Richard Lehman’s journal blog, 24 May 2009

Richard Lehman
Floppy iris, diabetes, virtual surgery, and blood pressure lowering are just a few of this week’s splendidly discussed topics in Richard’s blog.

JAMA  20 May 2009  Vol 301
Cataract surgery rarely goes seriously wrong, so when a number of older men were noticed to get complications due to floppy iris syndrome, ophthalmologists began to look for a cause. The iris, like the bladder neck, contains alpha 1a-adrenoreceptors which help to maintain muscle tone. The peak age for cataracts is also the peak time for benign prostatic hyperplasia, and in a Canadian cohort of 96 128 men over 65 undergoing cataract surgery, over 10% had been taking a-blockers immediately prior to surgery. But most a-blockers in this study, as in previous ones, come out quite innocent: only tamsulosin doubles your risk of cataract surgery complications. (N.B. this should not be confused with the floppy iris syndrome of gardens, which is usually caused by slugs, or by the incautious gardener stepping backwards on the iris.)

Our traditional view of cardiac myocytes is that they sit there from birth, beating away about 40 million times a year until after about 80 years they get tired and start packing up. In fact, a recent Swedish study shows that new myocytes are produced throughout life, albeit in rather modest numbers – 1% at age 25 and 0.45% at age 75. Bone marrow stem cells are known to turn into cardiomyocytes if they are injected into the myocardium, but nobody has yet shown that this can result in clinically meaningful benefit. This Dutch study is no exception, but at least it showed a small, short-term increase in myocardial perfusion in a group of patients with chronic myocardial ischaemia refractory to medical treatment. The scanner noticed the difference even if the patients didn’t.

“Come Sleepe, O Sleepe, the certaine knot of peace,
The baiting place of wit, the balme of woe”
writes Sir Philip Sidney in his 39th sonnet, perhaps inspiring the more famous passage in Shakespeare’s Macbeth. Those who can take a good night’s sleep for granted have little sympathy for those who can’t: Lady Macbeth interrupts her husband’s very promising speech on the subject with a brisk “What do you mean?” In Shakespeare’s day, poppy, alcohol and mandragora were popular sedatives, but taking sleeping drugs has always been considered a moral weakness by non-insomniacs. The modern equivalent of moral self-improvement is cognitive behavioural therapy, where instead of being ordered to snap out of it, you are taught how. We know this works for sleep disturbance, but this Canadian study is one of the few to examine how it interacts with drug treatment. In the short term, CBT and zolpidem together produce the best results, and for long term success, discontinue the zolpidem while continuing the CBT. I can feel it working … wake up! When is there ever going to be enough CBT available in the UK to treat every patient with insomnia?

All right, all right, I know I should be fitter. Twelve Japanese authors rub it in with this meta-analysis of cardiorespiratory fitness as a predictor of all-cause mortality and cardiovascular events in healthy men and women. The association is clear, thought the heterogeneity amongst the studies is pretty striking.

NEJM   21 May 2009  Vol 360
The most radical change in medical services in the last ten years has centred on the provision of rapid reperfusion for myocardial infarction. The evidence that it works for ST-elevation MI is well established, but for NSTEMI acute coronary syndromes the benefit of immediate versus delayed reperfusion therapy is less clear. The TIMACS trial helps to clarify the situation by showing that the difference between coronary angiography at a mean 14 hours and a mean 50 hours in this group is not great. You have to tinker about with the results a bit – those wretched composite end-points get in the way once again – to tease out the main message, which is that the patients worth whizzing off asap to the nearest catheter lab are the ones with high risk scores. As you thought. Better still, this paper is accompanied by an editorial which contains a very useful table of treatment strategies for acute coronary syndromes (meaning those without ST elevation). The bottom line again: “The magnitude of benefit correlates with the patient’s level of risk.”

Lancet  23 May 2009  Vol 373
“Diabetes is a mess,” I sighed a few weeks ago. It has just become a worse mess with this meta-analysis of the effect of intensive control of glucose on cardiovascular outcomes and death in type 2 diabetes. The headline message is that “intensive control of glucose” reduces non-fatal myocardial infarction by 17%. This conclusion is reached by analysing five trials, three of which have a roughly similar design – ADVANCE, ACCORD and VADT – all examining outcomes after reducing GHb below 7 for several years in typical cohorts of type 2 patients aged around 65+. The other two are wildly different – UKPDS, which randomised patients on diagnosis in their early fifties to regimes which produced long-term GHb levels over 7, and the PROactive study which randomised patients with established macrovascular disease to have pioglitazone or placebo added to their existing regimes. The authors of this paper, to be fair, spend almost a third of it discussing its limitations, and even manage to squeeze in a favourable reference to the recent editorial on the subject I wrote with Harlan Krumholz. But this “meta-analysis” seems designed to obscure the clear message of three trials that can actually inform real-life practice in long-standing diabetes, which is that lowering GHb below 7 in this large group has no clear benefit and increases hypoglycaemia. The other two studies lumped in with them address different questions entirely. People with diabetes need evidence which helps them to choose the treatment which will benefit them most as individuals, whereas conflating disparate data leads in the opposite direction.

Here is another meta-analysis, this time quite uncontroversial as it simply tries to establish the size and timing of the well-known relationship between gestational diabetes and later type 2 diabetes. The risk size varies from 3.28 to 22.27 in various clusters of studies: the mean risk ratio combining them all is 7.43. Very high, in other words, and deserving of preventive action if we can find out what works.

