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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.

2191  It was once the same with statins: while they could earn big money, new ones kept appearing. And I don’t mind that, because often there are useful differences within drug classes, as you can see from the latest Cochrane review of thiazides for blood pressure lowering. From the start, about 30 years ago, statins have had their fans and their detractors. It became obvious from an early stage that they had actions well beyond lipid lowering, and that these so-called “pleiotropic” effects included reduction of inflammation. This week’s NEJM tests this in two groups of patients with respiratory disease. In acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life threatening organ failure. A randomised trial aimed to recruit 1000 patients with ARDS and give them either rosuvastatin or placebo. It was stopped early for futility. In fact, the statin may have contributed to hepatic and renal organ dysfunction.

2201  There is a strong suggestion, based on retrospective observational evidence, that statins can decrease the rate and severity of exacerbations, the rate of hospitalisation, and mortality in chronic obstructive pulmonary disease (COPD). What’s not to like? Unfortunately, however, this large prospective randomised controlled trial, conducted at 45 sites across North America, shows that simvastatin 40mg daily does not decrease the rate and severity of exacerbations, the rate of hospitalisation, and mortality in high risk COPD patients. Another good teaching paper showing why RCTs are necessary.

JAMA 4 Jun 2014 Vol 311
2167  Fifteen years ago, I used to go to the local medical library to read JAMA with a sense of excitement. It felt smooth, and had lovely covers and relevant articles. Nowadays, I go to the website on Wednesdays with a faint sense of foreboding. Yet often there are many good things to be found, and this issue is an example. All the Viewpoint pieces are interesting, and one of them (the Detsky/Krumholz piece on making hospitals good for humans, which I commented on previously) is outstanding. The other topics covered are cause and effect in adiposity, big data in industry and academe, and a typically penetrating Ioannidis paper on complex environmental factors in disease.

2191  For a while, coronary artery bypass grafting was the commonest surgical procedure in parts of the developed world. Surgeons argued hotly about whether to do it on or off a cardiopulmonary bypass pump. Off-pump surgery was a badge of technical skill, and was supposed to produce less cognitive impairment in the post-op period. And as for the brain, so for the kidney. This massive multicentre CORONARY trial randomised 4752 patients to on- or off-pump CABG, and followed renal function in 2932 of these. There was less acute postoperative kidney injury in the off-pump group, but no difference in renal function at one year.

2199  Hmm. I’ve just told you that you can’t depend on retrospective observational evidence; but sometimes it’s all you can get. I suppose you could prospectively randomise thousands of older patients in Veterans’ hospitals to receive azithromycin-containing versus other drug regimens for pneumonia, and compare cardiovascular outcomes in the two groups. But this has not been done. Instead these investigators go through a complex process of propensity matching in 73 690 actual VA patients and conclude that: “Among older patients hospitalized with pneumonia, treatment that included azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality and a smaller increased risk of myocardial infarction.” Goddam it, this is a good mycin.

Lancet 7 Jun 2014 Vol 383

1973  Life is unfair. Men get a lot more cardiovascular disease than women. But once fasting blood glucose rises above about 6mmol/l, the reverse applies. The sugar effect may not be causal, but it’s a marker for something that is. Once it gets a bit higher, we call it diabetes, though I find this a perplexing term. Three authors have crunched through an immense amount of data from 64 cohort studies to discover what is known about the risk of stroke in women and men with diabetes. Women have a risk ratio of 2.28 for stroke if they are labelled diabetic, while for men the figure is 1.83. Not that this actually tells you anything about the risk of the person coming to see you: “we were unable to assess whether the excess risk of stroke in women with diabetes varied with different indices of glycaemic control or duration of diabetes because of insufficient data for these variables.”

1990  “I can’t help being fat doctor, it’s in my genes.” And it is. Not in some simple, deterministic Dawkinsian way, but by a complex interaction of genetics and epigenetics. Here is a genome wide study, which concludes: “Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue. Our findings suggest that perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people.” Life is unfair. Everything conspires to make fat people stay fat.

