Richard Lehman’s journal review – 14 May 2012

Richard Lehman JAMA  9 May 2012  Vol 307
1925    In a wonderful letter to Humphry Davy in 1800, Coleridge declared that science, as a human activity, “being necessarily performed with the Passion of hope, is poetical.”

All good science is inspired with the poetry of hope; but, alas, so also is a lot of bad science. If results are negative, then it is a lot easier to hope vainly that they contain hints of great things to come than to admit that years of effort have simply proved nullity.

And if a simple cheap intervention like intravenous glucose, insulin and potassium (GIK) seems to have promise in the treatment of acute myocardial infarction, all of us would much rather hope this is true than dismiss the possibility altogether.

Several randomised trials have proved that GIK makes no difference when given in hospital, so this double-blinded RCT investigates whether the same applies to GIK given by emergency service personnel to patients with presumed cardiac chest pain before arrival at hospital.

Again, there was no 30-day mortality benefit; but since (as a poet before Coleridge said) hope springs eternal in the human breast, the investigators draw attention to the fact that GIK was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality. Nah, that won’t quite do: when I have a myocardial infarct, I want to be alive at 30 days. This intervention is beyond hope: GIK RIP.

1959    Back to the world of hope, this time that probiotics will prevent antibiotic-associated diarrhoea. Again, a nice idea that costs next to nothing and has a certain mechanistic appeal: it’s just that when you do a systematic review of the evidence, it is all over the place.

By all means continue to hope that eating a daily pot of live yoghourt or drinking a concoction of lactobacilli will stop you running to the loo when you next need an antibiotic: but in fact nobody really knows, as there have been too few decently powered trials.

NEJM  10 May 2012  Vol 366
1759   $163,381 per year for the average patient. That is the US cost for lenalidomide according to the website of its manufacturer, Celgene. Multiple myeloma is a nasty disease, and lenalidomide is now standard last-ditch treatment to prolong life following relapse: not a matter of hope but of evidence.

Drug companies that charge £10K a month for life-prolonging treatment generally justify this on the grounds that research and development costs can be huge and the returns are uncertain.

The Celgene-funded trial described here was certainly expensive: 459 patients with newly diagnosed myeloma who were unsuitable for stem-cell therapy were recruited from 82 centres in Europe, Australia and Israel; and Celgene did not stint in offering the services of its staff either: “Employees of the company assisted with the study design, data collection, data analysis, and writing of the manuscript in collaboration with the senior academic authors.”

At 30 months, there was better progression-free survival in the continuous lenalidomide group. Now that may be worth something, but whether it is worth $163,381 per annum will depend on more than progression-free survival at 30 months: so read on.

1770   The next trial of maintenance lenalidomide in this week’s NEJM was the same size, with 460 patients; but since it was not company-funded, it managed to recruit these from about 17 centres in a single country (the USA).

Celgene’s only contribution was to provide its drug or matching placebo free of charge to myeloma patients who had undergone stem-cell transplantation.

In this study, 85% of patients in the lenalidomide group and 77% of patients in the placebo group were alive at a median follow-up of nearly 3 years. But since the mean survival for MM treated with stem-cell transplantation is now 8 years, does this really amount to $163,381- per-annum’s worth of benefit?

Moreover, while the trial conducted and written up by Celgene plays down the adverse effects from lenalidomide, this trial illustrates the heavy preponderance of severe haematological adverse effects and secondary cancers in the lenalidomide group.

1782   Now to France, for a very similar study of lenalidomide maintenance following stem-cell transplantation.

Again, the immediate benefit in terms of progression free-survival seems impressive, until you consider that this is an intervention of spectacular cost with diminishing benefits and increasing serious harms over time: it is far from clear whether the whole cohort of 614 patients would show any overall survival benefit, and the lenalidomide group would certainly have 2-5 times as many secondary cancers over the 8+ years that studies like this should report for.

The linked editorial is worth reading by anyone who thinks $163,381 per annum is a rather a lot of money for maintenance therapy of uncertain long-term benefit.

1792   I have had a lot of exposure to US cardiovascular outcomes research over the last year, and very enjoyable and formative it has been. I’m left convinced that there is no particular hierarchy of research in this area: good observational studies can be of the highest value, and qualitative or mixed-methods research can yield much more of practical value than some clever exercise in endless statistical adjustment and regression applied to a large database.

Randomised controlled trials are relatively uncommon in this field, so while they do not automatically count as top dog, they are always interesting. Given that elective percutaneous intervention is now a procedure with very small immediate risks (e.g. acute MI, dissection of the coronary artery), PCI is often performed in hospitals without on-site cardiac surgery.

If this interests you deeply, you can read all about it in a review. This massive trial (n=18,867) randomised patients needing PCI on a 3:1 basis to hospitals with or without cardiac surgery units. Readers who object to the word noninferiority must clench their teeth at this point, because that is what this trial showed. And anyone who claims that this word does not belong in the English language will be sent a punitive stream of e-mails until they beg for mercy.

