Journal Watch - April 2012

JAMA 25 Apr 2012 Vol 307

1717 Any budding young cardiology academic wishing to set up a publication of her own could do worse than start a Journal of Negative Stem Cell Trials in Heart Failure. There are enough of these to fill a volume every quarter-year or so, and editorials could reflect on all sorts of fascinating issues to do with how to wash bone-marrow cells, whether to pre-treat them with this or that, which bit of myocardium to put them in, whether tiny differences in this or that functional measure in various aggregated subgroups indicated that this treatment might actually work one day, etc, etc. This would save the rest of us from having the disappointment of bumping into these papers on a regular basis in the main medical journals. Ten years ago, they were really exciting, and we all took heart, so to speak; but the FOCUS-CCTRN published here is just another failure like the rest. The cells were autologous bone marrow mononuclear cells; they were introduced by transendocardial injection, mostly into male hearts damaged by ischaemia, and at six months there was no evidence that they were doing anything to any of 8 outcome measures.

1727 About 6% of infective endocarditis is associated with implantable cardiac devices, and the vast majority of the culprits are pacemaker batteries. So although the wires are in the heart, the germs are on the subcutaneous box and reach the heart valves through the bloodstream. The treatment is to get the device out as soon as possible: these infections carry a substantial mortality which increases with delay in removal.

1736 Recurrent severe migraine is a blight on anyone's life, for which there are a number of prophylactic drug treatments, none of them infallible, and many of them unsatisfactory. So a simple mechanical cure would be a great breakthrough, were it to exist. Botulinum toxin injections to the forehead muscles do alleviate some types of headache, as this meta-analysis shows, but the effect is modest and is only detectable in chronic migraine and chronic tension headache. Botox does nothing for the prophylaxis of recurrent episodic migraine in randomized controlled trials.

NEJM 26 Apr 2012 Vol 366

1567 When the first case-series reports of bariatric surgery for type 2 diabetes came out, it was clear that something huge was afoot. In many patients, blood sugar levels dropped and stayed down immediately after surgery, before there was significant loss of weight. Now we have two randomized controlled trials of surgery versus optimal medical therapy in poorly controlled T2DM, and the conclusion of the first paper states that "12 months of medical therapy plus bariatric surgery achieved glycemic control in significantly more patients than medical therapy alone." I don't think I've ever read such a gross understatement in the conclusion of an abstract - which is such a strange feeling that I don't know where to put it. "Significantly" here doesn't mean a statistical trick to magnify an unimportant change in the surrogate end-point of glycaemia. In fact you don't need statistics at all to describe the success of these treatments: gastric bypass and sleeve-gastrectomy cause massive weight loss (29kg and 25kg respectively) and would have eliminated the need for diabetes treatment in most patients had the HbA1c target not been set artificially low at 6%. The authors commendably advise caution until we have long-term outcomes, and I can hardly object to that. But this is a breakthrough, and will have profound consequences for the future management of T2DM.

1577 The Italian authors of the second paper are equally circumspect in their conclusion, but in the meat of their account of this trial they use the word remission. Biliopancreatic diversion achieved a remission rate of 95% at two years; gastric bypass achieved 75% in severely obese diabetic patients. Whoopee! But that isn't all. "Preoperative BMI and [postoperative] weight loss did not predict the improvement in hyperglycemia after these procedures." So these kinds of major surgery have some direct effect on beta-cell function which we don't fully understand. "Type 2 diabetes" - a complex metabolic disorder, now perhaps curable - has plenty of surprises left up its sleeve. All eyes should be on the detail of what happens following biliopancreatic diversion, in the hope that a simpler form of surgery or some new kind of medical therapy could result. But patience will also be needed: as in all diabetes trials, the outcomes that really matter are cardiovascular events, limb loss, blindness and renal failure. We still need to be certain we are doing more good than harm.

1596 Diagnosing appendicitis for me is a matter of simple rule-in and rule-out tests in the consulting room. The ones that haven't made it into the textbooks are the Mars bar test ("if I gave you a Mars bar now, would you eat it?"), the speed bump test ("did you go over any speed bumps on the way here and did you hold your tummy?") and the hopping test. If any of these are positive, there is a-priori evidence of an inflamed viscus, and the surgeons can work out the rest, especially if there are fever, RIF tenderness, rebound etc. Somebody needs to ascertain the diagnostic characteristics of these "frugal heuristics" which haven't yet made it into JAMA's Rational Clinical Examination series. Everything needs to be done to avoid recourse to abdominal CT scanning, which uses frightening amounts of radiation and really should be avoided in children. This study compared low-dose CT with standard- dose CT in 891 patients with suspected appendicitis in a single institution. "Low-dose" is a relative term, meaning about a quarter of standard dose: still very big. The negative surgery rate was the same in both groups, at just over 3%; and the perforation rate was the same too, at around 25%. To me, that suggests too much diagnostic delay: "if in doubt, whip it out", would be my watchword if I were a surgeon. Perhaps just as well that I'm not.

Lancet 28 Apr 2012 Vol 379

1561 "Unprecedented momentum is gathering to put physics into the centre of global health policies," declares The Lancet this week. Oops, sorry, that was last week. Let's try again. "Unprecedented momentum is gathering to put adolescents into the centre of global health policies." But no, this can't be the way forward at all. Let's put some grown-ups into the centre of global health policies. Otherwise we might have editors of international medical journals rushing about like teenagers from one conference to another, blogging crazily and spending all their time on Twitter while neglecting their homework. And that would be terrible.

1591 Peter Rothwell continues his investigation of the long-term randomized trials of aspirin for clues about the possible value of this drug in the prevention and treatment of cancer. Here he generates the hypothesis that the observed short-term reduction in cancer seen in five British trials of aspirin (for cardiovascular protection) may be due to a suppressant action on the mechanism of metastasis, especially for adenocarcinomas, and especially in smokers. This is interesting, but speculative, and these subgroup effects will need to be confirmed by large and lengthy prospective trials.

