Richard Lehman’s journal review—6 July 2015

richard_lehmanNEJM 2 July 2015 Vol 373
11 Liraglutide for weight loss. Like the second Iraq war, we knew for years that it was coming. The propaganda was laid out well in advance. “Obesity is a chronic disease with serious health consequences,” say the NovoNordisk authors. No it’s not, it’s a measure of body weight that carries certain risks. Likewise “pre-diabetes,” which is a blood level that in the majority of people does not lead to diabetes. And diabetes too is just an arbitrarily defined risk cluster, not a weapon of mass destruction. Moreover, if we are going to medicate every fat person in the Western world, we need long term outcome data, not just evidence of a drop in blood glucose and BMI. This 56 week trial recruited 3731 “patients” at 191 sites in 27 countries. Why? You could easily find that number of “patients” with BMI >30 (or >27 if at elevated risk) in any small township in the developed world. Nearly 80% of the people recruited were women. Why? “The sponsor, Novo Nordisk, planned and performed the statistical analyses, [and] provided editorial and writing assistance.” Why? Because everybody does it and the FDA doesn’t mind. Liraglutide will undoubtedly get its licence for use in weight reduction. Three mg daily would currently cost about £200 per month in the UK, and there are at least 15 million Britons who would meet the recruitment criteria of this trial. I make that a potential NHS bill of £36bn annually. Some NICE bargaining lies ahead. Let’s hope they will insist on long term outcome data, with a close look at the cost/benefit ratio and potential harms.

35 Aplastic anaemia is caused by the bone marrow packing up, right? Half right, it turns out. If I understand this American/Japanese study of bone marrow genomics (and it’s a big if), half of patients with aplastic anaemia actually display clonal haematopoiesis, and their marrows are a seething mass of unpredictable activity. Because it’s unpredictable, doing these analyses probably won’t help to individualise treatment. “Personalised” genome driven therapeutics is a lot more complex than we had hoped: once cell division has gone awry, it can be impossible to predict what it will do next.

48 Afamelanotide for Erythropoietic Protoporphyria. Now that’s the sort of title we look for in the New England Journal of Medicine. We immediately feel inadequate for never having heard of erythropoietic protoporphyria and we know that in 10 minutes we will deny ever having heard of afamelanotide. Well, why should we worry? Let’s move on.

8 Telling the truth was the central tenet of the Good Religion of ancient Iran (Zoroastrianism). I’m not sure what Zarathushtra would have made of the placebo effect. For a placebo to work, the patient must be deceived into thinking it might. So placebos are a work of druj (the Lie), and must emanate from Ahriman (or Satan), the father of lies. Using placebos must deprive the doctor of asha, or integrity, which is the true goal of human life. And yet there’s no doubt that they can provide symptom relief in all sorts of contexts and in quite complex ways. This perspective piece provides an interesting discussion. For example, “a recent study of episodic migraine demonstrated that when patients took rizatriptan (10 mg) that was labeled ‘placebo’ (a treatment that theoretically had ‘pure pharmacologic effects’), the outcomes did not differ from those in patients given placebos deceptively labeled ‘rizatriptan’ (pure expectation effect). However, when ritzatriptan was correctly labeled ‘rizatriptan,’ its analgesic effect increased by 50%. Similar results have been observed when other drugs, including morphine, fentanyl, and diazepam, have been administered openly and covertly and with procedures such as deep-brain stimulation for mobility symptoms in Parkinson’s disease.” But though this piece is fascinating and well written, it doesn’t discuss the Zoroastrian dilemma. Is it possible for doctors to use placebos effectively without losing integrity? And having lost that, is it possible to do truly good medicine?

OL There is no JAMA this week so I might as well catch up with papers on the NEJM website. Idarucizumab for Dabigatran Reversal. I guess most readers know dabigatran by now: it’s a direct thrombin inhibitor that’s been around for nearly eight years, marketed as Pradaxa. Nice when all goes well, but it can be a devil when it causes bleeding, because there is no antidote: hence the expression The Devil Wears Pradaxa. But now they have made idarucizumab. And they needed to make a lot of it because the effective dose to reverse bleeding due to dabigatran is 5 grams. Now we are told that monoclonal antibodies are really expensive to manufacture: a syringe filled with 50 micrograms of catumaxomab, for example, comes in at £2550. So if the same pricing was applied to idarucizumab, it would cost £255 000 000 per therapeutic dose. Market forces, innit? It’s a mad mab world.

OL It’s hard to believe that only 15 years ago, most of us didn’t know what “elute” meant. In fact, the word was borrowed from chemistry and changed its meaning when it was applied to coronary stents. Device manufacturers then made billions as every cardiologist rapidly switched from bare metal to drug eluting stents, on the basis of pretty flimsy evidence. The market for balloons to treat femoropopliteal artery disease isn’t the same size, but Lutonix-Bard clearly thought it was still worth a try. Because it is only in the artery for a short time, the paclitaxel-coated balloon doesn’t really “elute” the drug but simply pushes it into the arterial wall. And according to the LEVANT 2 trial, this produces slightly better outcomes at one year, although the Kaplan-Meier curve suggests that any advantage probably disappears not long after that. It will be interesting to see how much of a market share these balloons achieve on the basis of these data from a single manufacturer funded trial.

JAMA Intern Med July 2015
OL If you’re allergic to grass pollen, put some under your tongue. And then a bit more. It’s an appealing idea and to some extent it works. But the Italian authors of a systematic review and meta-analysis of the 13 randomised trials are not impressed. There was small symptomatic benefit and a small reduction in medication use. Sublingual immunotherapy for the treatment of seasonal allergic rhinoconjunctivitis is hardly worth it, they conclude.

