NEJM 3 Apr 2014 Vol 370
1287 Multitarget stool testing, you will be pleased to hear, is not the most important topic in the NEJM this week. There is in fact so much else on the NEJM website that I could take up the whole review dealing with nothing but online papers. So let us quickly dispose of these crap tests. There is a new one which includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. This was compared with a standard immunochemical stool test (FIT). Both were used on nearly 10,000 people at average risk of bowel cancer, who all underwent full colonoscopy too. “Multitarget stool DNA testing detected significantly more cancers than FIT did, but had more false positive results.” The old screening dilemma revisited: progress does not lie this way.
1298 We saw from that study that colonoscopy is the “gold standard” test for the detection of bowel cancer. But when human observations are concerned, gold seldom comes 24 carat. This study cunningly tests a proxy measure for operator thoroughness: it compares the adenoma detection rate of colonoscopists with their rates of interval colorectal carcinoma. Sure enough, the colonoscopists who pick up the most benign adenomas are also those who miss the fewest cancers.
OL From now on, teaching the crucial importance of proper design in randomized trials will be SYMPLICITY itself. I’ve already taken you through the essentials of this story, after being taken in myself, and there is a superb BMJ editorial as well. Here is the full report of the SYMPLICITY-3 trial which shows that after spectacular results in open label trials, renal denervation does not produce a significant drop in blood pressure which is persistently high after combined treatment with at least three drugs. Correction: it produces a very significant drop averaging 13mm Hg, whereas the sham control procedure produces a drop of nearly 12mm. Let’s just stop and think about that. If you lie a patient down and put a tube in an artery and pretend to fiddle about for half an hour, you can produce a long term reduction of their blood pressure nearly as great as if you actually ablate their renal nerve supply. Explanations on a post card please.
OL Whereas by funding SYMPLICITY-3, Medtronic lost themselves a potential market running into tens of billions of dollars, with this one they may have gained themselves a small niche market in people with aortic stenosis who are borderline for open valve surgery. Patients like this can benefit from transcatheter aortic-valve replacement (TAVR) with a balloon-expandable device, but Medtronic claim superior results from an alternative transcatheter bioprosthesis comprising a self-expanding nitinol frame and trileaflet porcine pericardial valve (CoreValve, Medtronic). Doing device trials is quite tricky, because you need operators to climb a steep learning curve, and here the first three patients enrolled in the trial at each study site were considered to be “roll-in” participants. They did not count in the figures but were there to familiarize the operators with the procedure. The bottom line as stated in the abstract is that “In patients with severe aortic stenosis who are at increased surgical risk, TAVR with a self-expanding transcatheter aortic-valve bioprosthesis was associated with a significantly higher rate of survival at one year than surgical aortic-valve replacement.” But a lot must depend on patient selection; and how many “roll-ins” you’ve practised on.
OL If I get heart failure with left bundle branch block, I would like to have biventricular pacing (or cardiac resynchronization therapy, CRT). I would want nothing to do with implantable defibrillators. Sudden death—especially beyond the age of 70—seems to me greatly preferable to a decline into weakness, breathlessness, dependency, and repeated episodes of near-drowning. However, in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), CRT alone was not on offer. You had to have the defibrillator, with or without CRT. Follow-up at a seven years confirms that CRT reduces all-cause mortality in people with mild systolic heart failure with LBBB from 29% to 18%, with a possibly harmful effect on those without LBBB. There is nothing here about symptom relief, which counts for more than survival to most people with HF.
JAMA Intern Med Vol Apr 2014
OL Three years ago, the NEJM published a trial of olmesartan in type 2 diabetes which showed that it reduced progression of albuminuria while increasing the rate of cardiovascular events. Ever since then, I’ve had a niggling worry about the use of angiotensin receptor blockers in diabetes, not to mention a healthy contempt for microalbuminuria as a surrogate outcome measure for anything. Now along comes a Chinese meta-analysis comparing outcomes in diabetic patients taking ACE inhibitors compared with ARBs. “Angiotensin-converting enzyme inhibitors reduced all-cause mortality, CV mortality, and major CV events in patients with DM, whereas ARBs had no benefits on these outcomes.” The comparators in the trials were placebo or other blood pressure lowering treatments. It seems that for most purposes, prescribing ARBs to people with diabetes is a waste of time. I expect this will filter into diabetes guidelines one day—perhaps in the next five years.
JAMA 2 Apr 2014 Vol 311
1308 Angst and weariness fill the journal reader. Every major trial of a sepsis intervention in the last decade seems to have been a flop. How nice then when a team of Antipodean researchers come out and tell us to stop our Pommie whingeing and listen to some good news. When they look at outcomes from 101 064 patients with severe sepsis from 171 ICUs with varied patient case mix in Australia and New Zealand, they find that mortality rates have nearly halved over the last decade. They don’t know why, but it has to be worth cracking a couple of tinnies.