1602 And then there is the more general question of whether aspirin has the ability to alter what is likely to appear on your death certificate, including the date. Frankly, this is a matter of indifference to me; I take daily low-dose aspirin, but only in the hope of avoiding migraine with aura. Overwhelmingly, you die of something you can't avoid, at a time not of your choosing, so it is a waste of time giving the matter any thought. Doctors in the last few decades, however, have taken it upon themselves to try and raise the average age of death in the population by any means possible, in the hope of seeming useful. In a widely discussed earlier study, the Rothwell team showed that daily low-dose aspirin has no effect on cardiovascular mortality in the general population but a detectable effect on cancer mortality. Here they concentrate on the short term reductions in cancer incidence, but get no further in proving any statistically significant overall prolongation of life from the general use of aspirin. The editorial puts this all into context, and also notes the omission of the two largest aspirin trials and other methodological flaws. So take aspirin if you have some reason to, but don't count on it altering your death certificate.

1613 Kawasaki disease is every doctor's and parent's nightmare: cause unknown, so rare that most doctors never see a case, thus easily missed, and potentially fatal due to coronary arteritis. There are about 40 cases a year in the UK, but this Japanese trial managed to collect 298 children with severe Kawasaki's and randomize them to receive intravenous immunoglobulin with or without prednisolone. The steroid-treated group were left with fewer coronary artery abnormalities.

BMJ 28 Apr 2012 Vol 344

Did you know that a lot of medicine can be done over the telephone? And that if you do that, you can save the NHS more than £1billion per year? No, I didn't either, but the Health Secretary has evidence that he cannot reveal. As for the evidence we can access, here are two studies in which telephone support was added to routine asthma management, and to smoking cessation aided by nicotine replacement. It didn't have the slightest effect. So perhaps we need to try harder and target the sickest patients with severe chronic disease. In an astonishing trial on the Archives website, which I shall come back to another time, this is just what they did. Mortality was nearly four times higher in the telemedicine intervention group. A great way to reduce health care costs, undoubtedly: do it to enough elderly patients, and you can probably save £3bn.

A useful observational study looks at risk factors for mortality from imported falciparum malaria in the UK over the past 20 years. I can hardly do better than quote the summary, in the hope that colleagues still in UK general practice will take note and keep their radar on: "Most travellers acquiring malaria are of African heritage visiting friends and relatives. In contrast the risks of dying from malaria once acquired are highest in the elderly, tourists, and those presenting in [should be from?]areas in which malaria is seldom seen." So if they come back from their exotic holiday with "flu", send them for a blood smear right away.

Arch Intern Med 23 Apr 2012 Vol 172

611 Most of my generalist readers are probably ready to pelt me with rotten eggs when I bring them another paper about stents, but I can't help telling you about this individual patient data meta-analysis of drug-eluting vs bare-metal stents for primary angioplasty because it's probably quite important. No, hold the ripe tomatoes too. All I'll do is give you the conclusion:

"Among patients with STEMI undergoing primary percutaneous coronary intervention, sirolimus-eluting and paclitaxel-eluting stents compared with BMS are associated with a significant reduction in target-vessel revascularization at long-term follow-up. Although there were no differences in cumulative mortality, reinfarction, or stent thrombosis, the incidence of very late reinfarction and stent thrombosis was increased with these DES."

Yes, read that again. To me that seems to say that these vastly more expensive stents, which also need a year of costly clopidogrel treatment afterwards, don't actually perform any better than bare metal stents for most patient-important outcomes, and any possible advantages seem to be balanced by disadvantages. Or have I missed something?

623 Another meta-analysis, this time of trials of warfarin to prevent stroke in people with nonvalvular atrial fibrillation. What's the biggest breakthrough here? Why, it's making sure people are in the INR target range. Because if they are, they have fewer strokes and fewer bleeds. Medicine is sometimes, though sadly not often, perfectly logical.

Plant of the Week: Cornus florida

I've never had much luck trying to grow flowering dogwoods on limy clay and in a Limey climate, but over here in New England they are among the greatest sights of the spring. They are native trees, growing on forest margins, but I haven't been able to get out and see them in their natural habitat. However, there is little need, as they have been planted by the hundred along the grander suburban streets of New Haven, where the older ones form magnificent mountains of flower in front of huge clapboard houses of various and exotic design.

Except that one should not say "flower" but "bracts". The true sexual organs of the cornel family are paltry affairs, but they are surrounded by these stupendous quadriform codpieces and crinolines of white, pink or red, presumably to attract the emerging insects of spring. The reddest ones are the creation of human hybridists working with natural sports, and we must be grateful for their patient efforts towards securing a true deep red, most nearly perhaps in "Cherokee Chief". There is also a purple-leaved form with purple-red bracts, called "Purple Glory", which I haven't seen.

I don't know if there are places in the UK where these trees flourish and display their splendour to an East American degree, but I rather doubt it. For us, they will always bring back memories of wandering down quiet streets of exuberant New England mansions and their gardens in spring sunshine: one of the world's truly delightful experiences.

JAMA 18 Apr 2012 Vol 307

1583 George Orwell predicted a nightmare world where soothing words would mean their opposites, and gave his dystopia the date of 1984. It was about that year that the term patient centred first appeared in the medical literature, coinciding with the time when the medical-industrial complex went totally out of control in the USA and patients were thrown entirely to the mercy of the market. Books and papers about patient-centeredness (sic) proliferated in America during the 1990s, but the momentum of medicine there has continued to career in the opposite direction. Now that total chaos and unaffordability loom, the US government has set up the Patient Centered Outcomes Research Institute with a hefty budget to find out how to put things right by finding out what systems of care work best for patients. A laudable aim and a fine-sounding name, certain to arouse suspicion among cynics everywhere; but this particular cynic is amazed and optimistic. To find out why, listen to the visionary speech which Harlan Krumholz gave to the PCORI Patient and Stakeholder group a few weeks ago: This goes way beyond the usual rhetoric of being nice and involving patients, and commits PCORI to a radical agenda of patient empowerment - the only way that health systems the world over can reclaim the true purpose of medicine. This article shows how Harlan's vision is shared by others in the developing organization.

