Richard Lehman’s journal blog—24 June 2013

Richard LehmanJAMA  19 June 2013  Vol 309
2449   If you give live attenuated measles, mumps and rubella vaccine to children with juvenile rheumatoid arthritis who are on immune suppressing treatment, are they going to make enough antibodies? Or might you risk a flare-up of their disease activity? A carefully conducted Dutch study finds that there is no need to worry: it is immunogenic without any observable increase in rheumatic flare-ups.

2457   The busy Dutch organised the next trial too, called GRANULOMA. The granulomas they were looking for were those of early sarcoidosis, and they set out to compare the diagnostic yield of bronchoscopy with transbronchial lung biopsies—the current standard method—with endosonography and intrathoracic nodal aspiration. It all sounds a bit challenging to those of us who are not accustomed to poking about in the thorax with sharp instruments, but the ultrasound technique gets the better yield in suspected stage I/II pulmonary sarcoidosis.

2473   Type 1 diabetes is on the increase, for reasons which are harder to understand than the increase in type 2 DM, but this study demonstrates that there is a definable group of children in whom the risk is predictable long before the disease develops. It looked at the levels of islet cell antibodies in three cohorts of children at increased risk of T1DM who had regular sampling from birth onwards. “All 3 studies measured autoantibodies against insulin, glutamic acid decarboxylase 65 (GAD65), and insulinoma antigen 2 (IA2) from multiple samples taken throughout childhood to identify the age of islet autoantibody seroconversion. …The majority of children at risk of type 1 diabetes who had multiple islet autoantibody seroconversion progressed to diabetes over the next 15 years.” Expect plenty of clinical trials of new interventions to follow.

2480   Here is an outcome analysis of thrombolysis for stroke which leads the authors to call for even greater effort to ensure that stroke patients get intravenous tissue-type plasminogen activator (tPA) as quickly as possible. That’s one way of looking at it. The odds ratios are pitifully small and the cost implications are huge.

2489   The indefatigable Peter Gøtzsche is ever one for taking the battle to the enemy. Here he and two colleagues present the findings of their Cochrane review of regular health checks. Until recently this would have been the equivalent of launching a paintball attack on the Statue of Liberty. “There were no statistically significant favourable or harmful associations of general health checks with these outcomes [cardiovascular disease, cancer]. There was no association with hospital admission rates, disability, worry, additional physician visits, or absence from work.” Americans, this is one health cost you can cut right away.

NEJM  20 June 2013  Vol 309
2345   Lying awake thinking of pandemic flu? Read a great little summary of what we know about the mechanisms whereby avian influenza can turn pandemic. It could go either way, but the chances are that H7N9 will just fizzle out. On the other hand, in 1918 that did not happen; people would fall down in the street, tens of millions died…

2355   Here’s what you might call a tick-off trial: one that disposes of an intervention in one good randomized go. Does intensive blood pressure lowering in acute haemorrhagic stroke improve outcomes? Take 2839 patients and compare: there is no significant difference in outcomes between the normally treated and intensively treated groups.

2366   Outcomes research began around 1720, but is often dated to the studies of tonsillectomy conducted by J Alison Glover in the 1930s, who found no difference in the rate of infections and school absence in areas where the rate of tonsillectomy approached 100% and those where it was 10%. (Incidentally, do not be fooled by the “Alison”—this was an affectation: he was born plain Glover and enjoyed proving his manhood by shooting large mammals of every kind, including the Hun in the Great War.) And yet there are many parents who swear that tonsillectomy transformed the lives of their children: we now think this is largely because it can cure obstructive sleep apnoea (OSA). The trial reported here randomised children with OSA to immediate versus delayed adenotonsillectomy. See what you think. The conclusion reads: “As compared with a strategy of watchful waiting, surgical treatment for the obstructive sleep apnea syndrome in school-age children did not significantly improve attention or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of beneficial effects of early adenotonsillectomy.”

2385   Crizotinib is a Pfizer-produced drug which costs $115K if you live long enough to take it for a year. In this open-label, company-funded trial in a subgroup of lung cancer patients, that bought 4.7 months of progression-free survival, but no overall survival benefit in the interim analysis (think it over: I conclude that this means it delays visible return of the cancer but you still die as fast). “Conclusion: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non–small-cell lung cancer with ALK rearrangement.” Hmm.

2395   As if embarrassed to print the preceding trial (though perhaps not to receive reprint money for it—we cannot know), the NEJM also prints a study of a patient who responded well to crizotinib but then relapsed quickly, showing that this was due to an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain of CD74–ROS1. Aha. But doesn’t the previous trial show that all patients who respond initially to crizotinib relapse quickly by one mechanism or another?