1327 Now back to angst and weariness. Can you really bear to read another review of screening mammography? I forced myself to dip in on your behalf and was pleasantly surprised. Given that this wretched form of screening is bound to persist in some form or other, how can we help women to decide whether or not to have it? A lot will depend on their absolute risk of breast cancer and how they personally judge between the risk of unnecessary anxiety and surgery and whatever reduction in the likelihood of death from breast cancer mammography may afford them. Here (provided free by JAMA) is a thoughtful guide to how the science stacks up at present. “Risk models and decision aids are useful tools, but more research is needed to optimize these and to further quantify overdiagnosis. Research should also explore other breast cancer screening strategies.”
Lancet 5 Apr 2014 Vol 383
1222 I’ve long since given up trying to discern any logic in The Lancet‘s choice of research papers. This is the second weak study of a type of anorexia nervosa intervention to appear this year, and like the previous one it comes from Germany. It shows that the results of day hospital management are as good (i.e. terrible) as those of in-patient management, for lower cost.
OL Statins, as I keep saying, are wonderful drugs. They should be offered to everybody and people should make up their own minds whether to take them, based on the evidence and their personal preferences. What I personally would not do, however, is take simvastatin at a dose of 80mg, because this maximizes the risk of adverse effects while producing a very small marginal benefit compared to a lower dose. But 80mg was the dose given to 70 patients with secondary progressive multiple sclerosis in a phase 2 placebo-controlled trial. The mean annualised rate of brain atrophy was significantly lower in patients in the simvastatin group (0•288% per year [SD 0•521]) than in those in the placebo group (0•584% per year [0•498]). How this 43% reduction in brain shrinkage converts into clinical benefit is uncertain from this relatively small and short RCT, but it certainly suggests that bigger trials with other statins are well warranted in a dreadful condition which is currently untreatable.
OL The whiplash industry must be worth millions (if not billions) of pounds, and I am not talking about ladies who offer strict discipline to their slaves. Or perhaps I am, because most physiotherapists are female. When somebody gets a painful stiff neck after a motor vehicle collision, urban myth dictates that they must rush to a physio to prevent long-term effects. It will all come off the insurance. Here is an Australian trial which examines the effect of a 20 session physio programme on whiplash that has already gone on for three months or more, versus simple advice. The results were identical. I don’t know how the physios will react to this. Perhaps they will just say “You should have come to see me sooner, darling.”
BMJ 5 Apr 2014 Vol 348
The last few years have seen a huge upsurge of interest in vitamin D. I’ve even taken it myself from time to time, and I think I’ll start again as a result of this meta-analysis which concludes that “supplementation with vitamin D3 significantly reduces overall mortality among older adults.” Not that longevity is necessarily good for its own sake, but there are so many things I would like to get finished before I die. Sorting out vitamin D dosing would be enough in itself, since “further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.” But I am leaving this to my wonderful former colleague Harold Hin, who has retired early to do just the work that is needed.
But what a mess this subject is. And who better to survey it than John Ioannidis, who famously authored a paper called “Why Most Published Research Findings Are False.” In the end, however, the conclusion is a bit of a cop-out: “Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.” I would love to dig deeper, but however much taking a vitamin D3 supplement may prolong my life, I don’t think it would give me enough time to explore all these associations.
The treatment of infantile colic is to give the parents one thing to try after another, until the baby gets to four months old and stops having colic. The probiotic Lactobacillus reuteri DSM 17938 used to be a colic remedy worth trying, but should probably be dropped from the list as a result of this trial. It seemed to produce marginally more “fussing” than placebo. So keep giving them placebo instead. Gripe water. Fennel. Aromatherapy. Gaviscon. Anything that will stop parents going mad for 12 weeks.
Plant of the Week: Pulsatilla vulgaris “Bell’s White”
There are many adorable spring flowers nodding in the wind at present, including native daffodils and fritillaries. But this particular wind-flower is a special favourite, and unlike the rest it provides a lovely tuft of finely-cut foliage for months after its flowers have faded.
The big boss of yellow stamens that all pulsatillas bear is seen to best advantage in the red and purple forms, I think; and for several years I avoided this white version because it can look washy and frayed. But when I caught sight of it on a market stall, waving its semitranslucent petals in the breeze, I decided to part with £3 in order to possess it. I think I shall be glad of this modest investment as it grows over the years, bearing an ever bigger cluster of pale pretty wind-blossoms every Easter.