Richard Lehman reviews the latest research in the top medical journals
NEJM 17 May 2018
Dual antiplatelets after minor stroke and TIA
The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial was devised to see if strokes in the three month period after a relatively minor ischaemic event could be reduced by adding clopidogrel to aspirin. The trial was stopped early for benefit after recruiting 4881 patients across 269 sites. The chance of benefit, though, was very small for any individual: a reduction in the absolute risk of major brain ischaemia from 6.5% (aspirin only) to 5% with added clopidogrel. Most of this happened in the first week. And there was a downside: major haemorrhage occurred in 0.9% of the combination group compared with 0.4% with aspirin alone.
Cryptogenic stroke and rivaroxaban
Cryptogenic is a great word, just waiting to be taken up by a rock band or a cult movie. It beats “idiopathic” any day, though it means much the same thing: medical ignorance disguised in cod Greek. Here’s a trial comparing aspirin with a factor Xa inhibitor for the prevention of recurrent stroke in patients with recent ischaemic stroke that was presumed to be from cerebral embolism, but without arterial stenosis, lacune, or an identified cardioembolic source. Rivaroxaban is a more powerful anticoagulant, and accordingly produced 2-3 times more bleeds. But for the prevention of further stroke, it showed no benefit over aspirin 100mg. Once again, the trial was terminated early, but this time for futility and possible harm.
JAMA 15 May 2018
Free of migraine with fremanezumab?
“Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.”
So nice to see JAMA insisting on this modest and accurate summary of this 12 week Teva Pharmaceuticals trial with a placebo comparator. But despite its obvious limitations, fremanezumab still managed to get itself hyped as a breakthrough in the American press over the last week.
Elizabeth Loder and Matthew Robbins provide an editorial on monoclonal antibodies for migraine prevention which is as close to perfection as you are ever likely to see. In the bizarre tradition of JAMA journals, you can read the first page online and the rest is behind a paywall: I urge you to try and get the whole thing. I would like to spend the entire review this week writing on this subject, but I can’t. Suffice to quote the final sentence: “The challenge will be to move from treatment based on general phenotypes to therapies that are based on a more sophisticated understanding of individual patients.” Migraine is a cruel, random, cryptogenic condition. The best preventive drug was developed from LSD in the 1950s, but can cause slow death in one person in 5,000. We have moved on surprisingly little since then.
JAMA Intern Med May 2018
Depot buprenorphine for opioid dependency
Buprenorphine is an effective drug for opioid substitution therapy, provided people take enough of it regularly. This isn’t difficult: there is the craving to remind you, and it’s just one sublingual dose of 8-16mg a day. However, Braeburn Pharmaceuticals decided there might be a market for a monthly or three-monthly depot subcutaneous injection instead, and rather unusually JAMA Intern Med has published the results of their 26-week randomised double-dummy double-blind trial.
The outcomes were “response” and freedom from illicit opioids on testing. In the population recruited to this trial, the depot injections were slightly better on the second count. Braeburn will argue that there is a niche for this preparation, but I would argue that it is a small and shallow one.
The Lancet 19 May 2018
NCDs and the triumph of lumping
This looks like being the most beautiful week of the English year, and already I’ve wasted over an hour of it reading about non-communicable diseases. There are five articles about them in this week’s Lancet, and two editorials (“2018 must be the year for action against NCDs”), but apart from the fact that NCDs aren’t catching, I’m not much clearer about what they actually are. All diseases that kill large numbers of people under the age of about 65 are bad, by definition. Some of them are preventable. If you substitute “bad stuff” for NCDs you will lose little. Governments and journal editors should not make orotund speeches about bad stuff unless they propose to do something specific about specifics.
“He who would do good to another, must do it in Minute Particulars,
General Good is the plea of the scoundrel, hypocrite, & flatterer:
For Art & Science cannot exist but in minutely organised Particulars,
And not in generalising Demonstrations of the Rational Power.”
