Richard Lehman’s journal review—28 September 2015

richard_lehmanNEJM 24 Sep 2015 Vol 373
1220 I suspect that good randomized trials of common procedures are difficult to do. Each French doctor probably has a favourite way of gaining central venous access, probably dependent on how they were first taught. But in this trial they were commanded to use the femoral, jugular, or subclavian route according to permuted-block randomization with varying block sizes. Who would dare to do otherwise when supported by funds from the French Ministry of Health Programme Hospitalier de Recherche Clinique National to the Délégation de la Recherche Clinique et de l’Innovation of the Caen University Hospital? Eh bien, it was a win for the subclavian. This route was associated with the fewest bloodstream infections and episodes of thrombosis, though it led to pneumothorax in 1.5% of patients.

1230 Once, nearly 40 years ago, I was left in sole charge of the fertility clinic at the Middlesex Hospital. But unlike other awful experiences from my junior hospital days, this one does not make me wake up in a guilty sweat. Then as now, the drugs prescribed to stimulate ovulation made little difference to the chance of a live birth. I prescribed clomifene. Today they prescribe clomifene. Or gonadotropin. Or letrozole. Here’s the latest multicentre randomised trial: “In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomifene.”

1241 Do you have trouble distinguishing between chronic obstructive pulmonary disease and asthma in your adult patients? You’re not the first: a Dutch paper discussed the problem in 1961, when these distinctions had yet to harden into a brutalist concrete structure of guidelines supported by randomized trials using recruitment criteria designed to perpetuate artificial diagnostic categories. The overlap between COPD and asthma in adults is so gross that it now has its own acronym: ACOS standing for asthma-COPD overlap syndrome. But I am glad that the authors of this clinical review of ACOS end up rejecting the term. All it does is add one more layer to an MC Escher multi-storey diagnostic car park where once you have driven in you can never get out, and every time you drive past the same spot you are given another inhaler.

JAMA 22/29 Sep 2015 Vol 314
1242 Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. Why did JAMA publish this 10-week trial where within 5 weeks every patient ended up taking a mixture of a cough syrup ingredient and an anticholinergic cardiac drug? Your guess is as good as mine. “Avanir Pharmaceuticals had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.” Avanir might just be buying up some reprints from JAMA: I don’t know. I only know that if you used this drug on someone with Alzheimer’s you would be completely in the dark about its mode of action, its long-term benefit or safety, or its effectiveness compared with other drugs.

1255 You may have noticed that I’m not, on the whole, a great fan of “health promotion” in its usual guises, but the TEXT ME trial has me impressed. It recruited mostly male Australians who had had a myocardial infarct or a definite diagnosis of coronary artery disease, and randomized half of them to receive 4 text messages per week for 6 months in addition to usual care. It’s a shame that its primary end-point was lowering of low density lipid cholesterol, but we can ignore that irrelevance. The main point is that in the intervention group, systolic BP was 7.6 mm lower, smoking was down to 26% v 44%, and there were significant increases in physical activity. Body mass index was also slightly down, but not enough to cause harm (people in this category are best to keep a BMI of 30-40). And over 90% of these denizens of Sydney were surprisingly grateful to be nudged in this way.

OL That Alzheimer’s trial forms an ironic backdrop to a Viewpoint piece which calls for an end to the expression “Conflict of Interest.” You can read this short article for free. I hope you can understand these key sentences: “First, the term conflict of interest is pejorative. It is confrontational and presumptive of inappropriate behavior. Rather, the focus should be on the objective, which is to align secondary interests with the primary objective of the endeavor—to benefit patients and society—in a way that minimizes the risk of bias. A better term—indicative of the objective—would be confluence of interest, implying an alignment of primary and secondary interests.” I keep reading those last two sentences in the hope that one day their meaning will become clear to me.

JAMA Intern Med Sep 2015
A little trial from Dartmouth looks at the influence on the words “breakthrough” and “promising” in people’s perceptions about new drugs. Not surprisingly they lead people to assume stronger evidence of benefit than these drugs really offer. Two of the authors, Lisa Schwartz and Stephen Woloshin, have just produced a great new website to counter misconceptions about a wide range of prescription-only drugs in the USA, called Informulary.

Lancet 26 Sep 2015 Vol 386
1261 Although named after a surgical instrument, The Lancet is a journal which tends to show a supercilious attitude towards those who plunge the knife. But its ten-thousandth issue is given over to surgical matters, including this paper about the desirability or otherwise of immediate cholecystectomy for pancreatitis associated with gallstones. Physicians will be happy to know from this Dutch randomised trial that such patients do not have to clutter their wards. Unless their gallstone pancreatitis is severe, they can be sent straight over for the surgeons to wield their lancets and laparoscopes. “Compared with interval cholecystectomy, same-admission cholecystectomy reduced the rate of recurrent gallstone-related complications in patients with mild gallstone pancreatitis, with a very low risk of cholecystectomy-related complications.”

