Richard Lehman’s journal review—2 December 2013

Richard LehmanNEJM  28 Nov 2013  Vol 369
2083   I like it that the NEJM has chosen to start this week’s firework show with a dud. Stand ready to be awed and deafened by the Mighty Thunderboosh! Pssh, sputter, pop. Sorry folks, that was it. So rather than the vaccine that heralds the end of HIV, we have the vaccine that teaches us valuable lessons that may lead one day to the vaccine that could end HIV. “At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants)… In April 2013, the data and safety monitoring board recommended halting vaccinations for lack of efficacy. The primary analysis showed that week 28+ infection had been diagnosed in 27 participants in the vaccine group and 21 in the placebo group.” Unfortunately, that’s the way most medical advances happen: following a string of failures.

2093   This issue of the New England Journal appeared on Thanksgiving Day. So let’s make it the subject of a family quiz.
1. In the following list, who is getting money from the most companies?
2. Which commercial sponsor appears most frequently?
3. Which drug do you think this paper might be about?
4. How many centres should it take to recruit 21,000 patients with atrial fibrillation?
5. What percentage of time within target INR would you expect for patients taking warfarin?
4. Do you think that a replication study might be a good idea?

Dr. Giugliano reports receiving consulting fees from Daiichi Sankyo, Janssen Pharmaceuticals, and Merck; lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, Merck, and Sanofi; and grant support through his institution from Daiichi Sankyo, Merck, Johnson & Johnson, Sanofi, and AstraZeneca. Dr. Ruff reports receiving consulting fees from Daiichi Sankyo, Bristol-Myers Squibb, and Boehringer Ingelheim and grant support through his institution from Daiichi Sankyo. Dr. Braunwald reports receiving consulting fees from Sanofi, Genzyme, Amorcyte, the Medicines Company, and Cardiorentis; lecture fees from Eli Lilly, Menarini, Medscape, and Bayer HealthCare; and grant support through his institution from Daiichi Sankyo, AstraZeneca, Johnson & Johnson, GlaxoSmithKline, Bristol-Myers Squibb, Beckman Coulter, Roche Diagnostics, Pfizer, Merck, and Sanofi. He also reports serving as an unpaid consultant for Merck and providing uncompensated lectures for Merck and CVRx. Dr. Wiviott reports receiving consulting fees from AstraZeneca, Bristol-Myers Squibb, Eisai, Arena Pharmaceuticals, Eli Lilly, Daiichi Sankyo, Aegerion, AngelMed, Janssen Pharmaceuticals, Xoma, ICON Clinical Research, and Boston Clinical Research Institute and grant support through his institution from AstraZeneca, Bristol-Myers Squibb, Eisai, Arena Pharmaceuticals, Merck, Eli Lilly, Daiichi Sankyo, and Sanofi. Dr. Halperin reports receiving consulting fees from Bayer HealthCare, Boehringer Ingelheim, Johnson & Johnson, Ortho-McNeil-Janssen Pharmaceuticals, Pfizer, Sanofi, Biotronik, Boston Scientific, and Medtronic. Dr. Waldo reports receiving consulting fees from Daiichi Sankyo, Sanofi, CardioInsight, Pfizer, and ChanRx; lecture fees from Sanofi, Pfizer, Janssen Pharmaceuticals, and Bristol-Myers Squibb; honoraria for clinical trial–related activities from Biotronik, St. Jude Medical, Daiichi Sankyo, Biosense Webster, Gilead, and AtriCure; and grant support through his institution from Gilead. Dr. Ezekowitz reports receiving consulting fees from Boehringer Ingelheim, Pfizer, Sanofi, Bristol-Myers Squibb, Portola Pharmaceuticals, Bayer HealthCare, Daiichi Sankyo, Medtronic, Aegerion, Merck, Johnson & Johnson, Gilead, Janssen Scientific Affairs, Pozen, and Coherex Medical; and lecture fees from Boehringer Ingelheim. Dr. Weitz reports receiving consulting fees from Boehringer Ingelheim, Bayer HealthCare, Bristol-Myers Squibb, Daiichi Sankyo, Janssen Pharmaceuticals, Pfizer, Merck, and Portola Pharmaceuticals. Dr. Koretsune reports receiving lecture fees from Daiichi Sankyo, Boehringer Ingelheim, Pfizer, Bayer HealthCare, and Bristol-Myers Squibb; and grant support through his institution from Daiichi Sankyo and Boehringer Ingelheim. Drs. Shi, Patel, Hanyok, and Mercuri report being employees of Daiichi Sankyo. Dr. Mercuri also reports holding a pending patent related to the clinical properties of edoxaban. Ms. Murphy, Ms. Grip, and Dr. Antman report receiving grant support through their institution from Daiichi Sankyo. No other potential conflict of interest relevant to this article was reported.

