Richard Lehman’s journal review – 23 January 2012

Richard LehmanJAMA  18 Jan 2012  Vol 307
265     Cangrelor is one of a number of reversible thienopyridine platelet inhibitors competing to replace clopidogrel. This could be an enormous market, but the BRIDGE study, funded by The Medicines Company, begins with a small niche: patients who discontinue antiplatelet treatment before elective coronary artery bypass grafting. The problem that this study is alleged to address is the risk of rebound coronary events in such patients, unless some kind of platelet inhibition is maintained up to near the time of surgery (using IV cangrelor, of course); but in fact a coronary end-point appears nowhere in the trial. Instead, the primary end points are bleeding during surgery and laboratory platelet function tests. These lab tests are the weakest of surrogates, and I am unconvinced that there is a problem here that cannot be addressed in a simpler way. This study really doesn’t belong in a leading medical journal.

275    Caffeine has a very important role in special care baby units, but this study shows that there is little point giving it to the babies. Previously it seemed that caffeine given to very premature infants with breathing problems can reduce the rates of cerebral palsy and cognitive delay at 18 months; but sadly follow-up at 5 years shows that any benefit disappears with time. Caffeine is strictly for NHS staff.

294    It was a long time before orthopaedic surgeons were persuaded to take seriously the problem of venous thromboembolism following lower limb arthroplasty, but postoperative prophylaxis is now a quality marker in most hospital systems. However, this analysis of 44 844 patients from 47 studies shows that even with standard treatment, one patient in 100 gets VTE before hospital discharge following total knee replacement, and in 200 following total hip replacement. And the editorial points out that this is not the largest problem: in a Californian study, 76% of THR-associated VTE events and 47% of TKR-associated VTE events occurred after hospital discharge. These patients need a much longer period of VTE protection, amounting to 12 weeks following THR, and 6 weeks following TKR. If I was the manufacturer of a new anticoagulant like idrabiotaparinux, I would be getting my RCT organized right away.

NEJM  19 Jan 2012  Vol 366
207    I managed to finish Mukherjee’s weighty book, The Emperor of All Maladies, in time to lighten my suitcase before returning to the USA, and I liked the way it ends on an ambivalent but somewhat optimistic note about progress in cancer. As our mechanistic understanding gradually develops through genomic analysis, so we can start picking away at one pathway and then another—a speeded-up, better-focused version of what cancer therapeutics has been doing over a period of seventy years. But one story after another illustrates how effective cancer cells can be at outwitting each new kind of targeted therapy. The example here is malignant melanoma, some strains of which melt away almost completely with the BRAF inhibitor, vemurafenib. But a few months later, the metastases usually come back: and they tend to be accompanied by a troop of other skin tumours such as squamous cell carcinomas and keratoacanthomas. This is related to the presence of RAS mutations, which in a mouse model can be inhibited by a MEK inhibitor. The future of cancer therapeutics may lie in this kind of sophisticated game of tag: but is this really going to be affordable by more than a few lucky individuals?  There is another Big C we have to conquer, which is never mentioned in Mukherjee’s book—Cost.

225    A lot of the costs of a health system depend on how often you do things, and often there is little evidence to guide decision-making. This very useful study explores the question of how often it is worth measuring bone mineral density in older women. Enrolment of women (almost entirely white-skinned) aged 65 and over began in 1986 at four sites in the USA, and there were five further BMD examinations up to 2004. “Our data indicate that osteoporosis would develop in less than 10% of older, postmenopausal women during rescreening intervals of approximately 15 years for women with normal bone density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia.”

250   An outstanding review of Cognitive and Neurologic Outcomes after Coronary-Artery Bypass Surgery does much to allay fears raised by studies over the last decade which seemed to indicate that CABG carries a high risk of cognitive impairment. “It is now increasingly apparent that the incidence of both short and long-term cognitive decline after CABG has been greatly overestimated, owing to the lack of a uniform definition of what constitutes cognitive decline, the use of inappropriate statistical methods, and a lack of control groups.” Older patient undergoing CABG are at high risk of cerebrovascular disease anyway, but “although some degree of short term cognitive decline may occur days to weeks after CABG, these changes are generally minor and temporary.”

Lancet 21 Jan 2012  Vol 379
229     Critical care units are places where desperate remedies are tried out on desperately sick people. If people on ventilators are choking to death with acute respiratory distress syndrome, then the temptation arises to use intravenous beta-adrenergic agonists.  This British trial (BALTI-2) showed that this induces tachycardia, arrhythmias, and lactic acidosis (as expected), and it was stopped once mortality in the treated group significantly exceeded that in the placebo group.

236    As I go through the journals every week, it’s always a relief to alight on a good observational study: at least the authors are probably trying their best to be honest. Most adolescents who self-harm grow out of it: a nice common-sense finding from following up nearly 2,000 schoolchildren from a mean age of 15.9 months up to a mean age of 29 years in Victoria, Australia. Quite a lot of useful work can be done by picking up the phone to chase a cohort from time to time. But there are few clues as to how to pick out the ones who will become recurrent, or who will kill themselves. Keith Hawton, who has been working in this field for at least 40 years, drops no hints in his editorial.

244   Here’s a really great observational study from Sweden looking at over half a million people who were admitted to hospital with an auto-immune disorder. Their overall risk ratio for pulmonary embolism during the first year after admission was 6•38 (95% CI 6•19—6•57). But it was particularly high for certain conditions: immune thrombocytopenic purpura (10•79, 95% CI 7•98—14•28), polyarteritis nodosa (13•26, 9•33—18•29), polymyositis or dermatomyositis (16•44, 11•57—22•69), and systemic lupus erythematosus (10•23, 8•31—12•45). It might seem a bit odd to give anticoagulants for ITP, but it’s looking as if that might be a good idea. Time for yet more trials using next-generation factor Xa and thrombin inhibitors.

