Richard Lehman’s journal review—30 January 2017

richard_lehmanNEJM  26 Jan 2017  Vol 376
Bezlotoxumab is an antibody that offers passive protection against Clostridium difficile toxin. This trial shows that if you give it with anti-clostridial antibiotics, it somewhat lowers the rate of recurrence. It is already on sale in the US, though in that strange country, drug prices are commercial secrets. President Trump has declared that drugs are way too expensive in the US. Way too expensive. He will change that. Yes, he will change that, and the way he will change that is to make the Food and Drug Administration unable to stop the flow of really expensive useless treatments. Americans need these treatments. The president will make sure Americans get these best treatments. All of them. Now the best treatment for recurrent C diff is someone else’s faeces. Maybe that is why he is offering his own to the American people right now.

Spotting dangerous devices
I don’t think that even Donald Trump could make the regulation of medical devices any laxer than it already is. I’ve even heard device company directors ask for tighter rules. As this article says, “voluntary reporting of adverse events . . . has resulted in incomplete ascertainment and an inability to evaluate the safety of medical devices in an active, prospective fashion (12 refs).” It really isn’t very difficult, and with universal patient held electronic medical records it could be done routinely at minimal cost. In this study, the investigators used an integrated clinical data surveillance system based largely on existing registries. They compared the performance of various femoral puncture closure devices, which are supposed to reduce bleeding and haematoma formation after angiography. One device was called Mynx. It proved just as mischievous as the famous Minnie of (nearly) that name—and its high complication rate stood out within the first year of data collection. 

JAMA  24 Jan 2017  Vol 317
Holy microbiome!
A fascination with poo comes early in life. For some medical investigators, it never goes away, and now their efforts are rewarded with weekly demonstrations of microbiome magic. This short article discusses how poo germs might be linked (bidirectionally) with obesity and type 2 diabetes. Expect to hear a lot more about the Firmicute to Bacteroidete ratio, noting that the key experiments were conducted in mice. Bulls will follow, perhaps.

Sharing decisions about surgery
Last week I asserted that shared decision making about long term treatment was a human right. I think the same can be said of decisions about surgical options, except perhaps in dire emergencies. This is very neatly set out in a viewpoint piece discussing the treatment options in acute appendicitis, perforated diverticular disease, and knee osteoarthritis. In each case there are non-surgical options, which are simpler and associated with less pain and shorter recovery time. On the other hand, they all carry a greater risk of operative treatment being required later on. So who should make the decision? “Physicians (meaning surgeons) should create a culture in which patients’ values determine the treatment outcomes that matter most. After all, patients are the ones who must live with the consequences.” The authors don’t underestimate the barriers:” Surgeons often lack the time or training to talk patients through these complicated trade-offs. They may have concerns about liability for untoward outcomes from unconventional treatment.” In fact, the surgeons I talk to seem to be getting on with shared decision making better than most kinds of physician. New types of consent form might be part of the way forward, both in surgery and in the rest of medicine.

Continuous glucose monitoring: DIAMOND & GOLD
It’s distinctly odd that the main regulatory mechanism for blood glucose should consist of hundreds of cell nests hidden in the organ that produces digestive enzymes. It’s proving extremely difficult to replicate them, either as tissue grafts or as insulin pumps. On the other hand, it’s quite easy to produce monitors that follow the up and down course of blood sugar in people with type 1 diabetes who inject themselves with insulin several times a day. So the flashy acronyms of these trials—DIAMOND and GOLD—hide a rather low carat message. DIAMOND was an American manufacturer sponsored trial of a continuous glucose monitor (CGM) made by Dexcom, and GOLD tested the same device without company sponsorship using a crossover design in Scandinavia.

In both trials, use of the CGM produced lower levels of HbA1c at six months than routine self-testing. The associated editorial usefully puts it all in context, pointing out the limitations of these short studies and the extra complexity for patients and clinicians involved in using continuous monitors. 

Lancet  28 Jan 2017  Vol 389
Dual citabines for pancreatic cancer
“If I had that, I’d go to a tropical island with a case of whisky. One way ticket,” whispered the registrar as we passed by the bed of a bright yellow, emaciated man on my first medical firm in 1973. I’ve probably told you that story before, but it bears repeating because the prognosis of pancreatic cancer has hardly changed at all since then. Until now. This British trial is not exactly a breakthrough, but it is definitely an advance, and it used two drugs that have been in clinical use for a long time: gemcitabine and capecitabine. “The median overall survival for patients in the gemcitabine plus capecitabine group was 28.0 months (95% CI 23.5–31.5) compared with 25.5 months (22.7–27.9) in the gemcitabine group . . . The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma.” Hard to argue with that. But when they stop working and I go greeny-yellow, please buy me that one way ticket to Antigua and a couple of sampling cases from the airport malt whisky shop. Actually, cancel the latter. It’s all overpriced, and there is plenty of nice rum on Antigua.