I love that last sentence.

JAMA Intern Med  25 Nov 2013  Vol 173
1941  Placebo Domino in regione vivorum—I shall please the Lord in the land of the living. Scholars among you may recognise this is the origin of the modern word “placebo.” The Latin for “I shall please” was written by St. Jerome as he sat in fourth century Palestine, with a stone of penance in one hand and his pet lion under his writing desk, as you can see in numerous lovely Renaissance paintings. He eventually succeeded in mastering the Hebrew tongue with the help of numerous Jewish converts to Christianity, but he made a few mistakes as he went along. In this case the holy man cheated and translated from the Greek Septuagint rather than the Hebrew text, because the original verse (Ps 116.9) actually means “I will walk before the Lord,” and that is what he corrected it to in a later version. But in the meantime his first version had become embedded in the Latin funeral rite, and in the Middle Ages people known as “placebo singers” would go around singing at funerals in order to get the free food on offer afterwards. Apologies to those of you who already knew this from your close reading of Chaucer. Now where was I? Ah yes, here is a study showing that there are wide differences in the effect of placebos used in trials of migraine. Placebos that involve sticking needles and knives into people work best.

1952    Those who have stayed with David Suchet through all 70 episodes of Poirot may remember one where the Belgian detective is confronted with a doctor who will not reconsider his diagnosis even after his mistake has killed the patient. “A doctor who is never wrong is not a doctor, Hastings. He is a butcher!” I have probably misquoted dear Poirot (due to the state of my little grey cells) so I shall now have to watch all the episodes again, just to check. The life, mon ami, it is hard. I was reminded by this study in which general internists in the USA were asked to diagnose four previously validated case vignettes of variable difficulty. “Our study suggests that physicians’ level of confidence may be relatively insensitive to both diagnostic accuracy and case difficulty. This mismatch might prevent physicians from reexamining difficult cases where their diagnosis may be incorrect.” Mon Dieu, Hastings, it is necessary to run!

1962   One problem is that doctors don’t like to be seen to look things up in front of patients. I got over this many years ago. Every doctor should unashamedly look things up in front of patients, turning the screen towards them so they can join in. I would actually make it a condition of medical training that youngsters should be taught to do this. If they don’t like what they see on Wikipedia, they shouldn’t moan but get down and edit it, citing their sources. Every doctor should revel in discovering areas of ignorance, and in sharing their learning with others. It is the only safe way to practice medicine. Jon Brassey has set up a great system for doing this called TILT (Today I Learned This), but hardly anyone uses it. Now look at this study and pull your socks up: “Physicians perceive that insufficient time is the greatest barrier to point-of-care learning, and efficiency is the most important determinant in selecting an information source.” Yes, and it’s up to us to put that right.

JAMA  27 Nov 2013  Vol 310
2164   The drug that really woke up Europe to the need for better safety and licensing controls was thalidomide: the whole ugly story is well told in Druin Burch’s Taking the Medicine. And yet this drug refuses to lie down and die, because of its unique combination of anti–tumour necrosis factor α, immunomodulatory, and antiangiogenic properties. Most GPs will know of a patient or two taking thalidomide for myeloma, and in the future we may even see it used in young people with Crohn’s disease which has failed to respond to first line treatment. In a small but well conducted double blind RCT “in children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at eight weeks of treatment and longer-term maintenance of remission in an open label follow-up. These findings require replication to definitively determine clinical utility of this treatment.”

2174   My mother was the daughter of a wealthy Polish doctor, and when she had a febrile illness, the maid would be ordered to put her under wet sheets so that she would lose heat. Fortunately she did not repeat that experiment on me and my sister during our innumerable childhood fevers in a cold bare English house in the 1950s. But the universal urge to cool down hot patients seems incredibly powerful: I am forever having to tell parents that they really don’t have to give paracetamol and ibuprofen continuously just because their child has a temperature. In this trial, we have French ICU doctors going several steps further and inflicting hypothermia on patients with severe bacterial meningitis. Not, one would have thought, an ideal situation for informed consent. The trial was called off when more patients in the hypothermia group died.

2184   The Danish peninsula and its islands hold 0.08% of the world’s population, and yet we derive as much useful medical knowledge from Denmark as from anywhere else on earth. Such are the benefits of whole population data collection. Do fluoroquinolone antibiotics cause retinal detachment? Let’s turn to a nationwide, register-based cohort study in Denmark from 1997 through 2011, using linked data on participant characteristics, filled prescriptions, and cases of retinal detachment with surgical treatment (scleral buckling, vitrectomy, or pneumatic retinopexy). There were no significant difference between users, past and present, and controls. “Given its limited power, this study can only rule out more than a three fold increase in the relative risk associated with current fluoroquinolone use; however, any differences in absolute risk are likely to be of minor, if any, clinical significance.” Good enough for me.

