Richard Lehman’s journal review – 2 April 2012

Richard LehmanJAMA  28 Mar 2012  Vol 307
1257    Medical conferences exist to affirm everything that hinders the progress of medicine as a compassionate and honest enterprise. They are a showcase for authority figures, pharma-funded research, half-completed work in the form of abstracts and late-breaking sessions; they use up prodigious amounts of money and carbon fuels; they reward high-tech flashiness and set no value on basic care and joined-up thinking: they reinforce a career structure and a social hierarchy in medicine which undermines the whole concept of patient-centredness. I’m glad to see all these feelings shared by John Ioannidis in this Viewpoint piece. John is a famous iconoclast who wrote the classic 2005 PLoS Medicine paper, Why Most Published Research Findings Are False. Here he proposes that nobody with any ties to industry over the preceding 3 years should be allowed to organize a conference. Also, that in order to ascertain the educational benefit of conferences, the next one should be randomized.

1273   Look into your hearts, my brothers and sisters! How few of you are saved from the perdition of cardiovascular risk! Just 1.2% of Americans can count themselves truly upright, by not smoking; being physically active; having normal blood pressure, blood glucose and total cholesterol levels, and weight; and eating a healthy diet. The rest are mired in sin—by genetic predestination or moral turpitude; and the world grows ever less righteous. According to the John Calvin of epidemiology, the late Geoffrey Rose, cardiovascular disease should have doubled since 1992, when he published his book The Strategy of Preventive Medicine. Instead it has halved. How depressing it must be for the Calvinists when so many sinners fail to die.

1307  One reason that so many sinners survive is the widespread use of statins in high-risk patients. Wistful for the enormous profits that these drugs brought in during the last two decades, pharma companies continue to search for a lipid-lowering drug which will add to the effect of HMG co-reductase inhibition. So what is the lipid subfraction that most predicts risk in people taking statins? Here’s a painstaking individual patient data meta-analysis showing that it is not low-density lipoprotein cholesterol alone, nor apolipoprotein B, but the totality of non-high-density lipoprotein cholesterol. Lower this, and you may have the next lipid-lowering blockbuster; or you may have nothing; or you may kill people.

NEJM  29 Mar 2012  Vol 366
1181, 1190   “Few adverse effects were observed, and few patients withdrew from the trials. Nevertheless, a 12-week follow-up period is too short to assess the safety of treatments targeting interleukin-17. Future trials involving larger numbers of patients treated and followed for a much longer period of time will be needed.” So says the sage editorialist, who also explains the interleukin 17 system and many other arcane pathways that may be involved in psoriasis. Nevertheless, the NEJM has thought fit to publish these trials, no doubt because we would all like to see better treatments for psoriasis, and this approach shows promise. It could also be that these papers may help Amgen and Eli Lilly get FDA approval for brodalumab and ixekizumab, respectively. As I’ve said before, the companies may find the need to buy many reprints of these papers from the NEJM: this has happened before, and is part of the normal business structure of medical publishing, hidden behind a wall of commercial secrecy. Whether this results in the best selection of studies, or improvement of clinical practice, is for you to judge.

1209   I have written a lot about patient-important outcomes in type 2 diabetes, but one that we can easily overlook is mobility. In obese people with T2DM, loss of mobility leads to a downward spiral of diminished energy loss, muscle atrophy, and increase in adiposity: worsening glycaemic control then leads to all the problems of insulin therapy in people who cannot exercise and are insulin resistant. We have all seen this happen to our patients, and it is likely to become a commoner sight throughout the world unless we can find an effective intensive lifestyle intervention—one that can be applied to millions of individuals. The Look AHEAD trial enrolled more than 5,000 patients and achieved a 40% reduction in loss of mobility over 4 years in its intensive intervention arm. This could be of generalizable importance. Methodology buffs will also be impressed with the sophistication of the analysis: “We used hidden Markov models to characterize disability states and mixed-effects ordinal logistic regression to estimate the probability of functional decline.” A worthwhile paper.

1227   Blindness is certainly a patient-important outcome in diabetes, and here is an excellent and optimistic review of diabetic retinopathy. Optimistic because the incidence of diabetic retinopathy is falling, and there are effective new treatments based on vascular endothelial growth factor (VEGF) inhibition. It is worth mentioning in passing that despite popular myth, glycaemic control has only a minor effect on eye disease in T2DM. The role of VEGF in the process, however, is crucial. Intravitreal glucocorticoids and VEGF inhibitors are playing an increasing role in the treatment of established eye disease. Intriguingly, inhibitors of the renin-angiotensin system have been found to confer specific protection against retinopathy in type 1 diabetes, and fenofibrate protects against non-proliferative retinopathy in type 2. What, a use for fenofibrate at last?