There are three kinds of outcome in diabetes trials: (a) surrogate end-points only (this applies to 82% of current trials);(b) patient outcomes which are undesirable but treatable (most retinopathy, symptomatic vascular disease); and (c) patient outcomes that have a permanent detrimental effect, varying from toe amputation to death. For some reason, it has become traditional in diabetes research to confuse these three classes of outcome as much as possible. The FIELD trial randomised 9795 patients with type 2 diabetes to receive fenofibrate or placebo, and three main outcomes have been reported. For major cardiovascular events, fenofibrate made no difference; for retinopathy requiring laser treatment (a type b outcome, which does not equate to visual loss), fenofibrate provided a reduction of 31%; and the study here shows a similar reduction in amputation events, significant only for toe amputation. The front cover of The Lancet bids us to “marvel at the unexpectedly large effect of treatment with a fibrate on both diabetic retinopathy and amputations.”  What we should really marvel at is that fewer than 10% of the patients in this study were taking a statin, so the results are impossible to extrapolate to a real-life population of diabetics on appropriate treatment.

There are two types of surgical cure for diabetes. One is bariatric surgery, which can cure more than 50% of obese diabetics using relatively safe and simple procedures. The other is pancreas transplantation, a complex and hazardous procedure often performed in tandem with renal transplantation. If you are poorly enough to warrant combined transplantation, you are twice as likely to live to two years if you get it done. Thereafter there are clear benefits in the regression of diabetic changes in all affected organs, but long-term survival benefit is not clearly assured.

BMJ   23 May 2009  Vol 338
If you lower blood pressure, you will lower the risk of coronary heart disease and stroke, irrespective of baseline BP. You will achieve this reduction much more effectively by using low doses of three agents than by using higher doses of one or two. These well-known but commonly ignored facts emerge once again from this immense labour of Polypill love by Law, Morris and Wald. The moral of this meta-analysis of 147 trials is that if everyone took BP lowering medication we would reduce myocardial infarction by 45% and stroke by 60%. They claim that it is therefore irrelevant to measure BP, but this is a non sequitur: they assume we agree that risk assessment as a whole is a waste of time. That is only the case if we ignore the right of individuals to decide which treatments they would like to take.

As a medical student, I was puzzled that gynaecologists used the laparoscope to examine the abdominal cavity while general surgeons did all their operations through large wounds which I held open with a retractor. Then about twenty years ago, they all started doing everything through laparoscopes and severed many an artery and bile duct while climbing their learning curves. Had virtual reality training been more widespread then, this might not have happened, and even now it doesn’t seem to be mandatory, or this RCT would not have got ethical approval. It shows that it is as stupid to let a surgeon do laparoscopy without training on a virtual reality set as it would be to let a fighter pilot fly without simulator training.

More about the (relative) futility of blood pressure monitoring. The PROGRESS study reported here in pico form shows that the random variation of BP is huge and undermines the reliability of office checks following changes to treatment. The accompanying editorial and Fiona Godlee’s Editor’s Choice both call for a complete rethink on how we treat and monitor blood pressure. Tempting though it is to imagine a world in which constant checking of BP and other risk factors became a thing of the past, I am not quite convinced that giving everybody a cocktail of drugs they mostly don’t need is the best answer.

The Diagnosis in General Practice series continues with an excellent article on chronic cough by Kevin Barraclough, accompanied by a piece on the “test of treatment” by Paul Glasziou and colleagues. We first discussed this pairing of “practice” topics and “theory” topics three years ago, and it’s nice to see it working so well. This is about what actually happens to patients: if you think you can do it better, tell us how. Kevin disputes the relevance of diagnosing pertussis serologically in chronic cough, but having had access to salivary testing I can assure him that it turns up all the time and it’s a very useful tool for calling an end to the diagnostic chase. Patients go from being frustrated and anxious to being impressed and intrigued, and immediately start diagnosing it in their friends and relatives. Sometimes correctly.

Ann Intern Med  19 May 2009  Vol 150
If the dowager has a hump, she will die more quickly. This is not just an association with osteoporosis but is independently linked with the degree of hyperkyphosis in older women.

Here’s a nice little study – well, quite big, actually, involving 164 US hospitals – showing that quality of outcome is not related to volume of coronary artery bypass procedures but to quality of adherence to non-surgical measures. A little hospital can do just as well as a big one, not by hiring a star surgeon but simply by ensuring good peri- and post-operative practice – appropriate prophylactic antibiotics, leg compression, statins, ß-blockers and aspirin.

Sitting on the desk by my right elbow are 147 pages of the clinical Quality and Outcomes Framework by which our practice will earn enough to keep me in the manner to which I am accustomed. If some kind reader would give me a locum for 3 months, I would go through this whole wretched thing and examine its evidence base critically, as I tried to with a single diabetic indicator. Nowhere is the whole exercise more tenuous and unscientific than with so-called chronic kidney disease. Patients with this non-disease are usually elderly with co-morbidities that actually affect their well-being, and the only trial which includes substantial numbers of such people is ALLHAT. We will get points for treating them with angiotensin-converting enzyme inhibitors and angiotensin II-receptor antagonists. This review of the current American guidelines recommending these treatments shows that there is little hard evidence to support their use in people over 70. Perhaps I should become used to a little less income.

Plant of the Week: Decumaria sinensis
At this time of year, every street in England should be filled with a sweet odour of orange blossom honey, wafted from this evergreen climber as it produces its creamy tufts of intensely fragrant flower. Why it isn’t planted everywhere is a complete mystery to me. I think we have the only plant in North Oxfordshire, where it grows up the house wall as easily as ivy, but much more readily controlled. It could cover walls, fences, sheds, tree stumps and anything you care all the year round and never need attention. And then every late May you would be blown away by its wonderful scent.