Richard Lehman’s journal reviews—20 June 2016

richard_lehmanNEJM  16 Jun 2016  Vol 374
Data about parasites
2335   I love it when it’s parasite time in the NEJM. Tenaciously clinging to the wall of the large bowel, tapeworms suck up the digested food that North Peruvians have carefully gathered and prepared, just like people who reanalyse or meta-analyse data that others have gone to the trouble of producing. Such tapeworms—I mean the Peruvian kind—can be eliminated by a number of strategies. The ones considered here involved screening of humans and pigs, antiparasitic treatment, prevention education, and pig replacement in 42 villages. A scaled up strategy of mass antiparasitic drugs for humans and Taenia solium vaccination for pigs eventually did the trick. At the end of the exercise hardly any village pigs were found to contain meta-analysts. I mean T solium cysts.

Let them take letrozole
OL   “The MA.17R trial was a phase 3, randomized, double-blind, placebo-controlled trial involving postmenopausal women with primary breast cancer who had received 4.5 to 6 years of adjuvant therapy with an aromatase inhibitor, preceded in most patients by treatment with tamoxifen. Within 2 years after completing treatment with the aromatase inhibitor, patients were randomly assigned to receive 2.5 mg of letrozole or placebo orally once a day for another 5 years.” The benefits of letrozole consisted of a 4% absolute difference in recurrence-free survival and 0.28% difference in contralateral breast cancer, both on the edge of statistical significance. There was no difference in overall survival. On the harm side, there was a 6% greater chance of bone fractures and osteoporosis taking letrozole. How much more useful this paper would be if it included a decision aid to be shared between doctors and patients.

Lower SBP no better in brain bleeds
OL   Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Haemorrhage. Thank you NEJM for publishing a trial of real clinical importance, called ATACH-2. It was stopped early for futility. Clinicians can content themselves with a systolic BP target between 140 and 179: a lower target brings no gain in lives or function.

Ixekizumab for psoriasis
OL   It’s coming soon to a dermatology clinic near you. Ixekizumab! Crazy name, crazy drug! Due for UK release on 1 July, 2016. Season tickets available at only £12 000 each, renewable annually. This seems to be the British position with this monoclonal antibody against chronic plaque psoriasis, as far as I can gather. According to this report of three phase 3 UNCOVER trials conducted by Eli Lilly, this stuff really works for most people, compared to placebo and also to active treatment (though it’s often hard to work out what the comparator was, and the trials’ outcomes are intermeshed in complex ways). Without going into any more detail, three quarters of the patients with moderate-to severe plaque psoriasis showed substantial resolution at just over one year. Ixekizumab is a recombinant, high-affinity, humanised, IgG4-κ monoclonal antibody, which selectively binds and neutralises interleukin 17A (IL-17A), the proinflammatory and primary effector cytokine of type 17 helper T (Th17) cells. This is tinkering at a deep level, and there were some worrying signals. This interleukin pathway provides a defence against fungal infection, so candidal infection occurred more in the active treatment groups. Many recipients also got nasopharyngitis, but the reporting of harms in the body of the paper is patchy, and the supplementary material is confusing. But never mind about these minor effects, which did not lead to discontinuation. Of much greater concern is the occurrence of 14 cases of inflammatory bowel disease in patients who had received the drug. And although there was no difference in cardiovascular events over 60 weeks, it is worrying to think that theoretically ixekizumab could make arterial plaque less stable for the same reasons that it mobilises psoriatic plaque. To say that the safety data “accounted for 3458 patient-years of exposure to ixekizumab” is unhelpful if the events you are most worried about are unlikely to accumulate in the first 60 weeks of treatment. “The initial draft of the manuscript was written by a medical writer paid by Eli Lilly . . . A second medical writer paid by Eli Lilly provided writing support during the review of the manuscript.” This seems to be standard practice, but it doesn’t strike me as the best way to ensure the unbiased reporting of medical science.

Crazy names part 2
OL   You liked ixekizumab. Well, wait for this. There’s a new Pfizer drug for acute lymphoblastic leukaemia. It prolonged survival in some patients, while for 11% it brought on veno-occlusive liver disease. And its name is: inotuzumab ozogamicin. Inotuzumab. Ozogamicin. You couldn’t make it up. Oh wait, somebody must have.
N.B. “Two employees of Complete Healthcare Communications, who were funded by Pfizer, developed the first draft of the manuscript under the direction of the authors.” This is further worrying evidence of an outbreak of agraphia among clinical investigators in industry funded trials.

JAMA  14 Jun 2016  Vol 315

Aspirin for ARDS: read & forget
2406   When I read the title “Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department” I thought, help, I’ll have to get my head round this. Acute Respiratory Distress Syndrome is something I’ve never witnessed under that label, which I think it acquired about 20 years ago. I imagined that it was a multifactorial and unpredictable physiological syndrome, but here they seemed able to identify at risk patients. What were the selection criteria and could aspirin really have an effect on the syndrome? I need not have worried. Aspirin had no effect so I can leave the matter alone and move on.

Opioids for chronic pain kill some
2415   The popularity of long acting opioids for non-cancer pain in North America is undoubtedly leading to thousands of deaths. Quantifying them, however, is a tricky business. Here’s an observational study from Tennessee that tries to use propensity scoring to allow comparisons between new episodes of prescribed therapy for long acting opioids or either analgesic anticonvulsants or low dose cyclic antidepressants (control medications). Allowing for time differences between groups, those prescribed opioids had at least a 64% higher mortality than people prescribed non-opioids in the first few months. In fact, it was over 90% in the case of out-of-hospital deaths, and this was only partly explained by unintentional overdosage. Here’s a situation where you could quibble about confounding and absolute risk differences, and speculate about causation, but the clear fact is that these drugs are dangerous.