Lancet  31 Mar 2012  Vol 379
1199   Hard on the heels of the BMJ’s exposure of the harms of metal-on-metal hip replacements comes this damning analysis of the National Joint Registry of England and Wales. There has been a tremendous vogue for these devices, especially in young patients. It was thought that the larger the head, the better. Now the evidence has belatedly caught up with orthopaedic fashion, and the truth is devastating. Metal-on-metal devices should never have been licensed, and the bigger the head, the sooner they fail. The opposite is true of ceramic devices. Metal on polythene devices also work well. This is a scandal of regulation which could probably still happen—for all we know, it is happening as we speak, in some other area of the lucrative, virtually free-for-all market of medical devices.

1205   The Higher Calvinism of cardiology is a terrifying religious system of predestination by genomics. Someone needs to write a satirical novel about it, like James Hogg’s grim tale of Scottish Calvinism gone mad in Private Memoirs and Confessions of a Justified Sinner (1824). The latest focus of genomic theology is interleukin-6 receptor (IL6R) signalling, one of the many ways by which the wrathful gene-god dooms the unworthy to suffer cardiovascular disease. Never mind that we know many other important ways, and that this one is just an aspect of general inflammation. The Church of Genomics demands that we must not pit our humble understanding against a list of authors and investigators which covers two pages of small print. The entire priesthood proclaim that by analysing 82 studies, they can affirm that “large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.” Aye, consistent with. What more can the faithful believer require?

1214   The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium is a much smaller group—a mere 100 or so—but by combining the results of 40 studies in 133,449 individuals, it too concludes that “IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials.” Well, hold on. Most of us accept that inflammation plays a role in the ulceration of arterial plaque, and hence cardiovascular events. IL6R signalling is part of that process. It is also part of our inflammatory defence system, and perhaps a host of other things we don’t fully understand. In the editorial, we learn that large-scale trials of decidedly worrying agents such as methotrexate and canakinumab are already under way for vascular protection based on interleukin pathways. I just hope these guys know what they are doing. It will take more than a few “seems” and “consistent withs” to make me believe this mechanistic logic, however hard won.

1256   Have you run out of things to worry about? Fancy mongering a new disease? Try hyposelenaemia. The basis for selenium supplementation, according to this review, is that “low selenium status has been associated with increased risk of mortality, poor immune function, and cognitive decline.” Alas, I am ignorant of my selenium status. I don’t even know my credit rating or my IQ. And I certainly shan’t rush to buy selenium from a “health” shop or online, because “supplementation of people who already have adequate intake with additional selenium might increase their risk of type-2 diabetes.” So why are these supplements on open sale? Shouldn’t we insist on a plasma selenium level first? Tell me, has anyone ever put “plasma Se” on a blood form?

BMJ  31 Mar 2012  Vol 344
Promoting exercise in sedentary patients is undoubtedly a worthwhile endeavour, but that does not mean we know how to do it effectively. A bit of exhortation now and again is unlikely to work, so the temptation is to refer patients elsewhere, and I have certainly written out lots of exercise prescriptions to local gyms. Unfortunately we don’t really know if this tactic works either. This systematic review from the Cambridge primary care department reaches a rather downbeat conclusion.

Florence Nightingale in the 1860s believed that hospitals were “an intermediate form of life,” dangerous to patients and soon to be superseded by teams of nurses who would look after sick people in their own homes. She really believed in the transfer of services to primary care, unlike most politicians who use it as a cynical excuse for disinvestment in hospitals. Hospitals in most places remain dangerous, inhumane environments: but absolutely irreplaceable, especially in the developing world. This survey of 26 hospitals from countries such as Egypt, Jordan, Kenya, Morocco, Tunisia, Sudan, South Africa and Yemen shows a high rate of potentially preventable patient harm. Mind you, so do many surveys of hospitals in rich countries. A study a couple of weeks ago showed that about half the hospital nurses in Europe would run away and do something else if they could. There is something about the culture of hospitals which needs hard work to repair.

Plant of the Week: Prunus avium

The wild cherry can be a pretty huge tree, growing to 25m high and across, and there is no finer spring sight than a fully grown one in flower. Its other names are supposedly the bird cherry, gean, or mazzard; but I have yet to hear an English villager exclaim “Why yon’s a glorious gean!” or “What a mighty mazzard that be!” though if I looked hard enough in the works of Thomas Hardy I might find such words.

It is the plant referred to in the lines of E A Housman, recited by every schoolchild of my period:

LOVELIEST of trees, the cherry now
Is hung with bloom along the bough,
And stands about the woodland ride
Wearing white for Eastertide.

Now, of my threescore years and ten,
Twenty will not come again,
And take from seventy springs a score,
It only leaves me fifty more.

And since to look at things in bloom
Fifty springs are little room,
About the woodlands I will go
To see the cherry hung with snow.

With only eight years left to go by Housman’s reckoning, I’d love to wander out into the woods of New England to admire the local cherry species – which are abundant, though smaller and less floriferous. But to save me time and effort, someone has planted the great European gean on my daily walk to work. It must be about 100 years old and it is entirely hung with snowy bloom this Eastertide. Loveliest of trees.