Journal Watch - December 2012

JAMA 19 Dec 2012 Vol 308

2469 Most healthy people don't take aspirin, so if you look at a long-term study of aspirin in relation to some clinical event, such as macular degeneration, you have to be very careful to allow for confounding by indication. And what is the main indication for aspirin? Why, it is cardiovascular disease. And what is the main cause of cardiovascular disease? Why, it is smoking. And what is the main cause of age-related macular degeneration? Why, it is also smoking. So you can go round some nice logical short-circuits if you just go comparing the amount of long-term aspirin use with the amount of macular degeneration fifteen years later. The Beaver Dam Eye Study provides a longitudinal data set to interrogate for associations between AMD and a number of factors. We don't know how many hypotheses these authors pre-specified before they put the data through their stats programme, but we do know they came up with a positive relationship between aspirin use and AMD ten years later. Do I believe it? No: and nor do the authors, really, because they ask for more studies. Their dataset just doesn't seem good enough to me to support this level of beavering. There is only point-of-time information every 5 years on smoking and on aspirin use: nothing you can really build a dose-related relationship out of, or even (in my view) a plausible hypothesis.
http://jama.jamanetwork.com/article.aspx?articleid=1486830

2489 The Look AHEAD (Action for Health for Diabetes) study is perhaps the largest randomized controlled trial of an intensive lifestyle intervention among adults with type 2 diabetes to date. And boy is it intensive: weekly coaching sessions for the first six months and a diet which induced weight loss of 8.6% in the first year. This achieved biochemical remission in 11.5% of subjects at the end of the first year, falling to 7.3% at the end of year 4. As with all diabetes interventions, it's the cardiovascular outcomes in the long term that will matter most, and we won't know those for a while yet. In the meantime, here is yet another great data mine for diabetes researchers - if they can get access to it. O that all studies of this kind were part of a global collaboration: if that happened we might even find out how to treat type 2 diabetes (at last).
http://jama.jamanetwork.com/article.aspx?articleid=1486829

2497 Two weeks ago, I took The Lancet to task for using most of its research article space to publish two Amgen-funded phase 2 trials of AMG145, its new monoclonal antibody to plasma proprotein convertase subtilisin/kexin type 9 (PCSK9). And do you recollect what does this does to people? Yes, it reduces their low density lipoprotein cholesterol. And what else does it do? - the girl at the back. "We don't know, sir!" - excellent, that is the correct answer. We really have no idea what this drug does to people in the long term. But here is yet another paper in a leading journal describing a 12 week phase 2 trial called GAUSS, showing that it reduces LDL-C in those who are intolerant of statins. This wouldn't be a way of softening up the FDA to make it available before the long-term safety and effectiveness data are in, would it? I do hope not, because all good children know that would be naughty and dangerous and wrong.
http://jama.jamanetwork.com/article.aspx?articleid=1389227

NEJM 20 Dec 2012 Vol 367

2370 "Genomewide Association Studies and Common Disease - Realizing Clinical UtilityAh, a rare slip in the copy-editing of the NEJM - in the last word,they have missed off the initial F.
http://www.nejm.org/doi/full/10.1056/NEJMp1212285

2375 A few years ago, somebody gave me a book of cardiovascular trial acronyms. It lay in our downstairs loo for a while, and I seem to remember that it had 700+ pages, one for each trial. Now, for your seasonal delectation, comes the FREEDOM trial which compares coronary artery bypass grafting with percutaneous coronary intervention in people with type 2 diabetes and multivessel coronary artery disease. And it comes out in broad agreement with BARI, CARDia and SYNTAX. Those of you who take your acronyms seriously (or spend a lot of time on the loo) will remember that each of these showed an overall advantage from CABG rather than PCI in these patients. So does FREEDOM, with an absolute reduction of 7.9% in major CV events. Since all the subjects in this trial were given maximal cardioprotective drug therapy as well, you could argue that in the light of COURAGE, there should also have been an arm in which there was no invasive treatment. Then we could really share decision making with this high-risk group of patients. But to be fair to the FREEDOM triallists, they recruited before COURAGE was competed, so they couldn't have known. Time for another trial, perhaps: but please no more stupid acronyms; there just isn't space in the loo.
http://www.nejm.org/doi/full/10.1056/NEJMoa1211585

