Richard Lehman’s journal review—28 July 2014

richard_lehmanNEJM 24 July 2014 Vol 371
371  Long ago I had a patient who kept having odd things happen to her. She infarcted part of her cerebellum, and then did the same to two fingers on her right hand. She was full of pains, her kidneys were failing, and her erythrocyte sedimentation rate (ESR) stayed high. When CRP became available in our little hospital, that stayed high too. Then, finally, somebody ran a brand new test on her—anticardiolipin antibodies. At last we had a diagnosis—antiphospholipid syndrome! Getting this label made absolutely no difference to her since she had already been given all the usual “empirical” treatments, like aspirin which made her bleed, and steroids which made her even huger and more diabetic. She died long ago, but for the last 25 years, I have been reading pieces about antiphospholipid syndrome in the hope of discovering (a) that somebody understands it and (b) that there is an effective treatment. Now a little bit of my hope has been fulfilled. Twelve years ago, some patients whose kidneys had been destroyed by this syndrome received renal transplants and were given sirolimus as an anti-rejection drug. Now 70% of them have functioning allografts, whereas for those who did not get sirolimus the percentage is 11. So sirolimus urgently needs investigating as a treatment for the more severe forms of the syndrome. And from biopsy and autopsy samples, it seems that the destructive process is driven by mTORC through the phosphatidylinositol 3-kinase (PI3K)–AKT pathway, which sirolimus suppresses. Serves me right for wanting to know.

JAMA 23 July 2014 Vol 312
An HIV themed issue, so I will leave it for experts.

JAMA Intern Med July 2014
Among the many articles I would like to write, if I were a controversialist rather than a retiring dweeb, would be “Antibiotics: the Case for Complacency.” But the thought of drawing on my head the combined ire of every public health physician from Dame Sally Davies downwards is a severe disincentive. Let me then merely point you to this Viewpoint, by James Floyd and Bruce Psaty, called The Potential Risks of Expedited Approval of Drugs for Acute Bacterial Infections. Acute bacterial infections can cause death. To prove the superiority of your new antibiotic against the best existing one you need to count deaths, cures, and speed of cure. There are no dependable surrogates. The authors cite the expedited approval last year of televancin for hospital acquired pneumonia on the basis of two non-inferiority trials. Televancin has since proved not only non-superior, but also more harmful. Wild talk of an imminent return to the pre-antibiotic era can cost lives. New antibiotics need to be as rigorously tested as all drugs—i.e. more rigorously, not less, than at present—precisely because we already have so many excellent ones. I have said enough and will say no more, except to commend Bruce Psaty’s other writings. When a young student of literature, he wrote a truly excellent account of Cicero’s moral theory of rhetoric, and later produced (for his doctoral thesis) a masterly book on Shakespeare’s King John and the contemporaneous Tudor play of the same name. That’s the sort of thing I’d love to spend my declining years dabbling in, before I and the entire globe perish from resistant bacterial infections.

But I shall spend a year or two yet tearing my hair out about the idiocies of current medical practice. That is why I have so little hair left. When I qualified in the 1970s, all the talk was about how the great days of medical progress had come to an end, that medicine was becoming unaffordable, that we needed to base practice on better evidence, that antibiotics would soon be useless, that doctors didn’t have enough personal contact with patients, that there was not enough emphasis on prevention, that hospitals were becoming outmoded and care should be transferred to the community, that we should look at the wider determinants of health, that America provided the worst model of healthcare in the world, that we should borrow more ideas from America, that the NHS was the ultimate moral standard of health provision/an outdated collectivist idea. Et cetera: dear children, there is nothing new under the sun. We spend our working lives fighting for what good there is until we tire and die. The immediate trigger for these thoughts is a paper about Comparative Outcomes of Catheter-Directed Thrombolysis (CDT) Plus Anticoagulation vs Anticoagulation Alone to Treat Lower-Extremity Proximal Deep Vein Thrombosis. I hope this is self explanatory because I don’t intend to explain it. Looking at over 90 000 hospital admissions for DVT, the investigators find that the percentage treated with catheter delivered thrombolysis doubled from 2.3% in 2005 to 5.9% in 2010. There was no difference in mortality compared with simple anticoagulation, but longer hospital stays, increased costs, and increased adverse events. And 35% of the CDT patients also received vena cava filter placement, a procedure for which there is no evidence either. The authors call for a randomised trial. But how on earth do these procedures still get adopted without any RCT evidence to start with?

