Richard Lehman’s journal review – 24 January 2011

Richard LehmanJAMA  19 Jan 2011  Vol 305
261   I’m of an age when the words cognitive decline in the title of a paper make me rush to read it – the exception being a self-assessment study in the BMJ a couple of years ago, which was just too scary. This paper isn’t scary; in fact it isn’t anything, really. It tells me that because my level of literacy is in the highest tertile (I assume so, anyway), I’m at no great risk of cognitive decline in the next 9 years – which I wish I could believe. I could be a tiny bit more certain if someone measured my serum β-amyloid 42/40 level, which of course they won’t unless I take part in another prospective observational study like this one. If this is high, you’re OK: if it’s low, your brain goes senile slightly faster.

267   It’s a well-known fact that perimenopausal American women flash, while English ladies prefer to flush. Both kinds go hot and sweaty, and both used to regard hormone replacement therapy as divine deliverance. But now that we don’t want to hand it over, we are forced to recommend alternatives. Try phyto-oestrogens: they don’t work, but they sound as if they ought to; or serotonin reuptake inhibitors, which work a bit for some women, although in my experience few persevere. The latest to join the slightly useful list is escitalopram. But when women stopped the drug, not only did the flashes return to their previous frequency but they also experienced withdrawal symptoms of lightheadedness, vivid dreams, sweating and/or nausea, each at a rate of 11-14%. Don’t go there, would be my advice.

NEJM  20 Jan 2011  Vol 364
205   PARP is a sound increasingly heard in oncology circles these days. This isn’t because Noddy is taking his car to cancer conferences, but because PARP inhibitors are being used as a last-ditch treatment for an increasing range of metastatic cancers. Their logic is explained in the editorial, neatly subtitled “If it’s Broke, Don’t Fix It”: PARPs are enzymes that repair single-stranded DNA (their full name is poly(adenosine diphosphate–ribose) polymerase) and if you stop this happening in rapidly dividing cancer cells, they screw up and die. If you had to use PARP inhibitors for long periods of time, all sorts of serious bodily malfunctions might start to occur, but for prolonging life in terminal breast cancer, the results can be impressive, as in this small study of iniparib added to standard chemotherapy in women whose cancers were triple-negative, i.e. did not carry oestrogen, progesterone or HER-2 receptors.

226   A Prospective Natural-History Study of Coronary Atherosclerosis: call me a dweeb, but that’s the kind of thing I like to see in the NEJM. It may not have any direct bearing on clinical practice, but with a title like that you know that you are going to learn some facts, and I have a Gradgrind-like hunger for facts. The big fact I learnt here is the importance of the thin-cap atherofibroma. This incredibly labour-intensive study followed up 697 patients after acute coronary syndromes with repeated angiography and state-of-the-art intravascular ultrasonography (grey-scale and radiofrequency). The important thing about the latter is that it doesn’t just measure the degree of stenosis, but can see inside the plaque to distinguish between ordinary mountains and volcanoes. Mountains can get big, but they don’t erupt: volcanoes do. Sure enough, most major coronary events in the follow-up period occurred either at the site of a previous event (a known volcano) or at the site of a thin-capped atherofibroma (a volcano waiting to erupt). Facts: which are interesting, I think.

236   Another huge study next, but one that ended up with only 9 subjects. These were blood donors whose samples were negative for hepatitis B antibody but positive for hepatitis B DNA. It took 3.7 million viral DNA tests to discover them. Six of them had been vaccinated, and had subclinical infection with no ill effects; whereas  two of the three unvaccinated donors developed clinically significant liver damage. Triplex nucleic acid testing looks like the way forward to detect blood-borne disease in blood donations during the seroconversion window – not just HBV but also HCV and HIV.

248   For all we know, vitamin D insufficiency may be the key to understanding half the ills of advanced societies in sun-depleted latitudes, from multiple sclerosis to atherosclerosis. But all we know does not amount to much, as this low-key review makes clear. We are not talking here about the generally agreed condition called vitamin D deficiency, but about the grey zone of serum 25-hydroxyvitamin D between 25-75 nmol/L, where debate rages in proportion to the lack of evidence from prospective trials. So the single author prudently concentrates on the few trials which actually exist, yielding equivocal data about fracture protection. Which may – or may not – be the least important aspect of this subject.

Lancet  22 Jan 2011  Vol 377
301   No trial of out-of hospital cardiopulmonary resuscitation makes cheerful reading, but this one is hailed as “striking” because it managed a survival rate of 9% in the intervention group. The intervention was a device that is placed on the chest to ensure that each compression is alternated with a brief period of negative intrathoracic pressure; plus an impedance-threshold device that augments this by limiting passive air entry into the lungs during chest compressions. This is all described and illustrated in the editorial. It took well over 2,000 CPR episodes to establish a just-significant difference between the effects of these devices in combination and standard unassisted CPR, which yielded a survival rate of 6%. The editorial reviews the mixed success of other trials and concludes that the devices are not yet ready for prime time.

