21 Nov, 11 | by BMJ Group
JAMA 16 Nov 2011 Vol 306
2099 Steve Nissen became something of a hero of mine when he showed how bad data from pharma-funded studies had been used to mask the fact that rosiglitazone (Avandia) was harming diabetic patients while lowering a surrogate end-point – blood glucose or glycated haemoglobin. But here he is leading a pharma-designed and funded study which shows that a particular drug – evacetrapib – improves a surrogate end-point, HDL-cholesterol, without any data about long-term harms or benefits to patients. The abstract concludes “The effects on cardiovascular outcomes require further investigation.” Since this drug exists to affect cardiovascular outcomes, and this trial tells us nothing about them, I cannot understand what it is doing in a leading medical journal. But there seems to be a huge amount of investment in this class of drugs – inhibitors of cholesteryl ester transfer protein (CETP) – despite the fact that the first to be licensed, torcetrapib, actually worsened CV outcomes, and was rapidly withdrawn. To think of “High-Density Lipoprotein Cholesterol as the Holy Grail” (title of editorial) is a recipe for sipping out of poisoned chalices: we should simply wait for the evidence from adequate studies using meaningful outcome measures.
2110 The discovery in the 1990s that bone marrow cells could differentiate into cardiac myocytes and repopulate damaged myocardium offered hope of a revolution in the treatment of myocardial infarction and heart failure. A number of trials published over the last decade have proved the concept but failed to benefit patients in any significant way. Marrow cells given early following percutaneous intervention for MI do grow enough new myocardium to improve the systolic ejection fraction in the treated group, but given later at 2-3 weeks post-infarct they do nothing, as this study shows. The editorial calls for better surrogate markers – but I think it is time we judged this treatment by changes that patients can notice.
2120 Reverse epidemiology is an intriguing paradox in heart failure: the fattest patients with the highest lipids survive the longest. Here’s evidence of the same phenomenon following first myocardial infarction: the higher your cardiovascular risk score, the better your immediate survival. Yes, I did read this properly: this is no case of raw Brussels sprouts. Looking at over 2 million patients admitted to US hospitals between 1994 and 2006, the investigators found an in-hospital mortality of 15% among those with no CV risk factors and 3.6% among those with a top score of 5 risk factors: and a convincing spread in the area between. Something strange is going on here: ischaemic preconditioning, perhaps.
NEJM 17 Nov 2011 Vol 365
1863 News of a partially successful malaria vaccine has been circulating for months: here is the first report from the RTS,S/AS01vaccine trial conducted in 7 African countries with 15,460 children as participants. This vaccine has the potential to reduce incident malaria by one third to one half. A big step forward, then, but overshadowed by more recent news of the discovery of a definitive vaccine target which may eventually lead to the complete eradication of malaria. About time too.
1876 The plump boy chosen by Peter Brook to play Piggy in the 1963 film of William Golding’s Lord of the Flies grew up to be quite lanky. Obese children do not have to grow up to be obese adults. Most do, sadly, and then they run high risks of diabetes and cardiovascular disease; but this analysis of four Finnish cohort studies shows that the lucky Piggies who cast off their childhood corpulence have the same cardiovascular risk as adults who were never fat.
Lancet 19 Nov 2011 Vol 378
1775 The most notable feature of this week’s Lancet is a letter with 41 signatories from the breast screening establishment attacking what they see as “an active anti-screening campaign orchestrated in part by members of the Nordic Cochrane Centre.” They accuse this campaign of being largely designed to back the prejudices of Peter Gøtzsche, citing the Lancet paper in which he first raised these concerns in 1995. At the end of their letter, they define themselves as “The signatories below, charged with provision and implementation of breast screening in many different countries” and then say “We declare that we have no conflicts of interest.” Hmm. Where is the invited response from the Nordic Cochrane Centre? Is this matter to be decided by an exchange of accusations or a debate based on the science? The modern Lancet, as so often, seems to prefer the age-old solution of a declaration by authority figures who know they must be right. How deluded the radical Thomas Wakeley was in 1823, when he set up The Lancet to question medical orthodoxy. It was all so much simpler when we had four humours, purging and leeches.
1779 We don’t know the cause of multiple sclerosis, so newly developed treatments target the inflammatory mechanisms instead. The same is true of many other conditions, such as psoriasis, rheumatoid arthritis and inflammatory bowel disease; and this approach has had a measure of success. Ocrelizumab targets B lymphocytes, specifically the CD20 B cells which can produce auto-antibodies in the central nervous system. This phase 2 trial proves the concept by demonstrating an enormous reduction (96% at the highest dose) in gadolinium-enhancing lesions on MRI in remitting-relapsing MS patients treated with ocrelizumab. So another surrogate success with uncertain meaning for long-term disability in MS. And for once the editorial does not indulge in hype, but soberly reviews this increment of possible progress in the context of other, half-proven treatments for MS.
1788 A primary care study from London and Bristol shows that GP practices which have received a training and support package on detecting and referring cases of domestic violence do indeed detect and refer more domestic violence. The size of the problem is huge, and it would be good to be certain that the interventions available are effective, on both an individual and a societal level. I couldn’t find the evidence in this study, but that was not its purpose: I just hope it exists.
