Richard Lehman’s final review of the latest research in the top medical journals

NEJM  26 Jul 2018
Plasma in the plane
There are some trials that are more to be admired for their fiendish logistics and their thrilling setting than for their actual results, and to me this is one of them. PAMPer stands for Prehospital Air Medical Plasma: it was a cluster randomised trial of thawed plasma given in air ambulances to people at high risk of haemorrhagic shock. The clusters of 16 patients were recruited from 27 air bases: this was partly due to the expense of constantly replacing frozen plasma, which has a shelf life of only five days. You can imagine the noise of the helicopters, the rush to find venous or osseous access, the smell of fuel and sweat. In the midst of all this, the medics discovered whether they had been given saline to administer, or freshly thawed plasma. They could give more or less anything else they wanted, including blood, and the patients had all sorts of injuries, singly or severally: single or multiple fractures, stab wounds, bullet wounds, and so forth. When analysed for the primary endpoint, which was 30 day survival, the plasma group did a little better: 23.2% vs. 33.0%; 95% confidence interval, −18.6 to −1.0%; P=0.03.

PD-1 blockade and advanced squamous skin cancer
Although we don’t usually regard squamous cell carcinoma of skin as very malignant, it kills between 4000 to 8500 people a year in the US. Here’s a phase 1 trial of a new agent for those with locally advanced lesions or metastases. Cemiplimab is a highly potent human monoclonal antibody directed against programmed death 1 (PD-1). The hype about this agent has focused on one lucky individual whose metastases simply vanished away with this drug, but the data are not mature and it seems that about half of patients respond initially to the drug and about 60% of these continue to show some response at one year.

Prophylaxis for hereditary angio-oedema
Kallikrein is one of those silly names that stays in your head forever from medical school: a brain worm. I’m not sure if we really know why the human body bothers to produce this particular protease, because it also produces an antidote to it, called C1 esterase inhibitor. Those who lack this inhibitor are prone to severe attacks of angio-oedema, which can occasionally be fatal. A drug that inhibits kallikrein in people with inherited C1 inhibitor deficiency would be quite handy, provided it is safe and affordable. This phase 2 trial shows that BCX7353, produced by BioCryst Pharmaceuticals, reduces the rate of angio-oedema attacks by about 45-75% when taken at doses of 125mg and above, for 28 days. It will be marketed to be taken daily for life. Phase 3 better be long, and the price better be modest.    

JAMA 24 Jul 2018
Escitalopram on the post-MI drug chart
Depression is a common sequel of myocardial infarction (MI) and carries a bad prognosis. Perhaps. Judging by the references in this paper, it’s not as certain or as strong an association as you might think. Moreover, most trials of antidepressants in people whose acute coronary event has been followed by depression have shown negative results, across a range of specific agents. But here is a definitely positive randomised trial of escitalopram, based on 300 Korean patients given escitalopram or placebo for 24 weeks, with 100% follow-up at a median of eight years. The absolute mortality reduction was 3.7%, with larger reductions for subsequent MI or PCI. “Further research is needed to assess the generalizability of these findings,” says the abstract. I think I agree. More RCTs of escitalopram in all post-MI patients (in case it is the new aspirin), or just those with “depression?”

JAMA Int Med  July 2018
The full echo
Although I recently had an echocardiogram, I have no idea what the nice lady was looking for, or indeed why. In the US it seems that Medicare spends nearly a billion dollars annually on echocardiography—most of which involves a complete report on both ventricles. This article suggests that some of the cost could be reduced by making fewer measurements. I’m not sure. Once the clinic has bought the machine, hired the nice lady, and she has squeezed all the jelly on, I think she might as well have a good look round while describing her holiday plans. Plop, whoosh, Corsica. It’s all very interesting for us old folk to listen to.

Ann Intern Med  24 Jul 2018
Poo-altering substances
Probiotics, prebiotics, and synbiotics: how polite and beneficial they sound. It’s bad enough to question whether these products really do what they claim to do in the dungy regions, but this systematic review goes further and asks if they might actually have harms. I’m a great fan of systematic reviews of harms. The trouble is that they almost invariably find that trials fail to mention them in any structured way. This one concludes: “Harms reporting in published reports of RCTs assessing probiotics, prebiotics, and synbiotics often is lacking or inadequate. We cannot broadly conclude that these interventions are safe without reporting safety data.” It’s almost as if the RCTs were designed to sell products rather than to assess their safety in human beings: a whole macrobiome of bad research that’s in serious need of improving.

