Richard Lehman’s journal review – 5 December 2011

Richard LehmanArch Intern Med  28 Nov 2011  Vol 171

1879         Recitative (Dido):
Thy hand, Belinda! Darkness shades me –
On thy bosom let me rest;
More I would, but Death invades me;
Death is now a welcome guest.
Aria (addressed to Aeneas):
When I am laid, am laid in earth,
May my wrongs create
No trouble, no trouble in thy breast;
Remember me, remember me;
But ah! forget my fate.
Remember me, but ah! forget my fate.

American patients with myocardial infarction who are taken to a hospital without a facility for percutaneous intervention might wish to sing this lament while they wait for an ambulance to take them to a more suitable facility. This process is called DIDO (door in door out) and according to US guidelines it should take less than 30 minutes. And so it does, in 9.7% of cases, according to this survey by the Yale CORE team and others. In nearly a third of cases, the DIDO time exceeded 90 minutes. Perhaps non-PCI hospitals should simply employ more nurses called Belinda and abandon the DIDO target. There are, after all, well over 50 musical compositions called Didone abbandonata; and you might be wise to upload these on to your i-pod to listen to while the morphine takes effect and you expire on Belinda’s bosom.

1894   Chronic disease management for tobacco dependence is the name given here to a telephone support intervention to promote smoking cessation, which achieved a 30% quit rate at one year compared with 23.5% with usual care. I’m really perplexed by the American fondness for giving things labels that don’t quite fit. Why call this chronic disease management? Why even think in these categories? Why not call this by its proper name of nicotine addiction, and treat it according to the well-established principle of harm reduction? You need people to stop smoking because it’s the smoke that kills them, not the nicotine or the tobacco leaves. On to the next study.

1901    We know that one moderately useful approach to smoking cessation is nicotine replacement therapy and I don’t know of any reason why people can’t stay on it as long as they feel a need for nicotine. We prescribe methadone maintenance to stop people suffering the harms associated with obtaining illegal opioids: so much more should we do everything we can to stop people killing themselves as a by-product of needing a fix of harmless neurotransmitter. In the USA, nicotine replacement products are fearfully expensive – more than three times the UK cost. In this trial they were given free to smokers who were not inclined to quit, and sure enough, while they had the free NRT, a few did quit; and then mostly relapsed. Societies wishing to encourage universal smoking cessation should ensure that lozenges containing nicotine cost the same as cough lozenges containing menthol, while racking up the price of tobacco. Doctors need not have much role in any of this.

1920   For decades, tight glycaemic control in type 2 diabetes has been preached as the best means of preventing cardiovascular complications, especially those classed as “microvascular.” The ACCORD and ADVANCE trials published in June 2008 should have blown this myth to pieces, but these large long-term studies were followed by an eerie silence from the diabetology community, which was firmly wedded to a “lower-the-better” model based on extrapolations from risk plots. Most doctors still cling to the delusion that allowing a person with T2DM to run at a glycated Hb level above 7% is sloppy medicine. On the contrary: this Canadian observational study of renal outcomes in diabetic patients with eGFR <60 provides more confirmation that the optimal HbA1c for the general 2 diabetic population is about 7.3 using current modes of treatment. Pushing it lower risks more harm than gain.

NEJM  1 Dec 2011  Vol 365
2055   Amongst the many mild culture shocks of living in the USA is the fact that you cannot walk more than about 200 metres in any built-up area without encountering illuminated letters of brown, pink, and yellow announcing an outlet of Dunkin’ Donuts. But surely not in the pages of the New England Journal! Well, admittedly it’s in their usual sober black designer typeface, but here is a study “Supported in part by a Dana–Farber Dunkin’ Donuts Rising Star award.”  And no, it’s not about the cardiovascular benefits of regular consumption of fatty pastry covered in sugary gloop: it’s about Interleukin-2 and regulatory T cells in graft-versus-host disease. This is not a theme on which I am usually apt to wax lyrical, but having touched on it a couple of weeks back, I am sure I must have whetted your appetite to learn more. You may remember that astonishing study where T-cells were fitted up with a chemical receptor that meant they could be used to kill off malignant cells, but as soon as they started to cause GVHD by attacking normal cells, they themselves could be killed off by a single injection of the antidote chemical. A sort of self-destructing magic bullet. This study is nowhere near as elegant, but probably much easier to apply to the many thousands of patients who suffer GVHD as a result of non-autologous bone marrow transplantation. The intervention was a daily injection of low-dose interleukin-2, and it resulted in remission of GVHD in about half of patients whose disease had failed to respond to steroids.

2078   Perhaps in atonement for all the profits it has made from reprints sold to pharma companies, or just from a playful sense of Schadenfreude, the New England Journal is giving everyone free access to a study which proved the opposite of what its sponsor, Astra Zeneca, hoped to demonstrate. Rosuvastatin, the Astra Zeneca “superstatin” was pitted against the “less powerful” and generically available atorvastatin. In fact this trial (SATURN) was a nasty case of comparing one set of surrogate measures (LDL-C lowering, HDL-raising) to another surrogate measure – coronary atheroma by intravascular ultrasound. That sounds awfully important, but we cannot be sure what it really means. The true relative benefits of these statins could only be properly demonstrated by huge, lengthy studies using end-points such as death and myocardial infarction. Given the margin of absolute benefit likely to emerge, such trials would be a complete waste of time and money: like most lipid-altering trials since the original statin studies of the 1990s.

