Richard Lehman’s journal review—26 September 2016

richard_lehmanNEJM  22 Sep 2016  Vol 375

Learning to love data parasites

Back in January, the chief editor of the NEJM joined many other leading journal editors in signing a radical proposal for data sharing tabled by the International Committee of Medical Journal Editors. But at the same time he co-authored an editorial saying that the research community was deeply worried about the prospect of data parasites invading its glorious body of work. Since then, the NEJM has published a good number of Viewpoints expressing different degrees of love or loathing for data parasites. My heart sank at the prospect of reading three more this week, so I decided to listen to Jeff Drazen’s podcast instead (which is a first for me). Having heard the negative gossip about the recent meeting of the International Committee of Medical Journal Editors, I had low expectations. But JD’s tone is very positive. In fact his discussion of the issues is quite similar to those we had five years ago when Harlan Krumholz set three of us to work with him on the Yale University Open Data Access project. The NEJM conversion may be coming late, and it may be too little for some, but it really is progress. And they are backing it up by releasing the SPRINT data.

Andexanet the antidote

My last evening of clinical practice two years ago was quiet. Somebody rang up to say that they were on warfarin and their INR was 8—what should they do? I said I’d sort out some vitamin K. Three minutes later they rang back to say someone had just come to their door with vitamin K. The system had worked without my doing anything. But what if they were having a major bleed after taking a factor Xa inhibitor? They would have to be rushed in for a bolus of andexanet followed by a two hour infusion of the drug. That’s what happened to 67 such patients in what is described as “multicenter, prospective, open-label, single-group study” i.e. a we-gave-it-and-it-worked trial. Actually, it didn’t work very well for 21% of the patients, but I’m not aware of any current alternative. It seems it will be priced accordingly.

A new class of antimalarials?

Malaria can be treated easily in most parts of the world, usually by using artemisinin based drug regimens. The exception is Southeast Asia, where these drugs have become less effective in a cluster of localities. Enter the imidazolopiperazines, a new class of antimalarial agents with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites. This paper describes outcomes in 41 patients with acute Plasmodium vivax or P. falciparum malaria who were treated with a new agent in this class, currently called KAF156.” There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients.” Is that a good start? I think we’ll wait and see. It was generally effective either as a three-day course or a single higher dose.

JAMA  20 Sep 2016  Vol 316

Sharing individual participant data

Now that the principle of sharing data is accepted, discussion has moved to practicalities. Individual participant data (IPD) are not easy to handle and analyze. For those who are interested, JAMA offers a short Viewpoint on the need to liberate IPD in the future. Let’s hope there will be a big push for more IPD meta-analysis, despite the extra effort and resources this will involve.

Wearable aid for obesity maintenance

Oh, the delicious irony. “Among young adults with a BMI between 25 and less than 40, the addition of a wearable technology device to a standard behavioral intervention resulted in less weight loss over 24 months.

Those who wore electronic activity monitors ended up with 2.6 kg more residual weight than those who did not. This is fascinating. Perhaps they were falsely assured by the device that they had done enough activity for the day. Or perhaps wearing the gizmo induced them to believe that physical activity is more important for weight loss than restricting food intake, which sadly is not the case.

Feeding allergens to babies

A big systematic review tells us what we already knew—that early egg or peanut introduction to the infant diet is associated with lower risk of developing egg or peanut allergy. But it also says two things which I hadn’t fully taken on board: “There was high-certainty evidence that timing of gluten introduction was not associated with coeliac disease risk, and timing of allergenic food introduction was not associated with other outcomes.” That rather cryptic second half about “other outcomes” refers to wheeze, eczema, allergic rhinitis, allergic sensitization, type 1 diabetes mellitus, coeliac disease, inflammatory bowel disease, autoimmune thyroid disease, and juvenile rheumatoid arthritis. Which is useful to know.

Antimicrobial resistance

I printed off this lengthy (open access) narrative review and sat down with it for half an hour in the hope that I might understand its last sentence:” Without a coordinated response, the postantibiotic age presaged by so many is a distinct and unwelcome possibility.” I was working on a urology ward at St Thomas’s Hospital in London in 1976 when one of our patients on the ICU was found to have a Klebsiella infection resistant to all the antibiotics then available. The ICU was closed for a few days and nothing more happened. I then went on to work in general practice for 38 years and ended up using the same small range of antibiotics in 2014 as in 1977, with exactly the same rate of success. But am I wrong to be complacent? The only new information I learnt from this paper is about the spread of metallo-β-lactamases from India and carbapenamases from the USA over the last 15 years or so. These seem to be new mutations, whereas the rest of the beta-lactamases are probably 2 billion years old, coinciding roughly with the emergence of eukaryotic life. And although these “superbugs” are of potential significance for hospital treatment of gram-negative infection, they don’t appear to be invading many hospitals anywhere in the world. There is a modest need for new strategies and drugs, but the article demonstrates that there are more in the pipeline already than there are bacterial mechanisms capable of outwitting them. The hype that surrounds this subject continues to puzzle me. There are far more important things for the United Nations and funders to worry about, not least the equitable delivery of health care, including antibiotics, to those who most need it/them.

