Richard Lehman’s journal review—24 February 2014

richard_lehmanNEJM  20 Feb 2014  Vol 370
699   This week, the NEJM is big on bevacizumab. Amongst the crowd of mabs, this is one of the best known: Avastin is a humanized monoclonal antibody directed against vascular endothelial growth factor-A which has been on the market since 2004. It has had its ups and downs, and this week is both a down and an up. Down goes any hope that it could be a useful first line treatment for newly diagnosed glioblastoma, even though these tumours tend to be highly vascular. This trial and the one that follows fail to show any useful effect from adding bevacizumab to standard treatment with temozolomide and radiotherapy.

734   But adding bevacizumab did have a small beneficial effect in patients with advanced cervical cancer. Unfortunately it only amounted to a median additional survival time of 3.7 months. This would come at a cost of around $50K: about average for new drugs for incurable cancer.

723   For some reason, tympanostomy tubes are known in Britain as “grommets” while in the USA they are simply known as toobs. Grommets are toobs designed to ventilate the middle ear space, and by and large these plastic foreign bodies are very well tolerated; but occasionally they become conduits for pus coming out of the middle ear space rather than air going in. Gunky ears in kids with grommets are a common sight for those who follow my humble avocation. The mighty challenges that face us are (a) do we dip the business end of our otoscope into this pussy mess, just so we can show that we have examined the child and (b) should we prescribe drops or an oral antibiotic? My firm advice is to keep your otoscope clean and prescribe drops. Our local ENT people recommend gentamicin and hydrocortisone drops, which always scares me a bit, because gentamicin is ototoxic; but they wave aside my concerns. This Dutch open-label trial used hydrocortisone–bacitracin–colistin eardrops and showed that these gave better results at two weeks than co-amoxiclav given orally.

744   The fundamentals of lung auscultation are set forth in a review article which avoids any modern nonsense about inter-observer agreement or predictive value, but just tells you what the sounds are meant to mean. I enjoyed reading this exercise in old-fashioned pedagogy, though some ancient classics such as whispering aegophony and the coin sign have disappeared in favour of modern ones such as “Velcro rales” and “squawks.” In cardiology, auscultation has largely been replaced by imaging that tells you what is really going on; but in “pulmonology” and in daily practice, doctors still take great pride in their guessing tubes. Perhaps the real leap forward in chest medicine—badly needed—will come when someone invents a simple kind of imaging that shows what the lungs are really doing rather than what they sound like.

JAMA  19 Feb 2014  Vol 311
682   Citalopram has become a very popular drug, though nobody knows how it works, or even, in many cases, whether it works. It is of course supposed to be a selective serotonin reuptake inhibitor with antidepressant effects, but this biochemical model doesn’t bear close scrutiny, and all I know about it is that many people with low mood improve within a month of taking it, and that they then find it hard to come off it. People with Alzheimer’s disease can’t tell you how they feel. Often they become agitated and hard to settle, and somebody had the idea of trying the effect of citalopram on them. Compared with placebo, it reduced agitation and caregiver distress, but had mild unwanted effects such as diarrhoea and a slight increase in respiratory infections and falls: higher doses also cause QT prolongation. Maybe it has a place in this sad situation.

692   As a would be designer of decision aids, I am always on the look out for situations of clinical equipoise. Take atrial fibrillation. The classic choices are between rate control or rhythm control, between various beta-blockers, or amiodarone or digoxin, or elective cardioversion; and between aspirin and warfarin or one of the fixed dose new anticoagulants. All very entertaining and ever changing. Now a trial comes along comparing drug therapy with radiofrequency ablation as first-line treatment for paroxysmal AF. The two work equally badly: recurrences are common. So is this a case of clinical equipoise? I don’t think so, because in this trial the rate of serious complications in the radiofrequency ablation group was 9%: an alarming 6% of the group had cardiac tamponade. Give me those pills please doc.

Lancet  22 Feb 2014  Vol 383
705   The Holy Grail of cardiac imaging would be a technique for spotting the atheromatous plaques most likely to rupture as opposed to those merely causing the most stenosis. It’s just possible that it has now been found, but it’s far from clear to a mere onlooker what the clinical consequences might be. A team from Edinburgh used the radioactive tracer 18F-sodium fluoride to identify the kind of plaque that is most likely to cause trouble. In a complex exploratory study, they took newly harvested plaque from people who had just had carotid endarterectomy and showed that marked 18F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. Concurrently they used the tracer in 40 patients with recent myocardial infarction and in 40 with stable angina, and located its presence using PET-CT imaging of the coronary arteries. They also used intra-coronary ultrasound on these patients to pick up calcification and necrosis. In this way they were able to establish that the areas of highest 18F-NaF uptake are in plaques which show the most dangerous characteristics. This is clever stuff, and is bound to lead to a wave of new studies using this relatively cheap isotope and PET-CT hardware wherever it may be available. Perhaps the insights this generates will one day permeate into the world of real-life patient management: in the mean time it is nice to see some good old British investigational science of world class.

