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Richard Lehman’s journal review—25 February 2013

25 Feb, 13 | by BMJ

Richard LehmanJAMA  20 Feb 2013  Vol 309
689    Long back in the last century, I was a hysterectomy robot. This was the lowest form of life in a London teaching hospital obstetrics and gynaecology department. I spent my days clerking patients and feeling gravid abdomens, and my nights (one in two) stitching episiotomies and writing out drug charts in between brief episodes of sweaty sleep. The following day would often be spent assisting at hysterectomies. My main function was to remain upright, with a retractor in one or both hands. Thank God that better robots have now been designed, ones that can actually take an intelligent part in the procedure. They allow the gynaecologists of the twenty first century to sit at a console remote from the patient, fiddling with her insides while they take sips of freshly brewed Starbucks. Does this improve patient outcomes compared with the normal procedure for benign disease, which is laparoscopic hysterectomy? Well no, but it costs more and is worth it for the Starbucks.

699    “Why do I keep getting colds all the time, doctor? My wife never seems to catch anything.” “It’s just bad luck, I’m afraid. It’s not a sign of anything wrong with your immune system.” Ever had that conversation? If not, you’ve never been a GP. However, in the future you will have to be more exact. You may need to reply: “I’m afraid you have a common but untreatable condition in which your immune system is in a state of decline due to shortening of telomeres in your CD8CD28—T-cells. Each time they divide—which is quite often—their telomeres get shorter and you get more susceptible to illness. This is happening all over you at this present moment and will continue to happen until you die. Have you by any chance made a will?” A preliminary study on healthy 18-55 year-olds shows that those with the shorter T-cell telomeres are more susceptible to induced acute upper respiratory illness.

717   Here’s a nice new JAMA feature: the Clinical Evidence Synopsis. The discovery about a decade ago that procalcitonin is a reliable marker for bacterial infection seemed very exciting and indicated that we might be able to rationalise antibiotic treatment for respiratory infection in the community. This is a very useful brief summary of the trials: as I’ve said before, it’s unlikely that this marker will come into general use until it can be done in real time for less than the cost of a course of amoxicillin.

NEJM   21 Feb 2013  Vol 368
368    These are stirring times in the wars of the fixed-dose oral clotbusters: drug companies are finally discovering if they have billion-dollar earners on their hands, or turkeys. Apixaban, a drug made by both Pfizer and Bristol-Myers Squibb, has had mixed fortunes so far, and is beginning to look rather like a large flavourless bird with a bib and a waddling gait. But all is not lost: turkey owners should take courage from Bernard Matthews and invent new ways of selling it. In this trial, Pfizer and BMS find a place where warfarin doesn’t already provide stiff competition and there is clinical equipoise. These are patients who have had unprovoked deep vein thrombosis and have completed their initial course of anticoagulation. The placebo arm shows a recurrence rate in this group of 8.8% in the first year; while those taking either 2.5mg or 5mg of apixaban twice daily had a recurrence rate of 1.7% and fewer bleeding events. So this is win-win-win: a reduction in VTE and bleeding and a lower than standard dose. Bootiful. But why no warfarin arm? Turkey is generally better than nothing, but is it generally better than chicken?

709    And now to the competitor drug dabigatran, which is also beginning to show some signs of being a flightless bird. Boehringer Ingelheim, its manufacturer, again selected patients requiring long-term prophylaxis against recurrent venous thromboembolism for this trial, but very properly included a warfarin arm. Now the main emerging worry with dabigatran is that it increases coronary events, as well as bleeding events, for which there is no antidote. In this trial, there were 13 acute coronary events in the dabigatran group and 3 in the matched warfarin group. But in the warfarin group there were more bleeding events (treatable with vitamin K). In both the active groups there was a tenfold reduction of thromboembolism compared with placebo. So where does this take us? Certainly not straight on to a world without warfarin and INR testing. The big flaw in this trial was that it recruited from 33 countries with variable levels of INR control, such that the warfarin group were outside the target range for more than a third of the time. In all warfarin-comparator trials, this is the most important statistic. As a result, this trial strongly suggests that in a properly monitored population with VTE, warfarin is a safer drug than dabigatran, certainly in terms of cardiac events and possibly even for treatable bleeding.

