Richard Lehman’s journal review—15 September 2014

richard_lehmanNEJM 11 September 2014 Vol 371
1016  Ticagrelor has had mixed fortunes since it was introduced as a new thienopyridine platelet aggregation inhibitor a few years ago. The PLATO trial left lingering doubts whether it is better than the much cheaper clopidogrel when used in acute coronary syndromes. Rather than attempting to resolve these, the latest trial (ATLANTIC) compares prehospital administration of ticagrelor with in-hospital administration in patients undergoing immediate percutaneous coronary intervention for ST-elevation myocardial infarction. There is no difference. The name ticagrelor keeps reminding me of Excelsior, in Henry Wadsworth Longfellow’s poem of that name:

THE SHADES of night were falling fast,
As through an Alpine village passed
A youth, who bore, ‘mid snow and ice,
A banner with the strange device,

but alas, several stanzas later:

A traveller, by the faithful hound,
Half-buried in the snow was found,
Still grasping in his hand of ice
That banner with the strange device,

His name was Herbert Seneca,
He worked for Astra Zeneca,
And ere he died he thought it nice
To use with every stent device

There, in the twilight cold and gray,
Lifeless, but beautiful, he lay,
And from the sky, serene and far,
A voice fell, like a falling star,

OL  Ah, there is much poetry in cardiology, although sometimes it can be hard to appreciate. A negative trial of Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure will not fill the hearts of most doctors with song. Many indeed may never have heard of ivadabrine, let alone used it, although it has been around for nearly 10 years. Its unique virtue is that it acts by reducing the heart rate via specific inhibition of the funny channel. Now funny channel inhibition has to be poetic. Only it’s a shame that it doesn’t seem to do anything.

OL  Since the COURAGE trial showed that most patients with stable coronary artery disease are as well off on medical treatment as with revascularization procedures, interventional cardiologists have fought back with attempts to find subgroups who might still benefit from their expensive ministrations. The diagnostic test that they favour is fractional flow reserve. To a mere outsider like myself that seems puzzling, since what matters is plaque stability, not some one time measure of perfusion, but I must not doubt the importance of FFR since it was the determinant in the FAME-2 trial. And in this trial, “In patients with stable coronary artery disease, FFR-guided PCI, as compared with medical therapy alone, improved the outcome. Patients without ischemia had a favorable outcome with medical therapy alone.” So what was the outcome? It’s not entirely clear from the abstract, where the naughty NEJM proofreaders have let through something called “myocardial infection.” And the full text also has some seemingly conflicting statements. The trial was not blinded and was stopped prematurely due to an excess of revascularization procedures in the medical therapy group. I will leave you to pore over the details of this trial, funded by the stent manufacturer St Jude. As for the poetry, that’s easy: every civilized person should know the lines from Milton’s Lycidas about FAME as the result of honest endeavour:
Fame is the spur that the clear spirit doth raise
(That last infirmity of Noble mind)
To scorn delights, and live laborious dayes.
(English Poems, 1645)

JAMA 10 September 2014 Vol 312

1002  There is more rather unpoetical cardiology in this week’s JAMA, but first read some masterly prose: Open Access to Clinical Trials Data by Harlan Krumholz and Eric Peterson. Go on, click the link: it’s free and will take you just a couple of minutes to read. It’s a perfectly stated argument for data openness. My only worry is that when data do become freely available, too few people will have the time, resources, and tenacity to dig deep into them.

1006  “Effect of Darapladib on Major Coronary Events After an Acute Coronary Syndrome: The SOLID-TIMI 52 Randomized Clinical Trial“—see what I mean about unpoetical? I defy anyone to find a convincing rhyme for darapladib. Or indeed for lipoprotein associated phospholipase A2, which it inhibits. This is supposed to interfere with plaque formation and inflammation.
So said Glaxo Smith & Kline
While working out their trial design:
Countless billions might accrue.
But given after ACS
Its effect was nil or less.
Alas, alas for darapladib:
Another hopeful drug has had it.

1024  If you followed my advice and read the commentary above, you will know it relates to a sobering article from the Ioannidis team about the re-analysis of randomized controlled trials. It seems that few indeed are the noble minds who are willing to scorn delights and live laborious days looking through the data from RCTs. And when they do so, what they achieve is seldom fame, but often disillusionment: “A small number of reanalyses of RCTs have been published to date. Only a few were conducted by entirely independent authors. Thirty five percent of published reanalyses led to changes in findings that implied conclusions different from those of the original article about the types and number of patients who should be treated.” Why do we place so little value on finding out the truth about the things we do to patients?

JAMA Intern Med September 2014
OL  When I returned to the UK two years ago after a wonderful year in the USA, I resumed out of hours visits to nursing homes full of demented elderly people. “Most nursing home residents with advanced dementia receive medications with questionable benefit that incur substantial associated costs” is a polite way of describing what I thought. I am quoting the conclusion of a survey of 460 such facilities in the USA in the year 2009-2010. I suspect things have got worse since then. We just keep learning further helplessness in the face of futile care, I fear. Whose job is it to strike a line through these lists of memantine, simvastatin, aspirin, Adcal-D, trazodone, alendronic acid, lisinopril, atenolol, and all the other pointless drugs being given to terminally demented people? Actually, dear fellow GPs, it is ours.