1999  And everything conspires to make people enjoying peace and prosperity get fat in the first place. A review called “Prevention and management of type 2 diabetes: dietary components and nutritional strategies” whistles bravely in the dark. We don’t really know what works, but in the meantime we are told to stick to a diet rich in wholegrains, fruits, vegetables, legumes, and nuts; moderate in alcohol consumption; and lower in refined grains, red or processed meats, and sugar sweetened beverages. Has a familiar ring.

2008  I may be older and fatter than I would like, but on the whole I am optimistic. I keep meeting brilliant young people who are brighter and kinder than most of my generation. The world has little need of me: it will be safe in their hands. And another pleasure is watching eminent authority figures changing their tune in line with evidence. Here is a review of cardiovascular outcome trials of glucose lowering drugs or strategies in type 2 diabetes. I was first author on two Editorials for The BMJ on this topic, and in 2010 the first one was not welcomed by the British diabetes establishment because it criticised the notion that HbA1c lowering below 7 was a worthwhile target in established T2DM. You can still see this idea going through its death pangs in the introduction to this article: “No trial results have shown unequivocal cardiovascular risk reduction with glucose lowering. However, results of the post-trial follow-up of the UK Prospective Diabetes Study, and of a meta-analysis of the four glucose-lowering outcome trials completed to date, suggest about a 15% cardiovascular relative risk reduction per 1% decrement in HbA1c.” I would lay a fair bet that the first bit of that came from Robert Califf and the “However” bit from Rury Holman. I don’t buy his suggestions of course, but I rejoice that almost all the rest of the piece is bang on, especially the conclusion calling for longer, better trials designed with patients.

The BMJ 7 Jun 2014 Vol 348

A very recent Cochrane review of fixed dose combination pills for reducing cardiovascular risk concluded that: “Compared with placebo, single drug active component, or usual care, the effects of fixed-dose combination therapy on all-cause mortality or CVD events are uncertain; only few trials report these outcomes and the included trials were primarily designed to observe changes in CVD risk factor levels rather than clinical events.” So we don’t know what “polypills” of various similar kinds really do to real outcomes. And I don’t think the Cochrane reviewers would change their mind in the light of the latest trial, which comes from New Zealand. To be sure, many more people take their medicines if they are all rolled into one pill; they also get more adverse effects, and frequently discontinue them. It’s a shame that people are not more like sheep, who will follow each other into a pasture, feed on the same grass, and die at an appointed time. “Among this well treated primary care population, fixed dose combination treatment improved adherence to the combination of all recommended drugs but improvements in clinical risk factors were small and did not reach statistical significance. Acceptability was high for both general practitioners and patients, although the discontinuation rate was high.”

A study of outcomes after administration of thrombolysis for stroke, in a population of 4 million Germans, concludes that treatment with recombinant tissue plasminogen activator within the first 1.5 hours after onset is highly effective, with a NNT of 4.5. The inconsistencies within this study are neatly explored in two rapid responses. Thrombolysis is a treatment of zero or marginal benefit for the great majority of stroke patients.

Surgeons who do more than 35 total hip replacements per year have better outcomes than those who do fewer: that’s the familiar message of a survey of Ontario orthopods. Long ago, in the days when the Lancet was less pompous, it ran an editorial suggesting that THRs could be done at high volume by specially trained technicians. I still think someone should run a trial comparing low volume and ordinary volume hip surgeons with technicians doing five a day.

Plant of the Week: Cornus alternifolia “Argentea”

This wonderful shrub has pride of place in our garden. At the moment it is bearing abundant small corymbs of white flower, which simply add to the brightness of its foliage. The leaves are delicate, and also mostly white, but with a central dash of green. You wouldn’t have thought they could, but they manage enough photosynthesis for the plant to grow ever taller and more elegant each year.

It is one of those naturally aristocratic plants, which simply don’t know how to look less than lovely. Every year, it puts up one or two leading stems that each produce a horizontal fan of delicate branches. So at two metres, and growing fast in this lush season, ours is one beautiful tier upon another. I can count roughly seven as I look out of the window. It’s hard to be sure because, although they are well spaced, there is some mingling, which only adds to the luxuriant effect of the whole.

This used to be a very expensive plant but has hardly changed in price over two decades, while much less desirable plants have caught up with it. Go for the best.

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