719   Here’s a nice teaching example of how not to do comparative effectiveness research, brought to you in all seriousness by the world’s leading medical journal. The research question is whether patients with symptomatic gastro-oesophageal reflux are better off taking proton pump inhibitors or having augmentation of the oesophageal sphincter with a magnetic device. So how would you design your study? An obvious choice would be to randomise two large groups of patients with GORD/GERD to continued treatment with PPIs or to implantation of the device. At some point or points you get a blinded assessor to measure quality of life, reflux symptoms, harms and so forth. No brain required. But what did the FDA allow the device manufacturer Torax Medical to get away with, and what do we now find in the NEJM? A before and after study of 100 subjects, no control group, the primary outcome a surrogate measure (oesophageal acid “normalization”), and the secondary measures a reflux score based on symptoms without PPI treatment, and the reduction in PPI use over the first year. The results were pretty awful considering that this is a benign symptomatic condition, and PPIs are now very cheap: six devices had to be removed, and 11% of patients had dysphagia at one year, falling to 4% at three years. Reflux symptoms improved in 92%—compared with nothing. A totally missed opportunity to find out the real-life effectiveness of this device.

745    I tend to read every review of tuberculosis I encounter in the journals, not because I see TB that often, but because I think the progress we make against this slouchy old killer is a good measure of the progress medicine in general is making. Here is a model of clear clinical writing that will bring you up to speed: ten pages of sentences that any normal human being can understand, and no genomics whatever. The outlook is much more optimistic than you would think from reading the popular press.

Lancet  23 Feb 2013  Vol 381
Here is an issue of the Lancet which makes me think that all interventional cardiologists should have their equipment confiscated and be sent to a re-education camp called COURAGE, where they will have to parade at dawn and recite the entire contents of that key paper until they can do it without hesitation, repetition, or deviation. Release will be on condition that they never carry out any invasive procedure on a patient with stable angina without first ensuring that they are on optimal medical treatment. Any infringement will be followed by permanent detention in the notorious punishment block of the COURAGE camp.

629   The SYNTAX trial was set up long before COURAGE, when everyone assumed that if there is a narrowing in a coronary artery, the best outcomes must follow from unblocking or bypassing it. So in 85 centres across the US and Europe, 1800 patients with stable three-vessel disease were randomised to insertion of paclitaxel-eluting stents or coronary artery bypass grafting. Here are the five year results of the SYNTAX trial, reported as if COURAGE had never happened. “CABG should remain the standard of care for patients with complex lesions (high or intermediate SYNTAX scores). For patients with less complex disease (low SYNTAX scores) or left main coronary disease (low or intermediate SYNTAX scores), PCI is an acceptable alternative. All patients with complex multivessel coronary artery disease should be reviewed and discussed by both a cardiac surgeon and interventional cardiologist to reach consensus on optimum treatment.” No. no, no! Patients with stable angina of whatever cause should run a mile from all cardiac surgeons and interventional cardiologists, easing off a bit and taking GTN if they get any chest pain.

639   There was a character called Dr Syntax who appeared in a series of comic novels from 1809 onwards, in which he stumbled pedantically through life insisting on the rules of grammar and little else. Perhaps he is the inspiration for this paper on the development and validation of the SYNTAX II score which looks at complex anatomical predictors of outcome from CABG versus stenting for stable angina, ignoring the fact that most patients will get the same outcomes from optimal drug therapy. Get real, SYNTAX doctors. Note that both these studies were paid for by Boston Scientific, which has an interest in selling TAXUSTM  stents.

651   And so the Stent Wars go rumbling on, in trials which continue to recruit large numbers of patients with stable angina (1611 of them in this trial alone) selected for PCI for reasons which are not apparent in the text. This time it’s a biodegradable polymer-coated biolimus-eluting stent with a thin-strut everolimus-eluting stent coated with a durable biocompatible polymer. Like you care. These studies should really be hived off into a trade journal of some sort.