BMJ   21 Jan 2012  Vol 344
The National Perinatal Epidemiology Unit in Oxford is two years late in reporting its survey of Perinatal and maternal outcomes by planned place of birth for healthy women with low risk pregnancies, during which time many smaller British hospital maternity units have been closed and replaced by stand-alone midwife led delivery units. To me, the figures given here lend no support to this policy. Up to 45% of primiparous women booked for midwife unit or home delivery ended up being transferred to hospital during labour, which I think is a shocking statistic. I quote from a Rapid Response by Margaret Treadwell: “For low risk nulliparous women without complications at the start of labour the risk of one of the serious ‘primary outcomes’ is: 22 cases out 4785 in a free standing midwifery unit, 28 cases out of 8018 in an obstetric unit. And for stillbirth; 0.4 per 1000 in a freestanding midwifery unit, 0.2 per 1000 in an obstetric unit. This is BEFORE adjustment for the increased risk profile of women choosing obstetric unit care and an acknowledgment that there may have been some data loss due to transfer. These figures do not reach statistical significance but perhaps we should pause for thought, dig a bit deeper and ask a few more questions before reconfiguring the entire country’s maternity services.” Too right we should.

How quaint that it needed the Whitehall II Prospective Study to prove that cognitive decline begins in the mid-40s. But young people should be consoled that as one gets older, one becomes more used to working in the absence of short-term memory, and better at pretending that no-one notices. By the time that one is truly convinced of one’s abiding wisdom, the chances are that Alzheimer’s has properly set in.

The standard method of diagnosing localized prostate cancer is by transrectal biopsy. As this paper cheerily notes, “TRUS-Bx can be associated with appreciable morbidity, including sepsis, pain, bleeding, and even death on rare occasions.” As part of the Prostate Testing for Cancer and Treatment (ProtecT) study, the investigators determine the acceptability of TRUS amongst 1147 British men who underwent 10-core biopsy following the detection of a raised PSA. About one man in five would have serious doubts about ever having the procedure again: testimony to true British grit on the part of the rest, I think. Naturally the degree of pain was the main determinant of reluctance, as discovered by Corporal Jones when he served under General Kitchener: “They don’t like it up ‘em, sir, they don’t like it.”

“Consider antineutrophil cytoplasmic antibody (ANCA) associated vasculitis when inflammatory disease cannot be ascribed to any other disease and inflammation progresses despite antibiotics.” Wise words, but you will have some trouble identifying these conditions in general practice, if my own experience is anything to go by. In fact, I would like to have grabbed this topic for the Easily Missed series, but here is a more extensive and learned disquisition by a team of Dutch specialists instead. Granulomatosis with polyangiitis is one form, which used to bear the name of the Nazi criminal Wegener; the other kinds are microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). These conditions used to be rapidly life-threatening and still are not altogether understood or conquered: so don’t delay referring anyone who is coughing or sneezing blood, looks ill, and has a spectacular CRP.

Ann Intern Med  17 Jan 2012  Vol 156
105    Did it ever occur to you that giving high dose vitamin D to an unselected cohort of patients with chronic obstructive pulmonary disease might prevent exacerbations? Me neither. But a group of Belgian chest doctors thought it was worth a try, and have proved that it doesn’t work. There has been a bit of a backlash against vitamin D lately, notably in a recent Lancet editorial deploring the increasing number of vitamin D assay requests in UK practice, but I remain modestly hopeful that some benefit will emerge from lengthy prospective studies. But not in COPD.

115   Obstructive sleep apnoea is generally regarded as a male prerogative: indeed it is often considered a form of deliberate moral turpitude by the wives and partners of those afflicted. But women gasp and snore and jump about in bed too, and they generally don’t do it on purpose. The penalty for this behaviour is nothing less than cardiovascular death, and the cure is continuous positive airways pressure. Here a group of Spanish investigators attempt to determine the degree to which CPAP reduces the increased risk of CV mortality in women, but their observational study is flawed and underpowered to reach a useful estimate. There is a definite trend to benefit, however.

123   Here’s another study comparing real autopsy with “virtual” autopsy using CT and MRI, this time carried out on deceased patients from German intensive care units. There were full comparisons in only 47 patients, and once again these tended to show that important cardiovascular causes, and even some cancers, were not picked up on imaging alone.

147    What happens in the UK if you send a patient to a private specialist or a tertiary centre for a second opinion? Invariably they repeat all the tests. In the USA, where patients are much freer to come and go and demand what they like, diagnostic and screening tests are a huge burden on the system, and a major factor in making health care unaffordable. Here a group of American physicians looks at the concept of cost-conscious, high-value care as an aspiration for their health system. They could learn a lot from the NHS, though I don’t suppose Newt Gingrich will be making this a central plank of his election campaign. The authors here identify 37 common clinical scenarios where a test does not reflect high-value care. If you have a bit of spare time, you could look up their list and try to think of 37 more.

Plant of the Week: Leucojum vernum

Before returning to the snow and ice of New England, we had a chance to enjoy the winter flowers of England. Our treasured rose, Grϋss an Aachen, was still trying to flower till after Christmas, and then came primroses and spring snowflakes, even before the snowdrops and aconites.

I don’t know if we have a special clone, but our variety of spring snowflake (Leucojum vernum) tends to flower very early indeed – usually at the same time as its smaller cousins, the snowdrops. These bulbs come from the woods and meadows and stream banks of central Europe, but we plonked them on a sun-baked bank of limy clay, where they have flourished ever since. Tough, therefore, and indispensable for their early presage of spring.