Lancet  12 May 2012  Vol 379

1763   Science for action-based nursing: a great addition to the treasury of Lancet headings, perfectly combining the meaningless and the pompous. This little piece bewails that fact that nurses have trouble basing their practice on evidence. Not like doctors, of course.

As for action-based nursing, that is the kind I like. Non-action-based nursing is the kind that ignores patients’ pleas for help getting up and going to the toilet, or the fact that their food tray is out of reach. There is plenty of that about, alas. It does not need science but basic humanity. And then there are the innumerable non-action nurses who have grown too senior to look after patients at all: what they need is not science but alternative employment.

1791   Non-inferiority: a great word. Though here it appears hyphenated, out of a British sense of propriety, and the trial fails to demonstrate it. Instead – and even better – it proves that one treatment for advanced Hodgkin’s disease is more successful than another, as well as involving fewer cycles and fewer adverse effects. We are taking here of BEACOPPescalated followed by PET-guided radiotherapy. Do I know what BEACOPPescalated  means? Of course not – read the paper yourself if you need to know.

1800   Pessary: a great word. If I didn’t know better, I would guess that it referred to a small land mammal related to the otter. Pessaries live socially in burrows containing several breeding pairs, and subsist on a mixed diet of roots, larvae and worms. Well, sadly (perhaps) not: the Pesario Cervical para Evitar Prematuridad (PECEP) Trial Group was, as its name suggests, more concerned to prevent premature delivery in gravid women with a short cervix. The pessaries are made of silicone and were inserted following ultrasonography showing a short cervix at 18-22 weeks. Although similar devices have been used for 50 years, this was the first randomised trial and it was highly successful, cutting the rate of delivery before 34 weeks more than fourfold.

BMJ  12 May 2012  Vol 344

That smoking cessation is a great good is undeniable, and varenicline undeniably helps many people to stop smoking.

Does it therefore follow that varenicline is a great good? This is a nice debating point, because smoking cessation is actually a surrogate end-point, albeit one directly linked with certain outcome benefits; yet these benefits can be outweighed by other considerations, such as direct cardiovascular harm from the intervention itself.

A previous meta-analysis seemed to show a 72% increase in risk of serious CV events from taking varenicline: this one shows no increase in risk. The main reason is ascertainment bias in the trials which had poor follow-up data from placebo groups; but the fact remains that we can never be full sure until the manufacturer releases full individual data from its trials for independent scrutiny, as should be mandatory in all cases like this.

Multidisciplinary care for breast cancer is a self-evidently good thing if it helps to support women through their traumatic disease journey. It is a self-evidently bad thing if it leaves nobody with overall responsibility and makes promises it cannot deliver – and that can happen too. These considerations apply whether or not it has a benefit on mortality. The chances are that it has, because in two adjacent areas of Scotland where it was introduced at different times, the rate of mortality fell more in the area which got it first. You can argue about the figures, but the principle is incontestable. Team care is here to stay – and we need to make sure it is as humane and well-coordinated as we can possibly make it.

A couple of weeks ago, I read with incredulity and nausea a statement called Guidance on collaboration between healthcare professionals and the pharmaceutical industry, produced by the Association of the British Pharmaceutical Industry and signed up to, inter alia, by the British Medical Association, of which I am a member. I don’t dare give the link in case it exposes me to derision by my American colleagues, because I don’t believe that even the AMA, with all its links to industry, could ever have put its name to something quite so disingenuous and servile. Anyway, thank God for Ray Moynihan, who gives it the once-over this week, ending splendidly:

“This latest guidance on collaboration is extremely welcome, not as a guide to practice, but as an Orwellian insight into a desperate attempt to defend the indefensible.”

Plant of the Week: Magnolia grandiflora

At this time of the year, I generally commend to your attention the wonderful Himalayan magnolia species with scented pendant flowers, M sinensis and M wilsonii. My wife forbids me to commend the American species M grandiflora because it looks gloomy all the year round in the UK: it flowers reluctantly in our warmer summers, and carries its large dark shiny leaves with a sort of morose persistence. I have to admit she is right, though we both forgive it everything when burying our noses in its huge beautiful white flowers with their intoxicating scent of spices, honey and lemon.

This we had ample opportunity to do while visiting its native habitat in Georgia – not the former Soviet state but the American colony set up by King George III of England to get rid of the London poor. In the South-East USA, the bull bay can become a huge tree, over 100ft in height and 18ft in circumference. Smaller cultivars abound in the parks of Atlanta and along the interstate highways, flowering generously by early May.

I am not saying that you should never grow this plant in England, especially if you have a warm wall to cover. But be prepared for a measure of disappointment, and make sure that you keep it publicly accessible, so that we can get to smell its flowers should they ever appear.