661   Next article in Selling Stents, aka the Lancet: “Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention.” Worth a year’s subscription just to read it.

BMJ  23 Feb 2013  Vol 346
When I learnt about the renin-angiotensin-aldosterone system in medical school 40 years ago, it was presented more as a physiological curiosity rather than a fundamental mechanism working with great rapidity to stabilise volume and electrolyte balance in most higher vertebrates. Then came the angiotensin-converting-enzyme inhibitors in the 1980s, followed by the angiotensin receptor blockers of the 1990s. Dual blockade of the RAAS became fashionable in both complicated hypertension and heart failure, until hard evidence started trickling in to show its harms and lack of effect. Even now, combining ACEIs and ARBs is written in to some guidelines and is widely practised in Europe and the USA. This meta-analysis adds in the direct renin blockers too. The ratio of harm to benefit of these combinations is almost always adverse—just don’t mix these drugs.

My young friend Joe Ross had his name on three papers in the leading journals last week, and now he’s on an entirely unconnected study in the BMJ. To those who know him, he comes over as a laid-back family man who does the best kids’ Halloween party in Connecticut; loved alike by students, patients, and colleagues etc. If I go on any more you may begin to go off him. We cannot all be Joe, but it is a very good thing that Joe can be Joe. Here he and some colleagues look at the effect on later prescribing of attending a medical school with a restrictive policy on access to drug reps. Those without exposure to these agents of persuasion as medical students were less likely to prescribe dubious psychotropic “me-too” drugs a few years down the line. Ban drug reps, and not only in medical schools.

How big is a piece of clot? A clottish question if ever there was, but one you need to answer if you are to have a useful discussion of pulmonary embolism. Our lungs are sieves for all sorts of debris: it is a part of their function, though largely unsung. Most of it does little harm, but big clots are bad news: “Pulmonary embolism is the most common cause of vascular death after myocardial infarction and stroke, and the leading preventable cause of death in hospital patients.” Here’s a really good review of the diagnosis and management of PE.

Ann Intern Med  19 Feb 2013  Vol 158
225    Acupuncture is a popular form of magical treatment with effects that depend entirely on the receptivity of the acupuncturee. Traditional acupuncture has a repertoire of highly practised mumbo-jumbo which probably makes it very easy for most recipients to distinguish it from sham acupuncture. Some especially credulous people go to acupuncturists for seasonal allergic rhinitis, and there has even been a randomized trial: “ Acupuncture led to statistically significant improvements in disease-specific quality of life and antihistamine use measures after 8 weeks of treatment compared with sham acupuncture and with routine management alone, but the improvements may not be clinically significant.” No comment.

271   Most ordinary doctors defer to ophthalmologists when it comes to treating eyes, hoping that hidden behind their strange Greek jargon and their slit lamps, they know what they are doing, as we assuredly do not. So it’s a bit disconcerting that for the very common condition of open-angle glaucoma, there doesn’t seem to be much clarity about hard outcomes. This systematic review concludes: “Medical and surgical treatments for open-angle glaucoma lower intraocular pressure and reduce the risk for optic nerve damage over the short to medium term. Which treatments best prevent visual disability and improve patient-reported outcomes is unclear.”

Plant of the Week: Helleborus orientalis

The coming of these diverse and beautiful flowers is one of the most wished-for moments in the garden year. This year they have come early, at least in our garden of alkaline clay, useless for many treasured plants but ideal for these promiscuously seeding, speckled lovelies.

We used to buy in yellows, double-flowered blacks and so forth at considerable expense, but now we just let them come up in whatever colour or form they wish from seed, keeping the nicest ones and disposing of the rest. I suppose if we ever have grandchildren, we may have to get rid of all of them, because they are very poisonous in every part. Yet for grown-ups, I don’t think there are any flowers I like better.

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