BMJ 19 Nov 2011 Vol 343
In a very few years I shall be officially geriatric, and I guess my risk of emergency hospital admission is increasing all the time. Naturally I shall make every attempt to get out as soon as possible, so if you see a balding figure in a bed-gown trying to run down the street with a drip stand still connected, hail a taxi and call my wife. This systematic review tries to make the case for a complete geriatric assessment (CGA) before every hospital discharge from age 65 upwards. Outcomes tend to be better after discharge from wards where CGAs are routine. Make of that what you will: I can’t see how it makes sense to assess everybody in the same way on the basis of age alone, but maybe I’m getting touchy on the subject.
These are heady times for the commercial UK weight loss organisation called Weight Watchers. They paid for a trial recently published in The Lancet which showed that they were superior to an NHS weight loss referral programme. Now the BMJ has published an independent trial comparing Weight Watchers with two other commercial providers and an NHS provider, and again it proves to have the best results at one year (mean 4.43kg reduction). In both studies the intervention length was 12 weeks, but in this trial, unlike the previous one, there was a significant number of subjects with BMI>35.
Arch Intern Med 14 Nov 2011 Vol 171
1804 Though I usually maintain a discreet silence as I sit in on the deliberations of the center for outcomes research and evaluation, America’s foremost cardiovascular outcomes research unit, I have gained something of a reputation for my incredulity at the vagaries of the US health system. Here Brahmajee Nallamothu, looks at the phenomenal rise of carotid stenting in the USA, despite a wholesale lack of evidence of superiority or even equivalence to carotid endarterectomy. So who is doing all these unproven procedures, and why? The simple answers are: cardiologists; because they get paid per procedure, and they are used to putting stents in arteries. This has even been given a name: the oculo-stenotic reflex.
1831 We are used to think of hip fracture in frail elderly women as a common precursor to death, but this need not be so in healthy older women. To be sure, their mortality risk is higher in the short term after surgery, but by one year it has returned to baseline, according to this prospective cohort study.
Ann Intern Med 15 Nov 2011 Vol 155
653 A Canadian trial looks at the safe interval for INR testing in patients on warfarin whose INR has been in the target range for 6 months. It’s a nice study which used sham INR results in the group being tested every 12 weeks rather than every 4 weeks. “The proportion of time that patients were within the target INR range and adverse events did not significantly differ between the groups. Longer monitoring intervals may be reasonable for selected patients receiving warfarin.” – a useful finding, which confirms the result of an earlier British trial.
660 Post-hoc subgroup analysis has got itself a bad name, but performed carefully, and then tested prospectively, it may offer a route to better decision-making with individual patients. Take the case of anticoagulation to prevent stroke in atrial fibrillation. The CHADS2 score was devised to stratify risk in AF patients not taking oral anticoagulants. But here the investigators of the RE-LY trial comparing warfarin with dabigtran use the CHADS score to take a look at the relative risks of stroke, bleeding and death in all arms of this trial, where overall the various regimens produced very similar benefits and risks. The CHADS score predicted all these events in these groups too, with bleeding risk keeping track with embolic risk in the warfarin group, but less so in the patients given dabigatran. In other words, in the riskiest patients, dabigatran rather than warfarin might be the safer treatment. This analysis was funded by the manufacturers of dabigatran, but I think this is a reasonable presumption until the hypothesis has been tested further.
Plant of the Week: Malus domestica
I grew up in a terraced house in Lincoln, with a crowded little garden at the back, overshadowed one side by a neighbour’s huge apple tree. This bore fruit of unearthly size and flavour: the apples were simply too large for childish teeth to get easy purchase, and so juicy that their sap ran down one’s chin in the attempt.
I have often wondered about stealing back to get a cutting, should the old tree still be there. It’s relatively easy – so I’m told – to graft cuttings on to dwarfing rootstock and get fruit within two or three years. But maybe it would taste nothing like those fabled apples of Lincoln autumns in the 1950s.
I came to the USA expecting to encounter pulpy, flavorless (sic) apples of the kind which are imported from the hotter parts of America by British supermarkets. What a pleasant surprise to find that the apples of New England are fully the equal of any to be found in the old country, and frequently superior. Presumably they mostly came over from England in the seventeenth and eighteenth centuries, by which time there was already a great profusion of varieties. Some taste like firmer varieties of the Worcester apple, while others – o bliss! – taste exactly as I remember the Lincoln apples of my childhood. These are huge, crispy local apples, wonderfully sweet and juicy but without any little stickers to give away their name. The nearest cultivar I have found here is called Honeycrisp.
It is said that there is an apple for every microclimate, so that there can be no general rule for the selection of a variety for your garden. I used to have a garden with an old tree of Blenheim Orange, a triploid variety raised just 20 miles distant and once very popular in England, until hybridized by Cox with the Ribston Pippin. Cox’s resulting Orange Pippin is less aromatic and characterful, but much more reliable. But it is of course a mistake to grow in your garden a variety which is always available in the shops.
We have gone one worse and have in our garden a tree grown from the pip of a Golden Delicious apple. For sentimental reasons, it can never be extirpated; and unfortunately its fruits are true to type, neither golden nor delicious but scabby and tasteless. However, an apple tree of any kind has many garden virtues: it produces lovely blossom in the spring, and its roots seem to encourage the growth of morel mushrooms, should you be very lucky. And a fully grown apple tree is an excellent framework for a vigorous climber, such as viticella clematis or even wisteria.