Richard Lehman’s journal review – 28 March 2011

Richard LehmanJAMA  23-30 Mar 2011  Vol 305
1165   In 1941, there was a rumour that the Germans were buying up large quantities of bovine adrenal glands from Argentina so as to produce a substance that boosted the flying powers of Luftwaffe pilots. Intense efforts to isolate this substance followed, but the war was long over by the time they resulted in the identification of Compound E, first used with miraculous effect on a patient with rheumatoid arthritis in 1948. Since that time, cortisone has been used as a definitive or adjunctive treatment for practically all know human ills. In this trial it was given as hydrocortisone 200mg daily to patients intubated for severe trauma and it resulted in a lower rate of ICU-acquired pneumonia. This French study is named for St HYPOLYTE, whose severe trauma resulted from having his limbs torn off by attachment to four competing dray-horses (one of many legends and many spellings). Compound E and ICU could have done nothing for him but he did gain instant admission to heaven.
1210    About ten years ago, I read the first accounts of cardiac troponin measurement and asked why this test was not universally available in British hospitals. Within a year it was – not that my jottings had the least part in that: it was simply and clearly the new gold standard for diagnosing cardiac muscle damage. I think this was the fastest adoption time for any diagnostic test in the last 30 years. It resulted in a new stratification of myocardial infarction, into STEMI and NSTEMI – the latter being troponin-positive without elevation of the ST segment – and hence a new epidemiological and clinical definition of MI. But all this was based on an arbitrary cut-off level of troponin. We know that any release of troponin into the blood must indicate at least damage if not death in cardiac myocytes, and sure enough, its prognostic value does not obey any cut-off. This study shows the clinical importance of this: ” In patients with suspected ACS, implementation of a sensitive troponin assay increased the diagnosis of MI and identified patients at high risk of recurrent MI and death.  Lowering the diagnostic threshold of plasma troponin was associated with major reductions in morbidity and mortality.”

1217   What do microalbuminuria, serum cholesterol, and blood sugar have in common? Why, they are all cardiovascular risk factors – and so lowering them is bound to lower cardiovascular risk. Wrong. It is perfectly possible to lower any one of these and increase CV risk – or to have no effect at all, other than incurring cost and adverse effects. The latter has been shown to be true of fenofibrate, definitively in the FIELD trial, published in 2004. So did sales of branded fenofibrate in the USA show a sudden decline around 2004-5? No, they showed a steady increase which continues to this day, despite further evidence of futility in the ACCORD study (2010), where fenofibrate was used in combination with statins. In Canada usage of this drug remained static. Harlan Krumholz, who helped to supervise the study, likes people to do their own thinking  Lots of US doctors, and some British ones, need to think why they are using this stuff at all.

1225   What do sexual intercourse and clearing snow have in common? In medical anecdote, they both trigger acute cardiac events, and this meta-analysis shows that  medical anecdote is right. Mind you, I seldom get very excited when clearing snow.

NEJM  24 Mar 2011  Vol 364
1093    Here is an interventional trial for moderate-to-very-severe chronic obstructive pulmonary disease which may change your practice, so it is worth getting hold of and reading carefully. It shows that once-daily inhaled tiotropium reduces exacerbation by more than a quarter compared with salmeterol. That has to be significant. Now consider how you might have gone about doing this randomised study yourself. Probably you would have included a few hundred patients from your own practice, and recruited another few thousand from a few other group practices, say in Glasgow. After all, the point of studying  COPD is that it is common and managed mainly in primary care. You might wish to recruit only from practices which had high rates of smoking cessation, as this by far the most important intervention in COPD, and the only one which makes a survival difference. Now actually this study – POET-COPD – recruited ten patients per centre in 725 centres in 25 countries. Half of them continued to smoke. As a result of this trial, pretty well all of them will now be taking inhaled tiotropium at whatever cost the trial’s sponsors, Boehringer Ingelheim and Pfizer, decide to charge – just over £1 a day in the UK at present. So if everybody in the UK with COPD used tiotropium, this would bring in £3 million per day. This might do some good to some COPD patients. It would certainly do no harm to Boehringer Ingelheim. And don’t forget that tobacco companies make profits too: support the world economy by buying shares in both.

1104    This is like a bad DREAM. In the DREAM study published in 2006, people with a fasting blood sugar in the zone between 5.3 and 6.9 were given rosiglitazone, which reduced their blood sugar by around 0.8mmol/L, so reducing the percentage of them crossing the line we set at 7 mmol/L to define  type 2 diabetes. The beauty of this approach is that you can scare vast numbers of people into taking a drug to prevent a “disease” that most of them would never have got anyway. If your drug happens to do more harm than good, like rosiglitazone, you will therefore end up killing people for the sake of an arbitrary biochemical threshold. Pioglitazone is a less dangerous drug in the same class, and “prevents diabetes” in exactly the same meaningless way. This Takeda-funded study shows no evidence that it does any objective or lasting good, but plenty that it causes weight gain through fat deposition and oedema.

1116    Toenail clippings – now they are what I call hard science. Not only do they support the noble profession of podiatry, but they can also be used to measure an individual’s level of mercury exposure. The problem is that so few people pay due attention to the scientific value of their toenail clippings: mine, for example, are either lost in the pile of the bedroom carpet or harvested to make plant compost. I will therefore never know the amount of mercury I have ingested from the regular consumption of turbot and all the other kinds of fish which are supposed to endanger us from their concentrations of methylmercury. But fortunately, through the wise foresight of medical researchers, the toenail clippings of no fewer than 173,000 Americans have been diligently preserved over a number of years: analysis of them shows absolutely no correlation between levels of ingested mercury and cardiovascular disease. One less thing to keep you awake at night.

