Richard Lehman’s journal review—2 February 2015

richard_lehmanNEJM 29 January 2015 Vol 372
407 A Canadian trial tells us a bit more about how to treat raised blood pressure in pregnancy. If women already have elevated BP or acquire it before 34 weeks of gestation without proteinuria, treating to a target diastolic of 100 mm Hg produces the same result as treating to a target of 85, in terms of pregnancy loss, high level neonatal care, or overall maternal complications. Naturally, those treated less intensively show a greater tendency for their BP to rise as the pregnancy continues.

418 Huge numbers of people now take angiotensin-converting enzyme inhibitors, and a few of them get angio-oedema as a result, which can happen even after years of use. As far as I could ascertain, fatalities are very rare and exclusive to people of African origin. I get mild angio-oedema now and again, though I’m not on an ACE inhibitor. I take an antihistamine and wait for it to go away. So, I guess, do most people: the treatment cost must be about 10p. Shire makes a competitor drug called icatibant, which in the USA costs between $5000 and $10 000 per shot. They have run a trial (n=27) to show that it works faster in ACEI-related angio-oedema than standard hospital treatment with intravenous prednisolone and clemastine—eight hours rather than 27. I can see this being kept in the back locker for those rare people with real airways compromise, rather than people like me with the occasional thick lip.

426 When I saw this trial of Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera, I went online to find out the cost of this Janus kinase (JAK) 1 and 2 inhibitor. Excluding VAT, the basic NHS prices are £1800 for 5mg tablets (60) and £3600 for 15mg or 20mg tablets (60). By contrast, hydroxyurea (hydroxycarbamide) sounds like the kind of compound any chemically inclined teenager with a flask and Bunsen burner could make in their bedroom. Astonishingly, 30 x1G tablets command a basic NHS price of £500. I feel like collecting my urine and setting up a factory. Anyway, the fact seems to be that ruxolitinib is a useful drug: “In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera.”

JAMA 27 January 2015 Vol 313
369 “It’s taken 4 billion years, but it was worth the wait,” I can hear the bacteria say to each other when they head for the intensive care unit. This is just the perfect environment for bacterial evolution: lots of desperately ill people, lots of antibiotics around, lots of tubes and wounds and damaged organs to host biofilms. How vainly we struggle against them is shown by this trial of chlorhexidine bathing in ICUs in Nashville, Tennessee, which assessed the effect of once daily bathing of all patients with disposable cloths impregnated with 2% chlorhexidine using nonantimicrobial cloths as the control. The disinfectant made no difference to central line–associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and Clostridium difficile infections.

390 There aren’t all that many dependable facts about prostate cancer and its treatment, but at least the Gleason score has stood the test of time. Unfortunately, it’s a histological staging system that requires multiple prostate biopsies, and its accuracy will depend on whether you hit the right spot. The prostate is not like the breast, where you can feel the bit you want to biopsy, or easily see it on ultrasound or X ray: it is—interrupt me if you have heard this before—the size and shape of a walnut and lies hidden under the bladder. This paper describes two methods of prostate biopsy performed at the same time on 1003 men and then compared for detection of lesions with a Gleason score of 4 or higher. I have tried to understand the detail but it has caused clouding of the brain and tightening of the perineum: the superior imaging mode seems to be a fusion technique combining magnetic resonance with ultrasound. If somebody approaches my walnut with 12 biopsy needles, this is what I will ask for.

JAMA Intern Med January 2015
OL This important study shows that people who are privately insured and attend an American hospital with chest pain, and undergo immediate investigations which are negative for myocardial infarction, still get later non-invasive testing in a third of cases. These patients had the same subsequent very low incidence of myocardial infarctions as the non-tested group, but were of course much more likely to proceed to invasive testing. “Compared with no testing, exercise electrocardiography, myocardial perfusion scintigraphy, and coronary computed tomography angiography were associated with significantly higher odds of cardiac catheterization and revascularization procedures without a concomitant improvement in the odds of experiencing an MI.” I don’t know how much of this goes on in the UK, but it is time it stopped.

OL Taking anticholinergic drugs when you are old is not a good idea. They have adverse vascular effects, which may explain why they are associated with an increase in total mortality, and also—as this study shows—an increase in dementia. In a cohort of 3434 people aged over 65 without dementia at baseline, a dose related increase was found in those receiving anticholinergic drugs, usually tricyclic antidepressants, first generation antihistamines, or bladder antimuscarinics. With up to 25% of hospital admissions in the elderly owing to iatrogenic poisoning, it is high time we started heeding John Yudkin’s Ten Commandments, especially “Honour the elderly patient, for although this is where the greatest levels of risk reside, so do the greatest hazards of many treatments.”

Ann Intern Med Vol 162 January 2015
OL Newly appeared on the Annals website are two articles reflecting on the challenges of sharing data from clinical trials. The first is by Mike Rosenblatt, executive vice president and chief medical officer at Merck, who attempts with two colleagues to paint the downside. How will we stop the vexatious use of data to start up scare stories, and how can we prevent reidentification of trial participants? Unfortunately, the examples chosen have nothing to do with open data from clinical trials, but never mind. Merck’s efforts in this field are well understood. The article by Steven Goodman, which follows, addresses the concerns of academe in a more positive way. To be sure, the chances of getting 100 papers out of a single study (think UKPDS) will diminish under the Institute of Medicine’s proposed timetable of 18 months to release the full dataset, but isn’t this what the world needs? The more important the trial, the faster its results should be available for independent scrutiny. Academic career paths need to change in order to benefit all patients and medical science.