2385 I don't know if Dickens tells us why Tiny Tim had crutches, but maybe he had systemic juvenile idiopathic arthritis. I'm no expert on this condition, but I can't believe that there aren't half a dozen or more third-line drugs for JIA once non-steroidal and steroidal anti-inflammatories have failed. I really don't understand why Hoffmann-LaRoche were allowed to run a placebo-controlled trial of the latest "biological", an antibody to the interleukin-6 receptor called tocilizumab. It lasted 12 weeks, and after that all the kids could get put on to open-label tocalizumab, which provides a high rate of remission at the cost of a significant incidence of neutropenia and infection. So how does this help us decide on the place of tocilizumab for JIA among all the rest? This is a long-term condition, and the disease is nasty but the risks of treatment are high. Long-term head-to-head trials are the only ethical answer: the rest is just marketing.
http://www.nejm.org/doi/full/10.1056/NEJMoa1112802

2396 "And oh look Tim, here is another Christmas present for you - a selective, fully human, anti-interleukin-1β  monoclonal antibody called canakinumab, brought to you by nice Mr Novartis. You will thank the gentleman, won't you Tim?" "Well indeed thank you sir, but begging your kind pardon, I don't see as you can tell if it will do me more harm than good until you've done them phase 3 trials and compared it with other agents targeted at the inflammatory pathways in systemic juvenile idiopathic arthritis if you catch my meaning sir. So I bid you a Merry Christmas if I may make so bold, and good night and all sir."

http://www.nejm.org/doi/full/10.1056/NEJMoa1205099

2407 Competitive blockade of the vasopressin V2-receptor is a great idea, but it's taken ages for a real use to emerge for it. Tolvaptan is sometimes used to treat hyponatraemia, and it also has been shown in preclinical studies to reduce progression in autosomal dominant polycystic kidney disease. This trial takes that idea a lot further, though not to the point of the hardest outcomes such as death and need for dialysis. What is shows is that tolvaptan slows the increase in kidney volume by nearly a half over 3 years, and also slows the decline in kidney function: but there were enough adverse symptoms (thirst, polyuria) and biochemical changes (hyponatraemia, hypokalaemia and liver enzyme elevations) to lead to a discontinuation in about a quarter of the subjects.
http://www.nejm.org/doi/full/10.1056/NEJMoa1205511

BMJ 22 Dec 2012 Vol 345

A worthy Christmas edition of the BMJ containing many delights. Two adorable dogs, including Cliff the poo-sniffer, who is the best known diagnostic agent for detecting C difficile; some wonderful historical items including an exhaustive account of the surgical thimble, and how Hitler introduced gastroscopic art to British medicine; suggestions for a medical uniform which deserves wide adoption; and a warning on the dangers of the tooth fairy (and GPs who can't perform otoscopy).

I'm delighted to see that Anthony Harnden has taken up my suggestion and investigated the predictive characteristics of the speed bump test for suspected appendicitis with a team of Oxford colleagues. It's actually amazingly good as a rule-out test, with a sensitivity of 97%. It has a poor specificity (30%) because any inflamed viscus will hurt when you go over a speed bump in a car. Now combine it with the Mars bar test, as I suggested (read Hershey bar or similar in the USA) - if your offer of a chocolate treat is firmly refused, and the speed bump test is positive, you need to send that child straight off to the surgeons.
http://www.bmj.com/content/345/bmj.e7396

Ann Intern Med 18 Dec 2012 Vol 157

878 How to keep Cliff away from your bed: take probiotics. The evidence isn't first class, say these meta-analysts, but it all points one way: that if you eat lactobacilli while taking antibiotics, you are much less likely to get Clostridium difficile afterwards. Woof!
http://annals.org/article.aspx?articleid=1390418

