Richard Lehman unpicks the problems of so much modern medicine
NEJM 19 Oct 2017 Vol 377
This week’s NEJM sports two trials of tofacitinib in psoriatic arthritis. If you are seized with an overwhelming desire to move on to the next item, please try to resist it. Regard this as a learning opportunity. Psoriatic arthropathy may be a relatively uncommon condition, but most of its inflammatory pathways are shared with commoner conditions such as rheumatoid arthritis and the inflammatory bowel diseases. There are actually not that many known pathways, and the commentary on the current trials summarizes them as:
- tumour necrosis factor
- interleukins 12, 17 and 23
- Janus kinase pathways.
The complexity comes when you get to all the drugs which have been developed to modulate these pathways: inibs and mabs in profusion, typically costing £690/month (tofacitinib) or £704/month (adalimumab). Methotrexate might cost £10 a month.
OK, so here you have the problems of so much modern medicine. Poor knowledge of aetiology (what actually causes psoriasis and what makes some people get joint involvement?), old cheap blunderbuss treatments (steroids, methotrexate, cyclosporin) with known harms and benefits, new very expensive drugs which are allegedly more pathway-specific, but whose long-term harms and benefits are less well-known. How do you sit down with a patient and decide which to use? Is the evidence fit for purpose, or do some of the trials seem to be more about marketing the latest drug than helping clinicians and patients work out which is best in a particular clinical situation?
With tofacitinib, we now have the OPAL Beyond trial, which shows that the active drug is more effective than placebo over 3 months. But over the course of 6 months, there were four serious infections, three herpes zoster infections, one myocardial infarction, and one ischaemic stroke among the 264 patients (mean age about 50) who received tofacitinib continuously. In the other Pfizer-funded trial, OPAL Broaden tofacitinib was compared both with placebo and with adalimumab. The abstract reports: “The efficacy of tofacitinib was superior to that of placebo at month three in patients with psoriatic arthritis who had previously had an inadequate response to conventional synthetic DMARDs.” Er, yes, but what about the adalimumab group? They did just as well. And moreover “There were four cases of cancer, three serious infections, and four cases of herpes zoster in (316, mean age 47) patients who received tofacitinib during the trial.” That seems an awfully high incidence for a trial lasting a few months. Sitting down with a patient who has psoriatic arthritis and a bang up-to-date decision tool, I’d be surprised if she opted to take tofacitinib.
JAMA 17 Oct 2017 Vol 318
Oral v subcutaneous semaglutide
In a phase 2 NovoNordisk trial of semaglutide there was a remarkable 1.9%* lowering of HbA1c, made even more remarkable by the fact that it was achieved by a peptide travelling through the stomach, where normally it would have been destroyed. This feat was achieved by the use of the absorption enhancer sodium N-[8 (2-hydroxylbenzoyl) amino] caprylate (SNAC) added to 40mg semaglutide daily. This combination proved equivalent in effect to 1mg weekly by subcutaneous injection, meaning that the oral dose of semaglutide was 280 times higher by mouth than it is in the standard injection. I find it hard to believe that absorption of the oral drug can be anything but highly variable, but in the end most participants ended up on the 40mg dose and showed a good glycaemic response. Gastrointestinal adverse effects were very common and most patients lost weight. Oral dose titration was important: of those given 20mg daily from the start, 27% had adverse effects which made them stop. I can sort of see where this is going, but it’s only going to be possible to interpret once we have some phase 3 trials with full pharmacodynamic and pharmacokinetic data.
*from 7.9% to 6%: i.e. a relative drop of 24%.
Adding oral drugs to insulin in T2DM
Most oral drugs for type 2 diabetes lower HbA1c% by 1 or less, as shown by a useful summary of the evidence from a Cochrane Review of trials where oral agents were added to insulin treatment. Adding back metformin is often worthwhile: “In individuals with type 2 diabetes mellitus who do not achieve optimal glycaemic control, adding an oral blood glucose–lowering agent to insulin monotherapy was associated with a clinically meaningful decrease in haemoglobin A1c of 1% and a decline in insulin dose.”
