Richard Lehman’s journal review—7 July 2014

richard_lehmanNEJM 3 July 2014 Vol 371
11  I don’t envy anyone with central lumbar spinal stenosis. The odds of benefit from surgery are slight. The pain can be there all the time and always gets worse on walking, which can limit activity severely. No wonder epidural steroid injections have proved popular. In this study, they were carefully given with lidocaine using fluoroscopic guidance, and at six weeks they resulted in a small but useful reduction in a disability score and a leg pain score. The control group, who received epidural lidocaine alone, fared equally well. Moral: you don’t need the steroids. It may even be that you don’t need the lidocaine. Saline may be as good. In fact, gowning up and inserting the needle may be enough. In a way, I would rather not know, especially if I had spinal stenosis.

22, 32  My heart sank last week when two papers appeared on the NEJM website with the titles Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease, and Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease. I resolved to ignore them. However, Harlan Krumholz ‘s comments on them really have to be read: “This research”, he said, “has absolutely no implications for clinical practice. It might one day be seen as a pivotal study that led to the development of remarkable drugs, but that is far away. I hope people don’t read it and think that it has relevance to their current decisions about treatment.”

42  In the late 1990s, Harold Hin, one of my practice partners, carried out a study of coeliac disease in adults living in our little town, using a newly available antibody test. We were astonished to find that 1% of Banburians had the condition, confirmed in every case by duodenal biopsy. Does that mean that they all had coeliac disease (CD) from birth? The latest study from a childhood cohort called TEDDY sheds some light on this conundrum. The Environmental Determinants of Diabetes in the Young (TEDDY) is a multinational study that follows children at high genetic risk for type 1 diabetes, with the development of coeliac disease as a secondary outcome. It happens that the genotypes that are associated with a high risk of type 1 diabetes are also associated with a high risk of CD. During the median follow up period of 60 months, 12% of the at risk children became positive for tissue transglutaminase antibodies, which are specific to CD. Seroconversion rates were higher in Sweden than elsewhere. So we are beginning to unravel the mysteries of coeliac disease, but there seems to be an environmental factor that we still haven’t pinned down and that is lurking in Sweden. Some kind of wholewheat cracker eaten with smoked fish, probably.

JAMA Intern Med July 2014
Four years ago, John Yudkin drew my attention to a study that had just appeared in the Archives of Internal Medicine, illustrating a new and radically patient centred kind of modelling for “utility versus disultility” in long term treatment. It appeared under the banner of “LESS IS MORE” and bore the title: “Variation in the Net Benefit of Aggressive Cardiovascular Risk Factor Control Across the US Population of Patients With Diabetes Mellitus.” It should have shaken the world but, as so often in this field, it was politely ignored because it ran counter to the standard model of practice. John had heard that the Michigan authors had another paper up their sleeve, dealing with the individual utilities or disutilities of varying degrees of glucose control in the same population. We grew so eager to see this published, that John went over to recruit Harlan K at Yale to join forces in urging Rod Hayward to complete work on it. I joined the trip and my life was changed, but the study has only now been published.

Everybody should read it. “Treating patients with HbA1c levels less than 9% should be individualized on the basis of estimates of benefit weighed against the patient’s views of the burdens of treatment.” Do you dare to have this discussion with your patients with longstanding type 2 diabetes mellitus? Or with any other patient you have “put on” long term treatment? “We estimate that the expected gain in QALYs for a 1-point change in HbA1c level in a 75-year-old is 0.06 years (22 days), even with the favorable assumption that glycemic control’s cardiovascular benefit extends to the elderly.” Now go back to their original paper and think hypertension.

Lancet 5 July 2014 Vol 384
29  To celebrate 4 July, the Lancet is stuffed with papers about the health of the United States of America. Do these ungrateful rebels who spurned King George’s gracious offer of pardon with their impudent Declaration really deserve such attention from a British journal? When did we last see the New England Journal of Medicine mark the birthday of Her Majesty the Queen with a special issue devoted to Great Britain? The two research papers in this issue are both American and mark the extremes of medical investigation. This first one is concerned with a question of great importance to millions of women, who have experienced one or two miscarriages before 20 weeks’ gestation. Women in this situation were randomized to 81mg aspirin daily taken with folic acid before conception, or to folic acid alone. There was no difference in outcomes.

