Last post on hydroxychloroquine (perhaps)

James “not this guy” Watson writes:

The Lancet study has already been consequential, for example, the WHO have decided to remove the hydroxychloroquine arm from their flagship SOLIDARITY trial.

Thanks in part to the crowdsourcing of data sleuthing on your blog, I have an updated version of doubts concerning the data reliability/veracity.

1/ Ozzy numbers:
This Australian government report (Table 5) says that as of 10th May, only 866 patients in total had been hospitalized in Australia, of whom 7.9% died (68 patients)… whereas 73 Australian patients in the Lancet paper were reported as having died. The mean age reported in the Lancet paper for Australian patients is 55.8 years. The median age for all Australian patients in the attached is 47 years, and for those hospitalized it’s 61 years. (Note the Lancet paper only included hospitalized people, up to April 14th).

2/ A very large Japanese hospital:
The Mehra et al. paper in the NEJM (Cardiovascular disease, drug therapy, and mortality in Covid-19, same data provenance, time period: Dec 20th to March 15th) gave the number of hospitals broken down by country. They had 9 hospitals in Asia (7 in China, 1 in Japan and 1 in South Korea) and 1,507 patients. Their follow-up paper in The Lancet presumably used the same data plus extra data up until April the 14th. The Lancet paper had 7,555 participants in Asia and also 9 hospitals. The assumption would be that these hospitals are the same (why would you exclude the hospitals from the first analysis in the second analysis?). Therefore, we assume that they had an extra 6048 patients in that time period.
Cases in China went from 80,860 on March the 15th to 82,295 by April the 14th (difference is 1435). South Korea: increase from 8,192 to 10,564 (difference is 2372); Japan: from 833 to 7,885 in this time (7052). This is a total increase of 10,859. If all cases in China and South Korea in the intervening period were seen in these 8 hospitals, then it would imply that 2241 patients were seen in 1 hospital in Japan in the space of a month!

3/ High dosing:
Almost 2 thirds of the data come from North America (66%, 559 hospitals). In the previous NEJM publication, the majority of the hospitals were in USA (121 versus 4 in Canada). Assuming that the same pattern holds for the extra 434 hospitals in this Lancet paper, the majority of the patients will have received doses of HCQ according to FDA recommendations: 800mg on day 1, followed by 400mg (salt weights) for 4-7 days. This is not a weight-based dosing recommendation.
The mean daily doses and durations of dosing for HCQ are given as: 596 mg (SD: 126) for an average of 4.2 days (SD: 1.9); HCQ with a macrolide: 597 mg (SD 128) and 4.3 days (SD 2). The FDA dosing for 4 days would give an average of 500mg daily, i.e. (800 + 3×400) / 4. Nowhere in the world recommends higher doses than this, with the exception of the RECOVERY trial in the UK.
So are these average daily doses possible?

4/ Disclaimer/background
It may be worth mentioning that I (or the research unit for which I work) could be seen as having a “vested interest” in chloroquine because we are running the COPCOV study (I am not an investigator on that trial). COPCOV is a COVID19 prevention trial in health workers. Participants will take low dose chloroquine as prophylaxis for 3 months (they are not sick and the doses are about 3x lower than given for treatment – so different population&dose than Lancet study). The Lancet study will inevitably damage this trial due the media attention. Understanding whether the underlying data are reliable or not is of extreme importance to our research group. Because our unit has been thinking/reading about (hydroxy)chloroquine a lot recently (and some people in the group have been studying chloroquine pharmacology for 40 years) we rapidly picked up on the “oddness” of this recent paper.

My conclusion from this is that post-publication review is a vital component of science. Medical journals need to embrace and stop pretending that peer/editorial review will solve all problems.

Perhaps the authors of that Lancet study will respond in the comments here? They haven’t yet responded on pubpeer.