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Richard Lehman’s weekly review of medical journals

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…

Richard Lehman’s journal review—9 June 2014

9 Jun, 14 | by BMJ

richard_lehmanNEJM 5 Jun 2014 Vol 370
2169  There is a story that when new antibiotics were arriving every few weeks in the late 1950s, drug companies had a hard time thinking up new names for them, all ending in mycin. So they started using a word generating machine, but stopped when it came up with godamycin. In the end, many of these me-too antibiotics fell by the wayside, and we are left with a trusty arsenal, which continues to cover the great majority of bacterial infections around the world despite 60 years of widespread use. For cellulitis in British primary care, oral flucloxacillin still cures about 90% of cases. But Staphylococcus aureus is a more adaptable bacterium than most, and it is good to see some new antibiotics for meticillin resistant SA rolling off the production lines of companies, such as Durata Therapeutics. The official name of this new one is dalbavancin, and it has such a prolonged duration of action that it can be given once a week. “Once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection.”

2180  It’s the same story with another new antibiotic called oritavancin, made by the Medicines Company. One IV dose of oritavancin is as good as vancomycin given IV twice daily for a week or more for skin infections. These new antibiotics are lipoglycopeptides. Expect plenty more, up to and including godamavancin. And expect them to be very expensive. more…

Richard Lehman’s journal review—2 June 2014

2 Jun, 14 | by BMJ

richard_lehmanNEJM 29 May 2014 Vol 370
2071  This week’s New England Journal is dominated by three papers on idiopathic pulmonary fibrosis. The editorial on them begins “I suspect that many of my patients have picked up on more than a hint of frustration in my voice when I tell them that the cause of their shortness of breath is idiopathic pulmonary fibrosis.” Well, yes, I expect they will share your frustration, especially when you tell them that they are likely to be dead within five years. So what hope do the new interventions bring? Really only a small glimmer. Nintedanib is an intracellular inhibitor that targets multiple tyrosine kinases, and these are thought to play a key role in sustaining the abnormal healing process which keeps producing fibrosis in the lungs. In this year long phase 3 trial, patients who took nintedanib felt no different from those on placebo, except that they had a little more diarrhoea. However, their forced vital capacity declined less and they took longer to experience their first acute exacerbation.

2083 It was a very similar story with this year long phase 3 trial of pirfenidone, an oral antifibrotic agent. It slowed progression as measured by FVC but this trial alone did not show a mortality benefit within its timescale. Combined with other pirfenidone studies, however, it seems the drug does have a significant effect on all cause mortality and on mortality from pulmonary fibrosis. more…

Richard Lehman’s journal review—27 May 2014

27 May, 14 | by BMJ

richard_lehmanNEJM 15-22 May 2014 Vol 370
1944  The introduction of pay for performance in the NHS attracted great interest in the USA, which is still trying to come up with similar schemes of its own. Martin Roland and Stephen Campbell both helped the UK government to set up the Quality and Outcomes Framework for primary care in 2004, and ten years on they reflect on its “successes and failures.” American readers should try to stick with this piece, which I suspect they will find a bit boring in places: as they read along, they need to look for the “successes.” It is just possible that initially, the QOF incentivized some poorer performing practices to do better at some genuinely useful things. After about two years, however, results levelled off at exactly the level of incentivization. And the government felt it had been conned into overpaying GPs. In succeeding years, the QOF has led to a dreadful downward spiral of gaming, financial retrenchment, meaningless overload, worsening accessibility, tick-boxing, depersonalized care, and deprofessionalized doctors. Americans, reform your system some other way. Britons, get rid of this cancer on the body medical.


Richard Lehman’s journal review—12 May 2014

12 May, 14 | by BMJ

richard_lehmanNEJM   8 May 2014  Vol 370
1799   The idea that malaria was spread by mosquitoes was first mooted in the 1870s, but it took twenty years to work out what really went on in the parasite’s life cycle. As far as I can tell, this was first achieved by Giovanni Batista Grassi, though Ronald Ross claimed the credit and got the Nobel Prize in 1902. By now we should know everything about malaria, and the disease itself should have been consigned to history. But this paper proves that is far from the case. It is an observational study of severe Plasmodium falciparum malaria in Tanzanian children. Like Manson, Grassi and Ross, these investigators took a lot of blood samples from subjects with malaria. What they found is somewhat of an enigma. Severe malaria in children is not linked to individual parasite burden. Mild malaria does not protect against severe malaria. There are some strange parasite-host interactions going on which do not obey the usual rules of immunology. If this sort of thing intrigues you, the full paper is free online.

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