Richard Lehman’s journal review—5 November 2012

Richard LehmanNEJM  1 Nov 2012  Vol 367
1677    Cancer screening campaigns—getting past uninformative persuasion is a topical subject on both sides of the Atlantic. Nobody writes better about it than Steven Woloshin and Lisa Schwarz, and in this Perspective piece they join forces with two colleagues to point the way forward. All past and many present screening campaigns have tried to induce fear and exaggerate benefit. In the case of mammography, this has brought discredit on the whole enterprise, and I can’t be alone in being thoroughly confused as to how to inform individual women. “In order to get past persuasion to informed decision making, we need to make it easy for doctors and patients to see the key data about screening tests’ benefits and harms in an appropriate context.” About time, indeed.

1687   “And the LORD said unto Moses, Say unto Aaron, Stretch out thy rod, and smite the dust of the land, that it may become lice throughout all the land of Egypt.” Exod 8;16. The third plague of Egypt was a missed sales opportunity for Topaz Pharmaceuticals, who could have rushed in with reprints of this paper and supplies of ivermectin lotion sufficient to treat the Pharaoh and his household, thus securing a lucrative dynastic contract for a couple of thousand years. In this randomized trial of ivermectin for head lice, the success rate at 24 hours was 95% and at two weeks it was 74%. During that time, the control group received an inactive placebo. Given that there are so many reasonably effective treatments for headlice available, a placebo-controlled trial seems a rather lousy study design to me, but I don’t want to lay myself open to a charge of ethical nit-picking.

1694    Progress in cancer therapy is generally a matter of slow and painful increments and subtle tweakings. Poor overloaded generalist clinicians can scarcely be expected to keep up with each twist and turn, and the leading journals should help us by selecting out only the trials which represent major advances in treatment. This trial reports a 3.6 month improvement in progression-free survival using a combination of dabrafenib and trametinib in metastatic melanoma with either BRAF V600E or BRAF V600K mutations, as compared with monotherapy using either agent. The price was a very high incidence of fever, chills, nausea, and diarrhoea. It was an open label trial which allowed crossover to dual therapy when disease progression was noted, so the absolute survival difference is impossible to compute. It is encouraging to note that 70+% of the patients were alive at 12 months but the real place of combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations cannot be judged from this trial. GlaxoSmithKline manufactures and sells both of these agents, and in keeping with its new openness policy, all researchers should now have access to the individual patient data from this trial. But even that cannot compensate for a suboptimal design which makes this study unfit to guide costly choices in the treatment of these dying patients.

1714   Zoledronic acid is a good drug: it works, and its patent has just expired. Its only disadvantage is the need for intravenous administration. So once a year, you have to sit down for a few minutes while it goes in, and then your osteoclasts are paralyzed and your risk of an osteoporotic fracture plummets. This Novartis-funded trial recruited 1199 men with up to three previous osteoporotic vertebral fractures, or a bone mineral density T score of minus 2.5 or less, and gave vitamin D and calcium to all of them and randomized half to receive either zoledronic acid 5mg as a single dose, or placebo. There was a 1.6% incidence of osteoporotic fracture in the treated group over the following year, compared with 4.9% in the placebo group. So yes, zolenronic acid is a good drug: but we knew that already. Was it really legitimate to use a placebo in these patients? We are talking here about very painful and disabling fractures leading to permanent deformity, not about head lice: this is definitely not ethical nit-picking.

Lancet  3 Nov 2012  Vol 380
1559   Dengue, pronounced denggy. That’s annoying enough. Then there is the disease itself, which is far more annoying, especially if you get the extreme break-bone fever end of the spectrum with vascular leakage syndrome. Half the world’s population is at risk from this virus, and about 100 million a year get it, of whom about half a million end up in hospital. But being a shy, Hobbit-like creature who rarely leaves the Shire, I have never seen a case. Hot foreign places do not suit me. I am glad that they now seem to be developing an effective tetravalent vaccine against dengue, though I doubt whether I shall ever use it myself. But billions of others may benefit. Let’s hope that Sanofi-Pasteur ensures that they have cheap access to it.

N.B. The abstract says that “Dengue vaccine was well tolerated, with no safety signals after 2 years of follow-up after the first dose.” A nice example of medical English meaning the opposite of plain English.

1568   And then there is the problem of the bleeding obvious, and how to avoid stating it. “Physical health and life expectancy are severely compromised in individuals who self-harm compared with the general population. In the management of self-harm, clinicians assessing patients’ psychosocial problems should also consider their physical needs.” I don’t know to whom Keith Hawton is addressing this piece of wisdom. I first met him in 1973 when I was a student and he was a psychiatry registrar just beginning a lifetime’s study of self-harming behaviour; and by comparison with that, my lifetime’s work in general practice must count as a bed of roses. But believe me, Keith, back there in the consulting room we GPs do actually consider the physical needs of self-harming patients. Some days it seems as if we do little else.

1583   How many subjects do you need in a randomised trial? Statisticians groan over this silly piece-of-string question every day, but the answer is simple: just so many as will prove that your intervention does or doesn’t work. Now if I bought a bottle of cough suppressant, I think I would want about a one in four or better chance of it helping my cough. In fact countless millions of people buy bottles of cough medicine every day with nowhere near this likelihood of it helping their cough, but the cough goes away anyway, and everybody is happy. But this terribly simple, terribly small RCT from Australia has discovered a cough suppressant that actually works for refractory chronic cough with a NNT of 3.6. It is called gabapentin, and the maximum tolerated dose is 1800mg.That’s it. Where are the 127 opinion leading centres in 24 countries each recruiting 6 patients, the hired ghost writers, the interminable lists of company payments, the carefully massaged p-values for composite end-points, and all the other tricks and ornaments that are usually so essential for a state-of-the art interventional trial in the modern era? Nowhere to be seen: just 62 coughing Australian out-patients, ten of whom dropped out. P=0.004.