OL In last week’s reviews I mentioned the overuse of antibiotics in nursing homes. Here’s a survey that gives some detail about the American situation. Antibiotic use ranges from 20.4 to 192.9 antibiotic days per 1000 resident days. Wennberg’s Law: if you want to detect bad practice, look at patterns of variation. If it’s nearly tenfold then some small area in this spectrum is right, and the rest has to be wrong. Antibiotic related harms showed a clear relation to rates of use, affecting all residents, not just those given the drugs. For once I feel on side with Sally Davies.

Lancet 4 July 2015 Vol 386
OL In case you haven’t noticed, I’m getting a bit sick of monoclonal antibodies. Perhaps we should call them sickenyoumabs. But wait, no, we might get sued by Novartis who already have a patent on a similar sounding compound called secukinumab. The US cost is just over $2000 per 150mg injection. It’s used for psoriasis and it’s already got its licence. Several trials have already been published. Here’s a placebo controlled trial in people with psoriatic arthritis, which showed that given weekly for a month and then monthly at a dose of 150mg or 300mg, it produced some benefit in about half of the participants at six months. These patients had already tried other drugs including TNF blockers with little success, so perhaps secukinumab will find a small place in clinical practice. The annual bill seems likely to be $30K-60K.

OL Phew, at last a trial that aims to cut costs and increase patient convenience. Needless to say, it was publicly funded. Patients with exacerbations of multiple sclerosis are often whisked into neurology units and given intravenous methylprednisolone 1000 mg, once a day for three days. I once asked a neurologist why they had to have it IV, and was told that the amount was so huge that it wouldn’t be tolerated orally. This French trial proves the opposite. And it had just the same benefit taken by mouth.

OL Does the world need a vaccine against Helicobacter pylori? We hear a lot about its associations with peptic ulceration and stomach cancer, but it’s part of the microbial ecology of most humans and getting rid of it for a lifetime takes us into uncharted territory. And now, thanks to Chongqing Kangwei Biological Technology, we may be able to do that by giving three doses of oral vaccine to children aged 6-15. I rather enjoyed reading about this trial, which used straightforward methods of randomisation and blinding in 4464 participants from 12 schools at one centre in Ganyu County, Jiangsu Province, China. In the first year, vaccine efficacy was 72%. By three years, some participants were already lost to follow-up, which is a pity because this is an important human experiment.

The BMJ 4 July 2015 Vol 351
A serious bit of fun: inspired by Edwin Gale, three Amsterdam juniors look at the phenomenon of the “supertrialist” in papers about glucose lowering therapy for diabetes. “Some authors have made a disproportionate contribution to the therapeutic evidence base; one third of the RCT evidence base on glucose lowering drug treatment for diabetes was generated by <1% of authors. Of these, 44% were company employees and 56% were academics who work closely with the pharmaceutical companies.” There’s also a spectacular graph, which shows something like a 50 fold increase in the number of RCTs for sugar lowering drugs between 1993 and 2013. You couldn’t make it up. It’s a kind of flooding. Even, to use a horribly overworked metaphor, a tsunami. I am running out of rant words.

But there is one drug that really works for diabetes. It’s called insulin. Whether any of the “advanced” insulins of the last two decades are any advance at all on the old beef or pork insulins is a moot point, but for type 1 diabetes, new delivery systems do seem to be making a real difference. An observational study from Sweden shows that among people with type 1 diabetes, use of insulin pump therapy is associated with lower cardiovascular mortality than treatment with multiple daily insulin injections. They adjust for what confounders they can, and find that over a seven year period, those using pumps had a hazard ratio of 0.55 (95% confidence interval 0.36 to 0.83) for fatal coronary heart disease, 0.58 (0.40 to 0.85) for fatal cardiovascular disease (coronary heart disease or stroke), and 0.73 (0.58 to 0.92) for all cause mortality. That really is good news.

As the GP overdiagnosis campaign gets going, I’m so glad to see this analysis piece from Martin Miller and Mark Levy about the GOLD criteria for diagnosing chronic obstructive pulmonary disease. “The current NICE guidelines and the GOLD strategy documents for COPD should be modified because they overdiagnose COPD in older men while missing the possibility of diagnosing heart disease; they also underdiagnose COPD in young women.” This has been obvious for ages, but NICE reminds me of the French generals who locked themselves up in a bastion 90 miles from the front when Hitler attacked, and would only accept written messages delivered by official motorcyclists. By the time they got their bits of paper, the German tanks had already outflanked them. Why, in 2015, does evidence synthesis proceed over a timescale of years rather than days?

Plant of the Week: Phygelius aequalis “Trewidden Pink”

The cape figwort most seen in garden is the one with soft yellow flowers called Yellow Trumpet. We’ve had it for ages, and on a hot clay bank it has taken to dying off bit by bit, while forming healthy suckers in a single direction. In this way, the whole plant appears to have moved itself by about a metre from its original position. I feel I need to report this interesting fact.

A similar fate has not yet befallen a clone called Trewidden Pink. In its third year, it is luxuriant with shiny semi-evergreen leaves and innumerable soft tangerine/pink trumpets.

When the wonders of June come to a sudden end, these little shrubs really come into their own. They seem to need no kind of maintenance and their suckering habit means you can give away bits to any passing admirer.