NEJM 19 Nov 2015 Vol 373
Spooky RSV trial
2048 There’s a hint of Porton Down about this phase 1 study of an oral treatment for respiratory syncytial virus (RSV). The 62 volunteers trooped in and the steel doors shut behind them. Two days later, masked personnel in white coats proceeded to inoculate them intranasally with four log10 plaque-forming-units of the RSV-A Memphis 37b challenge virus. They spent another two days in quarantine and were then monitored twice daily for signs of incipient RSV infection. As soon as these appeared, nasal samples were sent off for a polymerase chain reaction test to confirm that it was indeed RSV, and they were then given the mystery agent ALS-008176, or a placebo. At this point Sherlock broke in to the secret chamber, the lights went out, klaxons sounded, and the experiment had to be aborted. Ah no, that was just for the television: in real life the subjects continued to languish in durance vile until two weeks had elapsed. Those given the active agent had fewer symptoms and a smaller weight of collected snot, so showing some potential benefit from ALS-008176 in healthy adults with previous immune memory of RSV. This is an orally bioavailable prodrug of the novel RSV replication inhibitor ALS-008112, a cytidine nucleoside analogue. One has to believe there was some good reason that this Alios BioPharma study appears in the NEJM, even though this drug needs two further rounds of testing in scenarios that bear some approximation to real life.
Andexanet the Factor Xa antidote
OL And now it’s the turn of some healthy older volunteers to test a drug produced by Portola Pharmaceuticals. No need for any fancy doors and masks here, though the 101 participants of this phase 2 trial still enjoyed the hospitality of the study centre for eight days. Over the first four days they were given either apixaban or rivaroxaban, which (as you should know by now) are direct inhibitors of factor Xa. They then received a one hour infusion of either placebo or andexanet. Don’t worry if this name is strange to you: it is a recombinant modified human factor Xa decoy protein that is catalytically inactive but that retains the ability to bind factor Xa inhibitors in the active site with high affinity and a 1:1 stoichiometric ratio. In other words, it is a very expensive prospective antidote to these expensive new anticoagulants. For the volunteers, it worked perfectly: “Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects,” purrs the conclusion of the abstract.
Help, I’m in a fix! – oh man,
He’s bleeding on apixaban!
“Shush, here’s some andexanet,
Bung it in and cease to fret.”
In fact, as the accompanying editorial points out, we are well short of knowing how this drug will perform in the messy emergencies of real clinical practice.
JAMA 17 Nov 2015 Vol 314
Antibiotics for vulnerable kids
2013 My contribution to World Antibiotic Awareness Week was a Cochrane UK blog on shared decision making about antibiotic use in upper respiratory infections. I was happy to agree that, for most people, they are more likely to cause minor harm than measurable good, but this study shows that there are exceptions. “Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed.” The investigators chose azithromycin, and in a double blinded randomised trial this significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04). This is sailing close to non-significance, but I’m inclined to believe it works. However, widening the use of macrolides in the United States is problematic given that it already has more than its fair share of resistant respiratory pathogens, unlike the UK. Maybe this study won’t widen use but merely confirm existing good practice.
US hospitals showing COURAGE
2045 As I wrote last week in connection with long term follow-up from the COURAGE trial, interventional cardiologists can be slow to unlearn the oculostenotic reflex, whereby whenever they see a stenosis they insert a stent, with a minimum of cerebral processing. Nihar Desai’s survey of percutaneous coronary intervention in American hospitals stretches from two years after the publication of COURAGE to last year (2009-14) and is a classic in the literature of variation and deadoption in medical practice. What Glover discovered about needless tonsillectomy in the 1930s is still incompletely enacted in practice today. What COURAGE demonstrated in 2007 about stable coronary disease is showing similarly patchy adoption: ” . . . there have been significant reductions in the volume of nonacute PCI. The proportion of nonacute PCIs classified as inappropriate has declined, although hospital level variation in inappropriate PCI persists.”
JAMA Intern Med Nov 2015
Choosing Wisely beyond the comfort zone
OL The Academy of Medical Royal Colleges’s Choosing Wisely strategy that I helped to outline in The BMJ earlier this year has two phases: firstly, identifying low value procedures and secondly, promoting shared decision making. The first is easy and the second is hard. But I am worried that we could get stuck even in the easy phase. In this Special Communication, the authors identify 10 low value interventions and promise more to come. Most of them are either obvious or inapplicable to UK practice. We need to get outside the comfort zone and get to grips with procedures that both doctors and patients invest with more hope than they deserve: physiotherapy for most things, surgery for spinal stenosis, percutaneous coronary intervention for stable coronary artery disease, arthroscopic trimming for meniscal tears, interventional radiology for spinal fractures, repeated endoscopy for Barrett’s oesophagus: plus all your other suggestions. Each of these will need a careful evidence review and decision aid to support informed dialogue between patients and clinicians.
Lancet 21 Nov 2015 Vol 386
CLEAN those easy to reach germs
2069 In a challenge to his powers of chemical analysis, Sir Humphry Davy was presented with some purple-brown crystals when he boldly visited Napoleon’s Paris in 1813. He correctly identified them as a new element, which he called iodine, and claimed its discovery for Britain. It is hard to know whether he did this for his own vainglory or just to miff the French. He succeeded in annoying everybody and laying the ground for the use of alcoholic solutions of iodine as a medical antiseptic. By contrast, the medical antiseptic chlorhexidine is truly British. It was discovered in the early 1950s when the Imperial Chemical Industries was trying to produce new anti-malarial drugs. French physicians have now carried out the CLEAN trial comparing skin cleansing using povidone-iodine versus chlorhexidine alcohol solutions for preventing intravascular catheter related infections. They have proved that British chlorhexidine works better than French/British iodine.