Plant of the Week: Viscum album

The practice of kissing beneath mistletoe apparently only grew popular in the sixteenth century, and nobody really knows why. Any excuse will do, I suppose. At junior school we were told that Yule was a pagan festival when Druids would cull mistletoe from trees with a golden knife because they believed it was a magical evergreen emanation of the tree-spirit. That cut little ice with me, because I had never seen either mistletoe or Druids. As a result, when we were asked to draw such scenes with our crayons, my efforts lacked conviction. I much preferred doing baby Jesus in his manger, though my cows were notable more for imagination than for perfect verisimilitude. I find that this is a trait that I share with many other artists including Fra Angelico.

Few gardens contain mistletoe as a deliberate ingredient, but we have a great opportunity. A person whose memory we adore once helped her granddaughter to plant an apple seed in a yoghourt pot many years ago, and now we have a fast-growing apple tree which from time to time bears small scabby apples reminiscent of Golden Delicious. On this sacred tree we have sent up Clematis armandii to flower in March and Clematis viticella to flower in July. As the tree continues to grow, I think I might make a cut in one of its boughs and dress the wound with bird dung and mistletoe seeds. Later perhaps, when the mistletoe has grown and I have acquired a flowing white beard, I shall celebrate Yule by putting on robes and flourishing a knife covered in gold leaf; then I shall mount a ladder to cut the mistletoe from the tree while intoning nonsense in a loud Welsh accent.


JAMA 12 Dec 2012 Vol 308

2349 The run-up to Christmas never finds me in the best of moods, and now it seems that the editor of JAMA is trying to wind me up by showcasing all my pet hates. Well, some of them anyway: to showcase them all would require a space the size of the South Kensington Natural History Museum. "Chronic kidney disease as a prognostic marker - again - would you believe it! And in this study the comparator is an estimated glomerular filtration rate of 80 - would you believe it? They factor in albuminuria too, and conclude that "both low eGFR and high albuminuria were independently associated with mortality and end stage renal disease regardless of age across a wide range of populations." Well I never: bad kidneys get worse more often than good kidneys, CKD is a weak surrogate for poor vascular health, and eGFR and albuminuria are weak prognostic markers among hundreds of others: how fascinating. Let's go measuring them in everybody and then treat the surrogate markers. Bah, humbug!
http://jama.jamanetwork.com/article.aspx?articleid=1387683

2369 How is the mighty sea-god insulted! POSEIDON stands for A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction. If I were Poseidon, I would rise up from the ocean and impale the authors of this study with my trident for their acronym alone. I would mount upon my hippocampus (meaning a horse with a finny tail) and cause sea-monsters to devour them because they don't describe any patient-important end-points in their study. I would raise storms to destroy their ships because they use the silly term "ischaemic cardiomyopathy" to describe local damage and fibrosis caused by myocardial infarction. And I would send serpents to bite the editors of JAMA for publishing yet another study of stem cell treatment for heart failure that is of minor technical interest only: autologous cells gave slightly better physiological outcomes and graft success than allogeneic cells, but the patients involved cannot have noticed any difference. Wake me up when there is a stem cell treatment that helps people with heart failure in real life: I have read enough of these little short-term studies over the last ten years. Know that I am Poseidon and I shall smite you.
http://jama.jamanetwork.com/article.aspx?articleid=1388970

2380 And here's another trial of bone marrow mononuclear cells to repair myocardium: this time they were autologous cells given either 3 or 7 days after acute myocardial infarction viacoronary arteries. Again, no patient-detectable end points were measured: the primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging. "Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo." So away with you! Know that I am Poseidon and I shall smite you!
http://jama.jamanetwork.com/article.aspx?articleid=1388971

