Richard Lehman’s journal review—15 December 2014

richard_lehmanNEJM 11 December 2014 Vol 371
OL The clones! The clones! There is something of Edgar Allen Poe about this study, which describes how “clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death.” “Heh, heh,” whispers Vincent Price, “come and look at my clones. No, wait, they are YOUR clones! They lie in wait for you, death lies in wait. Your death. Farewell, my friend. The blessings of old age are necessarily mixed with fear.” But although the NEJM kindly makes this paper freely available to all, together with an editorial about Clone Wars, we are not about to see a new epidemic of haematological malignancies in older patients: we will just understand them better and probably devise new poorly predictive tests to worry people more. A second study spells out the same message.

Hear the tolling of the clones,
Bloody clones!
What a world of solemn thought their polyphony intones!
In the silence of the night,
How we shiver with affright
At the melancholy menace in our bones!
For every cell that floats
With mutations in its notes
Tells our groans.

(after The Bells, a poem by E A Poe, op. posth.)

OL If you are unlucky enough to develop the wrong clones, try and hold on. A cure for myeloma may soon be within grasp, but—Edgar Allen Poe again—not quite yet. Carfilzomib is the latest agent to arrive but nobody quite knows where it fits in. Standard therapy for relapsed multiple myeloma now includes lenalidomide and dexamethasone, and the manufacturers of carfilzomib (Onyx Pharmaceuticals) decided to add it to this regimen in a randomised trial, which recruited 792 patients with relapsed MM. This is an interim report, showing a favourable effect on progression and on quality of life, but “the median overall survival was not reached in either group at the interim analysis,” which I think means that too many people in both groups were still alive to tell if this drug makes any real difference. Since its basic cost in the United States is $1 658 per 60mg vial, and all patients required many, many vials, it would be nice to know. From the interim Kaplan-Meyer curve, it would seem that it makes some difference to start with, but that by 36 months this is largely lost.

OL The prevention of venous thrombosis is one of the biggest markets in medicine, and it seems strange now that for decades we got by using nothing but heparin and warfarin. Devilish cunning is now employed to find new ways to interrupt the clotting cascade in such a way as to prevent unwanted thrombosis without increasing the risk of bleeding. A new target is factor XI, and you will be interested to learn that factor XI levels can be lowered with FXI-ASO (ISIS 416858), a 2′-O-(2-methoxyethyl) (2′-O-MOE) second generation antisense oligonucleotide that specifically reduces human factor XI messenger RNA expression in the liver. Well, Isis Pharmaceuticals would like you to be interested anyway, and have persuaded the NEJM to accept what appears to be a phase 2 open label trial of the drug in 300 patients about to undergo unilateral knee replacement, with enoxaparin as the comparator. Their drug had an equal protective effect with less bleeding. But when you are thinking of giving a preventive treatment to millions of healthy people, you need quite a lot more evidence than this.

JAMA Intern Med December 2014
OL Controlling pain is one of the most important aspects of medicine, and the weak opioid tramadol is a popular choice of analgesic in many situations. But some people are unable to tolerate it because of nausea and dizziness, while others, it seems, may be suffering more seriously from less obvious adverse effects. Top among them I would put a serotonergic syndrome of mild agitation and restlessness, or even gross confusion in older patients, caused by doctors forgetting that you should never co-prescribe tramadol with serotonergic antidepressants. But it seems that tramadol may also cause hidden hypoglycaemia. This emerges from a study comparing prescribing of tramadol in UK general practice, using the Clinical Practice Research Datalink, with the Hospital Episodes Statistics database, to detect hypoglycaemia serious enough to lead to admission. In the first 30 days of tramadol use, the odds ratio for hypoglycaemic admission was 2.6, falling to 1.5 thereafter. “The initiation of tramadol therapy is associated with an increased risk of hypoglycemia requiring hospitalization. Additional studies are needed to confirm this rare but potentially fatal adverse event.”