Ann Intern Med 17 Oct 2017 Vol 167
Bioabsorbable everolimus stents: a requiem
A nicely conducted systematic review of bioabsorbable everolimus-eluting stents shows that they are three times more likely to thrombose within two years than permanent stents, and are associated with a 60+% higher rate of myocardial infarction which probably increases with time. The review is accompanied by an editorial called Requiem for a Scaffold. Moreover Abbott, the device manufacturer who made these stents, decided a few weeks ago to pull them from the market. So the coffin has been lowered and the first handfuls of soil are being thrown in…
The Lancet 21 Oct 2017 Vol 390
Bioabsorbable sirolimus stents: refusing to stay in the coffin
But it’s not all over yet. As the Abbott stent dies, the Biotronik bioabsorbable ultrathin sirolimus-eluting stent is born. Trying to follow the methodology of this paper will definitely make you lose the will to live. It is mostly about one trial in which the investigators “aimed to examine the clinical outcomes of a bioresorbable polymer sirolimus-eluting stent compared with a durable polymer everolimus-eluting stent in a broad patient population undergoing percutaneous coronary intervention.” OK: so that’s a non-biodegradable everolimus stent compared with the new one. Then “the primary non-inferiority comparison combined these data from two additional randomised trials of bioresorbable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent with Bayesian methods.” By doing this they exceeded “non-inferiority” and make the claim that their ultra-thin product is superior, and even that it “suggests a new direction in improving next generation drug-eluting stent technology.” No, no: haven’t we suffered enough already?
Inflammatory bowel disease across the globe
Ulcerative colitis, which often presents dramatically and can kill young people, was first described in the 1870s; whereas Crohn’s disease, which can present obscurely and still often takes years to diagnose, was first described in the 1930s. We don’t know what causes them or indeed how many diseases they really represent. A number of distinguished authors map the worldwide incidence and prevalence of inflammatory bowel disease in the 21st century by means of a systematic review of population-based studies. The illustrations are fascinating, with many gaps: most of Africa, for example, and more surprisingly Poland and the Balkans too. The clear pattern which emerges confirms that “Western lifestyle” and high latitude are associated with marked increases in the incidence and prevalence of IBD, but exactly why remains a mystery, and the authors wisely decline to speculate.
The BMJ 21 Oct 2017 Vol 359
Increasing self-harm in young Britain
As Ben Goldacre’s tweets constantly declare, my generation has done incalculable harm to young people in Britain. In this narrative, we have made housing unaffordable, pulled the ladder from behind us, filled the roads with cars, diminished the income of the young in favour of our fat pensions etc.—all of which is true, but largely unintentional. To this we (not including me, I hasten to add) have now added the intentional disaster of Brexit. I am ashamed to be old and British, but so far I have not self-harmed. This too we leave to the young, particularly young teenage girls. Read this survey based on the UK Clinical Practice Research Datalink, and depress yourself even more.
Lie down, poppet
Is the word “poppet” unique to British midwives? I can’t say I’ve ever heard it used outside a labour ward, except as an adjective to describe the steam valves which Sir Nigel Gresley used to achieve the beautiful clean lines of his express engines. Apparently it’s the same word as “puppet”, and was originally used of an object that people would stick pins into, like most women on labour wards. Maybe that explains it. Here’s a trial which tells us that if a nulliparous woman has been stuck with an epidural, she should remain supine during the second stage of labour. Don’t go walkabout, poppet, lie down.
Plant of the Week: Rosa “Mlle Cécile Brünner, Climbing”
Which exactly is “The Last Rose of Summer”? We have several roses at the moment which look good to go into November, of which the most surprising is the old French/Californian climber, Cécile Brünner.
From the time we first planted it, this was covered with sweet-smelling exquisitely formed smallish pink flowers every May-June, making it quite a sight on the corner of our village lane. The greatest authority on roses, the late Graham Stuart Thomas, comments that “Unfortunately the climbing form flowers only very sparsely after midsummer,” and for about ten years our plant obeyed his instructions.
But now that the dear man is dead, it has happily decided to go ahead and flower whenever it pleases. Over several years, we have had several generous flushes well into late summer, and this year we are enjoying the latest yet. The flowers are too high to pull down and smell, but they are still a joy to see from far around.
Later in the winter, the rose will need pruning hard to maintain its beauty for the year to come. This is never a pleasant task. I have previously referred to Mlle Cécile as Our Lady of Pain, because her widely flung branches are covered in sharp thorns, and it is virtually impossible to escape blood being drawn. It is a price worth paying.