Lancet 31 January 2015 Vol 385
430 The Bill & Melinda Gates Foundation does what the World Health Organization should be doing. Every billionaire should be forced to do the same, and the world would suddenly be a much better place. As it is, “4.4 million children younger than 5 years will still die in 2030. Furthermore, sub-Saharan Africa will have 33% of the births and 60% of the deaths in 2030, compared with 25% and 50% in 2013, respectively.” Just look at the pie chart for causes of death—one billionaire apiece should be tasked with abolishing child deaths from pneumonia, tetanus, diarrhoea, measles, malaria, meningitis, AIDS, and pertussis.

441 China has the wealth to sort out its own health problems, but first it must know how to map them. With names like Krumholz, Spertus, and Masoudi on the case, it can hardly fail to make progress with mapping their cardiovascular outcomes, as this study of ST-segment elevation myocardial infarction in China from 2001 to 2011 illustrates. But wait a moment: after the paper had gone online, somebody discovered a miscalculation in the weight of one of the urban areas in the study. It made no substantive difference to the conclusions, but when the authors reported it to the Lancet, the journal proceeded to retract the paper rather than publish a small correction. Now that the corrected paper has appeared in print, the Lancet takes the opportunity to congratulate itself on this noble deed.

The BMJ 31 January 2015 Vol 350
The latest trial of paying people to stop smoking is mildly positive. The participants were 612 self reported pregnant smokers in NHS Greater Glasgow and Clyde who were English speaking, at least 16 years of age, less than 24 weeks pregnant, and had an exhaled carbon monoxide breath test result of 7 ppm or more. They stood to earn £400 in shopping vouchers if they went through to “validated abstinence of exhaled carbon monoxide at 34-38 weeks’ gestation.” I think somebody may have got their absence and their abstinence mixed up here, but we get the drift. Sixty nine women out of 306 got their full prize money. In the control group (advice and nicotine replacement therapy) there were 26 CO-measured abstainers. Which brings us to the question of cost effectiveness. No information: I guess they are saving this for their next paper.

120 Five hundred and sixty six postmenopausal women, aged 50-79 at baseline (1993-98), followed through 2013. Now that’s what I call a proper cohort, and it tells us a lot about fracture patterns as women get older and their weight stays the same or changes. Here’s what the data from the Women’s Health Initiative Observational Study and Clinical Trials tell us: “Compared with stable weight, unintentional weight loss was associated with a 33% higher incidence rates of hip fracture (1.33, 1.19 to 1.47) and increased incidence rates of vertebral fracture (1.16, 1.06 to 1.26); intentional weight loss was associated with increased incidence rates of lower limb fracture (1.11, 1.05 to 1.17) and decreased incidence of hip fracture (0.85, 0.76 to 0.95).” So fatter women can slim without worrying that they are endangering their hips by loss of padding. Sorry, that sounds neither gentlemanly nor politically correct. I can never get it right.

How well does the number of randomised controlled trials match the priorities of the global burden of disease? Not very, you’ve guessed. This paper spells out the mismatch and concludes: “Overall, a weak association existed between global burden of disease and number of published randomised trials. A global observatory for research is needed to monitor and reduce the discordance between the output of randomised trials and global burden of disease.” Never mind the observatory, it’s time to line those billionaires up and give them each a condition to fund research into. To the tune of half their wealth. What else are they going to do with it?

And let’s make sure that those trials yield data about the outcomes that matter. Each week I rummage through about 30 meta-analyses, which confirm the dismal truth that most research effort is clinically useless. John Ioannidis has been saying this for a decade, and his latest confirmatory evidence comes from an analysis of all Cochrane systematic reviews (as of November 2013) that had evaluated interventions in preterm infants. “Most trials included in systematic reviews of interventions on preterm infants are missing information on one of the most common serious outcomes in this population.” Let’s land a COMET on the research community and insist on the use of “standardized clinical outcomes that would have to be collected and reported by default in all trials in a given specialty.”

Ten Commandments

I first blogged out John Yudkin’s commandments three years ago, in this form:
The New Therapeutics: Ten Commandments

• Thou shalt treat according to level of risk rather than level of risk factor.
• Thou shalt exercise caution when adding drugs to existing polypharmacy.
• Thou shalt consider benefits of drugs as proven only by hard endpoint studies.
• Thou shalt not bow down to surrogate endpoints, for these are but graven images.
• Thou shalt not worship treatment targets, for these are but the creations of committees.
• Thou shalt apply a pinch of salt to relative risk reductions, regardless of P values, for the population of their provenance may bear little relationship to thy daily clientele.
• Thou shalt honour the numbers needed to treat, for therein rest the clues to patient relevant information and to treatment costs.
• Thou shalt not see drug reps, nor covet an educational symposium in a luxury setting.
• Thou shalt share decisions on treatment options with the patient in the light of estimates of the individual’s likely risks and benefits.
• Honour the elderly patient, for although this is where the greatest levels of risk reside, so do the greatest hazards of many treatments.

They circulated widely in various forms, and appeared in a modified form in The Good GP Training Guide. We have expanded them a little and hope to publish a new version soon, available in a number of formats. Stonecutters are being recruited as we speak.

We would be glad to receive your comments and suggestions, especially whether you find the biblical language helpful or off-putting. Thou shalt bear thy questions on the wings of an angel to:

But keep in mind that I shall be off to Seville shortly to enjoy the warmth, architecture, food and wine, so please desist from worshipping golden calves if I am slow to reply.