Richard Lehman’s journal review—23 July 2012

Richard LehmanJAMA  18 July 2012  Vol 308
247    The coming of interferon beta as a treatment for multiple sclerosis in the mid-1990s marked a turning point. For patients with MS, it was the first glimmer of hope that there might be effective treatment on the way, even though it was costly and came with unpleasant side-effects, and was of marginal benefit only to a group of selected patients with relapsing-remitting disease. For the NHS it was a direct challenge: how to ration this drug without using the R word. I can even remember feeling a brief twinge of sympathy for the Major government. The trials were not very convincing, the benefit was measured in reductions in relapse which would never be felt by individual patients, but might amount to some overall benefit in the long term: and this patient group was needy and vocal and had public support. I suspect that interferon was one of the reasons that the incoming New Labour government set up NICE, specifically to make rationing decisions on the basis of best evidence. And yet the only end-point that matters is long-term functional decline, and the data just weren’t there. So interferon became “usual care” for relapsing-remitting MS, and it has taken 17 years for this Canadian study to appear and show that it has no useful effect. You can criticise the methodology: it’s a retrospective cohort study and the controls may not be impeccably comparable to the treated group; but it’s nonetheless clear that for the vast majority of patients with MS—and probably all—interferon beta is a futile treatment.

257    The arrival of interferon led directly to my becoming aware of the very limited evidence base for many major changes in medical practice. This then eventually led to my writing notes on the medical journals as they appeared, which slowly turned into these reviews; and eventually, by many a winding path, I ended up trying to conceptualize the field of outcomes research. My personal definition of this is any form of scientific enquiry which can bear directly on informed decision-making about healthcare by patients, health professionals, and society. It can therefore comprise everything from randomized controlled trials of interferon for MS—provided that they are honestly conducted in typical populations and are directed at patient-important outcomes—to comparing stroke mortality in individual hospitals. The methodology differs completely, but I need to know both if I am to have an informed discussion with the patient in front of me, or with those who are charged with organizing local services. I need summary information that I can trust and use in real time, yet the possibilities for bias are great. One classic stumbling block  in institutional comparisons is case-mix, and this Comparison of 30-Day Mortality Models for Profiling Hospital Performance in Acute Ischemic Stroke With vs Without Adjustment for Stroke Severity is a good teaching paper on the subject: “Adding stroke severity … to a hospital 30-day risk model …(for) acute ischemic stroke was associated with considerably improved model discrimination and change in mortality performance rankings for a substantial portion of hospitals.”

NEJM  19 July 2012  Vol 367
203    Here’s another great example of what I would label outcomes research: “From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality.” Brilliant. Here are data accumulated over 17 years for a patient population faced with an acute dilemma: I have this thing called “prostate cancer” and if I have a major operation I will probably be cured, but I stand a 4 out of 5 chance of erectile impotence and a 17% chance of urinary incontinence. If I don’t have the op my risk of becoming impotent is 44% (ancient as I am) and of becoming incontinent is 6%. Having the op converts my 8.4% chance of dying from prostate cancer to a 5.8% chance of dying from the cancer or its treatment. And ancient as I am, my chance of dying from anything over the mean period of 10 years’ follow-up is about 50%, whatever I have done. Now you can argue whether these data are really generalizable—whether the cancer was detected by PSA or caused symptoms, whether small differences in Gleason score might be important etc—but here, I would say, is a sound basis for shared decision making with most men who have localized prostate cancer.

214    The baffling diagnostic label of ANCA-associated vasculitis started to appear in rheumatology correspondence about my patients about 15 years ago, and I gradually twigged that this was a new term to cover what used to be known as Wegener’s granulomatosis plus another broad category of microscopic polyangiitis. They were lumped together because both are associated with antineutrophil cytoplasmic antibodies. This British genetic study shows that they are probably separate conditions after all: proteinase 3 ANCA–associated vasculitis and myeloperoxidase ANCA–associated vasculitis. Expect to see these terms in your rheumatology clinic letters before long, together with the usual instructions about methotrexate, prednisolone etc.

233   Eggs are a marvellous part of the human diet. So far I have only tried the eggs of certain birds, fish, and crustaceans, but I have no doubt that a gastronomic paradise awaits those who dare to essay the eggs of gastropods, insects, and reptiles. You could even try them in combination: slugs’ egg omelette with caviar suggests itself as a delicate summer dish, which might go well with British champagne. But alas, some are shut out from these delights because they have egg allergy. For most of them, the cure is to eat egg white in carefully graded amounts until they become desensitized. Oral immunotherapy worked for 55% of children in this small trial: most of the rest have to face a future without hope of eggy bliss.