723   Malaria is an interesting subject, and this new Lancet review is a great read. It’s written by a multinational team of authors but there is nothing confusing anywhere and it tells it like it is with a minimum of verbiage. I learned plenty of things which will never be of practical value to me, but that’s the point of any good writing: fascination. Not that malaria should even exist in the twenty-first century. Making it history is one of the world’s most important challenges, and on that the article has relatively little to say.

OL   But there is progress. It is very hard to quantify, as shown by the difference between the numbers of deaths attributed to malaria in 2010 by WHO and the Institute of Health Metrics: 655 000 and 1 238 000, respectively. But in another nice example of The Lancet‘s best genre, the epidemiological survey, it’s clear that some African countries are on the brink of eradicating malaria, while others have made little progress. Major threats in the offing are the waning effectiveness of pyrethroid insecticides (did you know that there are only four major types of insecticide?) and the emergence in the Far East of artemisinin-resistant strains of falciparum malaria.

How I was misled by The Lancet last week:
In last week’s Lancet, three articles celebrated the success of renal denervation for “treatment-resistant” hypertension. There was a report of the Symplicity HTN-1 trial emphasizing huge sustained reductions in BP, though there was no control arm and very incomplete follow-up, as I noted. There was a laudatory editorial and a profile of the chief investigator, Henry Krum, pointing out that Australia was a good place to do clinical trials because of its permissive regulatory environment.

But it had escaped my attention that the Symplicity-1 trial had already been superseded by Symplicity-HTN-3. This well-powered randomized trial using a sham control failed to meet its primary end point, a 10mmHg reduction in systolic BP. This had been announced by Medtronic on 9 Jan. And in fact Darrel Francis and colleagues in the renal denervation field had already pointed out the inherent flaws in the design and execution of Symplicity HTN-1 in a paper just published in the International Journal of Cardiology, another Elsevier journal.

This had managed to get under my radar, which isn’t too surprising; but it is quite worrying that it managed to get under The Lancet‘s.

BMJ  22 Feb 2014  Vol 348
Why is the incidence of pelvic inflammatory disease falling? It’s an interesting question addressed by an interesting editorial. It’s good to know that half of sexually active women aged 16-24 now report testing for chlamydia in the past year, but the figures don’t suggest that case-finding and treatment are the main cause of decline in PID. It could be an artefact of recording—after all, the only way you can really establish the diagnosis is by laparoscopy—but that’s not altogether convincing either. Maybe the pathogens responsible, including chlamydia, are just getting less pathogenic. I like the way they often do that. Some thought that the sexual revolution would lead to a pandemic of sexually transmitted disease, but the young have got away amazingly lightly, to the dismay of some old puritans. Not me.

Smoking cessation is hard work for a lot of people, and at least two classes of antidepressant can be used to help it. The relapse rate is so high that you would think it must be because people felt better smoking. But no, it is an effect of nicotine addiction pure and simple. A systematic review and meta-analysis concludes that, “Smoking cessation is associated with reduced depression, anxiety, and stress and improved positive mood and quality of life compared with continuing to smoke. The effect size seems as large for those with psychiatric disorders as those without. The effect sizes are equal or larger than those of antidepressant treatment for mood and anxiety disorders.”

Plant of the Week: Hepatica nobilis

These are little sweeties. I point them out to you most years, so I hope you have got some by now. They have lovely little flowers of soft blue, red, or white. The blues are the loveliest.

They can be hard to find, since they have none of the blowsiness that makes for a garden centre favourite. And in any case, few people visit garden centres in February, except to buy stone pigs and plastic gnomes. You must go to a specialist nursery or find a friend who is willing to split a plant for you.

I am afraid that our hepaticas are what Reginald Farrer would call miffy*. Most that I have bought have died, and we have but one ten-year-old clump which currently sports a single flower. I dream of a garden where there is a hepatica thriving in every sequestered nook among moss and trees. Alas, such a garden is not mine: nor may it anywhere exist. But try to make one if you can.

* I wrote this without consulting Farrer. Here he is, in that imperishable work of English prose, written in China in 1917, The English Rock Garden:

Anemone Hepatica is an invaluable, stemless little woodlander of all the alpine woods that our gardens know hardly less well. It luxuriates in damp woodland soil, and forms, in time, huge clumps; and it acutely resents being divided and disturbed. It has countless coloured forms, and a very miffy and expensive double white.”