Personalising smoking risk advice
For most smokers, the best thing you can do for their health is help them to quit. Maybe one good motivator might be to show them how smoking relates to their individual risk of bad things happening, and this is what this trial attempted. Smokers aged 18 and over who wanted to quit were randomised to receive either an individually tailored risk letter and invitation to attend a no-commitment introductory session run by the local Stop Smoking Services (intervention group) or a standard generic letter advertising the local SSS (control group). It worked, though at the disappointingly low level we’ve come to expect from smoking cessation trials: attendance at the first session of a SSS course was significantly higher in the intervention group than in the control group (17.4% vs 9.0%]. Note that this is just the attendance rate, not the quit rate.

How Americans die
The authors of this survey of premature death in the US derived little comfort from their exercise: “The magnitude of annual mortality increases in the USA is extremely unusual in high income countries, and a rapid public health response is needed to avert further premature deaths.” Well, Donald Trump has shown himself good at rapid responses: all it needs is for somebody to explain to him what public health means. He will be displeased to learn that while premature mortality has fallen between 2000 and 2014 in Hispanic individuals, black individuals, and Asians and Pacific Islanders, it has risen in young and middle aged (25–49 years) white individuals, and American Indians and Alaska Natives—primarily because of potentially avoidable causes such as drug poisonings, suicide, and chronic liver disease.

The BMJ  28 Jan 2017  Vol 356
PCSK9 inhibitors
A beautifully clear editorial explains what we know and don’t know about the much hyped new class of cholesterol lowering agents, the antibodies to PCSK9 (proprotein convertase-subtilisin/kexin type 9). At the moment we know that they are very good at lowering low density lipoprotein (LDL) cholesterol, but we don’t have any data about long term cardiovascular outcomes or harms. To that extent, the subtitle of the editorial, “New drugs, same old problems,” may be true, but in other ways it doesn’t reflect the careful arguments of the authors and I suspect it doesn’t come from them. The adverse effects of the PCSK9 inhibitors are almost certain to be different from those of statins and other lipid lowering drugs, and they may lie largely in loss of effect of time (which has already led to the withdrawal of one agent) and various unintended metabolic effects. Time will tell.

Who says you’re disabled?
A Swiss systematic review looks at the literature on inter-rater agreement in the assessment of disability. Millions of people’s lives are permanently affected by such decisions and billions of pounds/dollars/euros are spent or withheld as a result of them. The standard way of giving a numerical value to qualitative inter-observer agreement is Cohen’s kappa co-efficient, which, although a bit slippery to handle, is at least intuitive in the way it expresses agreement: 0 or less for no agreement, under 0.5 for lousy agreement, 0.8 or more for good agreement. The striking finding of this review was that in research studies, which were done for the sake of knowledge alone, kappa (κ) values were high because standardised assessment instruments were used. But in insurance based studies, where real lives and big money are at stake, κ -values were all over the place, even going into sub-zero territory for non-somatic disorders. Worse than a toss of the coin. Maybe things are better for disabled people in the UK now that the contract with Atos (of that coin) has been withdrawn. But I wouldn’t like to bet on it. “Despite their common use and far reaching consequences for workers claiming disabling injury or illness, research on the reliability of medical evaluations of disability for work is limited and indicates high variation in judgments among assessing professionals.” Badly constructed sentence, good sentiment.

A head to head drug RCT in The BMJ
Goodness, I wrote the previous section without realising that the next one would be about a drug called Atosiban. I like it already. Its competitor in this head to head trial is fenoterol, about which I couldn’t give a . . . fig. But actually, if you want to perform external cephalic version for breech presentation, you may be slightly better off using fenoterol than atosiban. Presentation at birth was cephalic in 35% (n=139) of the atosiban group and 40% (n=166) of the fenoterol group (0.86, 0.72 to 1.03)—only better than a toss of the coin if you toss it fewer than 20 times. The real clincher is price: 90 cents for fenoterol, 3180 for atosiban.

Distress and cancer mortality
Does being distressed predispose you to certain kinds of cancer? There are 16 British cohort studies that could provide data about an association, although in the end all these satnav suggestions end with the lorry getting jammed in the village of Residual Confounding. “After adjustment for age, sex, education, socioeconomic status, body mass index (BMI), and smoking and alcohol intake, and with reverse causality (by left censoring) and missing data (by imputation) taken into account, relative to people in the least distressed group (GHQ-12 score 0-6), death rates in the most distressed group (score 7-12) were consistently raised for cancer of all sites combined.” But the next bit—hypothesis testing by a prospective experiment—is simply not possible, so that’s where the lorry will remain stuck.

Plant of the Week: Prunus x subhirtella “Autumnalis”
The only excuse for not having a winter flowering cherry in your garden is gross lack of space (though it is a petite tree) or locally prevalent bacterial canker. Otherwise it is your public duty to grow one in a place where it can cheer people up during the dismal weeks of waiting for spring.

We’ve now lost three winter cherries to bacterial canker, so I consider that I am excused from further active service. The bacteria that kill Prunus species are two closely related kinds of Pseudomonas. This omnivorous genus is characterised by a massive genome, which allows it to outwit all human attempts to eradicate it. Once your prunus starts wilting, just cut it down, dig up its roots, and burn the lot.

But do try and grow it, at least once. All who see it will be reminded of the beautiful succession of flowering trees in the months to come: almonds, cherries, magnolias, lilacs, apples, hawthorns, and limes. Bring it on.