JAMA Intern Med  Sep 2016  Vol

Azithromycin doesn’t help asthma

Antibiotics may have benefits and harms that are yet hidden from view, but from the British AZALEA trial we can be pretty certain that azithromycin does nothing to help acute exacerbations of asthma in adults. The same probably applies to all antibiotics. The triallists ruefully observe that “For each patient randomized, more than 10 were excluded because they had already received antibiotics.” It seems that this is a socially ingrained practice in the UK, as it probably is across the world.

Antibiotic use in US hospitals

If hospitals are the breeding ground of resistant bacteria, that is as it should be. If I have an infection serious enough to end up in hospital, I expect to get some serious antibiotics. “Stewardship” is all very well but if I get sepsis I want the pharmacopeia  thrown at me. Maybe antibiotics are overused in hospitals. I don’t know. Their use in the USA has shown no change from 2006 to 2012, though there’s a trend towards using more broad-spectrum agents, which the stewards don’t like.

Lancet  24 Sep 2016  Vol 388

Children’s diarrhoea in Africa and Asia

The Global Enteric Multicenter Study (GEMS) mapped moderate to severe diarrhoea in children younger than 5 years in Africa and Asia, using quantitative real-time PCR for the first time. This technique is as definitive as we’re likely to get, and generated the following list, in descending order: Shigella spp, rotavirus, adenovirus 40/41, heat-stable enterotoxin-producing E coli, Cryptosporidium spp, and Campylobacter spp. Since these together are the second leading cause of mortality in children worldwide, I hope their elimination will be among the top five topics in medical journals over the next few years.

Sitting time, TV, exertion, and mortality

“Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women.”

Welcome back to the sedentary world, where diarrhoea may prolong life because it makes people run more than they usually do. I hadn’t previously encountered a “harmonised” meta-analysis, but it seems to be the kind where you feed in a mass of individual observational data and then test a hypothesis from them—or two hypotheses in this case. One is to do with sitting and physical activity and the other is to do with watching television.” High levels of moderate intensity physical activity (ie, about 60–75 min per day) seem to eliminate the increased risk of death associated with high sitting time. However, this high activity level attenuates, but does not eliminate the increased risk associated with high TV-viewing time.” I think it is time we got a dog. Cats just snuggle purringly on your lap, making it impossible to stop watching television, however bad the programme. Dogs whine and beg for walkies.

TheBMJ  24 Sep 2016  Vol 354

Losing fat in those genes

So far, 97 gene loci have been identified as accounting for about 2.7% of variation in body mass index. How impressive is that? I’d say it’s as impressive as 2.7% divided by 97. Prominent among them is the fat mass and obesity associated (FTO) gene, which despite its name hardly accounts for anything. This is shown by a meta-analysis of weight reduction trials involving 9563 participants in total.

People with the “obese” FTO genotype showed no difference in weight loss from the rest. Now I’m no statistician, but wouldn’t you have needed about a million participants to start finding an association? So far, precision medicine in this area is 97.3% imprecise despite identifying 97 genes. While you’re waiting, lose weight by eating less and doing more.

Firm evidence on asterides

Drugs ending in “-asteride” are 5-α reductase inhibitors. They are a drug manufacturers’ dream, because you can market them for symptoms of benign prostatic hyperplasia and male pattern baldness, without the millions of men involved ever being able to tell if they are doing anything. Men with these conditions also tend to be of an age when erectile function may, alas, start to decline. Could it be that taking these anti-androgenic drugs might worsen this? The only way to find out is to gather observational evidence—I mean from places like the UK Clinical Practice Research Datalink rather than directly, of course. This analysis of CPRD data finds that finasteride and dutasteride “do not seem to significantly increase the risk of incident erectile dysfunction, regardless of indication for use. Risk of erectile dysfunction increased with longer duration of benign prostatic hyperplasia.”

When to stop beta-blockers after MI

It’s a question that’s vexed cardiologists—and normal doctors—ever since the 1960s, when the first trials of β-blockade immediately after myocardial infarction showed a modest short-term survival benefit, partly mediated by a reduction in heart failure. Fifty years on, survivors of MI without heart failure carry on taking β-blockers for years, often indefinitely. Here is some observational evidence from a French database which doesn’t altogether settle the question of whether they should, but does put us in the right ball-park (have I got that right? What is a ball-park, by the way?). In 2679 consecutive patients with acute myocardial infarction and without heart failure or left ventricular dysfunction, early β blocker use was associated with reduced 30 day mortality in patients with acute myocardial infarction, and discontinuation of β blockers at one year was not associated with higher five year mortality. There’s a nice contrast with statins, confirming their benefit for secondary prevention: five year mortality was lower in patients continuing statins at one year (hazard ratio 0.42, 0.25 to 0.72) compared with those discontinuing statins.

Plant of the Week: Rosa “Mme Alfred Carrière” 

Almost all the roses in our garden are the older varieties featured in Graham Thomas’ wonderful works of scholarship, collected together as The Graham Stuart Thomas Rose Book (1994). This one is recorded in the section on Noisettes, as originating from Vve Schwartz, France, 1879. “Very far removed from our original Noisettes, but a wonderful plant and as perpetual as any.” This is true—our young one currently carries 20 palest pink blossoms with a lovely scent. “It remains one of the more popular old climbing roses to this day, and can compete on equal terms with modern roses in every respect, if we do not cavil at its pale colouring.”

We would not dream of so cavilling. It is a joy throughout the season, especially now in the last weeks of garden glory. It is thriving in badly drained soil on a north facing wall. It lacks self-discipline but this can be supplied by the gardener.