Richard Lehman’s journal review—3 January 2017

richard_lehmanNEJM  22-29 Dec 2016  Vol 375

Co-amoxiclav for OM in under-twos

This trial firmly establishes the superiority of a ten day over a five day course of co-amoxiclav for babies and toddlers with acute otitis media. The figures are clear: with only five days treatment, failure of resolution at ten days is 34%, whereas if ten days of treatment are given, it is 16%, and the babies suffer fewer symptoms. So here we have a nice simple trial to inform practice in a very common and distressing clinical situation. More is sometimes more.

Ocrelizumab for MS

As we close the door on ghastly 2016, what better to cheer us up than another expensive monoclonal antibody for multiple sclerosis? Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20, a cell-surface antigen that is expressed on pre-B cells, mature B cells, and memory B cells but not on lymphoid stem cells and plasma cells. The two OPERA trials lasting less than two years showed that it reduces progression of disability by a small amount in relapsing-remitting MS compared to interferon beta-1a; but the same can be said for a range of drugs. The real excitement comes with a signal for effect in primary progressive MS, a horrible disease for which there is no current effective treatment. The trial in question is called ORATORIO, reminding music lovers of the switch that Handel made from opera to oratorio in the late 1730s (see end-piece). Here is the cautiously phrased conclusion of the abstract: “Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann–La Roche).” This is agonizingly true. Nobody should get access to this drug for progressive MS except in the context of a carefully conducted extended study. And until that is complete, no money should change hands.

JAMA  20-27  Dec 2016  Vol 316

Herpes drug contest

In general, JAMA is mercifully free of trials designed to prove the superiority of a me-too drug over an existing treatment. In recurrent genital infection due to herpes simplex virus 2, there are several nucleoside analogues which have been used for decades, such as aciclovir and valaciclovir. Here the patient-important outcomes are cure, reduction in recurrence, reduction in transmission, and safety. For some reason, JAMA has decided to publish a phase 2 trial of a new type of anti-herpes agent, pritelivir, which measured a surrogate for just one of these. HSV shedding was detected in 2.4% (173 of 7276 ) of swabs during pritelivir treatment compared with 5.3% (392 of 7453) during valaciclovir treatment. Does this mean that these patients are less likely to transmit infection? We don’t know. The number of shedding episodes did not differ between groups. Then the US Food and Drug Administration placed the trial on clinical hold based on findings in a concurrent nonclinical toxicity study, and the sponsor terminated the study. So this paper actually tells readers nothing that could inform their practice.

Penalizing readmissions

The grip of the state on American hospitals is loose, but when it can get a hold, it can be effective. The Medicare and Medicaid (CMS) budget is edging towards $1000 billion annually, most of it spent through the deregulated US hospital system. Here’s a wonderfully comprehensive study of the effect of a Medicare penalty initiative for hospitals that were considered to be readmitting too many patients. The roster of authors includes lots of my friends. They looked at nearly 50 million Medicare admissions in penalized and non-penalized hospitals. The readmissions that Medicare wanted to reduce were for acute myocardial infarction, heart failure, and pneumonia: and lo! these readmissions fell more in the penalized hospitals. Also, changes were greater for those specific conditions in penalized hospitals, whereas there was no difference in trends by condition in non-penalized hospitals. A similar, smaller study in the Annals of Internal Medicine shows the same effect.

JAMA Intern Med  Dec 2016  Vol 175

Antibiotic prescribing feedback

The Medicare penalty study shows that financial sticks can be effective. At the other end of the incentive spectrum is the moral carrot. I am by nature more a carrot-dangler than a stick-beater, and I’ve seen moral carrots used very effectively to improve prescribing in UK general practice, whereas I think the Quality and Outcomes Framework in its income deprivation phase has been a disaster. Anyway, let’s go to Switzerland, where physicians were randomized to quarterly updated personalized antibiotic prescription feedback over 2 years (n = 1450) or usual care (n = 1450). Nibbling on the moral carrot achieved very little. “This nationwide antibiotic stewardship program with routine feedback on antibiotic prescribing was not associated with a change of antibiotic use. In older children, adolescents, and younger adults less (sic) antibiotics were prescribed, but not consistently over the entire intervention period.”

Does femaleness in doctors save lives?