NEJM 13 Dec 2012 Vol 367

2275 People with heart failure can die in three ways:(1) suddenly without warning, (2) by slow drowning, or (3) from something else. If I had heart failure, I would particularly want to avoid the second option, but implantable cardioverter defibrillators are specifically designed to move you from option one to option two. Whether to have an ICD is a very difficult decision to share with patients, because it means taking them to horrible places they can scarcely imagine. As doctors we have seen lots of people die from pulmonary oedema: would you want to show a patient a video of that? Or of someone undergoing repeated electric shocks from an implantable device? I know there are several centres developing shared decision aids for ICD placement, and I'll be interested to see what they come up with. There is a glimmer of reassurance from the trial described here, which shows a better way to programme these devices: "Programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher or with a prolonged delay in therapy at 170 beats per minute or higher, as compared with conventional programming, was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up."
http://www.nejm.org/doi/full/10.1056/NEJMoa1211107

2284 We are being encouraged to cherish our British pharmaceutical companies and see them as the wealth producers of the future for UK plc. And personally I would rejoice if GlaxoSmithKline were to produce an effective malaria vaccine and price it in such a way that malaria could quickly become a disease of history. If some of that money flowed back into Britain and paid for the NHS, so much the better. I would also rejoice if GSK were to identify the personnel responsible for the criminal fraud it has admitted to in the recent $3bn+ US settlement, and ensure they are brought to justice: and also if it were to deliver substantively on its promises to release full data from all its human trials. But none of this seems likely to happen any time soon. The GSK malaria vaccine described here only succeeded in preventing 26% of severe malaria in African children, despite being highly effective at producing anti-circumsporozoite antibodies. This particular route seems to miss the destination by 74% - and what's worse, it seems unlikely to take us any further.
http://www.nejm.org/doi/full/10.1056/NEJMoa1208394

2296 The other big idea of Mr Cameron and his advisers is that the NHS can be used to create wealth through the early adoption of new, British-made innovations. I don't know if any British firms are involved in the ultrafiltration business, but perhaps they should get in there while device regulation remains nearly non-existent. In the USA, Gambro sell something called Aquadex System 100 (CHF Solutions) specifically for use in fluid overload, which is supposed to be the answer when diuretic therapy appears to fail. The National Heart, Lung, and Blood Institute in the USA tested this claim in a trial involving 188 patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion who were randomized to ultrafiltration or stepped pharmacologic treatment (i.e. more diuretics). The diuretics worked better and had fewer adverse effects. So will all the hospitals that bought these devices now throw them away? It would be interesting to find out in a year's time. And do the sales that Gambro achieved in the USA count as national wealth creation?
http://www.nejm.org/doi/full/10.1056/NEJMoa1210357

Lancet 15 Dec 2012 Vol 380

It is the season of goodwill, so I shall praise The Lancet and quote Richard Horton at length. "Publication of the Global Burden of Disease Study 2010 (GBD 2010) is a landmark event for this journal and, we hope, for health. The collaboration of 486 scientists from 302 institutions in 50 countries has produced an important contribution to our understanding of present and future health priorities for countries and the global community." I agree. Might Elsevier do their little bit though, and remove the paywall in time for Christmas?

"What are the headline findings? First, although 52.8 million deaths occurred in 2010 (in 1990, the figure was 46.5 million deaths), great progress is being made in population health. Life expectancies for men and women are increasing. A greater proportion of deaths are taking place among people older than 70 years. The burdens of HIV and malaria are falling. Far fewer children younger than 5 years are dying. Infectious diseases are increasingly being controlled. In some parts of the world, there has been substantial progress in preventing premature deaths from heart disease and cancer.

But this hopeful picture is being challenged by old and new threats. Huge gaps remain in progress for some regions of the world. Tuberculosis and malaria are estimated to have killed around 1.2 million people each in 2010. 8 million people died from cancer in 2010, over a third more deaths than 20 years ago. One in four deaths was from heart disease or stroke. 1.3 million deaths were due to diabetes. Deaths from road traffic injuries increased by almost half. Blood pressure is the biggest global risk factor for disease, followed by tobacco, alcohol, and poor diet. And young adults are emerging as a new and neglected priority in global health: GBD 2010 finds that young adults, especially men, are dying in far higher numbers than previously appreciated. But the most afflicted continent remains Africa. Here, maternal, newborn, and child mortality, along with a broad array of vaccine-preventable and other communicable diseases, remain urgent concerns."

