Richard Lehman’s journal review – 4 April 2011

Richard LehmanNEJM   31 Mar 2011  Vol 364

1195     A great deal of what I report to you every week is discouragingly futile, but the conquest of serious viral disease still has about it the excitement of the great era of microbial therapeutics (c.1942-1962). Mind you, the eradication of a slow-burning virus like hepatitis C is more reminiscent of the painstaking development of multiple long term drug regimes for tuberculosis than the dramatic overnight cures produced by penicillin in septic patients.

Just like TB a century ago, hepatitis C lurks asymptomatically in a large number of people, many of whom either cure themselves or never get severe liver damage. But a proportion do, and these can die of liver failure or hepatocellular carcinoma: so once you have found hepatitis C infection, you must try to get rid of it. Ribavirin is like streptomycin in TB: it produces a good initial response but the virus quickly becomes resistant. So it is given with peginterferon, which blocks the resistance mechanism in most white people but not in a high proportion of black people. Now along come the oral HCV-protease inhibitors telaprevir and boceprevir, which bring us tantalisingly near to a cure for HCV-1 in the majority of white people, and about half those defined as black. This first trial recruited previously untreated people and gave them standard ribavirin/peginterferon with placebo or with boceprivir. The latter showed much better clearance, though a third still showed continuing viral RNA at 72 weeks.

1207    And now for the HCV-1 infected people who have not been cured by standard treatment. In this trial, those who continued on ribavirin/peginterferon had a 21% sustained virological response, against 59-66% in added the boceprevir groups. But all was not plain sailing: this drug leaves a bad taste in the mouth (literally) even before you get the invoice for it, and caused enough anaemia to warrant erythropoietin treatment in almost half the active drug group.

1218    In old age, underweight tends to carry a worse prognosis than overweight, but we can all agree that obesity in the elderly is a bad thing for its effects on joints, mobility, and the development of diabetes. Not that weight loss alone is sufficient: we would like our patients (and, dear reader, ourselves in the fullness of time) to be fitter, more independent, and enjoy life more for as long as possible. In this small trial, the diet regimen was startlingly effective, achieving a 10% drop in weight, whereas exercise alone achieved no weight loss. Combining diet and exercise actually lessened the weight loss slightly (9%) but achieved much better results in terms of overall function. The Victorian ideal of having a good luncheon followed by a 3-mile “constitutional” in all weathers has a lot to recommend it. Observe the benefits in Mr Gladstone, dear children.

1251    Here’s a very useful review of the care of transsexual persons. Statistically, you are not very likely to be involved in this: your practice would need on average to contain 12,000 males or 30,000 females (figures for adults from Netherlands, stable over time). Gender assignment surgery is described but not illustrated – it is no easy reading for the squeamish, but only 1-2% regret having it done.

Lancet  2 Apr 2011  Vol 377

1155   This week The Lancet takes a break from income-generating  pharma sponsored trials and concentrates on what it does best – promoting global health. For reasons I can’t fathom, it has become the mark of a good liberal to talk up the dangers of global warming while talking down the obvious threat of world overpopulation. Together with universal availability of effective and affordable contraception, there needs to be universal availability of effective and affordable early abortion. Limiting the use of early medical abortion to those who can access and afford doctors is never going to work, so a big welcome to this trial showing that in Nepal mid level heath workers can provide it just as safely.

1162   Nature’s way of limiting population is through child mortality, starvation and war. I don’t understand people who find these preferable to contraception and abortion – or are they proposing some as yet unknown solution? Monasticism? I have no trouble advocating a Western model where every child is precious and its survival to healthy adolescence is the highest aim of society. This paper on 50 year mortality trends in children and adolescents shows this happening to various degrees in Europe and America, north and south, plus a few other countries. Progress is spectacularly uneven, however, especially in “middle income” countries in Eastern Europe – Poland being about the same as the UK, while neighbouring Ukraine is among the most lethal of these countries to grow up in, and the very worst to be a young adult. If you are back-packing across Europe in your gap year, turn back when you have reached Bialystok. There is at least an hour’s worth of fascination in these figures and charts, but the main message to come through is that it has become as safe as it probably ever will be to be a pre-school child in a high income country, but there is still an unacceptably high risk of preventable death in adolescents and young adults, especially in middle-income countries.

1175   Another thing The Lancet is sometimes good at is reporting on and illustrating new surgical techniques: in this case the creation and implantation of tissue-engineered autologous urethras in five boys with urethral defects. This was successful in all the reported cases, for as long as six years to date. A very promising study.

1184   “Chronic pancreatitis remains a challenging disease. Resective surgery continues to be the definitive treatment for persistent pain, but is not ideal in a chronic inflammatory process. Micronutrient treatment might offer a viable alternative.” So, with due gloom and brevity, concludes a review of this condition: very heavy on pathology and speculation, painfully light on therapeutic options.

BMJ  2 Apr 2011  Vol 342

746   There are all sorts of reasons why surgery should be bad for patients with cancer. Reading Fanny Burney’s account of her mastectomy in 1811, you realise that patients who underwent surgery before the anaesthetic era were lucky to survive the appalling ordeal of  pain and blood loss. Even now there are reasons to speculate that perioperative epidural anaesthesia might relieve some of the physiological stresses of major abdominal surgery for cancer. However, this follow-up study of the MASTER trial showed no such advantage in terms of recurrence-free survival.

