Richard Lehman’s journal review – 23 August 2011

Richard LehmanJAMA  17 Aug 2011  Vol 306
711   Randomized controlled trials of new interventions have become something of a rarity in JAMA of late, so I was interested to see this account of two industry-funded trials of pegloticase, a genetically engineered uricase designed to lower uric acid in people with treatment-resistant gout. This drug already has FDA approval, presumably because they were convinced that it might be of benefit to a proportion of the 3% of gout sufferers who don’t respond to other methods of uric acid reduction. The small trials described here were done in 2006 and 2007 and they reveal that pegloticase lowers uric acid in fewer than half of these patients and doubles gout attacks in the first six months of treatment: we don’t know what happens beyond that. Infusion reactions were common and nearly all the patients developed antibodies to pegloticase, sufficient to neutralise any benefit in over a third of treated patients within the six month trial period. A pretty lousy drug by any standards, with unknown long term effects, and available to all Americans now thanks to Savient Pharmaceuticals and the FDA.

754   Medicine can’t go on the way it is – every thinking person agrees on that, especially in the USA, which manages to combine massive health expenditure with dismal hard outcomes. Yet in the face of the world economic crisis and global overpopulation, we go on doing more of the same. In my home university of Oxford, for example, the Regius professor called last week for a much bigger focus on genomic research, while the Clinical Trials Support Unit has taken a huge grant from pharma to run a trial of yet another lipid-lowering agent. But what the world needs is a vision of patient-centred medicine based on hard outcomes, and this is what Harlan Krumholz sets out here. This short piece – real world imperative of outcomes research – is a must-read for anyone who cares about the future of medicine.

756   The chief agency for change in the USA should be a new body called the patient centered outcomes research institute, but at the moment it lacks a clear agenda. This piece is about the challenges it faces, and it illustrates the problems all too well. It lacks focus and meanders from a general discussion of bench-to-bedside research to a specific complaint that doctors don’t prescribe enough thiazides for hypertension following ALLHAT. Hang on, what has all this to do with patient centred outcomes research? That’s not about benches, it’s not even about bedsides, it’s above all about free living individuals making rational choices about their treatment based on the outcomes that matter most to them.

762   This New Medicine, based on patient important outcomes, is not going to be easy. I am trying to compile a book about it with four keen young doctors and the problems and the gaps are huge. This editorial focuses on the mismatch between variations in processes of hospital care (Medicare’s 25 process metrics) and outcomes of care. If you look at enough hospitals, both tend to have a normal (Gaussian) distribution, but with rather poor correlation between the two bell-curves. And then there is cost…

NEJM  18 Aug 2011  Vol 365
591   Intra-operative awareness during anaesthesia is a rare but terrifying prospect, like being buried alive. As a friend has written, the idea of having to lie there helplessly and listen to several hours of surgical banter is enough to put anyone off ever having an operation. One theory was that this is due to some patients having a blunted response to anaesthetic agents, but this trial effectively rules that out. Awareness during anaesthesia correlated less with changes on an encephalogram than with measured end-tidal anaesthetic gas concentration. Give them enough gas and they’ll stay asleep.

601   It’s deepest mid-August and so what tends to be put out in the journals is peanuts. The role of the humble ground-nut in American civilization may have diminished somewhat since it peaked in the peanut-butter-and-jelly heyday of the 1950s, but contaminated peanuts still have the power to poison large swathes of the US population. A single peanut- crunching factory caused an outbreak of Salmonella typhimurium disease across 46 states from sea to shining sea – all carefully described in this paper, a classic in the archives of detective epidemiology.

Lancet  20 Aug 2011  Vol 378
667   This week’s Lancet is devoted largely to heart failure, described in the opening editorial as a “dangerous, debilitating, and common disease, subjecting patients, carers, and doctors to a substantial burden.” But really CHF is not a “disease” but the final common pathway of a number of diseases, a pathway that leads inevitably to death. A patient-centred view of heart failure will therefore take account of the patient’s desire to stay alive or to lead a more tolerable life, and the trade-offs between the two. It has been known for over ten years that most patients with HF, being over 70, value quality of life over quantity*; yet very little HF research reports on symptomatic benefit rather than mortality and rehospitalization, despite the existence of at least 5 well-validated symptom scores. All this is just a preamble to two studies of a new inotrope for heart failure, omecamtiv mecarbil. This has a fascinating new mode of action on the actin-myosin interaction of the cardiac myocytes, and I wish it well. These studies were not designed to assess its clinical benefits, just its safety and dose range. It will never be used in the community, because it has to be given intravenously. But if it is the precursor to oral drugs that make people with heart failure feel better while shortening their lives (like all previous inotropes), then this is a valuable advance, and just what many HF patients would like to choose.