1585 But the moment that you attempt to empower patients, you run into problems. Patients as well as doctors like to believe that there must be a single right answer for every problem, when very often there is not. As I've said before, Harlan's surname (meaning crooked wood in German) always reminds me of Kant's famous dictum, "out of the crooked timber of humanity, no straight thing was ever made". And it's no good torturing the evidence by exercises in subgroup analysis and modelling: in most of medicine, there is irreducible uncertainty. Here is a nice short philosophical piece by David Kent and Nilay Shah, headed with the splendid observation of George Box that All models are wrong, but some are useful.

1587 Three non-clinicians discuss the problems of continuous patient engagement in comparative effectiveness research. Now comparative effectiveness research is actually fiendishly difficult, for reasons I will try to outline very briefly in a moment; and securing patient involvement in research is also difficult, but absolutely essential. In fact it will be a measure of PCORI's success if it can demonstrate that every aspect of its research is genuinely patient-centred - i.e. that it listens to the patient voice at every stage, and that every output has direct bearing on decision making with patients and society. The ultimate measure of its success, ironically, will be the disappearance of the concept of the patient altogether.

1593 In this hefty themed issue of JAMA, there now follow five examples of comparative effectiveness research (CER), followed by a knotty editorial with the title Is It Time for Medicine-Based Evidence? And here is the problem for you and for me, dear Reader: you cannot properly assess a paper on outcomes research or CER without some understanding of the following methods - multiple linear regression or analysis of covariance for continuous (dimensional) outcomes, logistic regression for binary (dichotomous) variable outcomes, proportional hazards analysis or Cox regression when a time interval is relevant to a binary outcome (i.e., survival analysis), and Poisson regression when outcomes are measured as counts. Moving on, you then need to employ these techniques in one or both of two conceptual processes which can help to balance the characteristics of unmatched groups in observational studies: propensity scores and instrumental variables. There are plenty of statistics texts to confuse the unwary, but there is no simple, comprehensible guide to outcomes research for the non-specialist. I know, because I am trying to help write one. And I am hoping somebody else will deal with all this while I write about patient-centredness. So finally, back to this study. You need not read it: it is simply a good teaching example for those who want to understand the use of propensity scoring in retrospective cohort studies. The study concludes that without needing a randomized controlled trial, we can be pretty certain that adding bevacizumab to carboplatin-paclitaxel chemo for advanced non-small cell lung cancer makes no difference. And that is useful knowledge for decision-making.

1602 So we're getting accustomed here to the idea of extracting useful knowledge from unbalanced observational data. To do this requires both sides of the brain. Your left brain can immediately busy itself with the data, using extension tools like statistics software packages and tabulation methods. Here we're looking at nearly a quarter of a million American adults with serious trauma transported to hospital either by ground or by helicopter. What does your right brain tell you about this problem? Mine tells me that you cannot match these groups because there are simply too many confounders. But the left brain goes ahead and tries, using every gizmo it can lay its hand on. After performing all its tricks, it reports that there is an absolute mortality benefit of 1.6% in those transported by helicopter, and a small benefit in functional outcomes. And what does my right brain say about that? That you still cannot be certain you have really corrected for confounders to that level of difference, and that even if you had, it would be no argument to buy more helicopters as a strategy for improving trauma outcomes.

1629 Let's skip to the final study of the 5, which uses an instrumental variable approach to account for measured and unmeasured differences between patients with clinical stage T1a kidney cancer treated with partial or radical nephrectomy.

Briefly, the instrumental variable approach identifies an instrument (variable) that is thought to be associated with the treatments of interest but not with the outcome. Here there is a very striking difference in long-term outcomes: the hazard ratio for death in those treated with partial nephrectomy rather than radical is 0.54. Although my left brain struggles to follow every stage of the methodology, my right brain tells me that a difference of this magnitude is unlikely to be due to skewed assumptions or residual confounding.

NEJM 19 Apr 2012 Vol 366

1467 Now that we've finally escaped from JAMA and all this stuff about CER methodology, let's look at this first paper in the New England Journal. Being in the NEJM, funded by theNHLBI and conducted by a distinguished team of researchers, it must be right, and it concludes that "In this observational study, we found that, among older patients with multivessel coronary disease that did not require emergency treatment, there was a long-term survival advantage among patients who underwent CABG as compared with patients who underwent PCI." Proof at last of what we all suspected: new tubes must be better than stents. But hang on, what was the absolute mortality difference between these groups? The median follow-up period was 2.67 years, at which time the survival lines were beginning to diverge in favour of CABG, but not by very much. In the minority of patients followed to 4 years, the difference was statistically significant and stood at an absolute value of 4.4% provided one accepts the methods of the study. And what are these methods? Why, our new friends propensity scores and inverse-probability-weighting adjustment. So we are back to the problems of comparative effectiveness research with a vengeance. The left brain, without the help of complex statistical computation, cannot interrogate these results; while my creaky old right brain tells me that I cannot make use of this information in decision-making with patients, because there are too many variables to rely on such small differences. In fact I think we may need new methods of describing the confidence limits when using these two-stage weighting adjustments with unbalanced groups. So do we need another RCT comparing CABG with PCI using current methods? The editorial discusses this question, but not with any satisfactory conclusion. I think equipoise still best describes the clinical situation.

1477 Yippee! We've finally got away from CER and on to the best kind of medical paper - a randomized controlled trial conducted without industry funding, with a clear result that will be of benefit to thousands of patients with muscle-invasive bladder cancer. And British too! The simple trick is to give chemotherapy using fluorouracil and mitomycin C at the time of radiotherapy. This provides a sustained survival advantage without a significant increase in adverse effects.