748    Although I often comment on particular aspects of trials which I find reprehensible, I try on the whole to spare you any dweebish discussion of methodology. If, for example, The Lancet publishes an industry funded study which is negative for its primary end point but is talked up because it is positive for a secondary end point then I duly express my rage and move on. I expect you to know that the more secondary end points you pre-specify, the greater the chance of a positive outcome for one of them. If you examine the data for secondary end-points which you select after the trial (post hoc), you enter a significance-free zone where all you can legitimately do is generate hypotheses along the lines of “it’s interesting to note that 67% (95% C.I. 54-82%, p=0.04) of those who ate Smarties wore a yellow jumper” – so maybe we should do another study and also look at Maltesers and green jumpers etc. There are lots of books about this sort of thing but they often make it sound boring: it isn’t. It leads to cheating. It muddies the waters and can end up killing patients. Here is a systematic review showing how common it is in industry funded trials. This is what high quality medical journals should exist to suppress: instead most of them welcome anything that will increase profits from the sale of reprints to drug companies. So you have an powerful line up of vested interests trying to deceive you about the value of interventions, and on the other side here is a group of academics telling you to beware of whatever you read. No wonder they call themselves SATIRE.

749    At the risk of getting seriously dweeby, let’s move on to hospital standardised mortality ratios. Why? Because in all the publicity about the Mid Staffordshire NHS Trust, and in future cases like it, you will read that poor care killed so many hundred patients, as if these figures are definitive. This slightly dispiriting paper points out all the ways that they are not and perhaps cannot ever be.

754   The BMJ’s clinical review series maintains its high standards of quality and relevance with this piece about the investigation and management of unexplained weight loss in elderly patients. You’re mostly doing the right things anyway, and stop investigating and wait and see once you’ve got the baseline results back and normal. But do always try to get a proper dietary assessment and a check for cognition and depression. Also read young Chekhov’s A Dreary Story (1889) for a wonderful narration within the mind of a 63-year-old medical professor who has unexplained weight loss and wants to avoid the attentions of his colleagues. The one thing he can still do is give a good lecture: read Chekhov and learn.

Arch Intern Med  28 Mar 2011  Vol 171

507    There is a wonderful 1940s poster urging people to eat carrots with the figure of Doctor Carrot bouncing along, sporting the top hat and wing collar that we all like to wear on our rounds. Carrots, as we all know, contain vitamin A, and so help our brave Spitfire pilots see better at night. “Darling Buffy, shall you be flying tonight?”- “I’m afraid I can’t tell you my love” – “Shall we ever see each other again?”-  there is a full moon;  they kiss passionately – “Oh, but do promise me, dear, that you will eat up your carrots!”. It occurs to me to wonder if modern carrots contain so much carotene as an indirect result of Dutch patriotism in the early seventeenth century. Until then, carrots were brown or purple, but Dutch seedsmen were determined to create a new carrot to celebrate the House of Orange. Hence the ubiquitous orange carrot, super-rich in carotene: but the old kinds are lovely too, and if you want to try them go to Lincoln market by the cathedral, where there is a whole stall dedicated to differently coloured carrots.

Where was I? Oh yes, this is a study showing that “serum a-carotene concentrations were inversely associated with risk of death from all causes, CVD, cancer, and all other causes”. Buffy survived the war and married Thelma; and they can still be seen on afternoon walks in their blazers, all thanks to a daily diet of carrots.

544    Enormous effort has been expended over the last decade in all developed health systems to ensure that the maximum number of patients with acute myocardial infarction should receive immediate percutaneous intervention rather than thrombolysis. This large Belgian observational study looks at the difference in in-hospital mortality following the two treatments: in absolute terms it is 0.7%, with negligible gain in low-risk patients.

550   The persistent exclusion of older patients from ongoing clinical trials regarding heart failure is a symptom of our unwillingness to look at so many issues to do with this syndrome. If there are trade offs and joint decisions to be made, how many old people with HF want a longer life or a more tolerable life? How many would like to have a choice about ending their lives when things got intolerable? How good are we at relieving their cardinal symptoms such as weakness and breathlessness? What should the end-points of a trial in HF in older people really look like? At the moment, as this survey of RCTs shows, many triallists simply don’t want to address such questions; it is too inconvenient that the average patient with heart failure is 76 and always has comorbidity.

Plant of the Week: Osmanthus decorus

The honey scent of the osmanthus family is one of the joys of spring. The commonest source of this happy fragrance in British gardens is O. x burkwoodii, an easy and vigorous hybrid between O. delavayi and O. decorus. But it is worth growing the parent species if you can: the first for its dense habit and profuse flowers and the second for its hardiness and handsome large leaves. These are evergreen, lanceolate and shiny and will not fall off, unless the temperature falls below -20ºC. Unchecked, it will grow as a pyramid up to 4m high: worth the space if you can find it. The name of the genus is Greek for “fragrant flower” and it will be covered with these in early spring; “decorus” is Latin for comely, and that is what this plant will be all the year round, adding its elegant architecture to your garden.