Richard Lehman’s journal review—8 May 2017

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM  4 May 2017  Vol 376

Janus kinase inhibitor for ulcerative colitis

“In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo.” Is placebo the usual treatment for UC? Actually this sentence in the abstract does not do justice to the design of the three OCTAVE trials which are bunched up in this article. The participants received lots of other treatment too: “Patients were required to have had treatment failure with or to have had unacceptable side effects from treatment with at least one of the following agents: oral or intravenous glucocorticoids, azathioprine, mercaptopurine, infliximab, or adalimumab. Permitted concomitant medications for ulcerative colitis were oral aminosalicylates and oral glucocorticoids (at a maximum dose of 25 mg per day of prednisone or a prednisone equivalent), provided that the medications were administered at a stable dose throughout the induction trials; in the maintenance trial, tapering of glucocorticoids was mandatory.” So this paper about the Janus kinase inhibitor tofacitinib may be important, but I have no idea about its likely place in the management of UC in 2017. This needs a careful network meta-analysis based on individual participant data, and I hope that Pfizer, who ran the trials, will make this possible right away.

Bystander efforts in cardiac arrest

Without a randomised trial, it’s hard to be sure about the value of attempted out-of-hospital resuscitation for cardiac arrest. But since there’s unlikely to be such a trial, we’ll have to judge from observational evidence like this nationwide survey from Denmark. Data were available for 34,459 people, of whom 8.3% survived to 30-day discharge. Those who reached this point did somewhat better if they had received bystander CPR than if they hadn’t, in terms of brain damage or nursing home admission. But we are talking about small subsets of the 8.3% subset. It’s a signal for some effect, but there could be hidden confounders.


I know that there is deep logic in the naming of monoclonal antibodies, which tells you how they are made, but not what they do. But when you get to teprotumumab, isn’t it time to think again? Go on, try to say it. Bet you can’t without stumbling. Have a coffee, come back, and see if you can remember it without looking. See: if a word can’t be said or remembered, then it isn’t doing its job. It’s not even a word. If they called it preposterumumab, you might have a chance. It’s got silly. Sillymab. Sillyumumab. Sillyumusillymab. Sillysillyumuizumab. Teprotumumab is a human antibody against teprot. Oh no, that can’t be right. There is no such thing as teprot. Teprotumumab is a monoclonal antibody which binds to the insulin-like growth factor I receptor (IGF-IR) and it should be renamed igfirumumumab. You could use it for thyroid-associated eye disease. “In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001).

JAMA 4 May 2017  Vol 317

Conflicts of Interest

It’s two years now since the NEJM ran a series of three articles on “Reinterpreting Industry-Physician Relationships” and JAMA followed with one suggesting that we should be celebrating confluences of interest rather than conflicts of interest. Our eyes were led to a pastoral landscape in which clinician lambs lie down next to harmless pharma wolves, charmed by the soft flutes of garlanded shepherdesses. Alas, snarling voices soon broke the idyll. Call me an outsider, but American medicine just doesn’t look like that from where I am. And with conflicts of interest, appearances count—that’s a recurring theme in this special issue on the subject, containing 23 open-access Viewpoint articles. It is the central message of the tightest of these very variable pieces—”Why there are no ‘Potential’ Conflicts of Interest” by Matthew McCoy and Zeke Emanuel. Reading the rest is mostly a matter of endurance—it’s not that the subject isn’t important, but there is enough waffle here to fill an entire Circumlocution Office. And despite the number of articles, some important areas don’t get a mention. To me, one of the greatest problems in medicine is the collusion between academics seeking money and industry in search of a plausible narrative for selling products. Together, they create a delusive model which can last for decades: for example glucose lowering as the main target for type 2 diabetes, the renin-angiotensin system as the main target in heart failure, stents for aymptomatic coronary narrowing, LDL-C lowering as the key to cardiovascular risk reduction. The role of academe is to question lucrative dogma, not to join the feeding frenzy. However, to break the gloom you can switch to JAMA’s livelier sister-journal, JAMA Internal Medicine, and read a study of how financial conflicts of interest did not seem to influence voting behaviour at meetings of the US Food & Drug Administration.

JAMA Intern Med  May 2017  Vol 172

Antimicrobial training in Dutch hospitals

The Dutch Unique Method for Antimicrobial Stewardship is a thoroughly earnest exercise for improving the use of antimicrobial agents in hospitals. The acronym DUMAS commemorates the pleasure-loving French writer best known for his counts and musketeers. In this trial, the clinicians could load their muskets as they chose, but were told which balls were most likely to reach the target. The results were then counted. There was a 13% reduction in the prescribing of the drugs deemed inappropriate, but total antibiotic prescribing did not fall.

Alternate day fasting

I’m not sure if anyone has written a history of fasting, but it seems a very widespread phenomenon, mostly associated with religious cleansing of the body. Even among New England Protestants, Solemn Days of Fasting were occasionally imposed up to the eighteenth century. In modern-day Chicago, 100 people who wanted to lose weight agreed to be randomised to alternate-day fasting or a continuous calorie-restricted diet for a year. You’ll have read about this already. There was no difference between groups in weight loss achieved (a hefty 6%), adherence, or cardiovascular risk markers. More pain, same gain.

The Lancet 6 May 2017  Vol 389

Why do heart failure drugs work so poorly?

