Richard Lehman’s journal review—8 September 2014

richard_lehmanNEJM  4 Sep 2014  Vol 371
892    A terrific piece by Rita Redberg discusses sham controls in medical device trials. Whenever sham procedures are used in the control arms of such trials (or in surgical trials generally) they reveal a huge placebo effect. For example, renal denervation therapy produced huge sustained falls in recorded blood pressure in unblinded, uncontrolled trials in people with “resistant hypertension”. But when it was tested in a properly blinded trial using a sham control, it failed to detect enough difference to satisfy its primary end-point. She goes on to point out that percutaneous coronary intervention has never been tested against sham PCI. I’ve just learnt to my amazement that Darrel Francis at Imperial College is planning a trial to do just this in people with angina and single-vessel disease, and it’s still open to extra UK investigators on   

895   Getting a diagnosis of multiple myeloma below the age of 66 is seriously unfortunate. But in case you have a patient in that situation, you may want to read about this three-group randomized trial from Italy which concludes that “Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with melphalan–prednisone–lenalidomide, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival.” But for most of us it’s probably best just to skip to the editorial (p.961) which usefully summarizes where we now stand after a decade of real progress in the management of this nasty disease, which probably killed the great Turgenev.

906   And the editorial also guides you through a second multiple myeloma trial, this time on people ineligible for stem cell transplantation. Continuous lenalidomide–dexamethasone given until disease progression seems to be the new standard of treatment.

944   Next, a good clinical review of haemorrhoids, with an excellent illustration of rubber band ligation, a procedure I was previously somewhat vague about. When I started out as a GP, we used to do proctoscopy, and I used to incise thrombosed external piles from time to time. This review tells you to do it “with the patient under local anaesthesia” but this is going too far: you only need local anaesthesia around the haemorrhoid. Otherwise a good review, containing piles of information.

OL   And now, alas, to the much-vaunted PARADIGM-HF trial. This has been hyped as the biggest breakthrough in heart failure for at least 20 years.  A fixed dose of enalapril was compared with a substance called LCZ696. This turns out to have been a mixture of valsartan and sacubitril, a neutral endopeptidase inhibitor, and most participants ended up receiving a daily dose of 320mg of valsartan, versus 20mg of enalapril. A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died after a median follow-up of 27 months, at which point the trial was stopped prematurely. So just what are we looking at here? How can we distinguish the effect of the sacubitril from the effect of the high dose of valsartan? Well, we can’t. And this trial is a perfect example of everything that is wrong with heart failure trials. The mean age of the 8442 patients was 63.8, nearly  80% were male, and they were selected by reduced ejection fraction in 1043 centres across 47 countries. A logistic nightmare, but a great way for Novartis to spread influence. And Novartis then collected, managed and analyzed all the data itself. As I have said, a submaximal dose of one drug was compared with a maximal dose of another plus an extra ingredient. There was a run-in period, in which patients who were intolerant to the new treatment (12%) dropped out. Adding bias to bias, the trial was terminated prematurely. One of the primary end-points was hospitalization, which was ably demolished in a JAMA article I pointed out last week. And yes, there was a mortality benefit, but the number-needed-to-treat was about 35 to prevent one death in 2 and half years, in a population far removed from the elderly co-morbid patients we see in real life. As I draw to the end of a clinical career in which I’ve tried to help people with heart failure, I stand bemused. This is just how things have been done for the last 30 years, and it’s not good enough. At the very least, Novartis must make its full data set available for independent analysis. And before sacubitril is licensed, we need a properly designed trial, say between valsartan 160mg b.d. alone and valsartan plus sacubitril, in a typical population with heart failure. It will be very interesting to see what the FDA, the EMA and NICE decide.

JAMA  3 Sep 2014  Vol 312
923   Never mind the diet: just consume less. Boring as this is, it’s always the message where weight loss is concerned. The best diet for you is the one you can stick to, says this meta-analysis of named diet programmes for overweight and obese adults. For most people, this seems to be a low-carbohydrate diet. It usually carries the name of Atkins, though plenty of others got there before him.

934   And then there is bariatric surgery. This is the 135th systematic review of surgical procedures to reduce weight, and it justifies its existence by looking for long-term outcomes from randomized trials. This simply means follow-up for two years or more, and out of 7371 clinical studies they found 29 that met this basic criterion. The results are as expected: replumbing the upper GI tract with a gastric bypass procedure works better than gastric banding, while for gastric sleeve resection we lack adequate long term evidence.

JAMA Intern Med  Sep 2014
OL   Hypoglycaemia has overtaken hyperglycaemia as a cause for admission in people with diabetes, and sulfonylureas are the commonest oral agents responsible. What we often forget in the hurly-burly of clinical practice is that certain antibiotics are known to potentiate the glucose-lowering effect of sulfonylureas. According to this survey of Medicare claims in Texas, the antibiotic most likely to do this is clarithromycin, with a number needed to harm of 71, followed by levofloxacin, sulfamethoxazole-trimethoprim, metronidazole and ciprofloxacin. Not particularly common then, especially as the first three antibiotics are not usually first-line choices in the UK. There is an excellent commentary by Kasia Lipska on the wider issues.

Lancet  6 Sep 2014  Vol 384
857   How can the same author appear in the same week on papers about international standards for newborn weight, length, and head circumference by gestational age and sex, and about the efficacy of ß blockers in patients with heart failure plus atrial fibrillation? Only by being Doug Altman. He is the great guarantor of quality in the statistical analysis of clinical data, and he seems to me quite irreplaceable, since he is a great communicator too: his is the only book on medical statistics that you can actually read for pleasure. For me, his name on this paper is the only interesting thing about it. But if you are a neonatologist then do read on, and if you are an obstetrician you might need to read the next paper too, or at least keep it for reference. It sets out international standards for fetal growth based on serial ultrasound measurements.