American medical journals stay po-faced over the holidays, in a country where even the word Christmas cannot be uttered. But JAMA IM provided some seasonal cheer and much tweeting with this article about the life-saving qualities of female doctors. (Is there a Cotswold village called Much Tweeting? It should feature in the next Christmas edition of The BMJ). Anyway, investigators from Harvard examined over a million and a half Medicare acute admissions to find out if there was a difference in outcome according the sex of the hospital doctor. The ladies have it: patients treated by female physicians had significantly lower adjusted rates of mortality (11.07% vs 11.49%) and readmission (15.02% vs 15.57%) compared to those cared for by male physicians in the same hospital. I don’t know if there is a Cotswold village called Residual Confounding, but it certainly provides an endless supply of interesting observational papers.

Lancet  Dec 2016

Pelvic floor exercises, again

PREVPROL sounds like something set up by Leon Trotsky to encourage the permanent revolution of the proletariat. In fact it is the acronym of a trial of pelvic floor muscle training for secondary prevention of pelvic organ prolapse.

The participants were women who already had a significant degree of uterine or vaginal prolapse and they were randomised to pelvic floor exercises to see if these could stop it getting worse. The primary outcome was self-reported prolapse symptoms (Pelvic Organ Prolapse Symptom Score [POP-SS]) at two years. There was a one-point difference in the 28-point score in favour of the intervention at the end of the trial. This is described as “probably important.”

Mesh in a mess

If you happen to be a woman with the said prolapse, avoid mesh. This is the moral of the PROSPECT trial, which also used the POP-SS score. It pops up everywhere. The trial was the first adequately powered one to compare the outcomes of anterior or posterior vaginal prolapse repair involving either synthetic mesh inlays or biological grafts against standard repair in women. Result: “Augmentation of a vaginal repair with mesh or graft material did not improve women’s outcomes in terms of effectiveness, quality of life, adverse effects, or any other outcome in the short term, but more than one in ten women had a mesh complication.” But an observational study from Scotland concludes that there may still be a role for mesh if the aim is specifically to alleviate urinary incontinence. The investigators followed up a large cohort of women in Scotland aged 20 years or older undergoing a first, single incontinence procedure or prolapse procedure during 1997–98 to 2015–16, identified from a national hospital admission database. Long-term results for the incontinence surgery group showed that compared with non-mesh open surgery (colposuspension), mesh procedures had a lower risk of immediate complications (adjusted relative risk [aRR] 0·44) and subsequent prolapse surgery (aIRR 0·30) and a similar risk of further incontinence surgery (0·90 [0·73–1·11]) and later complications (1·12 [0·98–1·27]).  But for repair of prolapse alone, the results of mesh were definitely inferior to simple repair. It you’re wanting more discussion, go to the useful editorial.

Subcutaneous methotrexate for psoriasis

The makers of a pen for the subcutaneous injection of methotrexate decided to test their product against placebo for moderate-to-severe plaque psoriasis. They argue that “Methotrexate is one of the most commonly used systemic drugs for the treatment of moderate to severe psoriasis; however, high-quality evidence for its use is sparse and limited to use of oral dosing. We aimed to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis.” Well yes, but why then was the comparator not orally administered methotrexate? For sure, the subcutaneous drug worked much better than placebo, and there were only three serious adverse events in 91 patients receiving it over 52 weeks. But it’s not as if MTX is an unfamiliar drug without known long-term hazards. Again, I struggle to see the purpose of this trial as a guide to clinical practice.

Ebola vaccine success

No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035.”

A happy note on which to end a vile year.

Composer of the Week: George Frideric Handel

This is the time of year when the tunes of Handel’s Messiah and the texts chosen from the Bible by the Rev. Charles Jennens reverberate through many halls and heads. But Handel’s first really successful oratorio was not Messiah but Saul (1738). Jennens—the librettist of both—writes on the composer’s plans for this ostentatious new work:

“Mr. Handel’s head is more full of Maggots than ever: I found yesterday in His room a very queer Instrument which He calls Carillon (Anglice a Bell) & says some call it a Tubal-cain, I suppose because it is in the make and tone like a Hammer striking upon Anvils. ‘Tis played upon with Keys like a Harpsichord, & with this Cyclopean Instrument he designs to make poor Saul stark mad. His second Maggot is an Organ of 500£ price, which (because he is overstock’d with Money) he has bespoke of one Moss of Barnet; this Organ, he says, is so contriv’d that as he sits at it he has a better command of his Performers than he us’d to have; & he is highly delighted to think with what exactness his Oratorio will be perform’d by the help of this Organ; so that for the future, instead of beating time at his Oratorio’s, he is to sit as his Organ all the time with his back to the Audience … I could tell you more of his Maggots: but it grows late, and I must defer the rest till I write next; by which time, I doubt not, more new ones will breed in his Brain.”