All great stuff. Though I don't understand the bit about alcohol, a potent protector against cardiac disease. So pull open that bottle of malt whisky, give the fire a prod, and slump back and pore over the charts and tables in this fascinating issue of The Lancet. Assuming, of course, that you are a subscriber as well as an imbiber.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961719-X/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961728-0/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961690-0/abstract

BMJ 15 Dec 2012 Vol 345

The BMJ kicks off rather oddly with a Danish editorial on allergic reactions caused by methylisothiazolinone. This is a preservative widely used in paint and cosmetics and it causes allergic skin reactions which look like photosensitivity because they occur only on exposed parts of the body such as the neck, arms and face. I saw a woman with just such a rash a week ago and I hadn't a clue what was going on. I think everyone needs to be aware of this potential problem - and may wish to see this chemical banned from all consumer and occupational products, as the editorialists do.
http://www.bmj.com/content/345/bmj.e8221

It's odd how long it has taken our profession to realize that if you need a vaginal swab, it is perfectly OK to give the patient the means to do it and let her hand it back to you. The interesting thing about the two studies here - one on chlamydia and the other on gonorrhoea - is that self-taken swabs actually have a higher diagnostic yield than endocervical swabs taken by a health professional.
http://www.bmj.com/content/345/bmj.e8013
http://www.bmj.com/content/345/bmj.e8107

"Magic bullets with a hefty price tag" is an article mainly about monoclonal antibodies and why they are so phenomenally expensive. The author is from Tufts University, Boston, Mass. and he predicts that by 2014 these "biologicals" will account for 30% of the branded prescription market in the USA, at $166bn. The cost of a year's monoclonal antibody treatment for paroxysmal nocturnal haemoglobinuria is currently over $400,000 per year. He is keen to protect the manufacturers from any accusations of profiteering and never drops any hint that there could possibly be a different business model for developing and marketing these drugs. I think it's time that health care payers in all developed countries got real about the future, and joined together to set up a different way of doing things. To my mind, it can only lie in collaborative global not-for-profit development of targeted treatments: otherwise all medical innovation is going to become unaffordable, and absolutely unavailable to those who most need it.
http://www.bmj.com/content/345/bmj.e8346

Speaking of being unavailable to those who most need it, I am going to have another nag about the BMJ's Clinical Review series. My complaint is that it has become the best and most practical guide to clinical practice regularly featured by any medical journal; it's ideal for an international readership and exactly the kind of learning and teaching material required in the developing world. This week's Diagnosis and management of supraventricular tachycardia is an excellent example. But in countries where the HINARI agreement doesn't hold, few practitioners will be able to benefit from it, and where HINARI does apply, they will need to go through a cumbersome procedure via an academic centre. Open access must come, even if not in time for Christmas.
http://www.bmj.com/content/345/bmj.e7769

Arch Intern Med 10 Dec 2012 Vol 172

1707 If eating before having a blood test for lipid levels made much difference, you would expect there to be an overall increase in levels according to the time of the last meal. This cross-sectional study from Canada could detect no such difference in samples from 200,000 individuals whose samples were taken in the community. One more piece of evidence that we should give up advising patients to fast before measuring their cholesterol, and let them have their blood taken at a time to suit them.
http://archinte.jamanetwork.com/article.aspx?articleid=1391022

Plant of the Week: Schoenoplectus lacustris

I have been looking around the winter landscape over the last week, trying to spot the plant that looks best in frost and fog. My current favourite is the bulrush, appearing out of misty roadside ditches as one approaches, tall and white with rime, its bulbous frost-covered tips trying to catch a hint of the sun that shines above the morning fog.

