Richard Lehman’s journal review – 20 February 2012

Richard LehmanJAMA  15 Feb 2012  Vol 306
669    This week’s star Viewpoint piece is about The Unintended Consequences of Conflict of Interest Disclosure. It seems to me that twenty-first century medicine operates on roughly the same principle as the court of the Grand Vizier of the Ottoman Empire – prestige is judged by the number of bribes you are offered. Far from being a source of shame and reluctance to publish, these are routinely flaunted at the end of most interventional trials in the leading medical journals. I once counted 63 for a single individual; and perhaps he would argue that once you enter double figures, they begin to cancel each other out. How did we reach a state where the default setting of our medical culture is conspicuous corruption? As the authors here point out, this cannot go on: “Conflicts of interest, including fee-for-service arrangements, are at the heart of the astronomical increases in healthcare costs in the United States, and transparency is no substitute for more substantive reform.” And just as the US health system thinks of ways to get out of this hole, our British political masters are determined to push us into it.

674    One way in which JAMA lags behind other journals is in flagging up the role of the funder in interventional trials. It would have helped if we were told right at the beginning that Abbott paid for this study of paracalcitol in patients with an estimated glomerular filtration rate of less than 60 and echographic evidence of left ventricular hypertrophy. The title of the paper tells you little about the contents and the whole study (PRIMO) is a wonderful exercise in futility. It is completely free of clinical outcomes – a closed loop of nearly meaningless surrogate end-points relating to cardiac and renal function: and even on this basis it was a dud. Why on earth did JAMA think this worth publishing?

685    It took 60 centres in 11 countries to recruit 227 subjects for that PRIMO trial of paracalcitol (“Zemplar,” Abbott). This is not at all unusual in trials run by pharmaceutical companies on products still under patent, when the prize might be a large extension of indication. For good old amoxicillin this scarcely applies, and so for this placebo-controlled trial in acute rhinosinusitis, ten community clinics in St Louis proved perfectly sufficient to garner 166 subjects, and to prove that this particular antibiotic provides no symptomatic benefit at 3 days. There was some benefit at 7 days into the ten-day course given. This is not particularly new news, but the proximity of these two trials offers a nice demonstration of the marked difference between a pharma-funded study aimed at increasing market penetration, and a publicly-funded trial aiming to inform clinical practice. Tens of millions of dollars versus tens of thousands – and all ultimately from the pockets of the public.

713   There have been lots of recent studies linking short term air pollution and myocardial infarction and this systematic review and meta-analysis usefully combines the results of 34 of them. Small but statistically significant increases in MI can be traced to atmospheric pollution with carbon monoxide, nitrogen dioxide, sulphur dioxide and particulate matter. Another small item on the list of reasons why we need to end our dependence on carbon-based fuels.

NEJM  16 Feb 2012  Vol 366
591   Old- fashioned British general practice used to involve occasional bouts of physical exertion, such as wrestling with a patient in status epilepticus in order to give intravenous diazepam. I thought that this unique form of physical combat with an unconscious opponent had died out, but evidently it remains popular in America. This trial in older American children and adults in the pre-hospital setting shows that intramuscular midazolam given by paramedics is at least as effective as intravenous lorazepam. Worth knowing in all healthcare settings, as an alternative to the rectal, buccal, and intranasal routes.

601   It’s a familiar pattern: a pharma company (Sanofi in this case) pays for a trial based in 395 centres across 47 countries, in order to study the effect of its new drug semuloparin on the outcomes of 3172 patients receiving chemotherapy for solid tumours. The duration of the trial is 3.5 months and the end-points are venous thromboembolism, bleeding, and overall survival: the comparator is not a different low molecular heparin, but placebo. Sanofi writes up the study, with the bottom-line conclusion: “Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding.” Result: semuloparin continues to be used in most of the 395 centres and Sanofi is free to buy shed-loads of reprints from the NEJM in order to encourage clinicians to believe that their product is the one best proven to prevent VTE in chemo patients. The NEJM is free to sell these reprints without disclosing this to anyone (for “commercial reasons”), but can salve its conscience by printing an editorial criticizing the study for undue commercial bias. Both parties are winners, and cancer patients can now be treated on the basis of 3.5 months’ worth of outcome data, most of which will not even be in the public domain. This is nothing exceptional – it is the standard model of evidence-based medicine in 2012.

619   I’ve come across surgeons who were daunted at the size of their patients, but I didn’t realize that genomic scientists could be similarly affected, until I read here that “TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size.” I like the idea of thousands of gene gnomes swarming to tie down the Titin gene, like the famous illustration in Gulliver’s Travels. And this could turn out to be genuinely useful: “TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases.” Anything that brings some order and understanding into this perplexing group of disorders must be welcome, even if it takes decades to translate into therapy.

Lancet  18 Feb 2012  Vol 379
617   In the world of competitive science, it has been said that there are no prizes for coming second. It is high time we got rid of this way of thinking, especially in the clinical sciences, where collaboration needs to become the core value, where everybody should share data and where nobody should value precedence for its own sake. So let’s give a big cheer for this study of the new group B meningococcal vaccine, 4CMenB, which proves that it is immunogenic – just like last week’s study in JAMA.

