Richard Lehman’s journal review – 15 November 2010

Richard LehmanJAMA  10 Nov 2010  Vol 304
It’s not often that you see a paper in JAMA written by a real working British GP – so congratulations to Louis Levene from Leicester for an excellent study that seeks to inform US practice by showing what happens to coronary heart disease mortality in relation to the recorded characteristics of individual primary care trusts. This was quite a statistical feat in itself, but would have been even more useful had it been done on an individual practice basis – after all, the data are out there, literally for all to see. Anyway, rejoice: CHD in the UK has fallen by nearly a half in the last decade, and although there are regional variations, these are not due to variations in the quality of general practice, except in the detection of high blood pressure. Which could easily be remedied.

In this cohort, obesity in adolescence was significantly associated with
increased risk of incident severe obesity in adulthood,” say the authors. This cohort was the US National Longitudinal Study of Adolescent Health, 8834 kids followed up into adulthood, and the hazard ratio was 16; so “significantly associated” means “almost inevitably,” just as one feared.

The latest contribution to JAMA’s great Rational Clinical Examination series asks Does This Patient Have Malaria? You know the answer already – if there’s any need to ask the question, do at least one peripheral blood film. So why do an exhaustive literature trawl to find out all that is known about the predictive value of every clinical feature of malaria? Partly because it has never been properly done before, and partly because there are thousands of health workers in Africa and Southern Asia who have to decide when to treat for malaria in the absence of laboratory testing. As this paper proves, that is never a safe procedure: you cannot rule in or rule out malaria by any combination of history and examination, and the predictive value of these varies enormously according to local prevalence.

A neat Commentary piece discusses the dilemmas of interventional cardiology in the light of the COURAGE and SYNTAX studies which show that medical treatment is as effective as percutaneous coronary intervention for stable coronary artery disease. When the first study appeared in 2007, I asked if interventional cardiologists would now have the conviction of their COURAGE and stop putting stents into every stenosis they happened to see at angiography – what has been described as the “oculo-stenotic reflex.” All immediate stenting is lumped together as “ad hoc PCI” and accounts for more than 80% of PCI in the USA; done for acute syndromes, it is generally appropriate, but in other situations, often not. This is a thoughtful, balanced discussion which however tactfully bypasses one factor which may keep ad hoc PCI going in the USA – money. There may be a double incentive – patients and HMOs may want to save the cost of a second angiography; and cardiologists and their institutions may just want the extra dollars they get for putting in a stent there and then. This piece argues that there where there is clinical doubt there should always be informed patient decision-making, even if this means taking a two-week pause between the diagnostic angiogram and the procedure.

NEJM  11 Nov 2010  Vol 363
Romiplostim is a name that inspires me with thoughts of The Pelican Chorus by Edward Lear:
King and Queen of the Pelicans we;
No other Birds so grand we see!
None but we have feet like fins!
With lovely leathery throats and chins!
        Ploffskin, Pluffskin, Pelican jee!
        We think no Birds so happy as we!
        Plumpskin, Ploshkin, Pelican jill!
        We think so then, and we thought so still!

Romiplostim is, you may recall, a thrombopoeitin mimetic which is used in the treatment of immune thrombocytopenia and so a year or two ago I wrote a new stanza for this magnificent poem which goes:

They told us he had ITP;
His platelet count was very wee –
Doctor, I thought we’d nearly lost him,
But then they gave him romiplostim.
     Plostim, Pluffskim etc

In this trial, they’re still trying to establish a clear role for this drug in the treatment of ITP; given that it’s very expensive and needs to be given indefinitely, it will probably remain a second-line treatment for some time – see the editorial. Also, there is a rival orally available drug with an even sillier name: the platelet colony stimulator, eltrombopag. You might wish to recollect my verses on this too, ending Eltrombopag! Eltrombopag! O keep it in your doctor’s bag! Or, on the other hand, you might not.

The incidence of type 1 diabetes is rising, and more so in Finland than anywhere else. There are genetic factors which are HLA-linked, and the process is associated with the formation of beta-cell autoantibodies, but neither is sufficient without some environmental factor which may be dietary. Hence this far-sighted study of 230 newborn Finns with a strong family history of type 1 diabetes who were randomised to get either conventional cow’s milk derived feeds or a casein hydrolysate formula, when not breastfed. In fact the study was not powered to show a difference in the incidence of type 1 diabetes over the next ten years (which was 7 in the hydrolysate group and 9 in the conventional feed group) but it did show a halving of the incidence of beta-cell antibodies in the hydrolysate group.

