had quite variable results (and led to the FDA backing off on its use), including a smaller quasi-RCT also from Detroit (see http://gmodestmedblogs.blogspot.com/search?q=covid+hydroxychloroquine&updated-max=2020-06-16T04:12:00-07:00&max-results=20&start=7&by-date=false )

Limitations:

--the big one, as too often the case: this was an observational study, not an RCT. were patients alloted to different treatment groups based on some underlying clinical characteristics that might have skewed the results? it does seem that the sicker patients were more likely to get the meds, but were there unmeasured confounders (eg combinations of higher risk factors in some patients??, unmeasured gestalt or biases of the clinicians??)  Did the choice of meds vs no meds change other supportive therapies (this was a non-blinded study: did the clinicians perhaps unconsciously provide different and perhaps higher quality of care/more attention to those who they decided to give meds to??)

--some data were not available in this non-prospective study format: eg, mSOFA (a severity of illness score) was not available in 25%

--some patients also received steroids or (smaller %) tocilizumab. did these explain the different outcomes?? or was some combination with hydroxychloroquine +/- azithromycin explaining the differences?? It was impressive that the sickest patients (the ones put on meds) were much more likely also to be on steroids (up to 79% on hydroxychloroquine vs 36% on no meds). though giving the steroids, per their multivariate analysis, provided only a trend to benefit

so, impressive study in that it was so large and used standardized medication regimens (but not randomized patient assignment to treatment groups) in quite high risk patients.  they consistently provided the meds very early in the admission (82% in the first 24 hours, 91% within 48 hours) vs later in some of the other studies finding no benefit. their results are consistent with the mechanisms proposed: these meds are likely to work better if given earlier -- their antiviral and antithrombotic effects might alter the potentially severe trajectory of Covid-19, where the increased morbidity and mortality are often more related to the delayed hyperimmune, prothrombotic, hyperinflammatory response ("cytokine storm") to the virus rather than to the virus itself. But, we still await real RCTs for hydroxychloroquine, both for prophylaxis and early therapy. And, hopefully, they will be available soon and really answer the roller-coaster studies on whether hydroxychloroquine should play a role...

geoff

 

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