Lancet  22 June 2013  Vol 381
2135   After two weeks of waiting, the Lancet produces some research papers of generalist interest. So what have we here: “Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial.” Perhaps this will make sense as we go along. Ah yes, “daclizumab high-yield process (HYP) has the same aminoacid sequence as previous versions of daclizumab, but differs in its glycosylation profile.” So let’s look at the comparator: it seems to have been placebo alone. Hang on, is that the standard treatment for MS? Well, it seems that ethics panels in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, Turkey, and the UK between Feb 15, 2008, and May 14, 2010 thought so. So the primary end-point? “New or recurrent neurological symptoms (not associated with fever or infection) lasting 24 h or more, accompanied by new neurological findings at assessment by the examining neurologist.” That sounds OK. The two doses of daclizumab seemed to produce identical results, roughly halving the annualized relapse rate compared with placebo. How does this compare with other new treatments for MS? Well, it’s a new approach, and this was a phase 2 trial. Daclizumab works by knocking out CD25, the α subunit of the interleukin-2 receptor, and it needs some phase 3 trials which match it with all the other “promising” avenues of MS treatment. Until then, this study is of theoretical interest to neurologists.

2176   And the other research paper for the UK generalist? “Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study.” “Conclusions: We found no relevant association between maternal vitamin D status in pregnancy and offspring BMC in late childhood.” OK folks, unless you work in Ghana or Pakistan, or like to read generalities about global health, that was the Lancet this week.

BMJ  22 June 2013  Vol 346
When Fiona Godlee took these reviews on to the BMJ website, she assured me I could be as beastly as I liked to her journal; and this week, having been beastly about the Lancet, I would like to show my independence by dissing the BMJ. But the fact is I can’t find any reason to. In these reviews, I’m not an official “house writer” for the journal, but I’m proud to be part of a publication that is improving so rapidly and that engages with its readership with so much liveliness and candour.

Recently I’ve had the pleasure of working with UK Cochrane and seeing how the conclusions of their systematic reviews can change in the light of new evidence. But the most disturbing thing is to see the conclusions of some reviews change in the light of old evidence—evidence that was present before the previous review but only unearthed afterwards. Typically this consists of an important trial conducted by a manufacturer showing lack of effect, which was then never published. In this way, interventions of no benefit continue to be a cost burden to health systems, and “evidence-based” medicine remains merely “publication-based” (or biased) medicine. Once more the indefatigable Peter Gøtzsche wields his Danish battle-axe and looks at what happens if Cochrane reviewers go looking for hidden data. They get some from investigators, but scarcely ever from manufacturers. See also the plea from Peter Doshi et al: “Restoring invisible and abandoned trials: a call for people to publish the findings.” It’s a scandal that we still have to fight this battle.

Just what is telemedicine for? Is it trying to improve communication with patients, or avoid communication with patients? And what is the most important goal in hypertension research? Is it to put more people on more treatment with a number-needed-to-treat of 500, or to identify the 499 who will never benefit from their treatment? I am only an aged GP asking simple questions: I don’t know the answers. I’m glad to see the modest reporting of this trial of telemonitoring in the management of uncontrolled hypertension: “Supported self monitoring by telemonitoring is an effective method for achieving clinically important reductions in blood pressure in patients with uncontrolled hypertension in primary care settings. However, it was associated with increase in use of National Health Service resources. Further research is required to determine if the reduction in blood pressure is maintained in the longer term and if the intervention is cost effective.” And then, perhaps, some hard end-points? No, no, that would take much too long.

Oh, but we must above all help self-management in patients with chronic conditions: this will reduce costs, avoid hospital admissions, increase patient empowerment, and change a whole culture of dependency. In your dreams, but not in Salford. “An intervention to enhance self management support in routine primary care did not add noticeable value to existing care for long term conditions. The active components required for effective self management support need to be better understood, both within primary care and in patients’ everyday lives.” What—does this mean we should do good qualitative narrative research before we go plonking interventions into people’s lives? Whatever next.

And alas, the same applied to an exercise-based programme to reduce child obesity in Melbourne. But the nice part of the story is that both the control group and the intervention group showed a sizeable reduction in BMI z score.

Ann Intern Med  18 June 2013  Vol 158
877   Safety and Effectiveness of Recombinant Human Bone Morphogenetic Protein-2 for Spinal Fusion: A Meta-analysis of Individual-Participant Data. Oh, and there’s another one too:

890  Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Spine Fusion: A Systematic Review and Meta-analysis.

You can read these two papers in full for free, but who would want to? Well, the answer is anyone who is interested in open data, as Harlan Krumholz explains in a commentary called A historic moment for open science: The Yale University Open Data Access Project and Medtronic. I should not comment, because this piece also bears my name. But to see Harlan lead this amazing initiative to promote openness with the leading medical devices manufacturer, and succeed with perfect integrity, has been the high point of my professional life.

Plant of the Week: Parahebe “Avalanche”

The splendours of English June were ready to greet me after five nights in Peru. No more exotic trees with high orange flowers, or bougainvillea of red or purple, clothing the walls of pink and white houses: home meant an abundance of roses and remaining wisteria, and peonies and irises and every other perennial in full glory amidst the showers and the gusts of wind.

But let’s look below these and see what carpets the ground. On our sunny (theoretically speaking) front bank, we had a single plant of white-flowered parahebe, a wiry evergreen ground-coverer. I had to dig this up to make way for something else a couple of years ago, and pulled it apart and replanted it all over the place. Now it is foaming with masses of small white flowers wherever I put it, and increasing inexorably in coverage. And unlike a lot of ground cover, it is a thing of beauty in itself, and will grow in baked clay. It flowers for months and cannot be killed, even by me.