The British bulrush is quite a distant relative of the bulrush that features in everybody's favourite Bible story. Remember those picture books, and the sweet concern in the eyes of the pharaoh's daughter as she pushes aside the flags to discover Baby Moses, with her maidens in attendance. The kind of bulrush that formed the basket that Moses was floating in was probably Cyperus papyrus, a sedge of the Nile that never sees frost.


NEJM 6 Dec 2012 Vol 367

2175 This is the time of year when, as a GP who is still let loose on patients, I have to undergo my annual appraisal. I shall try to demonstrate that knowledge keeps entering my brain at a rate roughly sufficient to replace the increasing amount that leaks out. My main evidence comes from these reviews - and I can honestly say that I learn quite a lot every week. Unfortunately this week's journals are almost devoid of GP-useful content (I am omitting JAMA altogether because it is devoted to medical training in the USA), but here my main learning point for the week comes from this study: "Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis." Right: this is a new area for me, and probably for you. And it is going to affect an awful lot of you in the future, both as doctors and as parents. Chromosomal microarray analysis just needs a cell or two: it does not need cell culture, and it can easily be automated. The problem right now is that it detects many variants which are typically classified as benign, pathogenic, or of uncertain clinical significance, the last being by far the largest category, as far as I can judge from the three studies in this week's NEJM. So if your anxious, high-risk mother asks you "should I have an abortion?" or "will my child be normal?" your reply will often have to be "well, maybe: we can't really say". This could be the stuff of nightmares for thousands of parents until the science is properly sorted. The uncertainties are new and vast and will take many years to untangle, as the editorial makes clear. "Both pretest and post-test counseling by trained genetics counselors and geneticists are critical. Pretest counseling must include a discussion of the genetic principles of uncertainty and variable expressivity, the lack of precise correlation between genotype and phenotype, and the possibility that genetic variants that cause adult-onset disorders may be identified in a fetus or a parent. Post-test counseling should include interpretation of the results and an explanation of indicated follow-up studies and the possible implications for the family." Well, good luck with that: bear in mind that parents who are told their child may be abnormal can never be the same again, nor can their attitude to that child. Perhaps the most important point for clinicians to take home from these studies is that conventional karyotyping will still be needed to pick up some gross chromosomal abnormalities like triploidy (as in Down's syndrome), plus balanced translocations.
http://www.nejm.org/doi/full/10.1056/NEJMoa1203382
http://www.nejm.org/doi/full/10.1056/NEJMoa1201569
http://www.nejm.org/doi/full/10.1056/NEJMoa1208594
http://www.nejm.org/doi/full/10.1056/NEJMe1212303

2194 All around us, fungi lie in wait. They always get us in the end. If they get us while we are still alive, the results can be horrible. Fortunately our tissues are well designed to resist fungi, and they rarely manage to penetrate much beyond the surface; but it's a different matter when through human carelessness they can get straight into the epidural space or the cerebrospinal fluid. You will probably already have read about the Tennessee outbreak of CNS fungal infections caused by contaminated methylprednisolone from a single dirty compounding pharmacy: a nasty epidemic of fungal meningitis, posterior circulation stroke, spinal osteomyelitis, or epidural abscess that developed after epidural or paraspinal glucocorticoid injections. The fungi isolated were Exserohilum rostratum in 21 cases and Aspergillus fumigatus in one. Don't blame the fungi: they were only doing their job of growing where the conditions are right. An average toadstool produces 16 billion spores and if they all germinated and fruited there would be room for little else on Earth; and if all the fungal spores on Earth germinated and fruited at once there would be little room in the entire Solar System. On only one occasion did fungi really take over the world: for a period after the great Permian extinction 248 million years ago, when there was so much dead plant and animal matter that they enjoyed the brief triumph of the "terminal Palaeozoic fungal event." Most of the time, those spores just sit there, and wait, and perish. Blame the humans, not the fungi.
http://www.nejm.org/doi/full/10.1056/NEJMoa1212972