*in fact that has been known in general for over 3,000 years: see Psalm 90 (attrib Moses):
10. The days of our years are three-score years and ten: and if by reason of strength they be fourscore years, yet is their strength labour and sorrow: for it is soon cut off, and we fly away.

684   I do wish I didn’t have to report on this study called MESA, which alludes to another study called JUPITER, because it treads on all my corns. High-sensitivity CRP is a useful new predictor of cardiovascular risk, right? No, no! – it is neither new nor usefully predictive. We need better ways of determining which people should be given statin therapy for life, right? No, no! Statins are cheap and beneficial and if they give people muscle pains, they can be stopped. So we should use coronary artery calcium measurement by CT scanning to determine which people don’t need to take statins, right? No, no! Because you will be using huge amounts of money and radiation, and generating population-wide anxiety, all in order to save about 10% of the target population from taking a cheap and harmless drug. Now go away.

704   Four reviews of heart failure topics now ensue. They aren’t all that good, and the last, on telemonitoring in HF, simply flies in the face of the evidence. The first one deals with advances in basic science. I don’t wish to decry this work though I don’t suggest that anyone but a superspecialist should read this paper. The bench-to-bedside model will work this way: a new pathway will be elucidated (3-5 years); a drug which enhances or blocks this will be developed and tried on an animal model (3 years); Phase 1 and 2 human trials will follow (2 years); then clinical phase 3 trials (5-8 years) on patients with heart failure, mostly male with reduced EF, lying in Veterans hospitals and already on four different HF drugs. Some tiny benefit in a composite outcome of death and rehospitalisation may or may not result; if the trial is quite exceptional, it may use some patient-reported outcome measures too. I dare say we need this kind of research, but we so much more urgently need research on what helps make living and dying with HF more tolerable for our patients here and now.

BMJ  20 Aug 2011  Vol 343
More about outcomes research, I fear: I fully intend to become a bore on the subject. Surgeons were among the first to report on their outcomes (as individual case-series), and as far back as 1913, Ernest Codman was calling for the public reporting of end-results of surgical procedures in hospitals. We are still learning how to do it. Here no less a surgeon than Lord Darzi himself has a go at analysing variation in reoperation after colorectal surgery in England as an indicator of surgical performance. Our one-time czar and master is surprised at how much variation there is and how little of it correlates with procedure volume: 

“Even at a high caseload, however, there was substantial variation in both the trust (hospital) and surgeon team reoperation rates. There was a fivefold difference in highest and lowest reoperation rates after elective surgery (14.9% v 2.8%) among the surgical teams performing >500 procedures. There was a threefold difference in reoperation rates in trusts performing >2500 procedures during the study period (11.5% v 3.7%).”

Bell-shaped plots again. And how rarely complex systems behave simply. Welcome to our world, Dear Leader.

Ann Intern Med  16 Aug 2011  Vol 155
217   The encouragement of good clinical research in China is vital for the progress of medicine, and it’s even possible that Chinese traditional remedies might yield occasional useful discoveries. Artemisia annua for malaria is an often cited example, though in fact the Chinese used it for almost everything except malaria. Maxingshigan–yinqiaosan, as some readers may know, is a popular Chinese remedy for influenza. The popular Western remedy is oseltamivir. This trial compares one with the other or with both or nothing, and the primary end-point is time to fever resolution in laboratory-confirmed H1N1 influenza. So far so good. It’s mildly interesting that maxingshigan–yinqiaosan and oseltamivir achieved about the same 19% reduction in fever time and had made no difference to symptom scores, i.e. these are clinically useless interventions with barely detectable antipyretic effects. But if Chinese RCTs are to get into reputable journals, they really should go in for a bit of double-blinding. This one wasn’t even single-blinded.

Fungus of the Week: Lepiota procera

The true field parasol mushroom is beautiful to look at and delicious to eat, but I’ve had decidedly little luck finding any in Europe over the last 35 years. In fact the nearest I’ve come was in the covered market at Krakόw where there were piles of parasol caps about 15cm across, commanding higher prices than the neighbouring heaps of Boletus edulis. However, I have just found a couple growing by a sandy path in Connecticut.

The cap of this delicacy looks just like a parasol of pale creamy brown with darker ring-like ridges. These are even more marked in its cousin, the shaggy parasol. However, if you break open the flesh of the field parasol it remains white or very pale buff while the flesh of the shaggy parasol slowly turns bright orange. This is important because the field parasol is universally edible while the shaggy parasol can cause gastric upsets, despite tasting just as delicious. I can vouch for this, though in my case the upset tends to occur a little further down the intestinal tract.

These two large lepiotas are the only edible species to grow in Northern Europe. You can easily tell them from amanitas because their stems are thinner, taller, and tougher: also if you wobble the veil remnant about, it will move free of the stem. It is such a shame that nobody has worked out a way of growing them commercially.