JAMA IM  June 2016
Screening for bowel cancer
OL   This is a good week to sharpen your understanding of the issues around bowel cancer screening. Two editorials from people outside the gastroenterology/screening community take a critical look at what’s going on in the US. Rita Redberg’s piece here could not be clearer.

Despite a gut feeling (pardon the expression) that colonoscopy has to be better than flexible sigmoidoscopy, there’s no evidence for that, and we do know that it can cause more complications. Faecal occult blood testing is pretty hit and miss as an initial population screening stool—sorry, I mean tool; but so is a new blood test that is being touted in the US. This is the subject of an editorial by Ravi Parikh and Vinay Prasad on the JAMA website.

Both articles are open access and well worth going through. The evidence that bowel cancer screening saves lives (even on a disease specific level) is remarkably flimsy.

Lancet  18 Jun 2016  Vol 387
Keats, physician to all men
2498   John Keats grew up an orphan but chanced to have a relative who would pay for him to become an apothecary’s assistant. He got just enough support to become an official medical student at Guy’s Hospital and dresser to the famous Sir Astley Cooper, who thought well of his surgical skills. Books and essays about Keats the nearly doctor are fairly numerous and sometimes fairly good. This latest one places what is known about Keats’s decision to give up surgery in the context of contemporary writings about the need for physicians to have wide learning and sympathies. Nobody had wider or deeper sympathies than Keats, or learning more attuned to the visionary. There is no limit to what he might have written had he lived. The best evidence is in the fragments of the Fall of Hyperion:

                    … sure not all

Those melodies sung into the world’s ear

Are useless: sure a poet is a sage,

A humanist, physician to all men.

Safe drugs to help quit smoking
2507   It’s always nice when a randomised trial confirms what observational evidence has already found. Population-wide linkage studies have shown no evidence of neuropsychiatric harm from using bupropion or varenicline as an aid to smoking cessation. The triple-dummy EAGLES trial confirms this. Also,“Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo.” All good to know, but it seems to me that a government serious about protecting its citizens from the harms of combustible tobacco would simply make the stuff unavailable. E-cigarettes and safer forms of nicotine are everywhere. But don’t hold your breath: doing this would cost £9bn in tax revenue.

Going Dutch with tocilizumab
OL   “We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands.” “The funder of the study (Roche Netherlands) had a role in study design, data analysis, data interpretation, and writing of the report.” How many rheumatology outpatient departments are there in the Netherlands? Does this mean they all took funding from Roche? Is a “strategy study” the same as a randomised controlled trial? The waters here do not run clear. The problem is that the European League Against Rheumatism (EULAR) recommends early treatment in rheumatoid arthritis to achieve clinical remission and recommends an individualised treat to target approach. This makes it very difficult to assess the drug you are trying to promote. I mean test. If I read this trial right, it was initially a comparison between methotrexate plus placebo or MTX plus tocilizumab followed by a free choice of add-on drugs if that failed to achieve the clinical disease control target. At this point most of us would give up trying to look at the figures. This whole trial cries out for (a) release of data for independent analysis, (b) replication by an autonomous body, and (c) a head-on comparison with another agent. Believe the interpretation or not as you like: “For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards.”

The BMJ  18 Jun 2016  Vol 353
A grainy picture
Just take a look at The BMJ Research section on the website. It’s like a restaurant: potatoes, fruit and vegetables, alcohol (twice), and a side order of whole grain bread. It should be called the Confounding Diner. If you add up all the (confounded) studies of whole grain consumption, you get “further evidence that whole grain intake is associated with a reduced risk of coronary heart disease, cardiovascular disease, and total cancer, and mortality from all causes, respiratory diseases, infectious diseases, diabetes, and all non-cardiovascular, non-cancer causes.” This is truly wonderful. Whole grains are the elixir of life. But I suspect you might get a similar result for self-reported sandal wearing. The only way to settle this question is a large 10 year prospective trial based on daily stool grain counts, with groups adjusted for sandal wearing.

Danish fibrillation and NOACs
If you combine lots of heterogeneous observational studies based on faulty metrics, you can reach any conclusion you like. But it’s different when you can examine a single very large dataset. Denmark’s isn’t the biggest (that honour should go to the UK, but in fact it goes to Taiwan), but it is certainly among the best. Amid conflicting reports about which direct oral anticoagulant (DOAC, formerly NOAC) might be best for use in atrial fibrillation, this message from 61 678 patients newly started on treatment in Denmark is reassuringly simple for clinicians: “All NOACs seem to be safe and effective alternatives to warfarin in a routine care setting. No significant difference was found between NOACs and warfarin for ischaemic stroke. The risks of death, any bleeding, or major bleeding were significantly lower for apixaban and dabigatran compared with warfarin.”

Plant of the Week: Mimulus aurantiaca

This sub-shrub has sticky, aromatic, evergreen leaves and wonderful frilly, tubular, orange flowers. It’s found along the Pacific North American coast as far north as southern Oregon, so it can just about cope with most English winters, though we’ve lost a couple over the years.

It sprawls happily in any kind of soil and in full sunshine. There are various varieties around, based on a natural variation between yellows and reds and everything in between, rather as with nasturtiums. We can’t get enough of this colour range when associated with delphiniums, or at a lower level, with clear blue veronicas. It’s the essence of happy summer gardening.