Richard Lehman’s journal review – 26 March 2012

Richard Lehman JAMA  21 Mar 2012  Vol 307
1161    When in Japan, do not attempt to drop down dead. In 800 fire stations around the Islands of the Sun, teams of emergency medical service personnel stand ready to rush out and perform resuscitation for out-of-hospital cardiac arrest, which cannot be discontinued until an ambulance arrives and you are taken to hospital, barely alive or truly dead. This non-randomized study of Japanese CPR shows that if the emergency team used epinephrine (adrenalin), your chance of having spontaneous circulation when you arrived in hospital would be 18.5%, and if they did not, it would be 5.7%. On the other hand, your chance of being alive at one month without major neurological impairment would be 1.4% if you had been given epinephrine, and 2.2% if you had not. So I think we can conclude that epinephrine should not be given during CPR. Next we need to find out whether out-of-hospital CPR should be given at all, since there is no firm evidence one way or the other.

1185   A lot of elderly people get deaf. Hearing aids can be useful, but this does not show up well in overall assessments of quality of life. Many deaf elderly people have other health problems which require a multidisciplinary team approach. I thought I’d tell you this in case you don’t have time to read this Clinician’s Corner piece, and didn’t already know.

NEJM  22 Mar 2012  Vol 366
1079   We’ve all been hoping for early wins in cancer genomics, but they are tantalizingly slow to arrive. With a few dazzling exceptions, cancer therapeutics moves through a painful grind of incremental progress. Here the investigators performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had acute myeloid leukaemia. They were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin, and the prognostic findings were compared with an independent set of 104 patients. Several gene loci were identified that predict response to this kind of treatment. And so the grind goes on: all credit to those who undertake it.

1090   And here’s a study of the Clonal Architecture of Secondary Acute Myeloid Leukaemia: more evidence that in cancer biology, complexity rules. Secondary AML is the kind that arises from myelodysplasia, and I can’t do better than quote from the abstract: “Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones.” In the new world of genomics, don’t look for simple mechanistic targets: look for fractal patterns, Fibonacci sequences, emergent properties, and all the other beautiful and dangerous things that make the crooked timber of humanity so interesting, and so hard to predict.

1099   The first trials of thrombolysis for stroke were carried out twenty years ago, but treatment with alteplase still occupies a marginal place in the everyday management of acute ischaemic stroke, despite efforts to encourage its use within the small window of benefit. But what if there were a thrombolytic agent that was nearly twice as good? This publicly funded Antipodean study compared two doses of tenecteplase with a standard dose of alteplase with just 25 carefully selected patients in each group. The higher dose of tenecteplase definitely produced the best results (72% v 40% disability-free at 90 days), but we need a bigger trial.

1108    When monoclonal antibodies were first produced, nearly 40 years ago, we were told to expect lots of magic bullets for a wide array of hitherto untreatable diseases. My whole working lifetime has passed by in those decades, and only a handful of my patients ever received treatment with a monoclonal antibody, usually with broad and unpredictable effects. High low-density lipoprotein cholesterol is a common biochemical finding, whether due to heritable causes or not. It is certainly associated with worse cardiovascular outcomes. So what might happen if we give people with raised LDL-C a monoclonal antibody to the enzyme which promotes LDL-C production? This enzyme is called proprotein convertase subtilisin/kexin 9 [PCSK9], but I don’t expect you to remember that. And the monoclonal antibody to PCSK9 is designated as REGN727/SAR236553 (REGN727), and I don’t expect you to remember that either. In fact I don’t expect you to remember anything about this study at all, except that the stuff reduced LDL-C levels in a few healthy volunteers and a few subjects with familial and non-familial hypercholesterolaemia, and did them no immediate harm. Or good. Now just keep this in the back of your mind, for the ten years of phase 2 and 3 trials that it will need to see if it’s safe and if it reduces events.

Lancet  24 Mar 2012  Vol 379
1103   According to the most recent post-mortem studies, the chances of a man of my age having localized prostate cancer are about 50-50. Whether it is detected or not depends on how many sharp instruments are repeatedly used to sample tissue via my rectum, which is why I am staying firmly seated. If I were truly worried, I think I would rather castrate myself, like some Early Father of the Church. Or I could take dutasteride, thus contributing to the profits of GlaxoSmithKline, who funded this trial and did most of the writing up. At three years the only difference I might notice would be an increased risk of sexual dysfunction. All other discernible outcomes would be much the same, but if I allowed the needle back up my rectum, less progression of my low-risk “cancer” might be found (hazard ratio 0.62, 95% CI 0.43-0.89). I am staying firmly seated, and I shan’t be asking my GP for dutasteride. Maybe just for lidocaine, in case I take the castration route.