312   The ACCELERATE trial used amlodipine and alsikiren singly or in combination as treatment for newly diagnosed hypertension. Aliskiren, you may remember, is a direct renin inhibitor struggling to place itself in a market already full of generic drugs which work further down the angiotensin-aldosterone pathway, or lower blood pressure by other means. Its manufacturer, Novartis, spread this study across 146 sites all over the world, each recruiting 9-10 subjects. Most of the people only reached their target BP when they used the two drugs in combination, leading the investigators to conclude that “A move towards routine initial reduction of blood
pressure with combination therapy can now be advocated.” But this is an unwarranted extrapolation from a single trial; and anyway does it really matter whether you follow up the patient and then add a second agent a few weeks later, rather than use two from the start? Some people, myself included, do perfectly well on a single drug.

321   Ever since the aromatase inhibitors first appeared, I have tended to be rather dismissive of tamoxifen as a treatment to prevent the recurrence of breast cancer in postmenopausal women. But in this European trial there was no clear advantage in giving exemestane alone for five years after hormone-receptive early breast cancer over starting with the much cheaper tamoxifen and then moving on to exemestane after 2-3 years.

350   The Wakley Prize is awarded by The Lancet each year for an essay on a topic of international health importance, but over the last ten years I can’t remember any really outstanding contributions. This year’s anonymous essay is a brilliant exception: an almost unbearable narrative of trying to treat a crowd of terrified, badly injured students who suddenly arrived in a small Tehran hospital after being raided without reason by the Iranian militia. I think back on my months in 1974 in that wonderful, deeply civilized country as a medical student, pampered by a devout Muslim family who longed for the overthrow of the Shah. His secret police had, after all, killed their teenage son by way of a warning. And now the Iranians have this kind of thing, with the prospect of worse to come.

BMJ  22 Jan 2011  Vol 342
215   There have been lots of studies of the relationship between migraine with or without aura and the risk of stroke; likewise lots of studies of white matter hyperintensities and the risk of stroke; but this French population MRI study mixes all three for the first time. As someone who gets migraine auras with or without subsequent migraines, I resemble one of only 14 in the 780 participants in this study. The paper tells me that if someone did an MRI scan of my brain, they would probably find white matter hyperintensities, some perhaps amounting to infarcts. It doesn’t bode well.

218   Hereditary haemochromatosis was one of my original suggestions for the “Easily Missed” series, but we decided against it because, as this review states, “the challenge is to avoid both underdiagnosis and overdiagnosis.” Besides, it’s a complex topic which could not be dealt with on a single page. This Dutch overview takes six, and makes for rather dour reading, but that’s in the nature of the topic.

224   The BMJ’s new Therapeutics series (free on line) gets off to a reasonable start with an article detailing the evidence for the dabigatran and rivaroxaban as thromboprophylaxis in patients having hip or knee arthroplasty. You may remember that these are new oral anticoagulants, and that one is a direct thrombin inhibitor and one is a Factor Xa inhibitor, but can you remember which is which? The answer lies in their names. Again, the nature of the topic means that excitement is in short supply in this article – which is a pity, because the end of warfarin is an exciting prospect: here we only get as far as equivalence to enoxaparin.

Ann Intern Med  18 Jan 2011  Vol 154
77   There has never been a trial like this one of culturally appropriate storytelling to improve blood pressure. I know, because I work in a unit with a unique collection of culturally diverse stories of sixty different conditions, including hypertension ( We get over a million hits a month and lots of good feedback from patients, but we’ve never thought of making a therapeutic DVD of the kind used in this randomised trial in Birmingham, Alabama. This was an intervention aimed at African Americans with poorly controlled blood pressure, who were given either 3DVDs over 6 months of black Americans talking about their hypertension and how they managed it, or a DVD of general health advice. In those with poor BP control, the intervention achieved a difference over the control group of 11.9/4.22 mm Hg over 9 months.

94   Two things I got obsessed with for years were the volume/quality debate as it applied to my local small hospital, and heart failure. Now heart failure is a progressive but unpredictable condition with a worse prognosis than several disseminated cancers, and is the main cause for medical readmission in all advanced countries. This study of 4095 hospitals in the United States shows that on average, hospitals dealing with a high volume of heart failure work get better results, both in terms of readmission rates and death, but with higher costs. The challenge now is to define what these bigger hospitals do better, and spread the message: always bearing in mind that the final difference is not great (less than 20%).

131   Time for Clinically Relevant Comparative Effectiveness Studies in Type 2 Diabetes – so runs the title of the editorial on this latest diabetes trial. Oh boy, is it time! The diabetes trials of the last 40 years have brought us to the incredible position of being unable to tell whether any of the glucose-lowering drugs we use is actually beneficial, with the sole exception of metformin: and even then, all the evidence we have is based on an overweight cohort within the UKPDS trial. The pharma-sponsored trial here used the latest wonder drug (long term effects unknown), exenatide, as a additional therapy for type 2 diabetics using insulin glargine. I cannot begin to tell you how bad this trial is. Why, it is almost average…

Plant of the Week
: Galanthus nivalis

The snowdrops are out! Life begins again.