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Richard Lehman’s weekly review of medical journals

Richard Lehman’s journal review—27 October 2014

27 Oct, 14 | by BMJ

richard_lehmanNEJM 22 October 2014 Vol 371
1577 The whole point about tuberculosis is that it is slow. The discoverer of its causative organism, Robert Koch, called it the fungus-germ, or Mycobacterium. It takes 20 times longer to divide than most other bacteria. It is only after years of division that it can do terrible things. The old Welsh chest physicians I once worked for called this “galloping” TB, and recalled how it had carried off some friends of their youth. But even this word, when pronounced as “gahl-lopin” in a soft south Welsh accent, had a mournful slowness about it. Three trials in this week’s NEJM show that it does not pay to take shortcuts with this slouchy beast. Several new fluoroquinolone drugs kill off Mycobacterium tuberculosis quite rapidly in the laboratory and in animal models and were thought to offer the promise of a faster cure than standard rifampicin based regimens. In the first trial, moxifloxacin was tested in a randomised trial cunningly designed by academics based in the tiny windswept town of St Andrews in the Scottish kingdom of Fife. They spread their net across four continents, but they have shown that in uncomplicated, smear positive pulmonary TB, four months of a moxifloxacin based regimen is not dependably curative. more…

Richard Lehman’s journal review—20 October 2014

20 Oct, 14 | by BMJ

richard_lehmanNEJM 16 October 2014 Vol 371
1507  I hate military metaphors for cancer as much as anybody, but here is a study which describes hell in the leukaemia trenches. The 30 patients in the trial had acute lymphoblastic leukaemia. The youngest was 5 years old; most were under 20. All of them had relapsed after initial chemotherapy, which heaven knows is bad enough. Eighteen had then endured the horrors of allogeneic stem cell transplantation, and then relapsed again. Some had been through other experimental treatments. Now they were given an infusion of autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector. In all of them, this caused a cytokine release syndrome, which was severe in over a quarter of cases and had to be treated with the anti–interleukin-6 receptor antibody tocilizumab. The complete remission rate at the end of all this was 90%. So victory at a high price: the challenge now is to operationalise this treatment in a way that is bearable to patients and affordable to health systems. more…

Richard Lehman’s journal review—13 October 2014

13 Oct, 14 | by BMJ

richard_lehmanNEJM 9 October 2014 Vol 371
1381  With blood transfusion, it seems that less is usually better. This has been shown in renal patients and palliative care, and is now reconfirmed in septic shock. Fifteen years ago, the Canadian Critical Care Trial Group study showed that transfusing critically ill patients at threshold of 10 G/dl of haemoglobin produced worse outcomes than using a threshold of 7. Now Scandinavian triallists have gathered and randomised 1000 patients with septic shock in 32 general ICUs in Denmark, Sweden, Norway, and Finland: a logistic feat to be wondered at. They have shown that a threshold of 7 is as good as a threshold of 9, saving gallons of blood. In fact, it halves the amount of blood used. more…

Richard Lehman’s journal review—6 October 2014

6 Oct, 14 | by BMJ

richard_lehmanNEJM 2 October 2014 Vol 371
1285  Here is a trial which had me taking my glasses off and scratching my bald patch. Why on earth should a drug company—in this case Boehringer Ingelheim— want to pay for a trial of taking patients OFF a drug? And why in particular should it want to take people with chronic obstructive pulmonary disease off inhaled steroids while keeping them on a long acting beta-adrenergic agent (LABA), when we know that LABAs increase mortality unless you take them with an inhaled steroid? The latest evidence for this came in JAMA a couple of weeks ago. more…

Richard Lehman’s journal review—29 September 2014

29 Sep, 14 | by BMJ

richard_lehmanNEJM 25 September 2014 Vol 371
1189  This week we start with mepolizumab. Before we know it, we encounter losmapimod. Enough is enough. I think the World Health Organization should convene an extraordinary meeting of the International Nonproprietary Names Committee with the sole purpose of Stopping Silly Names. Medical practitioners are serious people and they should not be expected to trade in nonsense words. When humanized monoclonal antibodies were new and few, it might have made sense to end all their names in zumab, but now there are so many nobody can remember which is which. Mepolizumab is targeted against interleukin 5. The first of two trials in severe asthma with sputum eosinophilia shows that it allows a useful number of people to avoid the regular use of oral corticosteroids or to reduce their dose. In the 24 weeks of the trial, the rate of adverse effects was the same as placebo. more…