880    At the moment I am proceeding steadily through Wild Wales, in the rather overbearing company of George Borrow, who walked its roads and byways in 1854. He was struck by the deep literary knowledge of the Welsh speakers with whom he frequently shared a pint of cwrw (ale), and at one points declares to them that they are better by far than the Saxons of his own English race, who are only interested in bending the truth and making money. I get an overpowering feeling of the same thing when I read this week’s Lancet paper on deaths in young people aged 0—24 years in the UK compared with the EU15+ countries, 1970—2008. In that period, we lost our national consensus on social justice. The devil can take the hindmost so long as the richest rich get richer, and we don’t even want to know about what is happening to the underclass. Our democracy has long since given up any attempt to represent them, and we have all learned to feel powerless and just hope we can have a bearable old age and hand something over to our children who will live in the dreadfully unequal nation we have allowed ourselves to become.  “The UK has not matched the gains made in child, adolescent, and young adult mortality by other comparable countries in the 40 years since 1970, particularly for infant deaths and mortality from non-communicable diseases, including neuropsychiatric disorders. The UK needs to identify and address amenable social determinants and health system factors that lead to poor health outcomes for infants and for children and young people with chronic disorders.” I think the beginning of the second sentence is wrong. We have long since identified the determinants but our politicians have absolutely no interest in changing them. Or perhaps, indeed, they are truly powerless.

OL   The trials which established the role of beta-blockers in systolic heart failure came up with some surprising subgroup results, one of which was that the mortality benefit of ß-blockade did not seem to extend to patients with atrial fibrillation and reduced systolic ejection fraction. On the face of it, you would expect them to benefit most. I have already hinted at the deficiencies of these trials, which were dominated by younger male patients without major comorbidity, but we’ll let that go and congratulate the authors of this paper for coming together and performing an individual patient data meta-analysis based on the randomized trials. A clear message emerges: people with AF do not experience the benefits which people in sinus rhythm derive from taking ß-blockers for heart failure. I hope this message filters out to heart failure nurses as well as cardiologists.

BMJ   6 Sep 2014  Vol 349
Stephen Lock, editor of the BMJ in another age, banned the use of the expression “more research is needed” on the grounds that more research is always needed. But is that really true? It is positively unethical to waste time and enrol patients if the answer is already known. This seems to be the case in the case of preventing pain from propofol injections in adults and children. According to a paper which in this week’s  print BMJ, a systematic review of 56 trials in 2000 provided guidance for further studies on this topic, which for all I know may be of importance. Subsequently there have been another 136 trials, most of them poorly designed. By now, I would hope that any anaesthetist wanting to stick this stuff into me would know how to make it less painful.
In a superb analysis by Graham Cole and Darrel Francis, we’re taken through the sorry story of how perioperative beta-blockade for high risk patients became accepted practice due to the DECREASE trials, which have since been shown to contain internal inconsistencies and unverifiable data. If you meta-analyze all the other trials they show convincing evidence of harm. Now the specialist cardiology societies of Europe and the USA have come up with a shared August 2014 guideline in which they claim to have excluded the DECREASE data, but still come up with a positive recommendation. In fact they have been misled by including meta-analyses which still included the DECREASE results.  It’s a story that certainly decreases one’s confidence in the credibility of specialist society guidelines. As Larry Husten has said, guidelines should follow the same rules as declarations of war: only to be issued when there is absolute agreement and an urgent need.

Vitamins are good things, by definition, but how they affect us from the time when we are microscopic implanted blastocysts to the time we die is by no means fully understood. It’s hard enough to master the biochemistry and the cross-sectional studies, as this article about vitamin B12 makes clear. The barn-door stuff to do with pernicious anaemia and peripheral neuropathy is easy enough, but what levels of B12 constitute a “normal range” and what should we be measuring? Serum B12 is easy to measure, but the active metabolite holotranscobalamin has a much better physiological logic, and so does methylmalonic acid as a marker for deficiency. But their assays vary a lot. Harold Hin did some excellent work on this at my practice a decade ago, but we remain ignorant about the effect of this vitamin on us across the whole of our lives, from sperm to worm. And the other issue that Harold and I puzzled about is why so many patients on B12 injections get a buzz from them which seems to last for about 3 weeks, even when their serum levels are sky high.

Plant of the Week: Clerodendrum trichotomum var fargesii

This week I break my usual rule and write about a plant I have never possessed. Trish Groves sent me a picture of a small tree in her garden that she adores but was unable to identify, and I could identify it immediately because I had just seen it in the gardens of Bodnant, that true paradise of gardeners. Elizabeth Loder of Boston Mass. joined the conversation with pictures from her own garden, where the clerodendrum flourishes at the northernmost limit of its hardiness in the USA. She had fallen in love with it in the Arnold Arboretum and grown it from bare rooted postal purchases.

This must be the finest late flowering tree for our climate, with a canopy of white flowers in late August, beloved by bees, and in America by hummingbirds. I cannot say that I personally would take flight to smell them. And although Elizabeth describes the scent of their crushed leaves as resembling peanut butter, to me they have an altogether grosser odour.

The flowers are followed in very short order by highly ornamental seed capsules which open bright purple to reveal a central greeny black fruit. A truly splendid plant. Lacking space in our own garden to plant one, I am thinking of ways to foist one of these trees on a neighbour.