Richard Lehman’s journal review—19 December 2016

richard_lehmanNEJM  8-15 Dec 2016  Vol 375

Geographical variation in trials

This review article on geographical subgroup variation is a master class in how to think about and analyze randomised controlled trials. Salim Yusuf and Janet Wittes have been leading figures in the design and interpretation of RCTs for the last thirty years, and that shines through their paper. But I do find it a little too polite. It begins from the premise that all trials are done to determine the objective truth and equally well conducted across all geographical locations. But most of the RCTs I come across are funded by the manufacturers of the intervention and spread across many more centres than are required to recruit a sufficient number of participants. Then again, a basic principle of science is that all results should be replicated, but the literature is full of trials prematurely ended and never replicated, on the basis that it would be unethical to repeat a single experiment that appears to demonstrate benefit or harm. In this Panglossian world, nobody anywhere ever cheats, though billions of dollars are at stake. I hope this is true. Whether it is or not is something you won’t find hinted at in this paper, though I’d still recommend that you read it.


The Netherlands Organization for Health Research and Development is perhaps not the first place you would go looking for witty acronyms, but here are a lovely pair. The POT-KAST trial recruited patients undergoing knee arthroscopy, and the POT-CAST trial recruited patients treated with casting of the lower leg. This is definitely worth a podcast. They randomised the patients to a prophylactic dose of low-molecular-weight heparin (for the 8 days after arthroscopy in the POT-KAST trial or during the full period of immobilization due to casting in the POT-CAST trial) or no anticoagulant therapy. There was no difference in thromboembolism between groups. A pity they didn’t follow their acronym and randomise them to receive pot, so the lucky half could enjoy analgesia and mild euphoria.

Phenotype & genotype

Here is a study partly founded by the Ting Tsung and Wei Fong Chao Foundation. It is all about a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing. My heart aches, and a drowsy numbness pains my sense, as though of hemlock I had drunk. I dream of ancient China, and of two old men, Ting Tsung and Fong Chao (though the real Wei of the Foundation was female). They have flowing silken white beards and their faces are etched with the wrinkles of benignity. Drinking tea beneath the twisted trunks of an immemorial maple tree, they remember their lives as Confucian scholars, advising and remonstrating with officials sent by the faraway Son of Heaven. Turtles and carp gently disturb the pond: in the distance there are faint bells, and the sounds of grandchildren playing. All things pass away. Soon their lives will be over; they have done good service; the Middle Kingdom will remain. It is foolish to be anxious of what cannot be known and what cannot be changed. But now I wake, and read the summary of this study:

” In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway.” The old men return in a brief vision, and whisper: live well, and do good; it is foolish to be anxious about your genes.

JAMA  Dec 2016 

Zika babies in US

On the JAMA website you can find an article based on data from the US Zika Pregnancy Register, covering 442 completed pregnancies. Fortunately the Zika pandemic is waning and has never affected more than a few travellers from the UK, so the main interest for British readers will be to note that the incidence of microcephaly in these US pregnancies was about 6%—still nearly 100 times the normal base rate, but not nearly as high as in South and Central American reports.

JAMA Intern Med  Dec 2016  Vol 176

Burnout: which interventions work?

“We are all wounded in the battle of life, but we fight on” said Charles Dickens to his friend and biographer, John Forster. Doing real medicine is necessarily a wounding experience: the majority of doctors fight on, but increasingly complain of burnout. The nearer they are to the front line, the worse it tends to be, according to this systematic review of 19 studies of controlled studies of interventions to reduce burnout in physicians. Inevitably, given the context, institutional factors loom large in these studies. I don’t think there is any likelihood that we can learn a lot from them except in a generic “care for your workforce” kind of way—ironic at a time when the NHS workforce is being devalued and deprived of anywhere to put sick patients. In the end, a radical rehumanizing of medicine can be the only answer to burnout. I look forward very much to Ron Epstein’s forthcoming book, Attending: Medicine, Mindfulness, and Humanity.

End of life agitationare drugs the answer?