OL A cure for hepatitis C infection is now available, at a cost of around $100 000. So while this infection is present in up to 200 million people, not many of them are going to get anywhere near a proper treatment. Drugs, such as sofosbuvir and ledipasvir, are likely to be reserved for a few people with advanced liver disease who can access treatment through health systems able and willing to cover the cost. A new study of the natural history of hepatitis C infection shows that such a strategy is far from ideal. Fibrotic change in the liver occurs most rapidly straight after infection and tapers off after five years. If these drugs were as affordable as antiretroviral drugs for HIV, everyone with hep C infection would be treated for eight weeks. The virus would cease to do lasting harm, and hep C would cease to be a global problem, because it would cease to be transmitted. It just needs somebody to sort this out—beginning with the drug companies.

JAMA 10 December 2014 Vol 312
The print issue of JAMA this week is devoted to medical education in the US, so I’m just calling your attention to a short free piece on the website, which should persuade you that I am not alone in railing at the marginal benefits and stupendous costs of most newly marketed drugs:
OL Modern Drug Development: Which Patients Should Come First? ask Muthiah Vaduganathan and Vinay Prasad. Using a number of examples, including sofosbuvir, they conclude that: “It is time to return to a patient-centric approach to drug development and offer novel, breakthrough therapies first to the patients who need them most.” I am not sure that quite covers the problem. In the UK, we have the National Institute for Health and Care Excellence (NICE), but that would not stop the NHS being bankrupted if it tried, for example, to eliminate hepatitis C from the UK. It begs all sorts of questions about what treatments are “breakthroughs” and the patients who need them most; but most of all, about why drug companies can charge the prices they do.

Lancet 13 December 2014 Vol 384
2111 Does the world need new stents? No, but device companies need new products for when current ones go off patent. And the Lancet needs to sell article reprints as part of its stated business plan. But do you, dear reader, really need to read a paper entitled “Ultrathin strut biodegradable polymer sirolimus-eluting stent versus durable polymer everolimus-eluting stent for percutaneous coronary revascularisation (BIOSCIENCE): a randomised, single-blind, non-inferiority trial?” I would suggest not.

2123 At the moment, the manufacturer of the new meningitis B vaccine, Novartis, is locked in battle with the UK government about the pricing of its vaccines. The company funded a trial in which university students aged 18–24 years from 10 sites in England were randomly assigned (1:1:1, block size of three) to receive two doses one month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. In the first month, this had no effect on men B carriage, but in the group which received two doses of 4CMenB, carriage rates of the relevant meningococci fell by up to 39%. “An appropriate translation of this individual carriage effect estimate into herd protection will probably only be available after implementation of large scale vaccination programmes.” But should it cost £130 per vaccine dose to find out?

2132 It’s a relief to turn to a trial which compares two ultra cheap and cheerful interventions—oral co-trimoxazole versus intramuscular benzathine benzylpenicillin for impetigo. Not so nice to think that impetigo still affects more than 110 million children worldwide at any one time. This trial was carried out among indigenous children in seven remote communities in the Northern Territory of Australia. It showed that taking three days of oral co-trimoxazole was just as effective as a painful shot of penicillin.

2142 Another common bacterial infection in the children of poorer countries is chronic chlamydial conjunctivitis, causing trachoma and blindness. The causative organism has been around for over 200 million years. “Chlamydia trachomatis evolved with the dinosaurs, and all vertebrates have evolved with their own chlamydial strains. Trachoma remains the most common infectious cause of blindness.” With Christmas coming up, I’ll give you a bit more of this fascinating stuff: “As human beings evolved, occasional chlamydial conjunctivitis did not apparently lead to blindness. However, after the last Ice Age (about 8000 years BCE), when people were crowded in growing communities and hygiene was poor, the frequency of reinfection increased and blinding trachoma resulted. Crowding and poor hygiene lead to outbreaks of chlamydial infections in a range of birds, mammals, and marsupials. Trachoma rates increased greatly as crowding and poor living standards increased at the end of the Agricultural Revolution and the start of the Industrial Revolution, but waned in the 20th century as living standards improved. The disappearance of trachoma from more developed countries was hastened with the introduction of sulpha drugs in the 1930s and antibiotics in the 1940s.” Less delightfully, “Trachoma is still endemic in many of the poorest and more remote areas of Africa, Asia, Australia, and the Middle East. Active trachoma affects an estimated 21 million people with about 2.2 million blind or severely visually impaired.” Let’s hope the first quarter of the 21st century marks the time it ceases to exist.