Lancet 26 July 2014 Vol 384
OL  So now we know it: paracetamol does not make any difference to the time a person with acute low back pain recovers. Did anyone think it did? Surely this delusion only applies to the analgesics that are given the designation “anti-inflammatory” in the hope that they will have a stronger placebo effect. I have seen people with low back pain almost every day of my working life, and advised or prescribed paracetamol and/or NSAIDs to nearly all of them. But I’ve never harboured the belief that drugs could possibly speed recovery, and only held the weakest hope that they would kill the pain. According to this study from Sydney, paracetamol works as well as placebo, so that’s at least one good reason to recommend it.

OL  Now for a tick off trial. I like these, because once they are done they are done. When somebody has done a good RCT to determine if antepartum dalteparin reduces complications in pregnant women with thrombophilia, and found that it does not, the box is ticked. No more trials, unless you have got some massive grant from the manufacturer to go on and examine some promising subgroup. Which does not appear to be the case here.

The BMJ 26 July 2014 Vol 349
Last week I was pressed for time and omitted to comment on John Yudkin and Victor Montori’s splendid demolition of “pre-diabetes.” When the full story is known, the dissemination of this bogus concept will be seen as a classic illustration of how the machinations of a lobby of vested interests can triumph over complete lack of evidence. “We need a shift in perspective. It is critically important to slow the epidemic of obesity and diabetes. Rather than turning healthy people into patients with pre-diabetes, we should use available resources to change the food, education, health, and economic policies that have driven this epidemic.” I am optimistic that—thanks in substantial part to the efforts of these two authors—we have reached a tipping point.

This week’s exceptional issue of The BMJ is dominated by dabigatran and lipids. The blockbuster articles on dabigatran by Deborah Cohen, and Thomas J Moore and colleagues, are essential reading for industry followers, but the Editorial by Blake Carlton and Rita Redberg is the thing to read for everybody. The Food and Drug Administration thought the world needed new oral anticoagulants so desperately that it approved Boehringer Ingelheim’s Pradaxa on the basis of a single trial called RE-LY. “Dabigatran achieved blockbuster status, with sales of over $1bn (£580m; €740m) globally by April 2012 and $2bn in the US by 2014 despite increasing concerns about safety. By December 2011 adverse drug event databases in Europe, Japan, and the US showed thousands of serious and fatal haemorrhages in patients taking dabigatran, particularly older patients.” The selling point of Pradaxa was, of course, that you don’t need to do any blood monitoring, but in the unpublished parts of the RE-LY trial there was plenty of evidence that plasma level monitoring would improve dosing and help to avoid serious haemorrhage. “Society must consider the trade-offs of accelerated drug approval in terms of assurance of safety and effectiveness. A more transparent process of data collection and review would make important clinical data available without waiting for litigation and subpoenas, which is what it took to unearth some of Boehringer’s early concerns with dabigatran.” How many times do we have to say this?

For a variety of reasons, I spent weeks poring over the new NICE guidance on statins, summarized in The BMJ. It really came close to driving me mad, but nature came to the rescue by laying me low with a horrible complex migraine that lasted three days. Since then I have vowed to have no more to do with this document. To me, it’s the NICEst possible illustration of everything that is futile and outdated about guidelines. It barks endless orders (99 with subdivisions, and then some), which if taken seriously would leave no time for the rest of primary care, while providing nothing substantive to guide a genuine open dialogue with the individuals who are expected to take lifelong treatment. It covers its back by recommending dietary modification and activity before drugs, and exonerates itself by saying clinicians are free to do what they like after discussion with patients, but it provides nothing to aid such discussion except an endless list of study analyses. Which in turn brings us to the entirely inadequate state of the evidence for sharing decisions honestly with patients. I’m truly grateful to Ben Goldacre for summarizing this issue so brilliantly: “Mass prescription for modest individual benefit is new. Truly informed choice will require more than good intentions. We will need better data, from bigger trials, and better risk communication than for conventional medical treatment. Delivering this will require us to embed the gathering, communication, and implementation of evidence as seamlessly and cheaply as possible into the everyday routine of medicine. Without such innovation in the use of medical data, we can say only that statins are—broadly speaking—likely to do more good than harm. That is not good enough.”
(P.S. But mass prescription for modest individual benefit is not new. So-called “hypertension” needs to be the next field of battle.)

