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Richard Lehman’s journal review—11 March 2013

11 Mar, 13 | by BMJ Group

Richard LehmanJAMA  6 Mar 2013  Vol 309
887   The Greek for belt is zoster, while the Latin for girdle is cingulum. Add Greek for creeping (or snake) and you get herpes zoster, or break down Latin for girdle and you get “shingles.” Either way, you wish it not to happen, and wonder why it has. Concurrent infection and lowered immunity are often blamed, and so suspicion has fallen on the tumour necrosis factor alpha blockers which are commonly used in rheumatoid arthritis. But this study shows that RA patients taking TNF-α blockers are no more likely to get shingles than those who are taking “non-biological” treatments.

926   We’ve become accustomed to giving low dose aspirin to people at higher cardiovascular risk, and clearly people with intermittent claudication count as that. Most of them have smoked and all of them have narrowed leg arteries. This clinical review confirms that all anti-platelet therapies do indeed reduce adverse cardiovascular events in people with leg claudication. Clopidogrel may be more effective than aspirin. So should all patients with peripheral vascular disease be given a platelet inhibitor? Until the last few weeks, I’d have said of course. But people who have smoked are at highest risk of macular degeneration, and we now know that aspirin doubles that risk. We don’t know if clopidogrel does the same. So we really don’t know how to advise our patients about the balance between the risk of a heart attack and the risk of blindness.

It may take months or years before anyone gives us the answer, but it is literally at our fingertips. Anyone who has access to a good enough database such as the UK CPRD can feed in search terms such as aspirin, clopidogrel, claudication, PVD, myocardial infarction, and macular degeneration and get the figures. Put them through suitable statistical software and the observational data could be on line within hours. Anyone with the right skills, sitting in an office in Cardiff or Azerbaijan, could provide this information in real time to clinicians across the world. It is high time somebody set up this service.

NEJM  7 Mar 2013  Vol 368
893   Cut off from oxygenated blood, brain cells die very quickly. The wonder is not that thrombolysis makes so little difference in ischaemic stroke but that it makes any difference at all. The alternative to dissolving the clot is removing it using some type of endovascular procedure, but this takes even longer to organise because it requires a specialised unit with rapid access angiographic facilities. “Current endovascular approaches include endovascular pharmacologic thrombolysis, manipulation of the clot with the use of a guidewire or microcatheter, mechanical and aspiration thrombectomy, and most recently, stent-retriever technology.” Don’t ask me what the last item means.

This paper reports the results of a large stroke trial in which initial treatment with intravenous t-PA was followed by endovascular treatment of any kind preferred by the operator, in the hope of getting early lysis followed a little while after by vessel clearance. It was stopped early because of futility after 656 participants had undergone randomisation. Removing the clot after the damage has been done is not a recipe for success.

904   So how do the two strategies compare if deployed as early as possible in a head-on randomised trial? The answer is that they are equally bad. This Italian trial was much smaller than the previous one and again there was operator discretion when it came to the actual technique used for endovascular clot disruption/removal.

There are various signs of over-pragmatism in this trial—patients were treated within a maximum of 2.5 hours but randomised within 4.5 hours, and on the vexed question of consent during an evolving stroke, we are told that “competent patients gave written informed consent before enrollment; otherwise, a witnessed waiver of consent was possible.” Just so you know: if I have a big stroke, the intravenous treatment I would prefer is a soluble anaesthetic followed by a large slug of potassium chloride.

914   But it might still be argued that there is a place for endovascular stroke treatment if only we know how to select the right patients. Pleading from subgroups and “judicious selection” is always the last refuge of a failing intervention, and so it proves here. The patients who should benefit from mechanical clot removal are those with a “favourable penumbral pattern” on imaging—meaning a small core infarct surrounded by a lot of salvageable brain tissue.

So this trial was set up to compare endovascular treatment with usual care within a generous time frame (8 hours) and to stratify patients according to a favourable or unfavourable penumbral pattern. It ended up demonstrating that “neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care.”

Judging from these three trials, embolectomy seems yet another blind alley in the treatment of acute ischaemic stroke. Use t-PA in suitable patients caught within an hour or so: otherwise let nature take its often brutal course, because there is nothing you can do about it.

924   The next paper is aimed at people with chronic urticaria, and the abstract concludes: “Omalizumab diminished clinical symptoms and signs of chronic idiopathic urticaria in patients who had remained symptomatic despite the use of approved doses of H1-antihistamines.”

Now turn to the full paper: “In conclusion, during the initial 12 weeks of our study, omalizumab at doses of 150 mg and 300 mg significantly improved outcomes as reported by patients with chronic idiopathic urticaria who remained symptomatic despite the use of approved doses of H1-antihistamines. The number of patients who were treated was too small to draw any definitive safety conclusions, but serious adverse events were more common in the group treated with the highest dose of omalizumab. Further work is needed before the exact role of omalizumab in the treatment of chronic idiopathic or spontaneous urticaria can be defined.”

This paper doesn’t just bring me out in hives: I feel quite anaphylactic. If this short term trial doesn’t answer such basic efficacy and safety questions, what is it doing in a leading medical journal? The change in the itch score was only significant for the higher doses. The drug costs $24,000 per year at the highest dose. “The study was sponsored by Genentech and Novartis Pharma, whose representatives were involved in data collection (along with the investigators) and in the interpretation and analysis of the data… Editorial support and assistance with incorporation of revisions was provided by a medical writer who was employed by Genentech. All authors and contributors were under nondisclosure agreements with Genentech.”