The BMJ 13 December 2014 Vol 349
I think Trish Greenhalgh must be the busiest person in England. At some time in between doing everything imaginable that you and I try to skive out of, she has managed to plod through a document called Personalised Health and Care 2020. She and Justin Keen go through five major categories where the report fails to learn from the lessons of previous failure, and they conclude, with daring frankness, “We should be concerned about the lack of evidence for these proposals, and sceptical about the intentions of those who support them.” Personally, I have never heard or seen the word personalised used except to mean depersonalised and commercial.

“Previous positive associations between exposure to antibiotics in fetal and early life and subsequent childhood asthma could have been caused by confounding by shared familial factors, in addition to confounding by respiratory infections.” That’s the conclusion of a Swedish population study of 493 785 children born 2006-10, and it seems pretty definitive.

Pretty well everything written in medical journals is there to sell something—an idea or a product—and/or to further a career. You could say that sceptics like me are just part of the same game: “Big fleas have lesser fleas upon their backs to bite ’em, And lesser fleas have smaller fleas, and so ad infinitum.” The dissemination of medical knowledge consists of gathering a dataset, analyzing it, publishing the analysis, and (if it important enough) issuing a press release. A study of this process concludes that: “Exaggeration in news is strongly associated with exaggeration in press releases. Improving the accuracy of academic press releases could represent a key opportunity for reducing misleading health related news.” There is a superb editorial by Ben Goldacre about this, suggesting an easy means of naming and shaming the worst culprits.

General practitioners are there to do an impossible number of things, often badly, and above all to take the blame. We are lousy at spotting the early signs of cancer, says NICE, but then, being a poor ignorant subclass of medical practitioners, we should not really be expected to know what these are. This travesty of the truth is challenged in an excellent analysis piece, which sensibly concludes that: “Diagnosis may be swifter if facilitated by decision support interventions, better interactions between generalists and specialists, and easier access to diagnostics. Policy initiatives focusing solely on professional performance are unlikely to be effective.”

Poem of the Week: The Amateur Flute

I am by no means the first to parody Edgar Allen Poe’s The Bells. You could say that Poe himself was the earliest, in lines like:

And the people- ah, the people-
They that dwell up in the steeple,
All Alone
And who, tolling, tolling, tolling,
In that muffled monotone,
Feel a glory in so rolling
On the human heart a stone-
They are neither man nor woman-
They are neither brute nor human-
They are Ghouls:
And their king it is who tolls;
And he rolls, rolls, rolls,
A paean from the bells!

But the prize goes to this anonymous adaptation for the flute:

Hear the fluter with his flute,
Silver flute!
Oh, what a world of wailing is awakened by its toot!
How it demi-semi quavers
On the maddened air of night!
And defieth all endeavors
To escape the sound or sight
Of the flute, flute, flute,
With its tootle, tootle, toot;
With reiterated tooteling of exasperating toots,
The long protracted tootelings of agonizing toots
Of the flute, flute, flute, flute,
Flute, flute, flute,
And the wheezings and the spittings of its toots.
Should he get that other flute,
Golden flute,
Oh, what a deeper anguish will his presence institoot!
How his eyes to heaven he’ll raise,
As he plays,
All the days!
How he’ll stop us on our ways
With its praise!
And the people–oh, the people,
That don’t live up in the steeple,
But inhabit Christian parlors
Where he visiteth and plays,
Where he plays, plays, plays,
In the cruellest of ways,
And thinks we ought to listen,
And expects us to be mute,
Who would rather have the earache
Than the music of his flute,
Of his flute, flute, flute,
And the tootings of his toot,
Of the toots wherewith he tooteleth its agonizing toot,
Of the flute, flewt, fluit, floot,
Phlute, phlewt, phlewght,
And the tootle, tootle, tooting of its toot.