1590   Speaking of plain English, how would you rate this sentence: “Genome wide association studies identified susceptibility loci that—triggered by environmental factors—result in a disturbed innate (ie, disturbed intestinal barrier, Paneth cell dysfunction, endoplasmic reticulum stress, defective unfolded protein response and autophagy, impaired recognition of microbes by pattern recognition receptors, such as nucleotide binding domain and Toll like receptors on dendritic cells and macrophages) and adaptive (ie, imbalance of effector and regulatory T cells and cytokines, migration and retention of leukocytes) immune response towards a diminished diversity of commensal microbiota.” Is it in fact a sentence at all? And have you the faintest idea what it is about? It is in fact the second sentence by which a German professor introduces his review of Crohn’s disease. This may be a very good review indeed, but I do not have the courage to read it, any more than Hegel’s Wissenschaft von den Erscheinungsweisen des Geistes.

1606   Let us move on to Ulcerative Colitis. The second sentence here reads, “Bloody diarrhoea is the characteristic symptom of this disease.”  Hurray! The bloody flux! Few of the sentences in this review have more than two subordinate clauses, and they are all designed to make sense. Short paragraphs and good illustrations. If you read this piece, you will know all that you need to about an important disease and its current treatment. You will also learn how to write a clinical review.

BMJ  3 Nov 2012  Vol 345
A year ago I set up a Google group called PATH with the mission statement:
“PATH stands for Publish All Trials on Humans. Our aim is to ensure the
publication of all data from trials involving human subjects, as an
ethical obligation to the subjects who gave consent to take part in
research on the understanding that it would benefit everyone.”

Apologies if you never knew about it. I would invite you to join, but I think its work is now done, and we need to move to a new level, thanks above all to Ben Goldacre and Fiona Godlee. The month since the publication of Ben’s Bad Pharma has been a momentous one for the cause of open data sharing from human trials. The ethical argument has been put forward for more than 20 years by Iain Chalmers and tirelessly urged by Peter Gøtzsche to the EU Parliament and elsewhere: in the US it has had champions in Harlan Krumholz, Joe Ross, Cary Gross and others who are developing practical models for dissemination and analysis; but it is in Britain that all of a sudden the dam has broken and the cause has been taken up in the UK Parliament and by the Times. The pace of events threatens to overwhelm the patrician defences of the British medical establishment and the ABPI, so long in comfortable league with each other.

Fiona Godlee has taken a bold initiative in insisting that full data sets be openly available for all studies published in the BMJ from next year onward. Let other journals follow if they dare, or explain themselves if they do not. GlaxoSmithKline have praised this move, which mirrors their own. Bliss is it in this dawn to be alive. As Fiona says, “We should seize this moment with both hands.”

All credit too to Tom Jefferson, Peter Doshi, and colleagues for tirelessly pursuing Roche to disclose full trial data relating to Tamiflu, the drug which earned the company billions of dollars during the flu pandemic. And congratulations also to the BMJ for taking up their challenge, all the way to Sir John Bell, Regius Professor of Medicine at Oxford, President of the Academy of Medical Sciences, and a director of Roche.

So what we now need is a much bigger, more active movement to press home the cleaning up of the pharmaceutical industry, and I would urge you to join Ben Goldacre’s already phenomenal following on Twitter to keep up to date on this.

Yes, Jeeves was right: fish is good for the brain. I have told you this before: here is a systematic review of the protection afforded by fish consumption against the risk of cerebrovascular disease. It’s not just the oils: “the beneficial effect of fish intake on cerebrovascular risk is likely to be mediated through the interplay of a wide range of nutrients abundant in fish.” But actually I couldn’t give a hoot: “dietary science” is just a mess of confounders: I eat fish because I like fish.

This week sees the print version of the now famous Danish randomized trial of hormone replacement therapy that contradicts the Women’s Health Initiative and shows a cardiovascular protective effect from the early use of HRT. I will leave it to others to discuss the timing hypothesis and so forth. What we need are some good decision aids for women. I nearly said “patients”—but why should taking HRT turn people into patients? Why should doctors in fact have anything to do with an informed woman’s decision about using HRT for postmenopausal symptoms?

All doctors need to become competent diagnosticians. Yet most that I have encountered find it difficult even to use a two-by-two table to assess diagnostic tests. This is not going to change. This important article, based on a meta-analysis of coronary CT angiography studies, urges the adoption of 3 by 2 tables, with an intermediate category of “non-evaluable.” I believe the authors are right: and I believe also that once we have made this move forward, we then have to find ways of making it intuitive and practical for jobbing clinicians.

Plant of the Week: Quercus rubra

This is the best known of American oaks, and the symbolic plant of New Jersey, the state which was hardest hit by Hurricane Sandy. We’ve been hit too, but only by the cancellation of our flight home from JF Kennedy airport.

These red oaks are stately handsome trees, unlike most specimens of the European oak, Q robur, which have sprawling half-dead boughs (N.B. this is not due to modern industrial pollution or global warming—you can see it best in the rural paintings of Constable or Caspar Friedrich in the early nineteenth century). Red oaks have excellent healthy foliage throughout the season, which turns deep red in the autumn.

There is now a red oak lying horizontal on the Green of New Haven, felled by a gust from Sandy. The surprise is how poor its root system seems to hold such a mighty tree: small wonder it failed in thin sandy soil and high winds. I don’t know how well these red oaks fare in the English climate; I suspect they thrive best in the hot summers and freezing winters of the US eastern seaboard. You need to come over to enjoy them.