Richard Lehman’s journal review – 27 June 2011

Richard LehmanJAMA  22 June 2011  Vol 305
2525   Our understanding of the causes of the syndrome we label type 2 diabetes comes in dribs and drabs, and this study of the preventive effect of drugs given for rheumatoid arthritis or psoriasis on the incidence of diabetes counts as a drib; or perhaps a drab. The most protective drug seems to be hydroxychloroquinine, with a hazard ratio of 0.54, which may be due to direct action on the beta-cells; TNF-blockers also have a preventive effect (HR 0.62). Those searching for a drug to market for ‘pre-diabetes’ may find this exciting: for the rest of us, the answer is less likely to lie in toxic pharmacotherapy than in getting enough exercise, keeping reasonably slim and avoiding too much food with a high glycaemic index.

2532   Once people cross the magic threshold for diabetes by producing a fasting blood sample of 7mmol/L glucose or more, we try to prevent the risks of the condition by controlling blood pressure and glycaemia, knowing that this will do something to reduce adverse cardiovascular events. But what about the kidneys? We are told that diabetes is the leading cause of kidney failure in the developed world and that we should try to do better, which we interpret as giving more drugs. But the evidence base in favour of intensified BP or glucose-lowering treatment for renal protection is very poor, and overall we are not denting the problem at all, according to the latest data from NHANES III. The incidence of T2DM is increasing and the proportion developing renal failure is staying exactly the same in the USA. In fact as the proportion with albuminuria is falling a bit, the proportion with impaired creatinine clearance is rising a bit. Is albuminuria a surrogate of any value at all?

2540   Last week we learned that delays of 12 hours in transfer to emergency departments led to higher mortality in Californian patients with myocardial infarction. This study looks at something far more focussed: the effect of transfer times on patients with MI when they are shuttled from one hospital to another to undergo primary percutaneous intervention. We’re not looking at 12 hours here, but at a mean DIDO time of 68 minutes. This acronym does not refer to the abandoned Queen of Carthage from Virgil’s Aeneid Bk IV, but stands for Door-In,Door-Out. All transfer times over 30 minutes carry extra mortality, confirming that time equals myocardium, and that DIDO delay should be a cause for lament (I would suggest “When I am laid in earth”; set to Musick by Mr. Henry Purcell).

2556   Because “diabetes” is defined by a threshold level of fasting blood glucose, any drug that raises blood sugar causes “diabetes”. But do such drugs cause the progressive decline in beta-cell function and the increase in cardiovascular risk that we normally associate with type 2 diabetes?For example, thiazide diuretics raise blood sugar but reduce blood pressure, stroke, and heart failure. When you stop the thiazide, the blood sugar often returns to normal. It is now becoming clear that statins are associated with a small rise in “incident diabetes”, and this meta-analysis shows that it is dose-related. Still, the risk from a high dose of statin amounts to one in 500 to acquire the label “diabetes”, versus one in 155 to avoid a real cardiovascular event. It would be interesting to characterise further the outcomes of people developing “diabetes” while on high-dose statins. It is quite possible that many would have true progressive type 2 DM while others might remain static and perhaps revert to normoglycaemia if they stopped the statin. And in either case, it is events that matter, not labels.

NEJM  23 June 2011  Vol 364
2381   The primary prevention of anything should cause anxiety. If we go about it by screening, by immunisation, or by pharmacotherapy, the question is always the same – what is the cost and what is the harm?  As a result of this study, we could tell every woman over the age of 60 that by taking exemestane she would reduce her chance of getting breast cancer by 65%, with no evidence of long term harm or significant side-effects. Or we could tell her that she would have to take the drug for 3 years to stand a 1 in 94 chance of benefit, that we don’t really know the long-term effects, and that this would cost the NHS £100 per month. Both statements would be equally true.

2392    Tedious work, but somebody had to follow up 120,877 people for up to 20 years to help us understand what factors make Americans fatter by an average of 3.35lb every 4 years. I quote the increase in Imperial pounds because these are retained in the USA even in medical circles, and most readers probably remember that 1lb=0.45359237kg. Most readers will probably also remember that Sir Francis Drake first brought the potato to England, although he didn’t. These wonderful and various South American tubers are now the main dietary cause of obesity in the USA, according to this study. They are particularly delicious when deep-fried in oil – sorry, I meant to say pernicious, not delicious.  

2405    Now for some serious reflection on hepatitis C. If you can get access to the full text, begin on p.2429, and read through a typically thorough and informative NEJM clinical review of the topic, illustrated with a clinical vignette and artwork of psychedelic exuberance. Hep C, you will remember, is very common worldwide and leads to hepatic cirrhosis, fibrosis, and neoplasia in 15-30% of chronically infected people. In the UK we see it most commonly in intravenous drug users (45% are infected) and occasionally in people who had blood transfusions before 1992. Standard treatment with peginterferon and ribavirin produces mixed results – 52% of white patients and 28% of black show a response. But with the coming of boceprevir and telaprevir all this is set to change, so there is a nice upbeat air about this review and the two research papers. If your patient doesn’t want treatment now, relax: in a year or two even better drugs may come along. Meanwhile, the first study of telaprevir in treatment-naïve patients with chronic hep C shows a response rate of 69-75% in the two regimens tested against peginterferon-ribavirin alone, which here had a 44% response rate. This 26 week regimen is a major advance: as the review article states, ‘A sustained virologic response is associated with permanent cure in the vast majority of patients.’

2417   In a parallel trial of chronic Hep C patients who had failed to respond to standard treatment with peginterferon/ribavirin, or who had relapsed afterward, adding telaprevir showed even better success – up to 88% in one treatment arm. What a pleasant change from all those RCTs of lipid-lowering strategies which have to study huge atypical groups for many years to squeeze out some result of borderline statistical significance and no clinical relevance. Oops, I am running ahead of myself.