A few months ago, The BMJ came under attack from the high priests of the lipocentric religion for publishing a paper by Abramson and colleagues about the potential harmful effects of statins. Now The BMJ responds by publishing a far more detailed and scholarly traversal of the area by three authors from Johns Hopkins. The next step must be a massive prospective surveillance study—a useful job, perhaps, for the well-funded Clinical Trials Support Unit of Oxford.

Many years ago in these reviews, I called for a halt to trials of HDL-C raising drugs when I did a rough tally based on PubMed and found 200, without one of them showing substantive benefit. This meta-analysis finds 39 trials, which fulfilled stricter criteria, and comes to the same conclusion. Moreover it calls into question the whole lipocentric theory of statin action: “Notably, fine grained temporal analysis shows reduction in events from use of statins long before the plausible time at which lower lipid levels could mediate slower accumulation of atheroma and thereby could have had an effect. Whether the decrease in low density lipoprotein cholesterol level is the principal mechanism for the reduction of acute events by statins is, therefore, unknown.” This simple fact needs constant restating.

Another “self-evident fact” is that people who are in shock due to sepsis need fluid volume expansion. There have been recent reports that albumin containing fluids can actually increase mortality in adults (as they probably do in children), but this systematic review of the randomized trials shows that they are as safe as saline. But the Editorial goes further and says: “It is time to go back to basics and challenge our entrenched assumption that fluid resuscitation is beneficial for people in septic shock, rather than continue to argue over which fluid works best. The time is right for a randomised controlled trial in the emergency department setting of treatment according to the Surviving Sepsis Campaign guidelines compared with a strategy of minimal fluids combined with early use of vasopressors to maintain vital organ blood flow.”

If you prespecify a single hypothesis, and your result emerges with a p value of 0.05, then there is a 19 out of 20 chance that you have confirmed the hypothesis. The more hypotheses you prespecify, the greater the chance that one of them will be positive by chance. You would have thought that would provide enough leeway for anyone with a reasonable interest in scientific enquiry. Prove or fail to prove what you have stated before starting, and use any interesting subgroup debris to trawl for your next study. But no: at least a third of the research community don’t seem satisfied. “Large discrepancies exist between the planning and reporting of subgroup analyses in randomised controlled trials. Published statements about subgroup prespecification are not trustworthy, because more than a third could not be verified.”

The final sacred cow slaughtered in this week’s The BMJ is the need for care in the spacing of pregnancies. Using within individual comparisons, Australian analysts find no evidence that 0-5 month intervals between pregnancies have any effect on preterm birth or low birth weight. Interpregnancy intervals over 5 years are somewhat associated with low birth weight but not with preterm birth. To offer parents any advice on this matter would be to let bossiness triumph over evidence. And we must do our best to discourage this, even among midwives.

Plant of the Week: Agapanthus “Tornado”

The flowers of love are bulbous plants from South Africa. Botanists have fierce arguments about species divisions and even about where they belong in the plant kingdom. Gardeners care nothing about such things, but simply want them to be hardy and free flowering in beautiful heads of clear blue or pure white. These are supremely welcome in the balmy days of high summer, when so many garden things look dusty and show signs of seediness.

The hybridists are doing good work with agapanthoi. For busy people, the best plan is to visit a garden centre that has a good range of plants without being too laden with stone pigs, standard fuschias, flower themed tea cosies, and gifts for aunts and grandfathers. Plants seem to cost twice as much when thickly surrounded with these deplorable objects. You have to rush past them and find the section marked perennials and go for the globes of blue flowers under A. Seize upon one or more with the height and shade of blue that you are looking for, and rush back through the shop to the bit marked “TILLS Exit”. Pay with a credit card without looking at the bottom line. Admire your purchases at home. Tornado is about half a metre high and has lovely dark blue flowers, which prove to be veined on close inspection.