“When compared with the effect of β blockers and mineralocorticoid receptor antagonists, the magnitude of the clinical benefits associated with inhibition of the renin-angiotensin system in heart failure has been modest.” This is true, and it’s nice to have it come from Milton Packer and John McMurray, who have led the field for twenty years, during which I’ve courted unpopularity for pointing this out repeatedly. “Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions,” they say, and the same is true of increasing dosages. I still lose friends in the heart failure community by arguing the futility of uptitrating ACE inhibitors. But having discoursed on the limitations of ACEs and ARBs in heart failure, the authors of this review paper now propose the solution: potentiation of endogenous compensatory vasoactive peptides. That means stopping the breakdown of natriuretic peptides. But all the original trials of neutral endopeptidase inhibitors alone or in combination with ACE inhibitors flopped. Then along came the PARADIGM-HF trial. I don’t want to get too geeky here, but this had a contentious design and a dodgy comparator. This article packs in a lot of meat and should be read by anyone who treats heart failure, but I am not convinced that it holds the key to future therapeutic improvement. Perhaps nothing does. Perhaps better symptom relief is more important than a small and individually uncertain extension of survival in people near the age of 80.

Statins: pains in the mind or the muscles?

Statins are a pain in the mind. The worst migraine I’ve ever had came from trying to write an editorial about them for The BMJ. I gave up the attempt in the interests of personal survival. As a GP, I prescribed statins liberally and with conviction for nearly two decades. If people came complaining about muscle pains, I would reassure them, stop the drug for a while, and then try a different one at low dosage. Several patients, including some doctors, were desperate to continue because they had established coronary disease. But every time they tried to exercise, they hit a barrier, which disappeared after stopping the statin. Is this “muscle pain”? Would it have been classed as such in the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial? I’ve no idea. I’ve no idea how many elderly people taking statins have stopped going out to the shops because of what they put down to old age, or how much that may be due to statins. All I know is that when authority figures remote from primary care dig out old studies to prove that it’s all a figment in the imagination of the people who actually take or prescribe the drugs, I get rather cross and feel a migraine coming on. This silly argument can only be resolved with prospective studies and some understanding of how decisions are made in real life.

Weight Watching

The human body is primed to gain weight in times of plenty, and keep hold of it in times of dearth. Fighting this basic survival mechanism through will alone is impossibly tough for most people, especially when they are surrounded by food. Here’s a randomised trial of a weight reduction programme which favours Weight Watchers over 12 weeks, speculating that 52 weeks might be better. Read it if you will: it is open access. Five of the authors have received institutional funding from Weight Watchers.

The BMJ 6 May 2017  Vol 357

Deciding when to unblock stroke arteries

These are exciting times in medicine. Soon I’ll be too old to keep up with developments, but there are lots of brilliant youngsters who will ensure progress. I’m not talking about designing clever gizmos like platinum retrieval stents for clots in the anterior brain arteries. That’s great, but I mean the more difficult work of sharing decisions about such things with patients. Re-orienting medicine towards real common understanding is an art of which we know little and are taught less. It is a science too, of analysis, synthesis, and information transfer. It’s great to see The BMJ at the forefront of that science with articles like this one from the Netherlands about the development and validation of a clinical decision tool to guide intra-arterial treatment for stroke. It’s tough going but the result is a usable tool based directly on trial data.

Limited evidence leads to bad FDA approvals

Saving the best for last, here is a remarkable paper by a Yale medical student, Alison Pease, under the guidance of Joe Ross and Harlan Krumholz, among others. And it could not be more timely. An absurd delusion, common to Donald Trump, David Cameron, and Lord Saatchi, is that drug regulation is depriving patients of life-saving drugs through an excess of bureaucracy. On the contrary, regulators are desperately trying to protect the public from wave after wave of over-hyped, over-priced ineffective treatments based on worthless evidence. Both NICE in England and the Food and Drug Administration in America have come close to collapse, and for most of a decade the FDA has been pressured into giving fast-track approval to many products which have subsequently proved worthless. Here is a survey of 117 novel drugs approved for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials).

These were followed by post-approval clinical trials of varying quality and mostly inadequate size. Approximately 90% of postapproval studies of drugs for indications approved on the basis of surrogate markers also used surrogate markers of disease for trial endpoints. Do read this paper: I’m delighted and proud to admit that the authors are mostly friends, and Alison, whom I haven’t met, is clearly a coming star. But the main point is that fewer than 10% of approved indications were subsequently supported by one or more published randomized controlled, double blind studies showing superior efficacy based on clinical outcomes that examined the same indication for which the drug was first approved by the FDA after a median of 5.5 years after approval. In other words, the system is broke, and Trump wants to stamp on the bits that are left.

Plant of the Week: Gentiana verna

We’ve never kept a gentian alive for more than a year in our garden, and I don’t expect we’ll do any better with the little native spring gentian we’ve just carefully installed into our front rockery. The very word “rockery” breathes suburbia, and these are not suburban plants. Gentiana verna grows wild on limy moors that are saturated with constant fresh rain which drains away quickly: you can see their brilliant blue stars of flower in abundance in places like Teesdale and western Ireland, I’m told. But nowhere else in Britain, outside cultivation, where they live for a maximum of three years, according to experts.

At about £2 a piece, we’ve decided we can treat them as bedding annuals. It still seems a travesty, like keeping a kingfisher in a cage to admire its shiny plumage, and buying another each time one dies. But such is gardening. And spring gentians come and go more easily.