The recommendation to take blood pressure tablets at night, off the back of the Hygia Chronotherapy trial, hit headlines hard in 2019. Concerns have been raised about this 20-thousand-patient trial, especially by leaders in the field of hypertension. The main gist of the concerns is the impossibility of the study and its results but, as is often the case with concerns about a study, there has been no real resolution, only unconvincing rebuttal.

Prof Francis revisited the paper in a recent Tweetorial. While Twitter is not everyone’s cup of tea, it is a useful tool for quickly raising awareness. This is particularly important in the case of the Hygia trial because the question of blood pressure tablet timing affects millions of patients, and many doctors are completely unaware that doubt has been cast on the trial.

An expression of concern was published on the paper in April 2020 as follows:

” The editors would like to inform the readers of the article ‘Bedtime Hypertension Treatment Improves Cardiovascular Risk Reduction: Hygia Chronotherapy Trial’ by Ramon C. Hermida et al. Eur Heart J 2020; online that the content and conduct of this randomized clinical trial is currently under investigation. They therefore recommend to interpret the major results and conclusions with caution until further notice.”


Remember the paper? The one with the strange feature whereby they couldn’t bring themselves to write the word “randomized” in the flow chart?

The description of the randomization process is given here.


Oh dear. The only acceptable answer is C. (Or maybe D, I suppose, if you used Google Translate to do the poll.) Because here is what it said about the randomization method:

Oh dear. It is human nature to avoid lying. As a magistrate in British-ruled India once said to a witness who was obviously being untruthful, “Don’t tell unnecessary lies.” The interpreter conveyed this into Hindi, but unfortunately conveyed a different subtlety: “Judge Sahib says, you must tell lies only when it is necessary”.

If this ‘trial’ is real, I am the Queen of Denmark. I can think of two possibilities. Hypothesis 1. It wasn’t really randomized. They just said it was. My reasoning for this is that they tried really hard to avoid mentioning randomization. Search the paper for the string “rand” and you see it only 3 times.



Of the three cases above, how many of the mentions of the word “randomized” referred to the HYGIA trial itself (rather than other trials)? One. 

And on the first of those occasions, what was the reason for mentioning the word “randomized”? To explain what PROBE means.

I don’t recall ever seeing a paper about an RCT which had the character sequence “randomi” solely in reference to explaining an abbreviation, talking about OTHER trials, or reference lists. So I think these are fundamentally honest people who wanted to lie as little as possible. 



When you prevent CV death, you are always anxious that you don’t cause non-CV death. For example, if you give people antihypertensives, you might prevent strokes etc, but cause more hypotension and resultant falls etc. Moreover suppose you give ANY drug that just causes some fatal side effect outside the cardiovascular system. That would prevent cardiovascular death (because people who have died early because of the side effect, don’t then live long enough to get their CV death). The way we would detect that is that non-CV deaths would go up. That way we know we have either (a) reclassified CV deaths as non-CV, or even, (b) caused more non-CV deaths than the CV deaths we prevent. So trials generally check that NON-CV deaths don’t get increased, as that is the fear. However, we never find that NON-CV deaths get DECREASED. That would be too amazingly good.

Any competent fraudster would make sure that the non-CV deaths are roughly unchanged, or even slightly increased, so that they could say “It saves lives, at only a small cost” and that way seem plausible. However these guys obviously didn’t check the non-CV death totals, so they didn’t realise the implication of their made-up data.

What they accidentally reported was a treatment (moving one of your BP tablets to the night) that reduced NON-CV deaths by 39%! Wow! What do people die of, other than CV death? Mainly cancer. Plus a few other things. So if you really could reduce non-CV death by 39%, by just tweaking the timing of a BP tablet, you wouldn’t publish it in EHJ. You would publish it in a major *general* journal, e.g. Lancet / NEJM / JAMA. Or even the Bible. It would be an unimaginably large effect for a ridiculously small intervention with no pre-existing biological basis.




AN: I liked your Tweetorial last weekend.

DF: Well actually I don’t deserve the Nobel Prize. Unless there’s a prize for being the last [to notice the issues with this paper].

AN: So are you saying it is an observational study or didn’t take place at all?

DF: I am saying it is not a randomised trial. Alex, I might give you an envelope containing 2 £5 notes and ask you to pay £10 for it, and you might agree. On the other hand, if I prefaced that proposal with the claim that I am Napolean Bonaparte, you might be a lot less willing to trust in the envelope’s contents unseen.

AN: Isn’t it possible Hermida’s results could be true?

DF: No.

Because we as a profession are all very polite and avoid accusing people of lying, the poor old journalists have no idea what we are saying and report utter rubbish to unsuspecting readers. That is not the fraudsters’ fault. It is ours, everytime we say “Oh there are some issues to address”, “we should interpret this with caution” or “more research is needed”.
All those statements are correct but do not convey to the average journalist that this trial is made up and is newsworthy for its fraudulence rather than it’s science.

AN: What would the authors need to show in order for you to believe it was true?

DF: The investigators who randomised 20,000 people.

In the past I would have said the raw data. But now I know this is wrong. First, it takes ages. And there are endless permissions that need to be granted. A boring committee of boring people in the university will grind the process in a boring way and write a boring report and fail to draw even the conclusions a 10 year old would achieve in 10 minutes.

I have a solution that will work in the modern era in 24 hours.

All the investigators would need to do is tweet a list of the investigators who did the randomisation and how many each randomised. Those people will be known by lots of people on twitter who can give them a nudge to confirm or deny. Once a reasonable proportion of the randomisations have been confirmed by the randomising staff, I will shut up and beg a formal apology on bended knee. That reasonable proportion of randomisations doesn’t have to be 100% or 50%. Even 10% would make me start making doctor visits I can later parlay into a case of rapidly developing dementia or start a diet so that I could later claim to have a fatal-wasting disease in order to escape opprobrium.

AN: What do you think motivated this study?
DF: I am guessing that Hermida is just like me and Rasha Al-Lamee. We all have strong beliefs. In our case it was that stenting would be beneficial (the only question in our minds was in whom). In his case it was that a dipper phenotype is not only a favourable prognostic marker but it actually mechanistically is beneficial even if achieved by moving some of the blood pressure reduction from day to night i.e. without changing mean 24 hour blood pressure. The difference between us is that Rasha and I actually carried out the trial so we have been through the agony of having to change our point of view. He hasn’t had that yet.

Some of that is the fault of people who have encouraged him over the years thinking that it would be helpful but in fact entrapping him further. I do feel sorry for him. But if we allow feeling sorry for researchers who make false claims to take priority over feeling sorry for the many patients whose care is messed up by them, then we are the problem.



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