1489 And now, like a Common White Butterfly, we must return to the field of cabbage. CABG can, as all of you know, be performed with a cardiopulmonary bypass pump or without. Off-pump CABG is technically more challenging but is supposed to reduce the amount of debris reaching the brain during surgery. This trial (given the unoriginal acronym CORONARY - how much jollier BRASSICA might have been) randomized 4752 patients in 79 centres to have their cabbage done one way or the other. At 30 days, there was no significant difference in gross outcomes, but they acknowledge that "Neurocognitive outcomes and economic data may have an important effect on and substantially influence the ultimate interpretation of the primary findings."

1515 Here's a good update on alopecia areata, a T-cell-mediated autoimmune disease in which the gradual loss of protection provided by immune privilege of the normal hair follicle plays an important role. But I must leave you with these bald facts and rush forward to the remaining journals.

Lancet 21 Apr 2012 Vol 379

In his Offline column this week, Richard Horton tells us that this physics-themed issue of The Lancet is timed "to coincide with the death of Albert Einstein on April 18, 1955." Now this is an idea that Einstein would appreciate: what, after all, are 57 years and 3 days in the continuous fabric of space-time? In fact Einstein once wrote a letter of consolation to a bereaved friend using this idea. Or, as TS Eliot more gloomily declares as the beginning of Burnt Norton,

Time present and time past
Are both perhaps present in time future,
And time future contained in time past.
If all time is eternally present
All time is unredeemable.

RH reaches similar heights of mysticism as he tells us why physics is special. He had discovered that underlying everything in the material world there is physics. It follows, he declares, that "Physics is at the heart of our society and so our understanding of health."..."all of us interested in the future of health care, should declare and implement a passion for physics. Our Series is our commitment to do so." Yes indeed. Perhaps it is also time for our column to be renamed Offwall.

1489 My old practice used to number amongst its diabetic patients a Canadian lady who had been treated by Banting in the 1920s: she owed a 60 year extension of her life to the insulin he had just isolated from the pancreatic cells of animals. Animal insulins were still the only kind in use when I first took up doctoring, and very good they were. Many patients complained of hypoglycaemia without warning, and erratic control, when they were replaced by human insulins in the 1980s. But despite their lack of demonstrable superiority, these had almost entirely replaced the cheaper, older insulins within a few years. Insulin manufacturers managed to develop a highly effective mechanism for disseminating their expensive new products by means of trials sponsored by industry, peer pressure from academic diabetes centres receiving large funds from industry, and primary care nurses trained by industry. This mechanism was put into action again in another huge wave of marketing once the patents on human insulin expired, and the so-called analogue insulins - modified by a peptide of two - took over, further ratcheting up costs without any improvement in outcomes. The effect has been to make insulin treatment unaffordable in some developing countries. But still the search for profits goes on. The latest trick is to produce ultra-long acting insulins such as NovoNordisk's insulin degludec and seek to prove their advantage over existing basal insulin regimes. This trial in type 1 diabetes shows overall equivalence with insulin glargine, including in the incidence of hypoglycaemia. But fewer of these episodes occurred at night with degludec. In a trial in type 2 diabetes, the rates of hypos with degludec just managed to squeeze under the statistical bar and come out lower than glargine (95% CI 0.58-0.99). On open-label, manufacturer-sponsored trials of this sort do billions of dollars' worth of sales depend. The Lancet chooses to devote most of its research space this week to them, perhaps expecting good sales of reprints. It would be good to be told.

1551 Having declared his passion and commitment to physics, complete with the Royal We, Richard Horton has managed to pull in a singularly weak set of contributions for his Physics and Medicine series, the strongest of which is the last - mainly because it is much more about biology than about physics. It's a fascinating exploration of such things as fractal patterns in nature and the problems of scale in biological systems, and I would strongly recommend it.

BMJ 21 Apr 2012 Vol 344

As always, there are plenty of good things to read in this week's BMJ. I would particularly recommend Iona Heath's beautiful lament on the demise of the NHS -how a war-ravaged generation strove to create a fairer society, and how we are strangely set on destroying it; and Margaret McCartney's piece on why screening for streptococcus B in pregnancy may not be the unmixed good it is portrayed as in British newspapers. As for original research, there is PhD student-led systematic review of metformin plus insulin versus insulin alone in type 2 diabetes. "There was no evidence or even a trend towards improved all cause mortality or cardiovascular mortality with metformin and insulin, compared with insulin alone in type 2 diabetes. Data were limited by the severe lack of data reported by trials for patient relevant outcomes and by poor bias control." I used to think that the last 40 years of diabetes research had yielded just one fact that one could rely on: metformin is a good drug. Now, sadly, I'm not even sure about that.

Physicist of the Week: Michael Faraday

I - or rather We - declare and implement our passion and commitment to physics by this unique celebration of the life and work of Michael Faraday, timed to coincide with his death on 25th August 1867, give or take 145 years and a few months.

Faraday is the physicist everyone can love because he was kind to children and animals, and bad at maths. He led a life of blameless application, humility, piety, kindness and good sense: in fact his life, shorn of the physical discoveries, is literally too boring to read about. If you want proof, try Michael Faraday (1864),by John Hall Gladstone, free on Kindle. You will do better with The Electric Life of Michael Faraday (2009) by Alan Hirshfeld, a physics professor who explains some elements of Faraday's conceptual achievements, but fails utterly to match the drive and luminosity of Richard Holmes describing Faraday's mentor Sir Humphry Davy in The Age of Wonder. Faraday needs a biographer to match his stature. A really able writer with a knowledge of science is needed to explore the paradox of a man who achieved amazing feats through a mixture of conceptual freedom and endless meticulous experiment. Although Faraday was a religious fundamentalist, his God was the very opposite of Newton's (or Milton's) determinist tyrant, playing with billiard balls of all sizes from the atomic to the cosmic. Faraday dismissed ball-atoms and action at a distance: for him forces existed as fields and vibrations, and without a single mathematical equation he worked out the basis of electromagnetism and went a long way towards relativity and the modern view of the atom. Einstein always kept a portrait of him in his room. It took the genius of Thomson and Clerk Maxwell to create what we now recognize as the mathematical physics of the later nineteenth century out of the qualitative experimental descriptions of Faraday. While they toiled on the equations, he slipped gently into senility - childless, blameless and finally wordless: a strange and rather haunting hero of science.