2089   A thoughtful medical student wrote to me last week to ask my views on the future of genomic medicine, given the sceptical tone (to put it politely) that I often adopt in these reviews. Let me put it bluntly: if you are likely to get ill and/or die within 30 years, it’s pretty unlikely that you will see any benefit from the effort and resources currently going into genomic medicine. I don’t altogether grudge the eventual benefit to posterity but I do grudge the diversion of resources from clinical research which could benefit millions of people in the short and medium term. I’m filled with wonder and delight when genomics is applied with success to investigating the characteristics of cancer cell lines so as to develop tailored treatments: yet I still worry about the generalisability of these expensive and super-sophisticated methods. If you’re interested in the Genomics of Cardiovascular Disease, the NEJM here very kindly offers you a free guide: most of the article is taken up with hypothesis-generating associations which may or may not reveal new pathways and hence new interventions for CVD, given another decade or three. The only triumphs which have yet emerged are the alleles which govern the platelet response to clopidogrel, and those which might perhaps govern the therapeutic effect of beta-blockers in some patients with heart failure. For a brief and trenchant summary of what genomic medicine is likely to achieve, you still can’t do better than read Trish Greenhalgh’s 2005 RSM piece.

2110    Systemic lupus erythematosus is the subject of the other NEJM review. The very complexity of this account demonstrates how little we really understand this nasty and often devastating disease, and the dry conclusion doesn’t promise any imminent breakthrough:
“SLE is an autoimmune disease that predominantly affects women and typically has manifestations in multiple organs. Immune-system aberrations, as well as heritable, hormonal, and environmental factors, contribute to the expression of organ damage. Immune complexes, autoantibodies, autoreactive lymphocytes, dendritic cells, and local factors are all involved in clinical manifestations of SLE. Biologic therapies and small-molecule drugs that can correct the aberrant immune-cell function are being developed in the hope that they will be more effective and less toxic than current treatments.”

Lancet  3 Dec 2011  Vol 378
1917   “The global burden of disease attributable to seasonal influenza virus in children is unknown” we are told at the beginning of this 47 author paper. Not so much unknown as unknowable, I would have thought, since so many different viruses cause indistinguishable flu-like symptoms and respiratory disease in children; and even in the developed world we rarely carry out virological tests. Nonetheless the formidable team of investigators press ahead and reach conclusions which they think may be only 30% inaccurate. Global surveys of this kind are one of the few admirable features in The Lancet, but you do sometimes wonder what they are meant to achieve.

1940   I suppose that if you are a designer of electric kettles, your whole future depends on tweaking the design of a device which reached a perfectly satisfactory stage about 50 years ago. It’s getting to be the same with designers of coronary stents: in days gone by they had an exciting time fiddling about with new immune modulating ingredients, but now all they can do is fiddle about with permanent versus biodegradable polymers. At four years, there was no difference in outcomes. It’s so exciting, being back in the Stent Wars.

1949   Possibly the main reason we read reviews of uncommon, nasty, and untreatable conditions is that we might glean some scraps of hope to convey to our patients. My last patient with idiopathic pulmonary fibrosis died in 2000, the year I retired from my practice, so I won’t be seeing another one through to the end: though since the mean age of onset is 66, there is still time for me to get it myself. The scrap of hope here is that we are at least getting nearer to understanding the mechanism of fibrosis: not a non-specific inflammatory process but one specifically mediated by abnormally activated alveolar epithelial cells. The best hope for the future is to find something that will de-activate these cells; failing that, to deploy stem cells to recreate damaged lung. As things stand, mean survival from diagnosis is three years.

BMJ  3 Dec 2011  Vol 343
Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials.” Just the latest in a long line of such reviews, confirming what was perfectly obvious by early 2009, when I wrote a BMJ editorial on the subject with Harlan Krumholz. That said, I think this is the most thorough analysis so far: but the headline message hasn’t changed at all. For the great majority of T2DM patients, tight control has no benefit. There could still be a subgroup of people who might benefit, but we don’t know how to identify them.

For reasons I won’t try to explain, I developed a dweebish interest in the prognostic value of cardiovascular biomarkers some years ago. It struck me then, and has struck me ever since, that the only one with rock-solid predictive value is B-type natriuretic peptide and most of the rest might as well go in the bin. This study doesn’t address this issue directly but rather compares predictive values derived from observational studies with the values found in randomized controlled trials. The observational studies tend to exaggerate the usefulness of makers in many cases, including BNP: but it remains considerably better than the rest in absolute terms.

A really excellent clinical review of arthritis of the base of the thumb tells you all you need to know about this important cause of pain and functional disability – mostly but not solely in elderly patients. Splinting and exercises have a place, and so does injection with a steroid: the evidence base isn’t ideal, but injections provide relief in about 75% of cases, and don’t appear to do harm. Trapeziectomy is usually the operation of choice if non-operative methods fail.

Plant of the Week: Daphne bholua “Jacqueline Postill

It is time that I indulged in my annual celebration of this most indispensable of shrubs, covered in leaf and flower and filling the air with the most heavenly scent throughout the gloomiest months of the year. In most British winters it stays in leaf and flower well into March, but the violently cold weather a year ago completely denuded our 2 metre-high specimen. By May there was no sign of life in the plant and we gave up hope. Two younger specimens of a white-flowered cultivar that we had recently planted out were definitely stone dead.

But then a tiny green shoot appeared near the base. We left the most treasured plant in our garden and went to the USA in June. Now it has sprouted a mass of new leaves, and when we return next week we hope that there might be just one or two flowers to remind us of past blessings, and perhaps many more to come.