248    The symptoms of benign prostatic hypertrophy are a nuisance; so are the symptoms induced by most treatments, ranging from tamsulosin to daily tadalafil. Then there is surgery, not mentioned in this review. I’m told that there is evidence that open retropubic prostatectomy is better and safer than transurethral resection, but nobody has done a head-on trial. Just get used to finding a loo by night and by day would be my advice. I suspect we do most men a disservice by giving them drugs like alpha blockers and 5α-reductase inhibitors.

Lancet  21 July 2012  Vol 380
219    The dear old Lancet has the usual spread of articles this week, beginning with a global modelling paper from six prestigious centres which tells us to get off our bottoms and jolly well increase the average world life expectancy by 0.68 years. A surprisingly exact figure, given that nobody can possibly quantify the earth’s store of human idleness: but of course it is the sort of thing that gets into the news media and spawns a fine range of puritanical commentary pieces elsewhere in this Lancet. Why, it nearly had me going for a walk.

230   Another Horton favourite follows: clever men grow new vein on dead man’s, child’s life is saved. Or to put it another way, this is a proof-of-concept study demonstrating clinical transplantation of a deceased donor iliac vein graft repopulated with recipient autologous stem cells in a patient with extrahepatic portal vein obstruction. An interesting technical feat which has succeeded in one ten year old girl, needing no immune suppression. Why, you could almost say that further studies are needed.

238   Now for a randomized controlled trial: the question it seeks to answer is whether a 4-week course of flecainide is as good as a long-term flecainide for preventing the recurrence of atrial fibrillation after electrical cardioversion. For good measure, there was a no-treatment arm as well—not placebo, because allocation was not blinded. In fact, short term flecainide is probably not as good as long-term flecainide at preventing recurrent AF (but long-term has other dangers). The excellent editorial that accompanies the paper says that “non-inferiority could not be established.” This may sound ugly but is a necessary use of the technical term “non-inferiority”, because in this case actual inferiority was not established (95% CI -1.7 to 17.7, p=0.208).

BMJ  21 July 2012  Vol 345
First, an item that I forgot to include last week. A superb editorial by Dee Mangin, Iona Heath, and Marc Jamoulle discusses the challenge of multimorbidity. You may remember a couple of similar excellent pieces by Mary Tinetti which I pointed out earlier in the year. In most health systems, disease-specific guidelines by expert bodies have so distorted the priorities of care that the practice of true patient-centred generalism is almost impossible. There needs to be a radical shift away from target-driven tunnel vision to models which incorporate the goals of patients themselves as they face an increasing burden of complex illness. “Healthcare systems need to start to value and provide adequate support for the kind of iterative generalist care that focuses more on the person than on the disease entity and the necessary variation this entails. This would place equal value on the art of ‘not doing’—making complex decisions not to give treatments, not to order tests, and to stop current treatments when in the best interests of the patient.”

An increasing number of high-risk, mostly elderly individuals are receiving treatment with vascular endothelial factor inhibitors by intravitreal injection, usually for macular degeneration, but increasingly for diabetic macular oedema too. So it was a good idea on the part of these Canadian investigators to examine a large cohort of Ontarians who had received treatment with bevacizumab or ranibizumab to see if they showed an excess incidence of ischaemic stroke, acute myocardial infarction, congestive heart failure, or venous thromboembolism. They didn’t.

I spent the whole of my GP career wondering if I was giving appropriate care to people with acute knee injury. The problem was that I was usually just piggy-in-the-middle between a casualty officer who had sent them home with crepe and crutches and an orthopaedic surgeon who—if he could be contacted at all—could only offer a clinic appointment several weeks hence, followed by a further wait for the MRI scan which was obviously needed, and which I was forbidden to order. And in the meantime all I could offer was a sick note and bottle of ibuprofen. Here is a good summary of the investigation of knee injury, though its figures for sensitivity and specificity need more context; and the authors are NHS hospital doctors who are conveniently vague about how quickly investigations like MRI and CT need to be done.

Plant of the Week: Clematis “Kaiu

The challenge of this part of the garden season is to produce effects of charm and freshness to counteract the rank seediness which is otherwise likely to dominate the summer holiday weeks. Enter this unlikely American-Estonian hero – a vigorous child of the Appalachian Clematis viorna, covered with lovely pale grey-pink four-petalled nodding bells held out on elegant stems. This is the first year that ours has grown to maturity and it promises a great abundance of flower. Others who have grown it on similar alkaline clay say that it will carry on flowering happily for another two months.

It takes its name from the village in Estonia where it was first discovered as a wild seedling, with viorna as one of its parents. We have grown it on a trellis about 1.5m high by 3 m across, but it looks as if it will have to be kept under strict control in this space. I’d suggest growing it up a tree such as an apple or one of the larger magnolias. Cut it back pretty hard after flowering, and fingers crossed it will be fairly wilt-resistant. This is the dainty late summer beauty you have been looking for, and it should still be with you in October.