JAMA 11 April 2012 Vol 307

1489 The new editor of JAMA feels that his worthy journal needs a bit of livening up, and who can disagree? He has borrowed an old idea from the BMJ, in the form of head-on For and Against articles. "Should a 55-year-old man who is otherwise well, with systolic blood pressure of 110 mm Hg, total cholesterol of 250 mg/dL, and no family history of premature CHD be treated with a statin?" This is an awful question for several reasons. It implies that the doctor is the one who should decide, and the "patient" is the object who should, or should not, "be treated". But in what way is this man a patient? Why is he "otherwise" well? Is his illness being 55, having low blood pressure, or having a total cholesterol of 250 mg/dL? In this exchange of views, three doctors think he should "be treated", and two doctors (one the editor of Arch Intern Med) think he shouldn't. I would argue that it is none of their business: give him the evidence and let him decide.

1497 Gah, this is so boring! Are major and minor ECG abnormalities associated with coronary heart disease events? Yes. Does this mean that everybody should have a regular ECG? No. And why? Oh for goodness sake don't bother me - just go back to medical school or read Overdiagnosed.

1506 Next a Danish nationwide database study looking at everyone over 45 admitted with heart failure for the first time and treated with an angiotensin receptor blocker. Does it make any mortality difference whether they are given candesartan or losartan? No, provided they are given a decent dose (100mg losartan).

1513 If you aren't in America, why should you read a paper on Eliminating Waste in US Health Care? Two reasons - first it's by Don Berwick, and anything he writes is worth reading (though if you only have time for one piece, make it The Epitaph of Profession); second it has lessons for all health systems. Especially the NHS, as it becomes a feeding trough for all those nice private providers that MPs and Lords have shareholdings in. Failure to deliver the most effective care, failure to coordinate care properly: on these counts the NHS does very well compared with the US, but will improvement continue? Overtreatment, administrative complexity and fraud and abuse: what can we look forward to on these fronts? Surely the noble guardians of our legislature will protect our health care system from any such taint.

1517 The Rational Clinical Examination series may be struggling to maintain the standards of its glory days, chiefly because it is running out of topics: but blunt intra-abdominal trauma is a great topic and gets a great discussion. When I last worked in an emergency room, handheld ultrasound hadn't even been invented, but it now comes out top in investigative usefulness, though it can't entirely rule out a damaged viscus. If you deal with this kind of scary emergency, this paper is a must-read: and you also ought to be thinking about designing some on-the-ground research, since more is clearly needed.

NEJM 12 Apr 2012 Vol 366

1382 Another week, another drug which prolongs progression-free survival by about 4 months in an incurable cancer. This week it is the turn of olaparib, an orally available PARP inhibitor, for maintenance therapy in platinum-sensitive relapsed ovarian cancer. But the tale does not end with AstraZeneca taking this drug to the FDA for approval for ovarian cancer, and marketing it at the usual price of about $10k per month gained. Instead the company has recognized that there was no overall mortality benefit and has dropped the drug for this indication. Is this a welcome sign that "progression-free survival" is losing credibility as a meaningful end-point in cancer trials?

1393 Coronary computed tomographic angiography (CCTA) is a high-radiation procedure which is very good at ruling out significant coronary artery disease. This important study from the Commonwealth of Pennsylvania shows that it can be used in emergency departments to rule out coronary ischaemia at the cause of chest pain in patients with low-moderate probability. That way more patients can go home more quickly. But I can see drawbacks. For a start, CCTA picks up coronary artery disease in 9% of these patients, as opposed to a 3.5% pick-up rate if CCTA is not used. A lot of this will represent overdiagnosis of asymptomatic disease, and may lead to further (radiation- and cost-intensive) investigation. Secondly, the routine use of CCTA to save an average of 6 hours waiting for biochemical tests will drive up costs and increase the "defensive" use of radiation, meaning that in some instances patients going to different hospitals with recurrent non-cardiac chest pain and getting pretty massive cumulative X ray doses. I think this is a development to be welcomed with caution.

1404 Vorapaxar is a novel antithrombotic agent which works by preventing thrombin binding to platelets, by blocking the protein-activated receptor (PAR-1). To test such agents these days requires enormous trial sizes - this one recruited 26,449 subjects with a history of myocardial infarction, ischaemic stroke or peripheral artery disease to see how well it prevented further events. The prize for Merck would have been a new blockbuster drug for the whole secondary prevention market. But Fate, bleeding Fate, intervened and the trial was halted. There were fewer ischaemic events in the group who got vorapaxar rather than a thienopyridine, but more cerebral haemorrhage. Vorapaxar is an interesting drug which may have some kind of future, but blockbuster it is unlikely ever to be.

Lancet 14 April 2012 Vol 379

1393 In 1998, when I first started writing these brief notes on the journals for a few friends and colleagues, I decided that coronary artery stents were an interesting new development that I should tell people about whenever they cropped up in the literature. How dearly I (and you who have followed me) have paid for that decision! Paclitaxel, sirolimus, everolimus, zotarolimus... I have tried to make them interesting by pretending they were creatures from Star Wars, or minor characters from Antony and Cleopatra, or members of a zany family called Olimus, whose next son will no doubt be called boralotimus. And now it turns out we may have been looking at the wrong thing all along: what matters in the Stent Wars is not the drug these things elute, but the metal they are made of. According to this "comprehensive network meta-analysis" of 49 trials with 50,844 randomly assigned patients, the clear winner is a cobalt-chromium stent which elutes everolimus. For the first time in 14 years, my remarks on stents will actually be read by some interventional cardiologists, thanks to their appearance on the CardioExchange website run by the NEJM. OK you guys, start quarrelling about this study: the rest of us are off for a nice snooze.