633    If I’m sounding tetchy about pharma-funded trials this week, that’s because I particularly hate the kind that threaten enormous costs to health systems for tiny marginal benefits – especially where they play on our wish to do our best for patients with cancer. The logic for this GlaxoSmithKline trial is given thus: “The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy.” A hypothesis worth testing, though at current US prices, trastuzumab can cost $6K per month and lapatinib an extra $2.9K: fine while GSK are paying, and if there are robust benefits. The end-point measured, however, was purely histological – so-called pathological complete response meaning absence of invasive tumour in the breast or lymph nodes in surgery conducted after 18 weeks of treatment (with paclitaxel added for the last 12 weeks). The conclusion, written without help from GSK this time, is suitably modest: “Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting.” And if it is – which can only be determined by long-term follow up for all-cause mortality – how shall we make it affordable?

648    A very nice seminar on atrial fibrillation by Greg Lip and colleagues provides an excellent map of what has become quite a complex subject. Generalists as well as cardiologists will learn a lot from this painstaking account of the latest evidence on the treatment of a highly prevalent condition which most of us encounter at least once a day. As we gain more knowledge, treatment is becoming more patient-focussed, and more may sometimes mean less: “Lenient or strict rate control strategies might not provide great differences in outcomes, whereas the availability of non-pharmacological approaches has allowed additional possibilities for the management of atrial fibrillation in patients who are unsuitable or intolerant of pharmacological therapy.”

662    Fans of Sherlock Holmes will remember the passage in The Dying Detective where Holmes fakes delirium and attacks his dear friend Watson for being an ignorant general practitioner: “What do you know of the Tapanuli fever? Or the Black Formosa Corruption?” he rants. Modern GPs wishing to escape the opprobrium of Benedict Cumberbatch would therefore do well to read Chikungunya: a re-emerging virus.
“Ah, Watson, what are the vectors of this infection?”
“Species of the mosquito Aedes, I believe, Holmes.”
“Very good. I observe that you have been reading The Lancet, Watson. And which is the particular mosquito that may have caused the death in London of the man who lies on the carpet before us?”
“Aedes albopictus in all likelihood, Holmes. They say it may be carrying Chikungunya virus to temperate regions.”
“Watson, you excel yourself!  We must away to Baker Street for breakfast. I believe that Mrs Hudson has obtained some particularly fine kippers.”

BMJ  18 Feb 2012  Vol 344
Why are newspapers so bad at reporting the results of medical research articles? We are all very happy to blame the innate stupidity of reporters, their bias towards pharma, their bias against pharma, the dreadful state of scientific education in the UK, Rupert Murdoch, homeopaths, in fact anything other than ourselves; but might some of the fault actually lie with the poor quality of press releases from medical journals? Lisa Schwartz and Steven Woloshin have been examining these issues for many years, and one of their earliest papers was a lucid explanation of the difference between odds ratios and hazard ratios following widespread misreporting of a race-sensitive paper in the NEJM. As most doctors still struggle with this, I attach it here. Small wonder that reporters also struggle when we give them too little guidance – and here is a retrospective study which proves that bad press releases lead to bad newspaper articles.

Just because the BMJ hosts these remarks on its website does not stop me being beastly when the occasion demands. But this week (at the risk of sounding like a creep) I will say that the BMJ leads all the medical journals in providing debate and information about topical issues in medicine. This week it covers obesity treatments, commitment contracts, and new recreational drugs. Let’s take these in turn. Geoff Watts runs through obesity treatments present and future with a light touch. We have no effective drugs and we don’t really know how surgery works. But it does – and that’s a dilemma when most of the population is drifting towards overweight and obesity and the knife or the gastric band can scarcely be a general solution. Slimming clubs may have been the first to offer commitment contracts – money laid down against fulfilment of a health objective. The pros and cons are weighed up with no firm conclusion. As for new recreational drugs, you could scarcely wish for a better account of their effects and the treatment of their medical consequences. This is a must-keep article if your clientele includes the young and experimental.

Arch Intern Med  13 Feb 2012  Vol 172
209   Last year, Peter Rothwell and colleagues published a celebrated meta-analysis based on individual patient data from randomized controlled trials which showed that daily low-dose aspirin reduces total cancer mortality. This meta-analysis used summary patient data from a somewhat different set of trials and concludes: “Despite important reductions in nonfatal MI, aspirin prophylaxis in people without prior CVD does not lead to reductions in either cardiovascular death or cancer mortality. Because the benefits are further offset by clinically important bleeding events, routine use of aspirin for primary prevention is not warranted and treatment decisions need to be considered on a case-by-case basis.” I wish I could take you through the merits and faults of each analysis, but I am afraid you will have to do this for yourselves. The Invited Commentary by Samia Mora provides no help in resolving the clash of conclusions about cancer mortality.

219   Back to the issue of air pollution. The JAMA meta-analysis of particulate pollution showed an increased risk in the acute situation of less than 1% for MI, but a long-term study of cognitive decline in women in relation to particulate exposure indicates a stronger effect. Live in the country, and avoid tractors.

229    The same applies if you want to avoid acute ischaemic stroke. Even “safe” levels of particulate air pollution increase your risk. Move to Vermont.

Plant of the Week: Iris reticulata

It’s hard to gain inspiration to write about plants in New England in February, but when I resorted to giving you a Hardy poem instead a couple of weeks ago, at least it climaxed with an iris. And you may well be able to enjoy the odd iris in flower during February in England, if you have planted the bulbs of the Near Eastern species reticulata. I’ve done this from time to time in the drier, more Mediterranean spots of our garden, but they have never thrived. It’s certainly a lovely thing to see their flowers – I like the light blues best – unfolding fragrantly amongst the mire and frost of an English winter; but they do have a poor, shivery look about them, and I cannot blame them for giving up.