1144   I try quite hard on your behalf, dear reader: but I cannot report success with pharmacogenomics. There are two papers in this week’s NEJM which give separate HLA loci for carbamazepine-induced reactions in Taiwanese and European populations. Time and again I have troubled you with such accounts. They point to heartbreaking amounts of mass labour by gene gnomes in their caverns, lit day and night by fluorescent strips and banks of monitor screens, all in order to identify some new gene loci that fail to account for most of the response variation to drugs like warfarin or clopidogrel. Just about the only time their efforts bear real clinical fruit is when they turn their attention to the genomics of particular lines of malignant cells. Anyway, here is an authoritative review of Genomics and Drug Response, in free full copy from the New England Journal: choice entertainment for a spring afternoon.

Lancet  26 Mar 2011  Vol 377
1077   There are lots of attractive features about this trial: it addresses an important question, how to assess chest pain quickly and safely, and brings together the medical communities of several countries around the Pacific basin, using commonly available diagnostic tests and decision aids. Don’t try this at home though: you need a TIMI score that incorporates near-patient troponin testing, an ECG machine and a crash team in case something goes wrong. But although this decision rule sequence successfully identified people at very low risk of a serious cardiac event, they only comprised less than 10% of the cohort. And spare a thought for the dedicated principal investigator who comes from Christchurch, New Zealand, where no doubt his hospital remains damaged and overcrowded.

1085    Allowing oneself a little added girth seems to me one of the compensations of old age, and that is borne out by this interesting analysis of 56 prospective studies which looked at the contribution of body mass index, waist circumference and waist-to-hip ratio to risk of first-onset cardiovascular disease. Surprisingly, measures of fatness make almost no difference to risk beyond that predicted by age, sex, smoking status, diabetes, systolic blood pressure and blood lipids.

1103   A nice clear and comprehensive seminar takes us through all that is known and can be done for ventricular septal defects. Open patching on cardiopulmonary bypass has been done for 50 years, and remains the standard cure for those who need surgery – unfortunately the ingenious closed-heart procedures that have been devised all carry an unacceptable risk of complete heart block.

BMJ  26 Mar 2011  Vol 342
692   Two years ago, I got sucked reluctantly into public debate about the therapeutics of type 2 diabetes: I had come to realise that this an area of medicine where what we know bears no relation to what we need to know. All that has happened – and not happened – since then has increased my dismay. Tens of millions of people around the world take thiazolidinediones to reduce their blood sugar: so far all we know is that rosiglitazone increases cardiovascular risk, and that pioglitazone is a bit safer, though it is far from clear whether the small decrease in glycaemia that it achieves is matched by any improvement in patient-important outcomes. That much is clear from this systematic review and meta-analysis of 16 observational studies. Yet this week we also saw the publication of the preposterous pioglitazone “diabetes prevention” trial in the NEJM. Thank goodness for people like Kasia Lipska and Joe Ross in JAMA a couple of weeks ago, and Victor Montori and Nilay Shah in the editorial which accompanies this piece, who are prepared to speak out about the scandalous prevailing situation in which we know a lot about what drugs do to levels of glycated haemoglobin, but practically nothing about what they do to people with diabetes.

693   Statins reduce the risk of myocardial infarction; they have a slight effect on ischaemic stroke: for a time I wanted to believe that they prevented osteoporosis, several cancers, and a few other things that I have now forgotten, as they do not improve memory either. Also, they do not reduce atrial fibrillation. Carry on taking them all the same.

696   I have never managed an adult patient who needs home parenteral nutrition, and now I never will. But you might, and here is a nice clear, well illustrated Clinical Review to help you do it.

Ann Intern Med  15 Mar 2011  Vol 154
384   As I’ve told you many times, when you see a study with a title like “What distinguishes top-performing hospitals in acute myocardial infarction mortality rates?” in a top American journal, you can be pretty sure of seeing the name of Harlan Krumholz among the authors. See, for instance, this week’s JAMA. But wait, what have we here? This is a qualitative study – and a good use of qualitative methodology it is too: the difference between high performing and low performing hospitals is one of shared attitudes, not declared aims and methods. In fact it’s a marriage of quantitative research into the what – the hospital results – and qualitative research to produce human insights into the why. Nice.

401   When you call in a man to look at your central heating pump he does two things: he checks the electrics and makes sure that the pump is still circulating water. When treating a patient with heart failure – especially a younger person – it’s worth thinking in the same way. Is this pump in electrical synchrony? And is it getting enough oxygen to pump properly? A high proportion of people with HF will benefit from dual chamber pacing or resynchronization therapy – and this meta-analysis shows that it benefits people with mild symptoms as well as those in dire trouble. Remember revascularization of hibernating myocardium as well.

Plant of the Week: Prunus cerasifera “Pissardii”

This tree was something of an English Edwardian favourite, a purple-leaved and pink- flowered cultivar of the European wild cherry. I must say that I prefer it to almost all the blowsy Japanese hybrids which shout from suburban front gardens at this time of year. It is of slightly scruffy habit and grows to 10m or so over a century or more. Particularly lovely when surrounded by blue scillas or chionodoxas.