Richard Lehman’s journal review—1 December 2014

richard_lehmanNEJM 27 November 2014 Vol 371
2061 Antoine Bernard-Jean Marfan (1858-1942) was a French paediatrician who lived in the happy era of medicine when you could affix your name to new signs, symptoms, laws, and syndromes, and Marfan bagged at least one of each for himself. But, ironically, his name is immortalised by a syndrome distinctly different from the one he described—a fate which has also overtaken Drs Alzheimer and Asperger. Marfan (pronounced to rhyme with enfant) presented a girl with arachnodactyly and digital contractures, whereas Marfan (to rhyme with bar-fan) describes a hereditary disorder of connective tissue without contractures. In the full blown form of this autosomally dominant condition, the leading cause of death is cardiovascular disease, mainly progressive aortic root dilatation and dissection. To prevent this, beta-blockers have been generally used since an open label trial showed survival benefit in 1994. But theoretical reasons have been put forward that angiotensin receptor blockers might work better, and this trial pitted atenolol against losartan. At the end of three years, in 608 subjects aged 6 months to 25 years, there was no detectable difference between the agents. The primary outcome was a surrogate—the aortic root z score. And the trial was not adequately blinded. Be that as it may, it is good to note that in both groups the aortic root actually decreased in diameter as the study progressed.

2083 The Democratic Republic of Congo is not a nice place to think about. Perhaps that is why its Ebola outbreak has gone almost unremarked upon. The tale is quickly told: “The index patient was a pregnant woman living in Inkanamongo village who butchered a monkey (of an unknown arboreal species) that had been found dead by her husband. She became ill on July 26 and died on August 11. A local doctor and three health workers who undertook a postmortem cesarean section (to separate the fetus from the mother before burial, according to the local culture) also became infected and died. These health workers were evidently the source of further cases in this outbreak.” So this was entirely separate from the west African outbreak, and involves a different strain of ebolavirus. Just a tiny incident in this Francophone country twice the size of France, where 10 million people died under the personal jurisdiction of King Leopold II of the Belgians (1885-1908), and another 5.4 million have died since 1998 of diseases and malnutrition resulting from civil war.

OL Cometh the virus, cometh the vaccine. That is supposed to be how it works, and it is good to see that an experimental Ebola vaccine is out already and soon to undergo field tests. “A replication-defective recombinant chimpanzee adenovirus type 3–vectored ebolavirus vaccine (cAd3-EBO), encoding the glycoprotein from Zaire and Sudan species that offers protection in the nonhuman primate model, was rapidly advanced into phase 1 clinical evaluation.” Not the most elegant of sentences but it gives you the gist. It was immunogenic in 20 volunteers. They’re flying it out now.

JAMA 26 November 2014 Vol 312
2135 Back in those heroic days of medicine I alluded to above, a second year medical student at Johns Hopkins called Jay McClean isolated an anticoagulant from dog’s liver and called it heparin. This was in 1916, and had he called it McCleanin we might still remember him. It took another 20 years for a sufficiently pure and non-immunogenic liver extract to be produced for use as a human anticoagulant, and a further 50 years for low molecular weight heparins to be manufactured. However, although new is always more expensive, it is not necessarily better. A distinguished international line-up of authors use data from 2344 patients in the Prophylaxis for Thromboembolism in Critical Care Randomized Trial to determine whether LMWH dalteparin is worth the extra asking price compared with unfractionated heparin in ICU inmates. They conclude that it is. In fact, there is a cost saving driven by lower rates of pulmonary embolism and heparin induced thrombocytopenia, and corresponding lower overall use of resources with LMWH. Incidentally, old fashioned heparin is now made largely from pig intestine and bovine lung, which you’d think might preclude its use among hundreds of millions of religionists.

OL By far the most dangerous ingredient in the proposed polypills is aspirin, and the evidence that it prevents cardiovascular disease in the general population is very slender. But populations vary, and so do risk scores in those populations. Officially, 98.5% of people living on the islands of Japan are “ethnically Japanese,” but according to Wikipedia this has no established veracity, or indeed meaning. However, we can take it that they are ethnically largely similar, and may have subtly different physiological traits from Europeans or North Americans. The Japanese Primary Prevention Project (JPPP) was designed to determine whether once daily, low dose, enteric coated aspirin reduces the total number of atherosclerotic events (ischaemic heart disease and stroke) compared with no aspirin in Japanese people 60 years or older with hypertension, dyslipidemia, or diabetes mellitus. Nearly 15 000 people were randomised. Result: “Once daily, low dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors.”

JAMA Intern Med November 2014 Vol 174
OL Probably the aspect of clinical medicine I will miss least is the requirement to waste three hours annually undergoing “life support training.” I can now confess that for several years I managed to go under the radar and skip these sessions. And I have been a doctor for 40 years without ever encountering an out of hospital cardiac arrest. If I do, I shall pump the chest as hard and frequently as I can and hope that someone has called an ambulance. Even this may be too much—nobody knows, because this is an evidence free area. This Less is More paper reports on outcomes following out of hospital cardiac arrest, according to whether basic or advanced life support was employed. There was a considerable difference. Those given advanced life support were less likely to survive and significantly more likely to suffer neurological damage.

Lancet 29 November 2014 Vol 384
OL While the basic concept of performing chest compressions for out of hospital cardiac arrest has never been subjected to a randomised trial, mechanical chest compressors have been compared with humans. By mechanical criteria, they perform better. But in trial after trial, PARAMEDIC being the latest, they make no difference to mortality. Which really makes you want to do that trial with no compressions as the control; but nobody would let you. A huge, earnest industry of well meant meddling stands to suffer. If you so much as lift an eyebrow during a CPR training lecture, you are made to feel at best like an incompetent, at worst like a murderer.