Lancet 13 September 2014 Vol 384
957  This week’s Lancet is filled with massive global surveys paid for by the Bill & Melinda Gates Foundation. It takes the first page of each merely to list the authors. Progress in reducing neonatal, infant, and under 5 mortality during 1990—2013 has been spectacular, but it has failed to meet the very ambitious two thirds reduction aimed for in the Millennium Development Goals (MDG 4). The main laggard countries are in central and west Africa.

980  And it’s just the same with MDG 5, maternal mortality: a huge success story, described as failure, with central and west Africa producing the worst results. Fact: global maternal mortality has fallen at an accelerating rate in most places since 1990, the current rate being about 2.7% in a year.

1005  By contrast, the summary of the next survey is positive about quite modest progress: “The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated.” However, 101 countries (74 of which are developing) still have increasing HIV incidence. And these figures don’t tally with those of the World Health Organization. That’s discussed in an editorial called “Time for a revolution in reporting of global health data,” whose title might have had more impact had there not been two other editorial pieces featuring the word “revolution.” One from the editor himself.

OL  In the catastrophizing parlance of the Lancet, type 2 diabetes is sometimes described as a “public health emergency.” If people must use this kind of language, they should really be more careful to distinguish between a challenge, a problem, a disaster, and an emergency. Describing the rise in type 2 diabetes as an emergency suits pharmaceutical companies because they want to sell drugs for diabetes without waiting for substantive proof of long term benefit. I have made this point so often that I will let you off for yawning. But what have we here? A systematic review of glucagon like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes, which reads more like an advertising hoarding than a scientific paper. “GLP-1 agonist and basal insulin combination treatment can enable achievement of the ideal trifecta in diabetic treatment: robust glycaemic control with no increased hypoglycaemia or weight gain. This combination is thus a potential therapeutic strategy that could improve the management of patients with type 2 diabetes.” It’s so wonderful that they’ve even had to make up a new word to describe it. I think “trifecta” means something that has three effects, but there’s one fecta that counts above all in type 2 diabetes: reduction of vascular end points. And I excuse you a second yawn, but I just have to keep saying this as long as papers of this sort find their way into high impact journals.

The BMJ 13 September 2014 Vol 349

Unless something changes radically in the next day or so, the European Commission will move the European Medicines Agency from the Department for Health & Consumers to the Department of Enterprise & Industry. Quite right. After their surprise decision in 2012 to release submitted data about drug and device trials to anyone who asked for it, the EMA need to be reminded that it is their function to promote industry rather than safeguard patients. I have heard it from the very lips of manufacturers that if they had to put all their devices through long term trials, they would never be able to compete in the global market. The result is that you can put what you like into human beings with a minimum of regulation or none at all. Take hip and knee replacements. Existing ones work pretty well. But they don’t bring in new revenue streams for EU manufacturers. So why impede sales of new ones by asking for evidence? Even before its transfer, the EMA lets them all through: “We did not find convincing high quality evidence supporting the use of five substantial, well known, and already implemented device innovations in orthopaedics. Moreover, existing devices may be safer to use in total hip or knee replacement.” The investigators call for better regulation. It’s nearly enough to make you vote UKIP, except that British regulators are even laxer than the EMA, and our government more venal yet than the European Commission.

I’ve just been rereading the Anglo-Saxon Chronicle, which gives a vivid picture of the Danes a thousand years ago. Here is a typical entry from 1014: “Cnut proceeded south until he came to Sandwich. There he landed the hostages that were given to his father, and cut off their hands and their ears and their noses. Besides all these evils, the (Danish) king ordered a tribute of 21 000 pounds.” Hard to believe that they are the same people who today live so peacefully and happily in the confines of their little kingdom, collecting medical data to inform the rest of the world. From data covering every Danish pregnancy from 1997 to 2008, we can be sure that anti-epileptic drugs have no effect on miscarriage rates and are unlikely to have any on stillbirth.

Plant of the Week: Poliothyrsis sinensis

It is a dizzying experience for plant freaks like ourselves to visit the nurseries of Crûg Farm and Pan-Global Plants, where the owners go on regular expeditions to the mountains of China, Korea, and northernmost Vietnam to bring back plants never previously seen in the UK. In the gardens of these places, the range of stupendous oriental foliage is amazing and hardly a plant is identifiable even to the seasoned inspector.

I did however half-recognize a beautiful small tree in full flower at Pan-Global nursery at Frampton-upon-Severn. Given half an hour or so, I might even have named it. Poliothyrsis sinensis features in Bean, who says that it was introduced to England by EH Wilson in 1908. It has a lovely form and pointed dark green leaves, and bears great tufts of scented white flowers at the very end of summer. It is hard to get to them for bees. Intensely desirable if you have the room for it.