1403 Now children, what happens if you give somebody with type 2 diabetes a drug which increases endogenous insulin secretion? Their sugar levels go down, yes. It the drug is a sulfonylurea like glimepiride, they also have a risk of hypoglycaemia,and they may lose beta-cell function more rapidly. And don't forget that UKPDS tells us that if you combine a sulfonylurea with metformin, you end up with increased mortality - but that is by the way. In the phase 2 trial reported here, the investigators aren't interested in crude measures like coffin counts. Takeda have produced a new diabetes drug which works by activation of the free fatty acid receptor 1 (FFAR1), and it seems to stimulate insulin production and reduce blood sugar without any serious risk of hypoglycaemia. That's about it for now. The drug TAK-875 doesn't yet have a name and needs some phase 3 trials. Let's hope that these are double-blinded trials of this single drug, of sufficient power and duration to determine real microvascular and macrovascular end-points. Let's hope that the licensing authorities insist on such evidence, even though it may take five or more years to gather, and disregard all surrogates such as HbA1c, creatinine/albumin ratio, lipid fractions, rate of retinal changes, doubling of creatinine, etc etc. That way, for the first time in the history of type 2 diabetes, we might actually know what a specific treatment does to patients.

1412 Adolescence is a state from which most of us eventually recover. In some youths it is characterised by periods of chronic fatigue, and if these persist for a long time, they become chronic fatigue syndrome. I suspect that many factors often conspire to perpetuate CFS in adolescence, which can have devastating results for social development and education. The sensible Dutch have now devised a web-based cognitive intervention called FITNET, and in this trial it achieved spectacular success at six months: 75% school attendance and 85% absence of severe fatigue, compared with 16% and 27% respectively with usual care.

BMJ 14 April 2012 Vol 344

Health literacy is the subject of this survey of English adults. It's a term which has spread widely in recent years. In the grim judgemental days of my youth in Yorkshire, where everything carried its due apportionment of blame, people were graded according to intelligence, and separately graded by education, and further graded by literacy; but never graded by "health literacy" because health was not the kind of thing that proper Yorkshiremen were permitted to worry about. I think this composite term is useful for allowing us to address the fact that a third of the population lacks the ability to understand basic written health information. That does not mean that they are beyond the reach of explanation, or cannot share in the making of decisions about their care: it just means that it needs to be done in different ways, both directly and with the use of video. And low health literacy is of course associated with lower levels of health and poorer health outcomes.

Migraine with visual and sensory aura is a peculiar phenomenon, which I have had a lot of chances to observe lately, but cluster headache belongs to a different league of pain and autonomic dysfunction. Before the arrival of triptans and the discovery of high-dose oxygen as a treatment, I remember having to pretty well flatten patients with opioids to combat the intense pain and distress. Billed as the first review of the condition in the BMJ for fifty years, this one could hardly be bettered, and ends with a brief narrative from a patient who sought to beat her head with a telephone handpiece to relieve the pain, while trying to stop her children from noticing.

Arch Int Med 9 Apr 2012 Vol 172

555 Scraping the barrel of things to watch on Netflix the other night, we ended up sitting through a suitably interminable account of the 4,300 mile journey of exploration by Lewis and Clark in 1804-6, of the Louisiana Territories purchased by Thomas Jefferson. As they moved upstream, the diet of their men changed from ordinary beef to bison, then horse, then elk and antelope: when they reached the Western side of the Rockies, the river beneath them was thick with huge salmon, but such was their yearning for red meat that they preferred to barter with the local tribes for fattened dogs. Oh dearie me, how very unhealthy! Amazingly, none of them died on these epic travels through often hostile territory, and one or two made it beyond the age of 90. But we should not draw the wrong conclusions from this, because red meat consumption is once again shown in this study to be associated with an increase in total mortality and mortality from cardiovascular disease and cancer. There are many reasons why one should perhaps consider giving up red meat; personally I would not rank longevity as high as the feeling inspired by our next Netflix offering, Buster Keaton's Go West (1925), in which he is movingly befriended by a young cow called Brown Eyes.

Plant of the Week: Linnaea borealis

It is a nice touch that Carl Linnaeus, who was extravagantly vain in so many ways, chose this humble mountain alpine plant as the bearer of his name. It is a small ground-hugging relative of the honeysuckles, with lovely little elongated bell-flowers of white streaked with purple, said to be fragrant if you care to bend to within a few inches of the ground.

We went searching for spring wild flowers in the mountains of upstate Connecticut, and the Linnaea was all we found: the trilliums were not yet out. It a lovely little thing which I assume does well in colder gardens on acid soil. The plant we found used to be called Linnaea americana,but botanists have changed their mind and declared that just as there was only one Linnaeus, so there shall be only one Linnaea.