A month or three ago, the editor of the NEJM wrote to chide us about suspecting conflicts of interest in the reporting of industry funded trials. Now before the NEJM sells the usual pile of reprints to the sponsoring companies, will he seek assurances that they won’t be used to encourage off-label use of omalizumab for chronic urticaria? After all, the paper begins with heart rending descriptions of how desperate such patients can become, in sentences which read less like serious academic writing than advertising copy. Surely the NEJM has a responsibility to see that this paper isn’t used as such?

I will end this lengthy howl with an even longer extract from Elizabeth Loder’s wonderful recent BMJ blog:

When it came time to examine how medical journals might address their role in selling sickness and disease mongering, I suggested two possible strategies.

First, why not quarantine apparently ground breaking studies about new treatments or interventions in a special journal until the findings are replicated and long term consequences explored? Print copies of the journal would arrive in plain brown wrappers which undone would show the journal’s cover logo of a skull and crossbones. During quarantine, any news stories or summaries of research from this journal would travel with a sternly worded disclaimer, along the lines of those that accompany investment company advertisements. Something like the following would do nicely:

Warning! Taking any action on the basis of this research could result in injury or death. The results described in this study have not been replicated and the long term effects of this treatment are unknown. Past performance is no guarantee of future results. When subjected to further investigation, most published research findings turn out to be false.”

To fill the void, medical journals deprived of these sensational research studies could instead devote themselves to the promotion and prioritization of the less glamorous medical research that really matters: replication studies, comparative effectiveness trials, and long term pharmacosurveillance and safety studies.

My second suggestion was that several parts of a typical research paper are too important to be written by the researchers or anyone else with a vested interest in the outcome of the research. These include the portions where “spin” is mostly likely to enter into the paper, namely the title, abstract, results, and conclusion sections, and any summary or “what this study adds” statements that authors are now sometimes asked to supply. These portions of research papers should instead be written by disinterested parties with subject matter expertise.

I have no illusion that these things will come to pass but I can dream, can’t I?

Yes, and if enough people dream these same things, they will come to pass. They must.

Lancet  9 Mar 2013  Vol 381
805    Now here is what interventional research should look like. The ATLAS trial set out to whether women with early oestrogen receptor positive breast cancer should stop their tamoxifen after five years or carry on for a further five years. Here is a really important clinical question worthy of a very large trial powered to detect an absolute mortality benefit of 2-3%. That meant recruiting 20,000 patients, so that is what the investigators set out to do in 1996; but they stopped at 13,000 in 2005 after another trial had signalled that mortality benefit was highly likely. In fact the breast cancer related mortality difference that emerged is 2.8%, and the difference in all-cause mortality was zero. Full marks to the perseverance of these investigators and a magnificent contribution to clinical knowledge. But Richard Peto’s team can’t leave it at that. Instead of proposing that these figures should be used to allow individual women to choose whether or not to continue tamoxifen because the risks and benefits are so finely balanced, they extrapolate freely beyond the duration of the trial: “For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis.” I do wish great researchers wouldn’t do this, but behave like scientists and wait for the evidence.

825   We face a cunning and deadly enemy. “A major difficulty that has plagued MenB vaccine development is that MenB strains vary both in protein sequence of the vaccine antigens, and protein expression. Indeed, the relevant proteins might be totally absent in some strains. Therefore, bactericidal antibodies that kill a reference strain might not be active against a related MenB strain with low expression of that protein or those containing a protein variant.” I’ll be doing 13 hours of out of hours primary care after writing this. I’ve only seen meningococcus B twice in 40 years but it still makes me anxious whenever I see a febrile child, and I’ll be seeing dozens. An effective vaccine cannot come soon enough: fortunately the two trials reported here indicate that there may well be one out there already.

836   From the sublime to the ridiculous. Here’s the interpretation of this study: “Our results show feasibility, a good safety profile, and promising clinical and angiographic performance results up to 12 months for DREAMS. Our promising clinical results show that absorbable metal scaffolds might be an alternative to polymeric absorbable scaffolds.” What? Since when did “promising” and “might” amount to a clinically significant result? Has this even been edited for its English (“promising” in two successive sentences)? And who does the “our” refer to? Step up Biotronik, who made and named the DREAMS stent, paid for the study, and “had roles in study design; monitoring; and data collection, analysis, and interpretation.” Would they by any chance be interested in buying up a few reprints from Elsevier?

BMJ  9 Mar 2013  Vol 346
So what can I moan about next? When all else fails (which seldom happens), I can always fall back on surrogate end-points. You know the kind of thing: Glucoshine lowers blood sugar, raises HDL-C, helps weight loss, and provides significant (p= 0.002) improvement in erection maintenance time. Here is a study which looked at all randomised clinical trials published in 2005 and 2006 in six high impact medical journals. It simply compares the effect sizes in the trials which report surrogates and the effect sizes in trials which report patient important outcomes. Not surprisingly, the surrogates tend to have greater effect sizes. Note that this study does not attempt to follow up these interventions to see how the surrogates eventually play out in real patient outcomes: that would be much more depressing.

I live in a pretty English village just like Midsomer Mallow, and work among the dreaming spires of Oxford, like Morse and Lewis. Most days I come across at least one dead vicar in a well-tended cottage garden, and a couple of mutilated gay dons lying lifeless in the college quadrangle. In the evenings I watch Wallander, to make me glad I don’t live in Sweden. The weather seems so drab there and murder tends to be so much less stylish. Most of the murderers seem to be on drugs, or mentally ill; and so do most of their victims. But it’s time to get serious: this may actually be true. Here is a Swedish study showing that having drug dependency makes you nine times more likely to die from homicide; depression, and anxiety both double the risk, while schizophrenia lags with a risk ratio of 1.8.

Plant of the Week: Hepatica nobilis

If you have taken my advice from previous years, you will now be enjoying the lovely little flowers of this plant, sky-blue or white in a simple ring of round petals surrounding a few yellow stamens. A must for every garden.

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