2204 Renin starts off the renin-angiotensin-aldosterone cascade, and it was inevitable that it would become a target for pharmacological blockade; just odd that it took so long. Had ACE inhibitors and angiotensin receptor blockers and aldosterone antagonists not got there first, renin antagonists like aliskiren would undoubtedly have become first-line drugs for hypertension and heart failure. In this RCT, the drug is compared with placebo in diabetic patients with cardiovascular disease and/or renal impairment who were already on treatment with an ACEI or ARB. The initial results were good: aliskiren lowers blood pressure and reduces albuminuria. So why don't we prescribe it for all our high-risk diabetic patients, as we do other drugs for which we have only these end-points to go by? But wait: this Novartis trial actually measured death and cardiovascular events; and by the second interim analysis, these had become significantly more frequent in the aliskiren group. Oops: if only the trial had stuck to surrogates, all would have been well. But now there will be no market for aliskiren: she arrived too late on the scene, and was too well investigated.
http://www.nejm.org/doi/full/10.1056/NEJMoa1208799

2214 The fungi lie in wait: Apophysomyces trapeziformis spores sat silently in Joplin, Missouri, until on May 22, 2011, the town was struck by a tornado. In the most severe damage zone, people were flung about and hit by wreckage: they sustained wounds and fractures which then became infected with an unidentified organism, and 38% of those infected died. It took very sophisticated investigation to identify this usually harmless mould as the cause: sequencing of the D1-D2 region of the 28S ribosomal DNA yielded Apophysomyces trapeziformis in all 13 case patients. Blame the fungi, not the humans, and avoid tornadoes.
http://www.nejm.org/doi/full/10.1056/NEJMoa1204781

Lancet 8 Dec 2012 Vol 380

1995 The Lancet seems to have adopted a policy of filling its research section with reports of phase 2 trials. This is decidedly odd, since these trial are by definition useless to practising clinicians, dealing with preliminary safety issues and dose-finding in compounds which may be years away from licensing. Take the two Amgen-funded trials in this week's Lancet: they deal with a new monoclonal antibody AMG145 which reduces low density lipoprotein cholesterol. Of course, the drugs of choice we use when we want to reduce LDL-C are the statins, which are so cheap, safe and effective that any other intervention is going to have a very hard time finding a market. The first of these trials was conducted in 52 centres and recruited 411 participants: "For ethical reasons related to conducting a placebo-controlled study in which some patients would receive no active antihyperlipidaemia treatment, we enrolled patients with low cardiovascular risk who did not require cholesterol lowering therapy." OK, so these people were not actually "patients" at all but healthy volunteers with highish levels of LDL-C. And sure enough, AMG145, the new antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), resulted in lowering of LDL-C and seems not to have had any adverse effects in the short term.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961771-1/abstract

2007 The other Amgen phase 2 trial looked at the dosing and safety of AMG145 in 631 patients with hyperlipidaemia and a fasting LDL-C level above 2.2 mmol/L despite treatment with a statin and/or ezetimibe. Again, fortnightly or monthly injections of AMG145 reduced LDL-C levels. So the paper concludes that the next requirement is "a large phase 3 clinical trial with several years of follow-up to investigate the long-term clinical efficacy and safety of AMG 145 in patients at increased risk of cardiovascular events." Yes indeed: a trial with real end-points and an active comparator, which may with luck be completed and reported by 2020. Until then, this drug is of absolutely no interest to 99% of readers of The Lancet. So what are these lengthy reports doing in the UK's leading medical journal? Is the reprint income they may bring from Amgen really sufficient to justify such a waste of space? Exactly what is this journal supposed to be for?
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961770-X/abstract

2018 Perhaps I really shouldn't complain: at least there is one research paper of value in The Lancet this week. Here are the ten-year outcomes from a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate. This will help to guide shared decision making in a very difficult clinical area. "Exploratory analyses suggest that postoperative irradiation might improve clinical progression-free survival in patients younger than 70 years and in those with positive surgical margins, but could have a detrimental effect in patients aged 70 years or older." In other words, there is near equipoise between the two options. Time to construct an Option Grid, so that patients can ponder the harms and benefits of the two strategies according to their own goals and preferences.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961253-7/abstract