Richard Lehman’s journal review—22 September 2014

22 Sep, 14 | by BMJ

richard_lehmanNEJM 18 September 2014 Vol 371
1100  The way I have ureteric colic is so classical that just watching me sweat and groan is enough for anyone to make the diagnosis, even without the haematuria on the dipstick. I see the same thing all the time in out of hours primary care patients, and generally get the diclofenac injection drawn up after about two sentences of history taking while I dip the urine. I can’t remember ever having to refer anyone for acute imaging. But somehow acute nephrolithiasis manages to cost the US healthcare system $2bn a year, and it seems that most patients are investigated with an immediate abdominal CT. This is a dangerous procedure, partly because of the radiation load, but even more because of all the incidental findings that are bound to turn up. A large American trial compared CT with point of care ultrasound or full formal ultrasound. “Initial ultrasonography was associated with lower cumulative radiation exposure than initial CT, without significant differences in high risk diagnoses with complications, serious adverse events, pain scores, return emergency department visits, or hospitalizations.” I suspect that if they had had a no-investigation arm, the results would have been the same. more…

Richard Lehman’s journal review—15 September 2014

15 Sep, 14 | by BMJ

richard_lehmanNEJM 11 September 2014 Vol 371
1016  Ticagrelor has had mixed fortunes since it was introduced as a new thienopyridine platelet aggregation inhibitor a few years ago. The PLATO trial left lingering doubts whether it is better than the much cheaper clopidogrel when used in acute coronary syndromes. Rather than attempting to resolve these, the latest trial (ATLANTIC) compares prehospital administration of ticagrelor with in-hospital administration in patients undergoing immediate percutaneous coronary intervention for ST-elevation myocardial infarction. There is no difference. The name ticagrelor keeps reminding me of Excelsior, in Henry Wadsworth Longfellow’s poem of that name:

THE SHADES of night were falling fast,
As through an Alpine village passed
A youth, who bore, ‘mid snow and ice,
A banner with the strange device,
Excelsior! more…

Richard Lehman’s journal review—8 September 2014

8 Sep, 14 | by BMJ

richard_lehmanNEJM  4 Sep 2014  Vol 371
892    A terrific piece by Rita Redberg discusses sham controls in medical device trials. Whenever sham procedures are used in the control arms of such trials (or in surgical trials generally) they reveal a huge placebo effect. For example, renal denervation therapy produced huge sustained falls in recorded blood pressure in unblinded, uncontrolled trials in people with “resistant hypertension”. But when it was tested in a properly blinded trial using a sham control, it failed to detect enough difference to satisfy its primary end-point. She goes on to point out that percutaneous coronary intervention has never been tested against sham PCI. I’ve just learnt to my amazement that Darrel Francis at Imperial College is planning a trial to do just this in people with angina and single-vessel disease, and it’s still open to extra UK investigators on http://clinicaltrials.gov/ct2/show/NCT02062593.    more…

Richard Lehman’s journal review—1 September 2014

1 Sep, 14 | by BMJ

richard_lehmanNEJM 21-28 August 2014 Vol 371
711  I have a new little grandson called Timothy. He is lucky being born in August because respiratory syncytial virus generally lies low at this time of the year. Most babies get RSV at some stage of their first year, and the earlier they get it the worse it tends to be, with recurring bronchiolitis every time they get any kind of upper respiratory virus. So I’m hoping Tim won’t get RSV this side of Christmas, and that when he does he will shake it off as a mere cold. There is no effective treatment, although the NEJM seems to believe there may be one in the offing, as they have chosen to give space to a British phase 1 study of GS-5806, a novel oral small molecule that inhibits RSV entry at low nanomolar concentrations by blocking viral-envelope fusion with the host-cell membrane. That sounds like a pretty cunning trick, and in a challenge study in 54 healthy adults, it reduced the viral load and the severity of clinical disease. It also tended to reduce their neutrophil counts and raise their alanine aminotransferase. So not much use for my tiny Tim until it has undergone phase 2 and 3 trials in lots of adults and babies in the community. more…

Richard Lehman’s journal review—18 August 2014

18 Aug, 14 | by BMJ

richard_lehmanNEJM 14 August 2014 Vol 371
601  The usual wisdom about sodium chloride is that the more you take, the higher your blood pressure and hence your cardiovascular risk. We’ll begin, like the NEJM, with the PURE study. This was a massive undertaking. They recruited 102 216 adults from 18 countries and measured their 24 hour sodium and potassium excretion, using a single fasting morning urine specimen, and their blood pressure by using an automated device. In an ideal world, they would have carried on doing this every week for a month or two, but hey, this is still better than anyone has managed before now. Using these single point in time measurements, they found that people with elevated blood pressure seemed to be more sensitive to the effects of the cations sodium and potassium. Higher sodium raised their blood pressure more, and higher potassium lowered it more, than in individuals with normal blood pressure. In fact, if sodium is a cation, potassium should be called a dogion. And what I have described as effects are in fact associations: we cannot really know if they are causal. more…

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