Richard Lehman’s journal review, 10 December 2012

Richard Lehman NEJM 6 Dec 2012 Vol 367
This is the time of year when, as a GP who is still let loose on patients, I have to undergo my annual appraisal. I shall try to demonstrate that knowledge keeps entering my brain at a rate roughly sufficient to replace the increasing amount that leaks out. My main evidence comes from these reviews – and I can honestly say that I learn quite a lot every week. Unfortunately this week’s journals are almost devoid of GP-useful content (I am omitting JAMA altogether because it is devoted to medical training in the USA), but here my main learning point for the week comes from this study: “Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis.” Right: this is a new area for me, and probably for you. And it is going to affect an awful lot of you in the future, both as doctors and as parents. Chromosomal microarray analysis just needs a cell or two: it does not need cell culture, and it can easily be automated. The problem right now is that it detects many variants which are typically classified as benign, pathogenic, or of uncertain clinical significance, the last being by far the largest category, as far as I can judge from the three studies in this week’s NEJM. So if your anxious, high-risk mother asks you “should I have an abortion?” or “will my child be normal?” your reply will often have to be “well, maybe: we can’t really say”. This could be the stuff of nightmares for thousands of parents until the science is properly sorted. The uncertainties are new and vast and will take many years to untangle, as the editorial makes clear. “Both pretest and post-test counseling by trained genetics counselors and geneticists are critical. Pretest counseling must include a discussion of the genetic principles of uncertainty and variable expressivity, the lack of precise correlation between genotype and phenotype, and the possibility that genetic variants that cause adult-onset disorders may be identified in a fetus or a parent. Post-test counseling should include interpretation of the results and an explanation of indicated follow-up studies and the possible implications for the family.” Well, good luck with that: bear in mind that parents who are told their child may be abnormal can never be the same again, nor can their attitude to that child. Perhaps the most important point for clinicians to take home from these studies is that conventional karyotyping will still be needed to pick up some gross chromosomal abnormalities like triploidy (as in Down’s syndrome), plus balanced translocations.

All around us, fungi lie in wait. They always get us in the end. If they get us while we are still alive, the results can be horrible. Fortunately our tissues are well designed to resist fungi, and they rarely manage to penetrate much beyond the surface; but it’s a different matter when through human carelessness they can get straight into the epidural space or the cerebrospinal fluid. You will probably already have read about the Tennessee outbreak of CNS fungal infections caused by contaminated methylprednisolone from a single dirty compounding pharmacy: a nasty epidemic of fungal meningitis, posterior circulation stroke, spinal osteomyelitis, or epidural abscess that developed after epidural or paraspinal glucocorticoid injections. The fungi isolated were Exserohilum rostratum in 21 cases and Aspergillus fumigatus in one. Don’t blame the fungi: they were only doing their job of growing where the conditions are right. An average toadstool produces 16 billion spores and if they all germinated and fruited there would be room for little else on Earth; and if all the fungal spores on Earth germinated and fruited at once there would be little room in the entire Solar System. On only one occasion did fungi really take over the world: for a period after the great Permian extinction 248 million years ago, when there was so much dead plant and animal matter that they enjoyed the brief triumph of the “terminal Palaeozoic fungal event.” Most of the time, those spores just sit there, and wait, and perish. Blame the humans, not the fungi.

Renin starts off the renin-angiotensin-aldosterone cascade, and it was inevitable that it would become a target for pharmacological blockade; just odd that it took so long. Had ACE inhibitors and angiotensin receptor blockers and aldosterone antagonists not got there first, renin antagonists like aliskiren would undoubtedly have become first-line drugs for hypertension and heart failure. In this RCT, the drug is compared with placebo in diabetic patients with cardiovascular disease and/or renal impairment who were already on treatment with an ACEI or ARB. The initial results were good: aliskiren lowers blood pressure and reduces albuminuria. So why don’t we prescribe it for all our high-risk diabetic patients, as we do other drugs for which we have only these end-points to go by? But wait: this Novartis trial actually measured death and cardiovascular events; and by the second interim analysis, these had become significantly more frequent in the aliskiren group. Oops: if only the trial had stuck to surrogates, all would have been well. But now there will be no market for aliskiren: she arrived too late on the scene, and was too well investigated.

The fungi lie in wait: Apophysomyces trapeziformis spores sat silently in Joplin, Missouri, until on May 22, 2011, the town was struck by a tornado. In the most severe damage zone, people were flung about and hit by wreckage: they sustained wounds and fractures which then became infected with an unidentified organism, and 38% of those infected died. It took a very sophisticated investigation to identify this usually harmless mould as the cause: sequencing of the D1–D2 region of the 28S ribosomal DNA yielded Apophysomyces trapeziformis in all 13 case patients. Blame the fungi, not the humans, and avoid tornadoes.

Lancet 8 Dec 2012 Vol 380
The Lancet seems to have adopted a policy of filling its research section with reports of phase 2 trials. This is decidedly odd, since these trials are by definition useless to practising clinicians, dealing with preliminary safety issues and dose-finding in compounds which may be years away from licensing. Take the two Amgen-funded trials in this week’s Lancet: they deal with a new monoclonal antibody AMG145 which reduces low density lipoprotein cholesterol. Of course, the drugs of choice we use when we want to reduce LDL-C are the statins, which are so cheap, safe and effective that any other intervention is going to have a very hard time finding a market. The first of these trials was conducted in 52 centres and recruited 411 participants: “For ethical reasons related to conducting a placebo-controlled study in which some patients would receive no active antihyperlipidaemia treatment, we enrolled patients with low cardiovascular risk who did not require cholesterol lowering therapy.” OK, so these people were not actually “patients” at all but healthy volunteers with highish levels of LDL-C. And sure enough, AMG145, the new antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), resulted in lowering of LDL-C and seems not to have had any adverse effects in the short term.