Sumerian Proverbs for Medical Editors

There will be a prominent place for a capable scribe

A good word is a friend to numerous men

Good fortune [calls for] organisation and wisdom

Accept your lot and make your mother happy

Ignoramuses are numerous in the palace

From many oxen, is there no dung?

clay tablets from c 2000 BC

JAMA 4 Apr 2012 Vol 307

1394 A special dread settles on me this week as I know I am going to have to write about breast cancer screening. But let's leave the dread question of whole-population mammography for later, and consider the add-on benefit of annual ultrasound or single-screening MRI in selected high-risk women. While the war over breast screening rages unchecked in the letters and a book review in this week's Lancet, let's take refuge in this little corner of the battlefield, where at least the fog of war is not too thick and we can count a few weapons and estimate a few casualties. The volunteer combatants are women with dense breasts and at least one factor that increases their risk of breast cancer. The ultimate proof of victory, as in all screening studies, will be a reduction in total mortality. The casualty list should include every woman undergoing biopsy or surgery, because nobody comes away from these things altogether unscathed, be it mentally or physically. This study gives us a casualty list, including the number of enemy killed (breast cancers detected and operated on), but cannot give us any idea of the extent or the cost of victory, because it was run over a three-year period only. Our brave lasses certainly saw their share of action: 2725 over the age of 25 (!) went through annual mammography and ultrasound, and 612 ended up having MRI. During that time 110 had 111 breast cancer events: 33 detected by mammography only, 32 by ultrasound only, 26 by both, and 9 by MRI after mammography plus ultrasound; 11 were not detected by any imaging screen. Enough. We can tell from these figures that the three imaging modalities will pick up most cancers; but the true cost - mentally, physically and financially - can only be hinted at in a study like this. Only very long-term follow-up will give us a true estimate of overdiagnosis and the degree to which such screening detects cancers which would never progress. But in just these three years, a total of 1272 biopsies were performed - more than ten for each cancer detected. So this high risk group may well see a small reduction in all-cause mortality over the course of their "screening lives", but it will be purchased at a high cost in medical procedures and anxiety. In fact any woman undergoing this cycle of procedures would be extremely lucky to get away with a single fine-needle biopsy during her life - two or three would be more likely.

1414 Oral fluoroquinolones are cheap and ubiquitous these days, and lots of doctors take them abroad in case of traveller's diarrhoea. But beware: this case-control study confirms that they may carry a more than fourfold risk of retinal detachment. OK, still not a huge absolute risk, and usually fixable; but it may not be what you want to happen to you while you are cruising down the Nile, admiring Cambodian temple complexes or trekking to Machu Picchu.

NEJM 5 Apr 2012 Vol 366

1287 The successful EINSTEIN-PE trial of rivoroxaban has been talked about for a while, and you don't have to be Einstein to work out that this is very good news for Bayer HealthCare and Janssen Pharmaceuticals, who co-funded the trial. It was an open-label trial, pitting the new oral fixed-dose factor Xa inhibitor against an adjusted-dose vitamin K antagonist (in the States, they use dicoumarol as well as warfarin) for 3, 6 or 12 months after symptomatic pulmonary embolism. As far as I can tell (and you know I am far from infallible) the stuff did what the manufacturers put on the can: rivaroxaban was as good at preventing recurrences, and less likely to cause major bleeds than a coumarol/INR regime.

1298 This trial comparing two artesunate-based antimalarial regimens in patients with uncomplicated falciparum malaria is principally a fairly routine affair of showing that pyronaridine-artesunate was noninferior to mefloquine plus artesunate for the primary outcome. This is useful knowledge for those in the field, across Asia and Africa. But the study has rapidly become more famous for the unwelcome confirmation it brings of artemesinin resistant malaria in Cambodia. This is suggested by increased parasite clearance times in a subset of patients from the region which first produced strains resistant to previous antimalarial drugs. Those lethal little zoites may be on the verge of outwitting us yet again in the jungles of IndoChina: a sickening thought, after so many decades of effort, never quite sufficiently carried through.

1310 Here's a really thought-provoking study from Sweden showing that in the week after receiving a cancer diagnosis, the relative risk of suicide goes up by 12.6 and the RR for cardiovascular death by 5.6. Taken over the first year, the risk ratios are slightly over 3 for both. The immediate cardiovascular effects of a shocking diagnosis could hardly be more dramatically demonstrated, while the continuing physical effect could be partly explained by prothrombotic and inflammatory effects from the cancer itself. But the suicide figures once again raise the question of what is an "appropriate" response to a cancer diagnosis. Palliative care specialists, at least in the UK, share a religious predisposition to expect all cancer patients, at whatever stage, to bear their sufferings to the end, encouraged by promises (which may be undeliverable) of complete relief. To me personally, this interpretation of the will of God seems neither rational or generous, nor even always honest. The original Zarathustrian religion of good thoughts, good words and good deeds seems to me a better guide: it acknowledges that God (or good, or whatever you want to call it) can only act through man in the physical world. Suicide in the first week of diagnosis is likely to be an immediate distress reaction, almost certain to cause a lot of distress in others: it is not irrational, but is usually best averted if possible. But well-planned suicide in the face of impending suffering and death does not seem to me either irrational or ignoble, provided it is done with full consideration to others.

1319 The ancient Good Religion of Zarathustra dominated Iran for at least a thousand years, before the Arab conquest gradually led to the imposition of Islam from the mid-seventh century onwards. The Muslim tradition in Persia contains elements of both, as shown by the linguistic parentage of the name Faramarz Ismail-Beigi. How nice it would be to dwell on the history of this wonderful part of the world a little longer, but unfortunately we must move on to the topic of glycaemic management of type 2 diabetes mellitus, upon which the distinguished Dr Ismail-Beigi writes in this week's NEJM. You may perhaps be expecting some harsh words from me on this subject, but I must honour the Iranian tradition of intelligence, charm and moderation as best I can on this occasion. Prof. I-B acknowledges that there is a lot we do not understand about the disordered metabolic state that we please to call "type 2 diabetes", on the grounds that it is characterised by high levels of blood glucose and gradual depletion of beta-cell function. He goes through the evidence and finds that it is insufficient to guide any choice of agents beyond diet and metformin in the first instance. Pretty well everything we know about long-term effects - whether driven by treatment or disease processes - is derived from a single study designed in the 1970s, the UKPDS. Survivors of this group who were treated intensively at the outset with sulfonylureas and insulin show a "legacy effect" according to levels of blood sugar control, which the investigators attribute to the treatment - though not to the extent of suggesting we use these interventions as first-line treatment in 2012. Rather we should look at the subgroup of fatter patients who were given metformin, and extrapolate from them, since they had somewhat better outcomes. We should hope that these newly diagnosed patients maintain a glycated haemoglobin level of around 6-6.5%, as people who managed to stay at these levels did best in the long term. We can't tell whether this was due to treatment or because they had a more favourable disease process. This may not be the pinnacle of evidence-based medicine, but it is what specialists agree on when they meet in High Council to discuss what we should do with tens of millions of people with this condition around the world, basing their judgements on what happened to a few hundred British diabetics from the time of Mrs Thatcher. For more modern sugar-lowering interventions, we have no long-term data on harms or benefits, since no-one has thought it necessary to require them. About all this, Faramarz Ismail-Beigi is quite candid, calm and polite: so in the best tradition of Persian courtesy, I shall stay the same towards the whole profession of diabetology. Salaam, Khoda hafez.

