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Richard Lehman’s weekly review of medical journals

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…

Richard Lehman’s journal review—30 June 2014

30 Jun, 14 | by BMJ

richard_lehmanNEJM 26 Jun 2014 Vol 370
2478  Cryptogenic is a good word. It’s up there with “idiopathic” and “pleiotropic” and “diathesis” for covering gross ignorance with a smattering of Greek. “Cryptogenic” sounds as if it was first used to describe the odd symptoms that Superman experienced when exposed to kryptonite. However, its first use was recorded 30 years before the caped crusader first appeared in the skies above Metropolis in 1938. “Cryptogenic stroke” is a fairly recent term, covering 20-40% of incident stroke, and it challenges researchers to hunt around the garden looking for kryptonite hidden under stones. A patent foramen ovale! Ah yes, but it may be an innocent bystander. Atrial fibrillation (AF) then! Possibly, according to the EMBRACE study, but still unlikely to account for most unexplained ischaemic strokes. The Canadian researchers monitored 572 patients who had had an unexplained ischaemic stroke or transient ischaemic attack, half of them using standard 24 hour ECG, and half with a 30 day event monitor. Their mean age was 72, and the detection rate for AF was 3.2% versus 16.1% in the two groups. more…

Richard Lehman’s journal review—23 June 2014

23 Jun, 14 | by BMJ

richard_lehmanNEJM 19 Jun 2014 Vol 370
2387  If you have a patient who is taking an opioid for chronic, non-cancer pain and gets constipated as a result, what do you do? Prescribe a laxative. Well done. And advise them that for most people with chronic pain, opioid analgesics don’t work and are best weaned off. Even better. Or else you can (perhaps, in the future) prescribe naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist. It is such a neat idea. You block the peripheral μ-opioid receptors in the colon, thus unblocking the bowel, while the brain receptors continue to respond to the opioids as before. What’s not to like? Well, the price probably. And the aforementioned fact that most people can use cheap laxatives instead, and would be better off their opioids anyway. And the fact that the evidence from the trials published here is all over the place.

For those of you who like to keep up with the ways of industry, note that “The study protocols were designed by AstraZeneca with input from the academic authors, who served as consultants to the sponsor. Study conduct, monitoring, and data analysis were performed by Quintiles, a contract research organization, under the supervision of the sponsor.” “We conducted two identical multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 studies (KODIAC-04 [study 04] and KODIAC-05 [study 05]) at 115 centers (study 04) and 142 centers (study 05) in the United States and Europe.” The participants included people on a very wide dose range of opioids, provided they had been on them for four weeks or more, and irrespective of how many laxative regimens had been tried previously (if any). The result was that the active drug group “achieved response rates that were increased by 10 to 15 percentage points, as compared with placebo.” If this drug gets FDA approval, we will know the system is bust. But then we already do. more…

Richard Lehman’s journal review—16 June 2014

16 Jun, 14 | by BMJ

richard_lehmanNEJM 12 June 2014 Vol 370
2265  Obstructive sleep apnoea is often a result of weight gain, and unfortunately, once it is established, losing weight does not reduce it. But losing weight has benefits of its own (he sighs wistfully), as this trial of weight reduction, continuous positive airways pressure, or both for OSA demonstrates. I carry my flabby, insulin resistant, borderline hypertensive, tired all the time body around until the happy moment when I can put on my mask and feel the cool whoosh of air that signals sleep time. Would I do better to lose weight? Oh yes. It would not reduce my C-reactive protein (assuming it needs reducing), but it would certainly help reduce my triglycerides and insulin resistance (not that I have much idea about them either).

2276  In OSA, CPAP reduces BP. Nice to be able to use these abbreviations, because I have spelt them out above; well actually I haven’t spelt out BP. It stands for blood pressure. In a cohort of people with OSA and high BP, supplemental nocturnal oxygen was tried instead of CPAP for 12 weeks. Result: O2 a no-no for lowering BP in OSA. more…

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