The other Amgen phase 2 trial looked at the dosing and safety of AMG145 in 631 patients with hyperlipidaemia and a fasting LDL-C level above 2.2 mmol/L despite treatment with a statin and/or ezetimibe. Again, fortnightly or monthly injections of AMG145 reduced LDL-C levels. So the paper concludes that the next requirement is “a large phase 3 clinical trial with several years of follow-up to investigate the long-term clinical efficacy and safety of AMG 145 in patients at increased risk of cardiovascular events.” Yes indeed: a trial with real end-points and an active comparator, which may with luck be completed and reported by 2020. Until then, this drug is of absolutely no interest to 99% of readers of the Lancet. So what are these lengthy reports doing in the UK’s leading medical journal? Is the reprint income they may bring from Amgen really sufficient to justify such a waste of space? Exactly what is this journal supposed to be for?

Perhaps I really shouldn’t complain: at least there is one research paper of value in the Lancet this week. Here are the ten-year outcomes from a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate. This will help to guide shared decision making in a very difficult clinical area. “Exploratory analyses suggest that postoperative irradiation might improve clinical progression-free survival in patients younger than 70 years and in those with positive surgical margins, but could have a detrimental effect in patients aged 70 years or older.” In other words, there is near equipoise between the two options. Time to construct an Option Grid, so that patients can ponder the harms and benefits of the two strategies according to their own goals and preferences.

BMJ 8 Dec 2012 Vol 345
Two papers from the EPIcure study (read here and here) send out mixed messages about improved survival and outcomes in very premature babies over the decade 1995-2006. More very premature babies are being saved but their outcomes are poor, and there are many gaps in follow-up. The editorial summarizes it usefully: “Out of every 100 neonates born at 24 weeks, 60 will die despite intensive care, and of the 40 survivors 12 will have serious impairments. Only 11 out of 100 neonates born at 23 weeks will survive without impairments. Impairments were still present in 20% of neonates born at a gestational age of 26 weeks.”

“Medicine is a social science, and politics is nothing else but medicine on a large scale. Medicine, as a social science, as the science of human beings, has the obligation to point out problems and to attempt their theoretical solution: the politician, the practical anthropologist, must find the means for their actual solution… The physicians are the natural attorneys of the poor, and social problems fall to a large extent within their jurisdiction.” So said the great Rudolf Virchow (1821-1902) in the mid-nineteenth century, and here is a demonstration study from England in the twenty-first century: “Conclusion Decreases in unemployment and increases in average income in an area explained, to a large extent, why some local authorities “performed” better than others. Health inequalities between Spearhead and all local authorities widened during the period of rising prosperity, but they would have widened to an even greater extent had unemployment not fallen at a faster rate in more deprived areas. With worsening economic trends over the next 10 years, this research suggests that increases in life expectancy are likely to be smaller and health inequalities may widen at a faster rate than in the previous decade. Allocating resources to local authorities on the basis of their “performance” at increasing life expectancy is likely to reward more affluent areas rather than disadvantaged areas with greater needs, exacerbating the problem.”

Ann Intern Med 4 Dec 2012 Vol 157
Unless you have a perfect diagnostic test, all screening will cause overdiagnosis (and usually underdiagnosis too). Performed annually for high-risk individuals, low-dose computed tomography has been shown to reduce overall mortality as well as lung cancer specific mortality. But how many of the tumours excised would actually proliferate sufficiently to behave as true malignancies? The Italian authors of this paper believe that you can judge this by the volume doubling time, and they have gone through all the CTs in their screening programme in an attempt to judge this retrospectively. They conclude that “indolent” or slow-growing cancers account for about 25% of the tumours detected, and may represent overdiagnosis. I can see all sorts of problems with this method and the conclusion, but full marks for effort and for highlighting the issue before such screening becomes widespread.

For many years now I’ve been tracking the progress towards fixed-dose anticoagulation without INR monitoring in these columns. It’s a nice idea and of course an enormous market for drug companies: there are many agents and many RCTs. I’m amazed that the authors of this systematic review of their comparative effectiveness against warfarin could narrow the field down to just six, including trials for both atrial fibrillation and venous thromboembolism. Their conclusion is prosaic and rather obvious: “Treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment.” If you have an excellent system for INR control, and patients are compliant, then the extra cost of these agents is not warranted at present. But when they come off patent, things may change, and INR testing may disappear and become one cost less for all health systems.

Plant of the Week: Helleborus niger

The pure white Christmas Rose is one of the few small plants to choose December as its month to flower. In consequence, it is often covered with dead leaves, snow or mud. With those bright white flowers set against dark cut leaves, it looks lovely in garden centres and we have all spent our £6+ on fine showy pots of it, sometimes several times, only to find that it never reappears the next year. I suspect that although it is full of toxins that kill humans, it is quite tasty and harmless to gastropods.