37  And now for a paper that is bizarre even by the Lancet‘s standards. Biomarin Pharmaceutical have produced a “biological” product, which is aimed at reducing phenylalanine concentrations in adult patients with phenylketonuria (PKU). It has been crafted from recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol and its acronym is rAvPAL-PEG. In the US, there are about 10 000 adults with PKU. This was a phase 1 trial in 25 of them. “The sponsor designed the study, provided central data collection, and did the initial data analysis and interpretation of pharmacokinetic results. One medical writer created an initial outline of the report, and another helped to prepare the report for submission.” This was a single dose trial of a treatment designed for lifetime use. At the only dose that produced a useful reduction in blood phenylalanine, three out of five subjects developed a generalised rash. “By the end of the study, all participants had developed antibodies against polyethylene glycol, and some against phenylalanine ammonia lyase as well.”

Interpretation: “Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0•100 mg/kg was fairly safe and well tolerated in adult patients with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. In view of the development of antibodies against polyethylene glycol (and in some cases against phenylalanine ammonia lyase), future studies are needed to assess the effect of repeat dosing.” It’s terrifying to think that Biomarin may be planning phase 2 trials of this stuff. Maybe this is why the Lancet decided to publish this trial: to warn people with PKU.

The BMJ 5 July 2014 Vol 349
There is only one BMJ, just as there is only one Netherlands, Levant, Prince of Wales, Sudan, Ivory Coast, and United States of America. But to celebrate its nice new website, the BMJ has become The BMJ. So the two leading British medical journals now carry the definite article. How cute we are.

Network meta-analyses are a mixed blessing. Experts argue that by using a bayesian random effects Poisson regression model, you can preserve randomised treatment comparisons within trials. But that begs the question of how you can achieve dependable comparisons between trials, robust enough to guide clinical practice. Unfortunately I was born with loss of function variants on my STATS-WONK alleles and cannot work that out. This network meta-analysis would have us believe that the era of COURAGE has come to an end: thanks to better drug eluting stents and techniques for coronary artery bypass surgery, people with stable coronary artery disease will now experience fewer deaths and myocardial infarctions if they have early invasive treatment. But I couldn’t dig out the figures that would allow me to share any decisions confidently with actual patients. I fear that this meta-analysis, which is very hard to confirm or contest, will simply be used as a pretext for interventionists to return en masse to their bad old habits.

Most weeks I am politely asked by a medical journal to peer review at least one paper. This can take me a couple of hours or more of unpaid work, but I am usually mug enough to say yes. I always try to make it clear that the only expertise I can offer is that of someone who has seen an awful lot of patients and read an awful lot of journal articles. Peer review is often derided as an ineffective and obsolete ritual. Maybe it is. Certainly if you look at it as a way of checking reporting accuracy, it is pretty hopeless, as this survey of BioMed Central series medical journals reveals. If this is what journals expect me to do, they can forget it. They should have in-house people to do this kind of thing, or they should hire someone with a fully functioning set of STATS-WONK alleles and a reasonable hourly rate.

I spent a year in the company of two doctors from Brazilone of them a professor of cardiologyand glimpsed a picture of a half developed health system, with greatly varying patterns of primary provision. Why is it that doctors everywhere prefer to enjoy autonomy and wealth and live comfortably in cities rather than do hard, unsexy, tiring work in remote townships among the needy poor? This, essentially, is the big problem for all developing health systems throughout the world. The first to come up with an answer will achieve the best results for its population. It is happening in some parts of Brazil, which has set up the Family Health Program (FHP), the largest primary health care programme in the world. “FHP coverage was negatively associated with mortality rates from cerebrovascular and heart diseases (ambulatory care-sensitive conditions) in both unadjusted and adjusted models for demographic, social, and economic confounders.”

Plant of the Week: Nicotiana tabacum

The lovely, night scented garden nicotianas are relatives of this evil plant, which is the source of most commercial tobacco. It was not only King James I of England who detested the new practice of tobacco smoking in early seventeenth century England. The first great English nonsense poet, John Taylor (1580-1653), wrote the following around 1620:

Barbarian Verses

Certaine verses written in the Barbarian tongue, which I thought good to insert, because they tend to the honour of Tobacco.

Vaprosh fogh stinkquash slavorumques fie fomintoshte
Spitterspawlimon, loatherso hem halkish spewriboshte
Mistrum fog smoakrash, choakerumques olife trish trash.
Dam dirticun belchum, contagioshte vomarroshe:
Whifferum, puffe gulpum, allisnuff huff fleaminon odish,
Rewmite contaminosh diabollish dungish odorish.

from The Origins of English Nonsense, Noel Malcolm, London 1997.