(A Vision of the Last Judgement William Blake)
It’s time to get out in the garden. In honour of Blake we have planted a fig and a vine and much honeysuckle, though these days we seldom go there naked to read Paradise Lost to each other. A pity, since it is a most excellent poem. It’s interesting that in book XI Milton joins today’s moralists in putting down most non-communicable diseases to poor lifestyle choices:
“… by Intemperance more (shall die)
In Meats and Drinks, which on the Earth shall bring
Diseases dire, of which a monstrous crew
Before thee shall appear… Immediately a place
Before his eyes appeard, sad, noysom, dark,
A Lazar-house it seemd, wherein were laid
Numbers of all diseas’d, all maladies
Of gastly Spasm, or racking torture, qualmes
Of heart-sick Agonie, all feavorous kinds,
Convulsions, Epilepsies, fierce Catarrhs,
Intestin Stone and Ulcer, Colic pangs,
Dæmoniac Phrenzie, moaping Melancholie
And Moon-struck madness, pining Atrophie
Marasmus and wide-wasting Pestilence,
Dropsies, and Asthma’s, and Joint-racking Rheums.
Dire was the tossing, deep the groans, despair
Tended the sick busiest from Couch to Couch;
And over them triumphant Death his Dart
Shook, but delaid to strike, though oft invokt
With vows, as thir chief good, and final hope.”
Tranexamic acid fails to limit intracerebral bleeds
This is quite a week for stroke drugs, with anticoagulants at one end, and procoagulants at the other. Tranexamic acid is great at reducing mortality from bleeding due to trauma or childbirth. But it is not very good at limiting the damage caused by intracerebral arterial bleeding. In the Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2) trial, there was a promising early reduction in deaths and serious adverse effects, but by 90 days this had lost statistical significance. Do we need another, bigger trial, or should we just call it a day?
The BMJ 19 May 2018
Nudge, nudge, text, text for diabetes
“Healthy eating is an important part of your diabetes treatment and it will help you in controlling your blood glucose levels. Ping!” New Zealanders with poorly controlled type 2 diabetes and a mobile phone were randomised to receive messages like this, and were assessed “Ping! Looking after your feet will help to prevent issues in the future. Check your feet daily & contact your doctor, nurse or podiatrist if there are changes” …sorry about that; yes, they were assessed mainly by HbA1c change at three and six months. “Ping! Hi Richard. Make sure you have fun activities scheduled regularly. Doing something enjoyable helps reduce stress & improves mood.” Just hang on while I stamp on my mobile phone. Now where was I? Yes, the trial used an automated short messaging service and was called SMS4BG. It had a small effect on HbA1c, but not much on anything else. I think it could be worth offering to those who don’t find it terminally annoying.
Born fat with a fag in the mouth
Somebody should write an up-to-date biography of JBS Haldane (1892-1964), a fascinating polymath and scientist who often ran ahead of his time. I approached his 1932 volume of essays called The Inequality of Man with a certain trepidation. Nobody would dare publish a book with that title today. But actually it is a humane argument against what he calls scientific Calvinism, the idea that our traits are fixed at birth and yet still subject to moral judgment. Haldane argues that if men are born genetically unequal, it is society’s duty to provide those with a poorer hand with more help and less rejection. Now that genetic Calvinism has made a return in the guise of Mendelian randomisation, we are told that there is likely to be a common heritable factor that leads people who are fat to smoke as well.
The trouble with studies like this one (based on the UK Biobank with replication of results from the Tobacco and Genetics (TAG) consortium) is that they are very difficult to interrogate. And if this finding happens to be true, the main message is that we should be less judgmental of fat smokers and make sure that they get replacement nicotine for as long as they need it. Which may be forever, if they are to avoid gaining weight.
Plant of the Week: Wisteria floribunda “Hon-beni”
When did you last see a pink wisteria? I fear they have been pushed out of suburban England by the march of Good Taste. They used to be quite a common sight in the 1970s and 80s, and I can’t say I am entirely sad to see some of them go. There cannot be a worse plant to set against a red brick house wall. But against golden Cotswold stone, or grown over a pergola, they can look wonderful.
It’s true that we have never gone so far as to grow one ourselves. But then we rather lack space for a lingerie-coloured monster in our garden or on our house wall, which is already occupied by a fabulous clone of white Wisteria sinensis. If pink were the only colour that wisterias came in, they would still be the most beautiful large plants in the temperate world. But it has to be said that the commoner lavender-blue and white forms are even finer.
The Japanese clone “Hon-beni” is the commonest of the pink wisterias, but don’t ever rely on names or descriptions. A wisteria is a lifetime’s investment in work and training. You want one where the flowers appear in long tresses before the leaves come out. They must be of the right shade of pink, and heavily fragrant. To get the right wisteria, you need to see it in early flower at the nursery. So you are probably two or three weeks too late: but there is always next year.
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