1112   The nearest place to heaven on earth is New Zealand, but there is a serpent in this paradise (not literally: there are no snakes in New Zealand). There is guilt and inequality, even in this haven of non-violence and social progress. The white majority, descended mostly from British colonists of the nineteenth century, feel a legacy of bad conscience towards the Maori population, descended mainly from Polynesian colonists of the thirteenth century. Legend has it that all Maori people take their ancestry from just 13 individuals who survived the first journey in a boat that had lost its way. When British settlement began, they were deprived of much of their land by the Treaty of Waitangi, and barely survived extinction from European infectious diseases and economic domination over the next century. Born from fishers and hunter-gatherers, they have a “thrifty genotype” that helped them to get through times of famine, and their legends extol the low glycaemic diet of fish and moa meat that they kept to until white settlers arrived. This came just after the final extinction of the moa, a large flightless bird whose culinary qualities will remain legendary until someone manages to recreate it from surviving DNA. Clearly this is an urgent challenge for scientific gastronomy, but I digress. The point is that the Maori in New Zealand today, are showing increasing levels of hospital admission for acute infectious disease. Social deprivation and poor access to services play a part, and likewise their very high levels of obesity and hyperglycaemia, legacies of their ancestry in an age of abundant carbohydrates.

1142   “Large-scale randomised trials are urgently needed to inform how to best care for individuals with subclinical thyroid disease.” I would suggest that few things are less urgent than such trials on people with accidentally discovered borderline levels of TSH. But you may like to read this review and make up your own mind.

1155   Thyrotoxicosis on the other hand is definitely important, and it was the first diagnosis I ever made—at the age of 15 on the mother of a friend, who had a swollen neck and bulging eyes and shaky hands, like a description I had read in a chemistry textbook. She responded to surgery and carbimazole, and maybe radio-iodine. I don’t think there have been many advances in the 46 years since then, apart from beta-blockers for temporary symptom control: in fact this excellent review of the condition admits as much in its final paragraph.

BMJ  24 Mar 2012  Vol 344
I searched in vain for original research to inform your practice or your thinking in this week’s BMJ, but there is a gem of a piece by Lisa Schwartz and Steven Woloshin on the website, with the promise of more Not So Stories to come:

First an apology and retraction. Two weeks ago, I praised an MRC-funded study which claimed to show a clinically significant from continued use of donepezil or memantine in patients with moderate to advanced Alzheimer’s disease. Margaret McCartney pulled me up on this: although the study was conducted by good investigators and had no pharma funding, it still grossly overstated the significance and reliability of its results. These were tiny differences which would never be noticed by the patients (by definition) and scarcely by their carers, since the disease progresses inexorably whatever you do. If I had to fix a budget for my locality, I would rule out the use of these drugs in this population. And as soon as I return to the UK, I shall buy Margaret’s new book, The Patient Paradox: why sexed-up medicine is bad for your health.

But now to Steven and Lisa’s Not So Story. Re-enter donepezil, now off-patent at 10mg, but still patentable at 23mg for three years’ worth of lucrative sales, if only the U.S. Food and Drug Administration could be persuaded. There is actually a head-on study comparing the 10mg with the 23mg dose and showing no benefit and more adverse effects. So how did Eisai, the drug’s manufacturer, persuade the FDA to allow this formulation to be marketed? By the usual box of tricks—direct-to-public marketing, grossly misleading advertising to doctors, blatantly repeated on the labelling: all of which caused enough demand for the FDA to give way. Quis custodiet ipsos custodes?

The other good thing on the website is an editorial called “Putting Patients First.” A tired old cliché?  Maybe: but also the responsibility we carry now more than ever before, and the one thing that will save the NHS from the destruction willed upon it by politicians of every flavour. And this is a superbly written piece, arguing that everything we do should begin and end with the patient experience. Perhaps that is why it is behind the BMJ paywall, so that patients can’t read it and get ideas above their station.

Ann Intern Med  20 Mar 2012  Vol 156
405   Aha, here is the latest trial of a drug for type 2 diabetes, paid for by its manufacturers. This one is called Long-Term Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Receiving High Doses of Insulin: A Randomized Trial. Now, what do you as a prescribing clinician need to know about the “long-term efficacy” of a drug which you will be discussing with your patient who has type 2 diabetes? Well, obviously it would be nice to know it if reduces the likelihood of cardiovascular events, blindness, renal failure etc. over a period of say ten years. Efficacy would imply that it is cost-effective compared to other treatment options. And what do we have here? A 24-week study showing that it reduces HbA1c and weight in some patients taking large doses of insulin. “However, this study could not evaluate long-term effectiveness and safety concerns that have hindered approval of this drug by the U.S. Food and Drug Administration” mourns the Annals summarist. Ah well, perhaps the FDA has its uses after all.

Plant of the Week: Magnolia cylindrica

The magnolias of New England are suddenly all out at once, as their flower buds have been irradiated by sunshine at temperatures of 25 degrees or more. The overwhelming favourites here as everywhere are M kobus var stellata and M x soulangeana. They are lovely and fragrant and always welcome at this time of year, but just a weeny bit boring.

The magnolia I always most desired, and possessed briefly, is the one known as “cylindrica (of gardens)”. The “of gardens” is a sniffy botanical term implying that this may not be exactly the plant first described by its discoverer – in this case no less than the greatest of plant hunters, E H Wilson of Chipping Norton. Though this is a beautiful plant both in flower and in seed, it is actually very rare in gardens—in fact I have never seen it in one, except in my own, which soon became its graveyard. So do try to find M cylindrica (of gardens), but when you do, prepare a luscious bed of well-rotted dung for it, and keep it away from limy material of any sort. Send me photos of its lovely white flowers with their pink bosses, and it bright red seed pods in autumn. I shall then regard you with gratitude, mixed with faint and friendly resentment.