BMJ 8 Dec 2012 Vol 345

Two papers from the EPIcure study send out mixed messages about improved survival and outcomes in very premature babies over the decade1995-2006. More very premature babies are being saved but their outcomes are poor, and there are many gaps in follow-up. The editorial summarizes it usefully: "Out of every 100 neonates born at 24 weeks, 60 will die despite intensive care, and of the 40 survivors 12 will have serious impairments. Only 11 out of 100 neonates born at 23 weeks will survive without impairments. Impairments were still present in 20% of neonates born at a gestational age of 26 weeks."
http://www.bmj.com/content/345/bmj.e7976
http://www.bmj.com/content/345/bmj.e7961
http://www.bmj.com/content/345/bmj.e8252

"Medicine is a social science, and politics is nothing else but medicine on a large scale. Medicine, as a social science, as the science of human beings, has the obligation to point out problems and to attempt their theoretical solution: the politician, the practical anthropologist, must find the means for their actual solution... The physicians are the natural attorneys of the poor, and social problems fall to a large extent within their jurisdiction." So said the great Rudolf Virchow (1821-1902) in the mid-nineteenth century, and here is a demonstration study from England in the twenty-first century: "Conclusion Decreases in unemployment and increases in average income in an area explained, to a large extent, why some local authorities "performed" better than others. Health inequalities between Spearhead and all local authorities widened during the period of rising prosperity, but they would have widened to an even greater extent had unemployment not fallen at a faster rate in more deprived areas. With worsening economic trends over the next 10 years, this research suggests that increases in life expectancy are likely to be smaller and health inequalities may widen at a faster rate than in the previous decade. Allocating resources to local authorities on the basis of their "performance" at increasing life expectancy is likely to reward more affluent areas rather than disadvantaged areas with greater needs, exacerbating the problem."
http://www.bmj.com/content/345/bmj.e7831

Ann Intern Med 4 Dec 2012 Vol 157

776 Unless you have a perfect diagnostic test, all screening will cause overdiagnosis (and usually underdiagnosis too). Performed annually for high-risk individuals, low-dose computed tomography has been shown to reduce overall mortality as well as lung cancer specific mortality. But how many of the tumours excised would actually proliferate sufficiently to behave as true malignancies? The Italian authors of this paper believe that you can judge this by the volume doubling time, and they have gone through all the CTs in their screening programme in an attempt to judge this retrospectively. They conclude that "indolent" or slow-growing cancers account for about 25% of the tumours detected, and may represent overdiagnosis. I can see all sorts of problems with this method and the conclusion, but full marks for effort and for highlighting the issue before such screening becomes widespread.
http://annals.org/article.aspx?articleid=1467428

796 For many years now I've been tracking the progress towards fixed-dose anticoagulation without INR monitoring in these columns. It's a nice idea and of course an enormous market for drug companies: there are many agents and many RCTs. I'm amazed that the authors of this systematic review of their comparative effectiveness against warfarin could narrow the field down to just six, including trials for both atrial fibrillation and venous thromboembolism. Their conclusion is prosaic and rather obvious: "Treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment." If you have an excellent system for INR control, and patients are compliant, then the extra cost of these agents is not warranted at present. But when they come off patent, things may change, and INR testing may disappear and become one cost less for all health systems.
http://annals.org/article.aspx?articleid=1355171

Plant of the Week: Helleborus niger

The pure white Christmas Rose is one of the few small plants to choose December as its month to flower. In consequence, it is often covered with dead leaves, snow or mud. With those bright white flowers set against dark cut leaves, it looks lovely in garden centres and we have all spent our £6+ on fine showy pots of it, sometimes several times, only to find that it never reappears the next year. I suspect that although it is full of toxins that kill humans, it is quite tasty and harmless to gastropods.


 

 

 

 

 

 

 

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Page last edited: 07 January 2013