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Richard Lehman’s weekly review of medical journals

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    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…

Richard Lehman’s journal review—11 August 2014

11 Aug, 14 | by BMJ

richard_lehmanNEJM 7 August 2014 Vol 371
497  A new gene for breast cancer susceptibility? The PALB2 gene locus has been known about for several years, but this study puts it firmly on the map by intensively investigating 362 members of 154 affected families. The risk for female PALB2 mutation carriers, as compared with the general population, is 35% by the age of 70—about the same as for BRCA2 mutation carriers. The editorial explains why this is so: both genes work in concert to repair double strand breaks in DNA. This is a very fundamental process, and you would have thought that any impairment to it would lead to a whole range of cancer risks, but in the case of PALB2, the risk seems to be mainly of breast cancer (in men as well as women) and Fanconi’s anaemia. Therapeutic efforts for carriers of BRCA and PALB2 mutation carriers are focussed on inhibition of PARP, causing cells that contain broken double stranded DNA to die rather than turn cancerous. more…

Richard Lehman’s journal review—4 August 2014

4 Aug, 14 | by BMJ

richard_lehmanNEJM 31 July 2014 Vol 371
397  Set aside half an hour to enjoy this week’s New England Journal. The key articles are all about malaria, and they are free. You might expect an account of The Origins of Anti-Malarial Drug Resistance to be both boring and depressing, but this one by Randall Packard is neither. It is beautifully written and I found it quite exhilarating. The key to eliminating drug resistance in malaria is quite simple: improve the living and working conditions of gem miners in the Pailin province of Cambodia. For decades, men from surrounding countries have flocked to these mines to earn a few months of money by digging for long hours, surrounded by water filled shafts and sleeping outside by night. When they get a fever, they pay half their earnings to get subtherapeutic doses of artemisinins. They are the breeding ground of resistant malaria and take it back to their homes across South East Asia. I’m struck by the parallel with Rudolf Virchow’s miners in his famous Report on the Typhus Epidemic in Upper Silesia (1848), where he states that the outbreak could not be solved by treating individual patients with drugs or with minor changes in food, housing, or clothing laws, but only through radical action to promote the advancement of an entire population, which could only be achieved by “full and unlimited democracy” and “education, freedom, and prosperity.” more…

Richard Lehman’s journal review—28 July 2014

28 Jul, 14 | by BMJ

richard_lehmanNEJM 24 July 2014 Vol 371
371  Long ago I had a patient who kept having odd things happen to her. She infarcted part of her cerebellum, and then did the same to two fingers on her right hand. She was full of pains, her kidneys were failing, and her erythrocyte sedimentation rate (ESR) stayed high. When CRP became available in our little hospital, that stayed high too. Then, finally, somebody ran a brand new test on her—anticardiolipin antibodies. At last we had a diagnosis—antiphospholipid syndrome! Getting this label made absolutely no difference to her since she had already been given all the usual “empirical” treatments, like aspirin which made her bleed, and steroids which made her even huger and more diabetic. She died long ago, but for the last 25 years, I have been reading pieces about antiphospholipid syndrome in the hope of discovering (a) that somebody understands it and (b) that there is an effective treatment. Now a little bit of my hope has been fulfilled. Twelve years ago, some patients whose kidneys had been destroyed by this syndrome received renal transplants and were given sirolimus as an anti-rejection drug. Now 70% of them have functioning allografts, whereas for those who did not get sirolimus the percentage is 11. So sirolimus urgently needs investigating as a treatment for the more severe forms of the syndrome. And from biopsy and autopsy samples, it seems that the destructive process is driven by mTORC through the phosphatidylinositol 3-kinase (PI3K)–AKT pathway, which sirolimus suppresses. Serves me right for wanting to know. more…

Richard Lehman’s journal review—21 July 2014

21 Jul, 14 | by BMJ

richard_lehmanNEJM 17 July 2014 Vol 371
203  Niacin is an abundant natural B vitamin, which lowers bad cholesterol and raises good cholesterol. What’s not to like? Well, niacin, unfortunately. In doses that make any difference to lipid levels, it is very likely to make you feel sick, get flushes and/or rashes, and/or feel muscle pains. So Merck decided to market it in combination with laropripant, a prostaglandin antagonist that is meant to combat its unpleasant effects. Even so, a third of people who were recruited to the present trial could not continue past the run-in phase with the active combination. And now that the full results are out, we have confirmation that this dual agent definitely does not offer any cardioprotection despite its “favourable” effect on lipids. Worse still it causes bleeding, raises blood sugar, and shows a tendency to increase mortality in those who can tolerate taking it for three years. The Clinical Trials Support Unit (CTSU) at Oxford did a great job of running this trial with funding from Merck, following its usual rules of independence. In doing so, it provides a great illustration of the fact that lipid fractions are very unreliable surrogates for cardiovascular outcomes. But we knew that already, and it seems a great pity to me that many superb researchers were tied down for so long on a project that has made such a small contribution to clinical knowledge, whatever it may have contributed to the funds of CTSU. more…

Richard Lehman’s journal review—14 July 2014

14 Jul, 14 | by BMJ

richard_lehmanNEJM 10 July 2014 Vol 371
107  I was very confused by this paper. It describes two trials of three drugs for premenopausal breast cancer with various permutations, and the bottom line is that all the interventions give the same result. Or, if you are a sponsor of the trial, you can report: “In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence.” That is just about true: 88.8% of the women in the tamoxifen group were recurrence-free at five years, compared with 92.8% in the exemestane group, but there was no difference in mortality. This figure was reached by pooling the two trials, though they were not identical. One of them used a variety of means for ovarian suppression and the other only triptorelin. OK, enough of this. If you are a woman with premenopausal breast cancer, demand an option grid to explain the possible adverse effect of these regimens, as well as their minutely different long term benefits. And if you are unhappy at the summary reporting, just think of the bad old days when that might have been framed as a “30.5% reduction in recurrence at five years.” more…

Richard Lehman’s journal review—7 July 2014

7 Jul, 14 | by BMJ

richard_lehmanNEJM 3 July 2014 Vol 371
11  I don’t envy anyone with central lumbar spinal stenosis. The odds of benefit from surgery are slight. The pain can be there all the time and always gets worse on walking, which can limit activity severely. No wonder epidural steroid injections have proved popular. In this study, they were carefully given with lidocaine using fluoroscopic guidance, and at six weeks they resulted in a small but useful reduction in a disability score and a leg pain score. The control group, who received epidural lidocaine alone, fared equally well. Moral: you don’t need the steroids. It may even be that you don’t need the lidocaine. Saline may be as good. In fact, gowning up and inserting the needle may be enough. In a way, I would rather not know, especially if I had spinal stenosis.

22, 32  My heart sank last week when two papers appeared on the NEJM website with the titles Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease, and Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease. I resolved to ignore them. However, Harlan Krumholz ‘s comments on them really have to be read: “This research”, he said, “has absolutely no implications for clinical practice. It might one day be seen as a pivotal study that led to the development of remarkable drugs, but that is far away. I hope people don’t read it and think that it has relevance to their current decisions about treatment.” more…

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