Lancet  30 Nov 2013  Vol 382
Sex and The Lancet—no, I can’t see the television series taking off. But this week’s Kinsey style report on the sex lives of Britons has certainly drawn an unusually wide readership to our hallowed journal. I can think of few better ways of passing the time after lunch.

1781   The survey reported is actually called Natsal-3, standing for National Surveys of Sexual Attitudes and Lifestyles. Unfortunately you have to get past the Lancet paywall before you can see what others of your age group are getting up to in bed. I refer to the tabulated data of course. Ever so interesting. Pity I don’t know what bits to tell you about. But gosh, who would have thought that so many people…

1795   Here’s the bit about sexually transmitted diseases. In this study they examined lots of urine samples for Chlamydia trachomatis, type-specific human papillomavirus (HPV), Neisseria gonorrhoeae, and HIV antibody. Of these, only HPV is common, and the authors take comfort from increasing uptake of vaccination, as well as increasing attendance at sexual health clinics by the young.

1807   I consider myself incredibly lucky to have been born into the first generation for whom sex could be enjoyed easily without the risk of pregnancy. But still, it happens. About 16% of pregnancies counted in this study were definitely unplanned, with almost twice that number being classed as “ambivalent.” As expected, the highest rates are in the youngest age groups.

1817   And then there is performance and satisfaction. “Among individuals reporting sex in the past year, problems with sexual response were common (41•6% of men and 51•2% of women reported one or more problem).” Dissatisfaction peaks at 55, and the authors are careful and detailed in their analyses. These really are worthwhile articles, but impossible to summarise usefully.

1830   Next the effect of poor health. “Poor health is independently associated with decreased sexual activity and satisfaction at all ages in Britain. Many people in poor health report an effect on their sex life, but few seek clinical help. Sexual lifestyle advice should be a component of holistic health care for patients with chronic ill health.” I wonder how often anyone offers this.

1845   And finally there is non-volitional sex, reported by almost one woman in ten in the survey. Again, it is very much a problem of younger women. A cross-sectional study like this cannot reveal its lasting harm to individuals, but it is likely to be huge: and it happens to a huge number of individuals.

BMJ  30 Nov 2013  Vol 347
Martin Roland writes brilliantly about the new proposals for Urgent Care in England: “Several solutions are based more on wishful thinking than on evidence. Although self management and care planning are cited as evidence based solutions to rising demand, evidence for their cost effectiveness in reducing the use of secondary care is weak outside a small number of conditions. There is also an over reliance on the new NHS 111 phone service, which duplicates some existing services, uses relatively inexperienced call operators as first line contacts, and probably increases emergency department attendances and ambulance call-outs. The use of inexperienced staff for triage also ignores evidence from hospitals that senior members of staff are better than juniors at keeping patients out of hospital. Evidence from Denmark suggests that the costs of out of hours care would rise rather than fall if nurses were substituted for doctors in triaging out of hours calls.” Oh boy, all this is so true.

Surgery for spinal stenosis can be life-changing. Often the change is in the wrong direction. Never let a surgeon near your spine unless (a) you are desperate (b) you know his outcome figures (c) you have taken a second opinion (d) you have made plans in case of paraplegia and (e) you have absolutely forbidden the use of any devices. A Dutch trial seeks to discover if interspinous process device implantation is more effective in the short term than conventional surgical decompression for patients with intermittent neurogenic claudication due to lumbar spinal stenosis. It was not. In fact it might increase reoperation rates.

A population cohort study from England finds that women who are pregnant are at greatly increased risk of thromboembolism if they are admitted to hospital for any reason. The relative risk of VTE is somewhere between 8 and 40 overall – but the article is careful to frame this in subgroups and to give absolute figures too. And it remains elevated in the month after discharge.

Panicked by the success of the AllTrials campaign, industry spokespersons are keen to point out that non-publication of trials is becoming a thing of the past. Good. So what do they propose to do about the findings of this study which shows that 32% of industry-sponsored large RCTs completed by 2009 have still not been published? Moreover, by “published” the authors just mean publication of summary data in the usual limited format, not the full datasets that we really need to make an informed judgment. We have a long fight on our hands.

Plant of the Week: Viburnum farreri

Thank you, Reginald Farrer, for bringing this plant back from the Himalaya to spread its kind scent into English gardens at the gloomiest time of the year. Those little pink pom-poms justify the presence of this otherwise undistinguished shrub in every garden. He himself modestly named it Viburnum fragrans, but it seems to have been renamed in his honour after he died on his final plant-hunting expedition.