The pharmacology of clopidogrel suggests that its effect might be cancelled out by omeprazole, and this happens in lab studies but not, it seems, in real life. The COGENT study was funded by Cogentus Pharmaceuticals to test out a fixed dose combination of clopidogrel with omeprazole 20mg versus clopidogrel alone in patients being started on dual antiplatelet therapy – i.e. taking aspirin as well. Cardiovascular events were similar in the two groups – though statistical power was inadequate – while those receiving omeprazole had fewer gastrointestinal bleeds. The chief casualty was Cogentus Pharmaceuticals itself which filed for bankruptcy in January 2009, so this trial was stopped prematurely “when the sponsor lost financing.”

This carefully conducted study of surgeons in the Netherlands confirms the astonishing fact that you can halve surgical mortality by making surgeons adhere to checklists. The drop is small in absolute terms – from 1.5% to 0.8% – but immensely impressive all the same. The editorial helps to explain the reasons why and to put it all the available study data into context. There is an unanswerable case for making surgical checklists universal and compulsory. Eleven checklists containing nearly a hundred questions may seem like bureaucracy gone mad, but I suggest you insist on them before you next sign a consent form to go under the knife.

Lancet  13 Nov 2010  Vol 376
One of the compensations for spending every weekend for the last 12 years commenting on the main medical journals is being able trace the course of medical progress. This is rarely an unmixed pleasure – in the case of malaria, for example, we are talking about a disease which would have been eradicated in the mid-1960s had the superpowers not decided that trips to the moon and weapons of global destruction were more important. However, in the 1990s there was much excitement about the herb Artemisia annua which had been used for centuries in western China to treat fever, and which by a happy coincidence actually cured malaria. Production of various artemisinins proceeded apace, but it has taken until now to prove that intravenous artesunate is superior to quinine in the treatment of severe falciparum malaria in African children.

A huge trial called SEARCH was set up in Oxford in 1998 in the hope of demonstrating that 80mg of simvastatin would be better than 20mg at preventing further coronary events in survivors of MI, and that additional benefit would result from lowering homocysteine. In fact it has shown neither. The high dose simvastatin group showed a 26-fold increase in significant myopathy, an expected fall in lipid cholesterol (LDL-C), but no significant difference in vascular events at a mean of 6.7 years. Yet in the summary this is taken to mean that high dose simvastatin is preferable, since that fits into a general meta-analysis of statin trials on p.1670. Now medicine has been taught alongside logic in Oxford for 850 years, but I think there is still room for improvement. Consider the following three statements:

  • there is a continuous association between the observed level of LDL-C and coronary heart disease (CHD)
  • all statin drugs lower LDL-C
  • all statin drugs lower CHD in the same proportion that they lower LDL-C.

Does it therefore follow that:
1. statin drugs lower CHD entirely by means of lowering LDL-C
2. all drugs that lower LDL-C will lower CHD to the same degree as statins?
I would like to think that any canny medieval Oxford schoolman would immediately answer no to both deductions. Or rather quod non erat demonstrandum. In the case of (1), the best we can say is that this is a reasonable hypothesis, but a hard one to test. In the case of (2) we can say that this is a weak hypothesis, since every drug class has a mixture of actions, and so far no LDL-C lowering drugs other than statins have been shown to lower CHD. Nor should we prescribe them until they have. But the writing committees of these two studies, sharing a number of Oxford notables, behave more like theologians than logicians. LDL-cholesterol to them is an infallible surrogate, and anything that lowers it must be good, even though they have only studied statins. It’s enough to make you want to burn your gown. As for The Lancet: this is the second time in two weeks that they’ve let triallists write a summary which misrepresents the result of trial which was negative for its primary end-point (SEARCH this week, VITAL last) – not good enough.

BMJ  13 Nov 2010  Vol 341
Do you like PROMs? When I was 16, I didn’t mind queuing for tickets outside the Albert Hall and standing in the top gallery, but now I buy tickets on-line so we can sit down and actually hear the players. But I hadn’t realised until quite recently that this abbreviation also applies to patient-reported outcome measures, of the kind I used to look at in the context of heart failure. Suddenly these kinds of PROMs have become fashionable politically and get repeated mention in the White Paper “Liberating the NHS” – although they were never designed for service development but as end-points for clinical trials. Their quality and relevance varies widely, as I’m learning rapidly. This ground-breaking study devised an instrument with a high degree of inter-observer agreement to allow the assessment of PROMs in cardiovascular trials. Suffice to say that in many of the trials where they appear, they are used badly or irrelevantly, while in 70% of trials where they should appear, they don’t.