OL The driving narrative of medicine is that newer is better, and more of it is better than less. I greatly admire JAMA Internal Medicine for challenging these assumptions with its articles called Less is More: I don’t think they’ll have any trouble carrying on the series indefinitely. My fellow editors and I are not having any difficulty carrying on with our BMJ series Easily Missed either. Pyogenic vertebral osteomyelitis is easily missed, and when treating it with antibiotics, less can equal more. Staphylococcal infection of a vertebra is not especially rare: I spotted two in 30 years of general practice. Naturally, you want to treat if for as long as it takes to be sure the staphs are really dead. Typically, that is 12 weeks. But in this French trial, patients randomised to six weeks of treatment showed the same cure rate at one year.

OL The leading figures in US cardiac outcomes research combine to examine trends in door to balloon (D2B) time and mortality after ST elevation myocardial infarction in 423 American hospitals, between January 2005 and December 2011. Their findings are paradoxical. Shorter patient specific door to balloon times were consistently associated at the individual level with lower in-hospital mortality and six month mortality. And during those six years, the median D2B fell from 86 minutes to 63. “By contrast, risk adjusted in-hospital and six month mortality at the population level, independent of patient specific D2B times, rose in the growing and changing population of patients undergoing pPCI during the study period.” So the investigators are explaining a paradox of worsening overall outcomes by a change in the population over that period. But if that is true, don’t we have to repeat all the trials comparing pPCI with thrombolysis, for example? I’m not entirely sure what is going on here. I leave these things to Harlan Krumholz, who is final author on this paper.

1953 I guess it wouldn’t do to pass by this issue of the Lancet without addressing liver disease in the UK, something that Roger Williams and colleagues do at 44 page length. We must not grudge them their moment of hepatomegaly. Although the liver is the least likely of the body’s organs to fail and kill Britons, it is trying its best to overtake the kidney, thanks to our increasing levels of alcohol consumption and obesity. These moral failings do not escape censure, nor do our delinquent GPs, who are failing to spot the early signs and use their magic powers to change people’s habits. And obviously with a quarter of the population showing fatty changes in their livers, owing to fat, we need more liver specialists. The risks associated with fatty liver disease, by the way, closely match those associated with fatty neck disease, so we also need more neck specialists.

The BMJ 29 November 2014 Vol 349

To share decisions about treatments, you need to know their benefits and their harms. People differ widely in how they balance the two, and you can’t know their preferences without giving them accurate information and then asking them. So what we most need to practice proper medicine is dependable, updated summaries of knowledge about numbers needed to treat and to harm, plus ideally some information that helps us apply these population figures to individuals. That should be the prime product of the science of medicine and the foundation of our art as doctors. But across a bewildering range of clinical situations, you look for the NNT and the NNH, and you can’t find them. I know, because I work for both the UK Cochrane Centre and for the Option Grid programme. In this paper, Doug Altman and colleagues look at 92 Cochrane reviews and examine them for selective reporting bias of harm outcomes within the studies included. The single primary harm outcome was inadequately reported in 76% of the primary research papers, and if anything, the reviews themselves were even less good at summarising data about harms. Oh boy, there is a lot of work to be done before we can apply the science of medicine to the art of sharing decisions with patients.

At the age of 55, men and women face an identical risk of cardiovascular events over the rest of their lives. The women will tend to live a bit longer, and the distribution of events will not be the same in them as in men. I hadn’t thought of it like that before I read this study from the Netherlands. In 2888 citizens of Rotterdam followed up for 20 years, men proved more likely to develop coronary heart disease as a first event, while women were more likely to have cerebrovascular disease or heart failure as their first event—usually at a later age.

When oral contraception became widely used in the 1960s and 70s, nobody knew what its long term effects might be. It is a miracle that it has proved so safe. This is confirmed in the 36 year follow-up figures from the Nurses’ Health Study of 121 577 women who were almost evenly divided between pill takers and non-pill takers. “All cause mortality did not differ significantly between women who had ever used oral contraceptives and never users. Oral contraceptive use was associated with certain causes of death, including increased rates of violent or accidental death and deaths due to breast cancer, whereas deaths due to ovarian cancer were less common among women who used oral contraceptives.”

Fungus of the Week: Clitopilus prunulus

The sodden end to November is bringing up fine crops of fungi everywhere, as if the whole earth is fruiting from inner decay. To my surprise, I found this growing under the side of a concrete slab today. Its vernacular name is The Miller, because it smells distinctly of freshly milled flour.

There are three fungi which carry this distinctive mealy smell, and two of them are very nice to eat. The third is poisonous, though probably not deadly.

They are fortunately easy to tell apart. The squat, firm mushrooms which appear in mid April-May among grass have white to off-white gills, very crowded, and smelling distinctly of flour. These are St George’s mushrooms, Calocybe gambosa, and nothing else like them appears at that time of year.

Our present subject grows in autumn, usually in woods, and has a short stem and a big wavy off-white cap. The gills are between white and a pale pink beige. The smell of meal is even stronger than with the St George’s sort.

And then—rather rare, but strikingly handsome and pleasantly fragrant—is Entoloma sinuatum. This has a cap of ivory to light grey, and gills that can start yellowish and then become dark pink-brown. I have only found it once, in October, and took about a pound of them home for identification, hoping that they were edible. But with its flesh turning red in front of me, I realised my mistake in time. The great mycologist Quélet was not so lucky and suffered accordingly, but survived to name this fungus “the Miller’s Purge.” It continues to deceive Frenchmen to this day and is sometimes referred to as le grand empoisonneur de la Côte-d’Or.