OL The PPROMT study belies its name by being one of the most drawn out trials in the history of obstetrics. It took place at 65 centres in 11 countries (Australia, New Zealand, Argentina, South Africa, Brazil, UK, Norway, Egypt, Uruguay, Poland, and Romania) between 28 May, 2004, and 30 June, 2013. I’m surprised by this scale since it addressed a common obstetric issue: if someone has ruptured membranes near term but fails to go into labour, is it better to induce or to wait? The investigators reach a firm conclusion based on maternal and fetal outcomes in 1839 women in their randomised trial of immediate induction versus expectant management: “In the absence of overt signs of infection or fetal compromise, a policy of expectant management with appropriate surveillance of maternal and fetal wellbeing should be followed in pregnant women who present with ruptured membranes close to term.” You can pick among the detail: there were few adverse outcomes in either group, but slightly more maternal infections in the delayed group, with more caesarean sections and neonatal distress in the immediate delivery group.
Vanishing stents and worse outcomes
OL Since I got myself stuck with reporting stent trials about 15 years ago (there were even radioactive ones in those days), I guess I have to tell you the latest about the newly fashionable bio-absorbable stents. Call me a cynic, but they seem to me a classic case of “evergreening”—replacing a patent expired product with something almost identical. And possibly something slightly worse, according to this meta-analysis: “Compared with everolimus-eluting metallic stents, everolimus-eluting bioresorbable vascular scaffolds had similar rates of repeat revascularisation at one year of follow-up, despite inferior mid-term angiographic performance. However, patients treated with a bioresorbable vascular scaffold had an increased risk of subacute stent thrombosis. Studies with extended follow-up in a larger number of patients are needed to fully assess the long term advantages of everolimus-eluting bioresorbable vascular scaffolds.” Advantages?! How did that word creep in?
The BMJ 21 Nov 2015 Vol 351
H1N1 shot safe in pregnancy
Cast your mind back to the early days of the H1N1 flu pandemic. Early reports of the case fatality in Mexico were truly alarming—over 20% perhaps. Then a mother died in Scotland. Pregnancy and the post-partum period emerged as strong risk factors for severe or fatal infection. We hoped a vaccine would emerge quickly and it did. It was rapidly deployed in pregnant women; and now we can look back and see if it did their babies any detectable harm. This Swedish study looks at 275 500 births: of these offspring, 41 183 had been exposed to vaccination with Pandemrix, a monovalent AS03 adjuvanted H1N1 influenza vaccine, during fetal life. There was no difference in rates of stillbirth, neonatal death, or later death in these children.
A bleed or a stroke in AF?
Here is a cohort study of 4602 people from Denmark of mean age 78: within two years, 40% of them were dead. That shows us that surviving a hospital admission for gastrointestinal bleeding while taking anticoagulants for atrial fibrillation carries about the same prognosis as having a disseminated cancer or grade 3 heart failure. I found that quite surprising. The study went on to examine the death rates in those whose doctors decided to put them back on anticoagulants compared with those who stayed off them. Entirely predictably, the latter group (27%) had a higher mortality rate, though a lower rate of rebleeding. This is a good study to illustrate the impossibility of drawing conclusions about clinical management from this type of observational evidence.
Why most new meds are junk
I recently had the pleasure of writing an analysis piece about drug regulation with Huseyin Naci, and here is another analysis from Huseyin in which he asks why the drug development pipeline is not delivering better medicines. The market value of the industry has grown from $203bn in 1990 to $506bn in 2010. But genuinely valuable new products are rare compared with me-too medicines and evergreening products. Having unexpectedly had quite close dealings with people from industry in recent years, I know that many of them would like it to be otherwise. But internal mechanisms ensure that marketing takes precedence over genuine innovation, and current systems of pricing and regulation provide perverse incentives. The authors conclude that “Concerted regulatory action is needed at the international level to reward the development of clinically superior medicines”. Concerted regulatory action at the international level… now that sounds like a good idea, for so many reasons and for so many things.
Dish of the Week: Kangaroo with nasturtiums
Kangaroo meat has appeared sporadically in British supermarkets over the past 20 years, but of late so rarely that when I saw kangaroo steaks for sale in Morrisons at two for £5, I pounced. Back at home, congratulations were muted. I was left with the challenge of cooking a kangaroo themed meal for one.
Generally speaking, it is a good idea to serve dubious meats in attractive ways. Or you can go to the opposite extreme, as when I once served fried rooks’ livers with raw sauerkraut, grapefruit, and whelks. I thought the roo steak might look nice on a large nasturtium leaf. Ours have grown to near dinner plate size this year, and the flowers also make nice hot eating with this beef-like meat. It was all very simple: the marsupial responded well to simple cooking on a very hot griddle with butter and a few scraps of shallot, deglazed with red wine, placed on the nasturtium leaf and decorated with a few wild mushrooms and flowers. Fit for a Governor General.