Lancet 7 Apr 2012 Vol 379

1310 This cluster-randomized trial from British general practice compared computer-generated reminders about medication dangers with something they grippingly called PINCER - "a pharmacist-led information technology intervention, composed of feedback, educational outreach, and dedicated support". You can choose which you hate most - this description or the acronym. The end-points were: non-selective non-steroidal anti-inflammatory drugs (NSAIDs) prescribed to those with a history of peptic ulcer without co-prescription of a proton-pump inhibitor; β blockers prescribed to those with a history of asthma; long-term prescription of angiotensin converting enzyme (ACE) inhibitor or loop diuretics to those 75 years or older without assessment of urea and electrolytes in the preceding 15 months. Fair enough, I suppose (though I suspect some surprises when someone eventually looks at the end-points in "asthma" patients given very low-dose β blockers versus those given β agonists): and of course the PINCERed practices did better. So what should you commissioning guys invest in? More paid-for interference - sorry, I mean outreach and dedicated support - by community pharmacists, or punchier, clearer computer reminders?

1331 "Knee-replacement surgery is frequently done and highly successful." I can vouch for that - not because I've had it, but because a lot of my patients had it done by the first author of this review, and they have fared well. During my GP career, I've seen this procedure grow up from a last-resort, almost experimental operation to a routine procedure for painful osteoarthritis. The technology seems to have improved steadily over that time, though with the present pitiful standard of device regulation, there is nothing to stop some new prosthesis winning most of the knee surgery market before it turns out to be a disaster. I refer of course to the metal-on-metal hip scandal; but I've seen it happen with some other kinds of innovative knee surgery, like the carbon ligaments once favoured by another local surgeon. The international epidemiology of TKR is fascinating for its insights into the variability of preference-sensitive surgery in different health systems. In the UK, demand for TKR may actually have peaked - or is it just being rationed more effectively?

BMJ 7 Apr 2012 Vol 344

Ah, a plate of plain white rice. How like the research pages of the BMJ this week: bland, unappetizing, and badly in need of some original additions. Maybe that's why the journal let through this terrible study which traces the links between white rice consumption and diabetes, by a series of population survey methods which have BEWARE OBVIOUS CONFOUNDERS written all over them: perhaps they just wanted newspaper coverage and rapid responses. They certainly got plenty of the latter, and I will let them do their work unhindered by any further comment from me.

Well, maybe this is interesting, if it is confirmed in other studies: women who have had surgical treatment for treatment for human papillomavirus-associated vulval or cervical disease are less likely to experience recurrence if they have had previous vaccination with quadrivalent HPV vaccine. This is based on retrospective pooled data from interventional trials.

Ann Intern Med 3 Apr 2012 Vol 152

491 And now, as I warned you, we must return to the battlefield of breast cancer screening. I defy anyone to reach clarity on this subject: the nature of the data just doesn't allow it. So we are on the horns of a real dilemma here. We need women to make up their own minds on whether to go for this kind of screening, but we cannot inform their choice in a way which is either easily comprehensible or free from our own value judgements. By saying this, I'll probably draw fire from both sides in this debate -the screening enthusiasts who will say there is clear evidence of benefit and women shouldn't worry their pretty little heads about the matter but just go along and have their breasts X-rayed; and the sceptics, led by the redoubtable Peter Gøtzsche, who will say that the benefits are dubious or non-existent and the harms are all too real. Each side will then go through a selection of mainly observational studies to try and prove their point. At this point I tend to find some excuse to slip out of the room, glad that I am a man, and that I no longer have to give my advice to anyone: muffled cries of anger pass me by as I make my escape. But for your sakes, dear readers, let's take a passing look at this latest observational study from Norway. Leave aside the costs, the anxiety and the needle biopsies and concentrate on how many detected cancers can be considered as overdiagnosed. "The number of cases of breast cancer found in screened women was compared with that in matched unscreened women. Investigators estimated that 15% to 25% of cases of breast cancer detected represented overdiagnosis." OK guys, you be downloading the paper and discussing the methods, and the meaning of "overdiagnosis". I'm just nipping out to get some coffee...

Plant of the Week: Ribes x gordonianum

The flowering currants are classic spring bushes to be looked forward to with special pleasure. As forsythias scream their yellow at the spring winds, hard by battered expanses of browning magnolia flower, and cherry trees filled with blowsy pink, it's a relief to look down at or below head height and see the intriguing brick and pinkish yellow flowers of this unassuming but essential little shrub.

It is a quintessentially British plant, discovered as a chance hybrid in Ipswich in 1837. It carries the reds of Ribes sanguineum subtly blended with the yellows of Ribes odoratum, in open clusters of small bell-shaped flowers with bright yellow and red stamens. I keep trying to detect the spicy fragrance of odoratum but the feral rankness of currant-bush tends to predominate. Nonetheless, this tousled, prickly, loveable scamp should be in every garden to welcome the spring.








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Page last edited: 08 May 2012