When drafting a topic list for the BMJ “Easily Missed?” series, subarachnoid haemorrhage came near the top, because a study ten years ago showed that 50% of SAH was not spotted at first presentation to a UK GP. This is 40% too much (there will always be a few atypicals and outliers that nobody can spot). Clinical decision rules for such a condition, however, should have a sensitivity of 100%, and these three from Canada achieve that. Oddly enough, sudden onset does not feature in any of them. And I had not realised that SAH is rare before the age of 40, despite my helping to commission and edit the Easily Missed article, which should be read alongside this one.

Population screening for chronic kidney disease was foisted on UK primary care four years ago, without any proof of clinical relevance or cost-effectiveness. A tenth of the healthy British population now exist in a new state of “disease” which makes no sense whatever, in terms of anything, including economics as analysed in this Canadian study.

The surgical checklist that halved operative mortality in the Netherlands involved nearly a hundred items (see NEJM above), whereas this study in an Oxford surgical emergency unit is called Lean. Lean by name and lean by nature – it’s a short, sensible checklist, and the outcomes in this report are to do with process rather than clinical outcomes. So far, so good. But still insist on the big list before you go under the knife.

Arch Intern Med  8 Nov 2010  Vol 170
Delay From Symptom Onset to Hospital Presentation for Patients With Non–ST-Segment Elevation Myocardial Infarction. If you’re a veteran scanner of titles in the US cardiovascular outcomes literature, the next thing you’ll look for is the name of Harlan Krumholz in the authors list – ah yes, there it is, and so too is the name of Brahmajee Nallamothu, co-author of the thoughtful commentary piece on PCI in this week’s JAMA. As a result of their work, and that of Henry Ting and John Spertus, who also appear in the credits, we know a huge amount in great detail about the workings of acute cardiology in the USA, despite the great variety of institutional arrangements. As a result of this exercise, for example, we know the exact time delay and clinical characteristics of 104 622 patients admitted to 568 US hospitals with NSTEMI – and realise that there has been no reduction in the delay time between 2001 and 2006.

Now the interventional trials for ST-Elevation MI tell us that time means myocardium, so great efforts have been made in the US as in the UK to ensure that door-to-balloon time should be as short as possible. But what have we here? A study of 8771 patients admitted to a Michigan hospitals group between 2003 and 2008 which shows that although door-to-balloon time improved dramatically, outcomes remained the same. More data from UK studies quickly please: and since  we do not have 568 acute hospitals and they all belong to one organisation, this should be a piece of cake compared with Harlan’s work. 

From time to time, serious medical journals like to publish pieces about chocolate, which are sure to get them a mention in the global news media. This research letter also involves women, thus allowing journalists to trot out their very funny jokes about the dear ladies and their chocolate. A group from Perth, Australia followed up a female cohort for 10 years to examine the effect of calcium supplements, and happened to ask about chocolate intake in their questionnaire. Here they report that chocolate consumption seems to have a dose-related protective effect against vascular disease in women. Ooh, come on girls, have another.

Fungus of the Week: Cantharellus infundibuliformis

The main fungus season is coming to an end, but if you are lucky like me and know a wood which contains this fungus, then you can go on another few weeks looking for these and for wood blewits. These little brown fungi grow in huge abundance in some places, and with great regularity, so once you know the spot, you can come back every year. The trick is to spot them in the first place. Mossy places in mixed woods are best.

They are known as autumn chanterelles, and their hollow yellow stems, wavy edged caps and rubbery texture make them hard to confuse with any other small brown fungi. They rarely harbour larvae and keep well in the fridge. The best thing is that they dry very easily and successfully so if you find them by the thousand – a common occurrence – you can preserve them for all-year use. In fact the dried ones often taste better than the fresh They are versatile and go very well with fish. When you next find a nice turbot, compose a sauce of leeks and wine and cream and incorporate in it some fresh or reconstituted autumn chanterelles. Fishy heaven.

P.S. I am in the job of collecting patient experiences at the moment, but didn’t know of any about surviving amanita poisoning until this piece by Richard Eshelman appeared in the Guardian Saturday magazine: Read and heed!