1269 Dutch surgeons also feature in the next trial, which is not for the faint-hearted. Across the Netherlands, Belgium, and Italy, patients with perforated diverticulitis and purulent peritonitis were randomised to treatment with laparoscopic lavage, Hartmann’s procedure, or sigmoidectomy + primary anastomosis in a parallel design after diagnostic laparoscopy. This paper reports the comparison between lavage and sigmoidectomy, and this bit is called the LOLA trial. The other arm is known as DIVA, and together they are known as The Ladies. Gah. Boys will be boys. Now imagine you are looking down the laparoscope into the peritoneum of such an unfortunate person, be it a lady or gentleman. Under the rules of the trial, if what you see looks faecal, they don’t get enrolled. If it just looks purulent, they do. Ninety patients in, the LOLA sub-trial was called off by the safety committee because of an increased event rate in the lavage group. But actually at 12 months, four of the lavage group had died compared with six in the sigmoidectomy group. So this trial really hasn’t got us a lot further.

1278 I had a read through this review called “Acute appendicitis: modern understanding of pathogenesis, diagnosis, and management” in case it had new insights into this common and still rather enigmatic surgical emergency. By and large I was disappointed. Its epidemiology remains mysterious: the lifetime risk for appendicitis is 16% in South Korea, 9•0% in the USA, and 1•8% in Africa. There are clearly two kinds: rapidly perforating or relatively indolent. But no-one knows how to differentiate them, or what really causes them.

BMJ 26 Sep 2015 Vol 351
Drug regulation is a mess, in ways that can be hard to comprehend. In the UK, the first and main hurdle is the European Medicines Agency, with the UK’s own MRHA waiting in the wings to pick up any leftovers, and then NICE which decides on which new products should be funded by the NHS. Each of these bodies is prey to various kinds of political and commercial pressure. The British Medical Journal could do us all a big favour by bringing these into the open for discussion. Instead we get two papers (here and here) about the problems of an entirely different system several thousand miles away. The US Food & Drug Administration is simply a warning of what happens when the bar is set far too low. Raising it is one of the most urgent tasks if medicine is to progress and be affordable. Neither the US nor the UK government seems much interested in such a perspective: both prefer to focus on the earning potential of their drugs and devices industries.

Now for something completely different: a prospective multicentre observational trial based in seven early pregnancy assessment units around the United Kingdom. The question is simple and could hardly be more important: by what criteria can you safely diagnose miscarriage? It’s something that used to crop up every week of my working life, and even more frequently when I was working out of hours. I won’t attempt to compress the conclusions since you can easily go to the full article. But here’s the gist: “Recently changed cut-off values of gestational sac and embryo size defining miscarriage are appropriate and not too conservative but do not take into account gestational age. Guidance on timing between scans and expected findings on repeat scans are still too liberal.” Congratulations on a study that is clearly reported and will change practice.

In the competitive world of scientific academe, repeating someone else’s work does not confer much advantage. Yet replicability is the foundation of science. And in medical science, that can be really difficult, or even impossible. We can’t fix the subjects of our enquiry like a physicist might fix the nucleus of a bismuth atom to bombard it with particles of fixed energy: we deal with free-living individuals and the vagaries of diagnosis, comorbidity, changing treatments, habits and social factors. That makes the data from human studies so uniquely valuable, and is the reason I go on about it so much. Graham Cole and other members of Darrel Francis’ team are doing great work on uncovering signals for misreporting in human trials. In this paper, they conclude that “Discrepancies in published trial reports should no longer be assumed to be unimportant. Scientists, blinded to retraction status and with no specialist skill in the field, identify significantly more discrepancies in retracted than unretracted reports of clinical trials. Discrepancies could be an early and accessible signal of unreliability in clinical trial reports.”

Fungus of the Week: Macrolepiota procera

The true parasol mushroom is lovely to see and lovely to eat. It wears a jaunty and rather friendly air, like a golden retriever among fungi. Unfortunately you have to be quite lucky to find one. When you do, you can hardly mistake this species for anything else. The cap on a mature specimen becomes flat and is off-white with a sprinkling of brown scales. It is held aloft by an elegant darker stem which usually has a banded pattern. There is always a ring on the stem, and if you try gently to move it up and down the stem it will do so.

The caps can grow to the size of small plates and are much prized in the markets of Warsaw and Krakow. Whole or in pieces, these should be cooked rapidly in butter and on their own to appreciate their delicate flavour. You can distinguish this species from the similar Shaggy Parasol because the cap is less shaggy and the flesh does not turn orange on breaking. To me this distinction is important, for gastrointestinal reasons. Others can eat the shaggy sort without unfortunate consequences.

Quote of the Week:

“Somewhere there ought to be an NHS Museum of Pointless Initiatives, where every centralising, witless progenitor of Another Damn Good Idea That Will Save Money After Costing Some should be forced to spend a week or two in silent contemplation before being allowed to proceed with their heroic pilots and their leaden roll-outs and their oddly (but invariably) much quieter windings-up.”

Quoted from the Health Services Journal by Nigel Hawkes, who writes “I’d like to credit the author of this outburst, but, as is invariably the case with the more entertaining comments in the HSJ, it was anonymous.”