2439   More exuberant NEJM artwork alleviates the tedium of reading about n-3 fatty acids in cardiovascular disease. These pics are majorly groovy man, and worth sticking on the front of your exercise book. Sorry, I was just having an Austin Powers flashback moment. There is no other reason to wade through this account of feeble hypotheses and bad trials, except to note that you must eat as much fish as you can, up to the age when you would like to die suddenly. Because according to GISSI, fish oils do prevent sudden death. Perhaps on my 85th birthday I shall eat oysters, lobster, and turbot and then forswear fish forever, hoping to drop dead with a glass of champagne in my hand.

Lancet  25 June 2011  Vol 377
2181    I have grieved over the SHARP trial for many years. I first learnt of it from a friend who had just joined the Clinical Trials Support Unit at my home university of Oxford. I wondered that he should want to spend some of the best years of his life working on a trial that at very best could only yield results of borderline significance. I wondered that the unit, which has done so much good work in the past, should undertake a study designed to do no more than find a market niche for ezetimibe in patients whose cardiovascular risk is increased by chronic renal failure. Enough said: this study tells us nothing about ezetimibe except that it was safe for the duration of this study in this group of patients. The comparator should clearly have been a more powerful statin, anyone’s natural choice when simvastatin fails to produce enough LDL-C lowering. In real life it would be SHARP practice to use expensive, unproven ezetimibe instead.

2193   From time to time I have sat watching modern youths playing endless computer games in which they arm themselves with various kinds of ammunition and rescue a damsel in distress from the clutches of a Nazi/Soviet/Al Qaida unit hidden in a building with lots of stairs and doors and booby traps. At least that is what I think was going on: I usually doze off early on. I think the people who write the programmes for these games also design stent trials, because whenever I wake up in the middle of reading one, the sensation is exactly the same. Is bivalirudin hiding behind that pile of wood? Is that a paclitaxel-eluting stent that just went into the Tora Bora cave complex followed by an evil man in a turban? Where are the Gestapo hiding sirolimus? Do I really care? Gosh, it can’t be that time already.

BMJ  25 June 2011  Vol 342
Another area of permanent warfare in cardiology is the use of anti-platelet agents. A huge market awaits the pharma company which develops a drug which is better than aspirin, or at least that is better than clopidogrel. In the past I have called this the Quest for the Holy Grel, and readers who like this kind of thing can also feast themselves on a therapeutics article comparing clopidogrel and prasugrel; whereas in the PLATO study the competing grel was ticagrelor. The BMJ doesn’t often publish subgroup spin-offs of trials like this, especially not any which could conceivably be thought of as promotional: but if ticagrelor really is superior to clopidogrel in patients selected for non-invasive management of acute coronary events, then it is perfectly legitimate to point this out. Astra-Zeneca, who paid for the trial, are hardly likely to see this as a huge market opportunity. As for the Greek philosopher who gave his name to this trial, I am sure he would want to encourage a Symposium on the whole subject of antiplatelet agents and the non-invasive management of STEMI, preferably with the traditional accompaniments of wine, fish and flute-girls.

High risk prescribing in primary care patients particularly vulnerable to adverse drug events – get squirming, because we GPs are all guilty. This Scottish study is worthy but unnecessarily dull because it does not tabulate its data. And of course it cannot cover the entire range of our malfeances. Many more studies are needed – my favourite would be a survey of co-prescription of drugs causing serotonergic toxicity. I hardly do a single session out-of-hours without seeing a patient who is taking a serotonin reuptake inhibitor alongside a contra-indicated drug such as tramadol, trazodone, or a tricyclic antidepressant. No wonder so many of them are jittery.

Ann Intern Med  20 June 2011  Vol 154
781    A great deal of the clinical decision-making we do is dependent on accurate measurement of the blood pressure. I spent a few years trying to deduce what this actually meant from the literature as it stood in the mid-1990s, and concluded that we scarcely knew what we were doing. We were given an ambulatory BP monitor for use in a research project, which we held onto and used for many years. But the literature about ABPM versus office readings was confusing then and is not much better now. On the other hand, a single office reading is never good enough to warrant a change in treatment, even if a QOF reminder desperately urges us to make one. This study makes the case for home readings as standard procedure. And the accompanying editorial makes a powerful case for a complete overhaul in our sloppy standards of BP measurement.

798   Last week’s excellent review of appendicitis in the BMJ made little mention of multidetector CT scanning as a diagnostic tool, which rather reassured me as I find the doses of radiation involved in this procedure quite alarming. Unfortunately it is a good diagnostic procedure, as this single-centre prospective US cohort study demonstrates. The temptation will be to do CTs on every adult coming in with suspected appendicitis, for medicolegal reasons if not clinical. If this happens, I think we might need a tattoo to accompany each CT so that nobody is exposed to more than say 3 Sv in a lifetime. (A little test: explain the relation between rads, rems, Grays and Sieverts).

Fungus of the Week: Stropharia rugosoannulata

A fungus already? I’m afraid so, as I write from New England where they are coming up in abundance after days of thunderstorms. Most of them are amanitas and russulas of dubious edibility, but this stropharia is a prized esculent and is even grown commercially. So I was very pleased indeed when I found one this afternoon, and I have just eaten it on your behalf and can pronounce that it meets expectation. I must now hasten to complete the links and send out these reviews before I succumb. All British stropharia species are small and poisonous, by the way.

I should really be telling you all about the wonders of New England trees and shrubs, forests of oak and maple with an understory of sassafras and sumachs: but these must wait for another time. There are plenty of plants to enjoy in Old England at this time of year, and English gardens are much more richly stocked than most American ones, especially with good roses. But the fungi in eastern America surpass expectation.