Cannabis smoking and the lung: weedy evidence
On a similar note, I’ve been telling you for 20 years that bad evidence abounds, and that all observational evidence is bad unless proven otherwise. That said, some heroes of epidemiology did prove otherwise—think of John Snow and cholera, or Richard Doll and tobacco smoking. It’s a reasonable assumption that smoking hemp mixed with tobacco carries similar dangers to smoking tobacco alone. Personally, I’m predisposed to favour anything that dulls the pain of existence, so cannabis has my vote, even though my sole experiment with hash cakes resulted in zero effect. But I think all smoking of dried plant substances must come with a presumption of serious harm, and it seems to me a shame that the legalisation of cannabis (here weirdly called “marijuana”) should not specify a harm-limiting mode of intake. This systematic review concludes that “Low-strength evidence suggests that smoking marijuana is associated with cough, sputum production, and wheezing. Evidence on the association between marijuana use and obstructive lung disease and pulmonary function is insufficient.” But you could say the same of tobacco if you only looked at similar small scale, time limited studies in mostly young populations.

Sharing data from journal publications
Here’s a rare example of a short paper with my name among the authors. Now that I’m a late life professor at a highly respectable university, I must try and do this more often. The real credit here belongs to my wonderful colleagues across the water at Yale. By happy chance, I was party to their efforts to open up data sets from clinical trials and persuade medical journals to adopt full data sharing policies. But how has this affected the authors concerned? “Despite barriers, our results are encouraging for data sharing efforts; respondents reported that many sharing requests are being made and granted under existing journal policies.”

The Lancet  28 Jul 2018
Outrageous drug prices
“Journal article pricing is generally reminiscent of consumer goods pricing, where the practice is often to set a price as high as the market will allow. However, it is absurd to regard a researcher or university with a serious commitment to science as a consumer pondering, for example, what car to buy. Working out the value of an academic publication and the production cost would seem more appropriate; these two approaches are not in conflict with each other.”

I’ve done a slightly naughty thing here. The original ran:

“Drug pricing is generally reminiscent of consumer goods pricing, where the practice is often to set a price as high as the market will allow. However, it is absurd to regard a patient with a serious and life-long disease as a consumer pondering, for example, what car to buy. Working out the value of a drug and the production cost would seem more appropriate; these two approaches are not in conflict with each other.”

I hope The Lancet will forgive me. Far be it from me to suggest that the whole edifice of medical journal publication is overdue to crumble in the face of open publication on pre-print servers, allowing real time discussion of full data sets, and creating a path to recognition that does not depend upon the whims of editors bound to the medical-industrial complex.

The BMJ  28 Jul 2018
Patients’ roles and rights in research
“Full partnership with patients is essential to any modern research enterprise,” write Paul Wicks, Tessa Richards, Simon Denegri, and Fiona Godlee. Yes. Patient-prioritized themes, patient-codesigned studies, patient-chosen outcomes. It’s by printing editorials like this that The BMJ makes itself the greatest force for good in medicine today.

Closure on PFO closure?
And here, finally, is another cause for hope in the future of medicine. Evidence based medicine is an empty aspiration without a constant stream of clear, uncontaminated patient centred evidence, conveyed to patients and clinicians in real time. This latest infographic about patent foramen ovale closure to prevent cryptogenic stroke is an illustration of the current state of the art. Why isn’t the world rushing to support the fantastic MAGICapp programme? To adapt it for use in all contexts, in order to improve clinical practice and enable real shared decision making? Return, O Earth, return.

Plant of the Week: Corydalis flexuosa ‘Père David‘
You probably planted this lovely little space filler back in early spring, when you were charmed by its dainty bronze leaves and its shy soft blue flowers. But now if you look for it, you will find just a few dead looking remains. Has the drought killed it? Was it really just a fleeting annual sold as a perennial?

With luck, it is not dead but sleeping. I was going to call this aestivation, but apparently that term only applies to the summer dormancy of insects, fish, and amphibians. In botany it applies to the arrangement of petals and sepals in a flower bud before it opens. This is the sort of useless fact you will now have to look elsewhere to find, because this summer I am not going into aestivation but into proper retirement from writing these weekly comments on the main journals.

I have been deeply touched and flattered by the kind messages I’ve received about them, and I do hope I have thanked everybody properly. Alec Logan’s piece in the BJGP makes me feel that I have died, gone to heaven, and read my own obituary. But like Père David’s little corydalis, I hope to reappear above ground before long. There are a few more things I would like to say about the shared understanding of medicine before I finally add to the general richness of the soil.