One driver of burnout is not being able to deliver the kind of care that you would like to give to patients. Or maybe I should have put that the other way round—not being able to deliver the care of kindness. Here is a trial of risperidone, haloperidol or placebo in American hospice patients with delirium. “Distressing behavioral, communication (sic), and perceptual symptoms of delirium were significantly greater in those treated with antipsychotics than in those receiving placebo.” Patients not receiving drugs were more likely to get personalised care and of course had fewer adverse effects. The accompanying editorial ends by pointing out that “physicians need to let go of the idea that dopamine receptor blockade is the answer to treating distress in these patients. Some distress cannot be medicated away.” And yet we feel forced to adopt this approach far too often. Remember this trial: not only does it not work, it actually causes harm.

Beta-blockers in elderly post-MI

Not wishing to appear dweeby, I didn’t point your attention to a paper that appeared in The BMJ in September that described ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. It’s an appealing thought that you can dispense with randomisation provided you are clever enough to adjust for every confounding factor; but I don’t believe it. I would not like to play Batman to ROBINS-I, though admittedly there are situations where the only evidence you are ever likely to get is observational. An interesting study of nursing home residents provides a borderline example. Ever since ISIS-1 we’ve known that ß-blockers improve survival after myocardial infarction. Does this apply to nursing home residents who get MI? Yes, says this observational study: mortality is 26% lower in those who were given ß-blockers. But this could easily be a case of indication bias: it may be that the residents who seemed most likely to die didn’t get them prescribed. And there is a good reason for that, because this study also shows that ß-blockers speed decline in those with existing functional or cognitive impairment.

Lancet  10-17 Dec 2016  Vol 388

Another Alzheimer’s drug bombs

In a 2014 study, the failure rate in trials for new Alzheimer’s drugs was found to be 99.6%. Here is another for the bin list: leuco-methylthioninium bis(hydromethanesulfonate) as an add-on treatment for mild-to-moderate Alzheimer’s disease. It did not meet its primary end-point in a large trial. However, the time may not have come to forget this egregious name altogether, since there is another trial of LMTL as first-line treatment. It is supposed to work by stopping brain tau protein forming the typical tangles found in AD. Amazingly, when the add-on trial was reported in July, The Times ran a front-page headline “Scientists create the first drug to halt Alzheimer’s. Brain deterioration stopped by twice-a-day pill. ‘Wonderful’ discovery raises glimmer of hope.” Ahem.

Steroid inhalers for all asthma subgroups?

Here’s a pharma-funded follow-up study of a trial showing that their drug is good for all asthma subgroups. Normally I’d be sceptical, but in this case the drug is an inhaled corticosteroid and the observational evidence suggests that in mild recent-onset asthma, once daily, low-dose budesonide decreases severe asthma-related event risk, reduces lung function decline, and improves symptom control similarly across all symptom subgroups. Budesonide is now off patent and costs £17.71 for 100 daily doses of 400 mcg in the UK. But in the USA it’s a very different picture: Wikipedia suggests $100-200 per month.

BMJ  10-17 Dec 2016  Vol 355

SDM for low-risk chest pain

SDM stands for shared decision making. The more I use the term, the less I like it, but the more I think about the concept, the more it seems to me a possible way out of the mess that medicine is in. Victor Montori writes beautifully about this. He also does great work on decision tools. These have to be very context specific, and the context here is the US health system, where there are strong cultural, legal and financial incentives to over-investigate low risk patients who present to emergency rooms with any kind of chest pain. Does the provision of a shared decision aid make much difference to this? No, not much, but a little. Admissions for cardiac testing were 15% fewer in the intervention arm. The decision aid, which took one minute of clinical time to administer, also increased patient knowledge and engagement.

Plant of the Week: Pyrus communis “Doyenné du Comice”

This is the time of partridges and pears, and I love eating both, though seldom together. Comice pears start to appear in English shops in November and become scarce around the end of January. They need to be big, irregular, and grown in a cold climate.

The Comice started as a French com-ees in 1849 but is now most definitely a British comiss. If you happen to have a big warm wall you could grow this kind of pear tree as an espalier, but I always think it is a waste of garden space to grow food which you can buy in shops. Since comices are easily the best pears, there is little point in growing any other kind, so save your nice wall or orchard space for some other sort of fruit altogether: an unobtainable variety of peach, perhaps, or a rare fig from Read’s Nursery, or a Blenheim Orange apple tree.

Keep your big, ugly green-brown comice pears in a warm room and test them daily for ripeness by gently pressing near the stem. Cut and peel them with care over a plate with plenty of tissue to wipe the juice off your fingers after eating. Bliss.