Richard Lehman’s journal review—20 April 2015

richard_lehmanNEJM 16 April 2015 Vol 372
1489 Your learning task this week is to memorise “proprotein convertase subtilisin–kexin type 9 (PCSK9).” The next big lipid lowering debate will be all about inhibitors of PCSK9, and somebody should urgently invent a popular name for them. I suggest fatins (fat lowering injections), to rhyme with statins. There are two of them at the moment: alirocumab and evolocumab. In this trial, alirocumab was given as an injection every two weeks to two thirds of 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 1.8 mmol per litre or more and were receiving treatment with statins at the maximum tolerated dose. The rest had a placebo injection. “At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was −62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks.” The trial was not powered to detect a fall in actual cardiovascular events over this period, but as its name ODYSSEY LONG TERM implies, it means to go on:
To strive, to seek, to find, and not to yield. (Last line of Ulysses by Tennyson)

1500 And now for fatin number two. Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9), as you already know: the phrase is already tripping off your tongue. This is Amgen’s answer to Sanofi and Regeneron’s alirocumab, and it has chosen to call its trial OSLER. The effect of the two antibodies seems to be very similar. Again, the early signals point to a substantial fall in cardiovascular events, but only time will tell. This will be a hard fight, but it isn’t clear how big the potential market will be. After all, the real Osler is quoted as saying “The first duty of the physician is to educate the masses not to take medicine.” The statins wars will soon become the fatins wars; and I hereby declare copyright on the word fatin. I am willing to sell this to either drug company for a million dollars. Everyone has their price and mine is very reasonable.

1510 Behçet’s disease is apparently quite rare in the United States, and much commoner in Turkey where Hulusi Behçet described it in 1922. The Greeks protest that Hippocrates described something similar 2500 years ago in his Epidemion (book 3, case 7), and in any case their 20th century dermatologist Adamantiades has a better claim than the Turkish upstart. So how to say Behçet? I have been told (though not by anyone Turkish) that it should be pronounced to rhyme with how an upper class Englishman a hundred years ago would have pronounced “hatchet.” Betchet to rhyme with hetchet. And how to treat it? Nobody really knows, as its cause remains a mystery. Its worst effects include scarring lesions on the anus, genitals, and eyes, accompanied by mouth ulcers which are non-scarring. Apremilast is an oral phosphodiesterase-4 inhibitor, which is shown in this trial to reduce the occurrence and severity of mouth ulcers while it is taken, at a basic cost in the US of $22 500 a year.

1519 I recently watched a TV documentary about Jonas Salk and the development of polio vaccination, which included endless clips of American kids cutely rolling up their sleeves and trying not to cry when being injected one after the other with the Salk vaccine through the same needle of fearsome size. The villain in the programme was Salk’s less glamorous rival Sabin, who was working on an oral vaccine. As a kid from the 1950s who had both, I can tell you that I much preferred Sabin’s vaccine to Salk’s (though, for the record, I did not cry, but felt my mother’s joy that I was now safe from a disease which had killed or crippled other kids in my street). So full marks to the people who are trying to come up with an aerosolized vaccine against measles. Alas, in this Gates funded trial in Indian kids, it conferred less immunogenicity than the injected measles vaccine.

JAMA 14 April 2015 Vol 313
1425 A large database study finds that there is a relationship between getting gestational diabetes before 26 weeks and having a child who is subsequently placed in the autistic spectrum. The Kaiser Permanente tracking system is probably one of the best in the US, but it’s still hard to know how robust this finding is, but it seems certain that it is not a drug related effect.

1435 I have a kind of déja-vu feeling about this report on 15 year outcomes in “nonelderly” patients with mitral disease requiring valve replacement who have been treated with either bioprosthetic and mechanical prosthetic valves. Maybe it’s because I have read too much cardiac outcomes research, or because I am approaching the end of nonelderliness. Anyway, in patients aged 50 to 69 years undergoing mitral valve replacement in New York State, there was no significant survival difference at 15 years in patients matched by propensity score who underwent mechanical prosthetic vs bioprosthetic mitral valve replacement.

1451 “Acute stroke intervention: a systematic review” is a very good update article because it goes a bit further and wider than simply a systematic review. This is a really fast moving subject, and the necessary rush to get patients assessed and treated means that primary care doctors are not involved except occasionally to ring for a blue light ambulance on behalf of the patient. But it’s an area of interest to everyone, since anyone can have a stroke. The two studies of thrombectomy that I recently commented on are still sitting on the NEJM website, and it’s only a week or two since a paper appeared which should be practice changing in a different way. This describes a computerised decision aid, which can help patients and their relatives make very fast decisions about thrombolysis on an individualised basis. It was developed in Newcastle (UK) and every stroke unit around the world needs to know about it.

JAMA Intern Med April 2015 Vol
A randomised controlled trial shows that a single 5mg dose of zoledronic acid provides two years of improved bone density measurements in elderly women (mean age 85) in US residential homes. On the other hand, more women in the active group died and had fractures. Is this a case of futile research, or of research that confirms futility? The authors claim we need more research, but would that be the ultimate in futility? My take home message here is to stop bisphosphonates in older women who are no longer able to live independently. From this study, I can’t see what possible good they might be doing, unless oral agents are different from zoledronate.

Ann Intern Med April 2015 Vol 162
465 I don’t find much to report about from the Annals these days, but here are two important contributions to the debate about futile interventions. This one from the printed journal of 7 April reports outcomes from a series of patients with lumbar spinal stenosis randomised to surgery or physical therapy (physiotherapy) between 2000 and 2007. “Surgical decompression yielded similar effects to a PT regimen among patients with LSS who were surgical candidates. Patients and healthcare providers should engage in shared decision making conversations that include full disclosure of evidence involving surgical and nonsurgical treatments for LSS.” So who has these honest conversations in the US? I suspect it will be a contentious topic even in the UK, when it comes to the crunch in the Choosing Wisely campaign.

OL Over 10% of the NHS budget goes on diabetes, a figure considered insufficient by Diabetes UK, who recently ran a diabetes awareness drive. For a while, a man using a public convenience was compelled to stare at their advertisements, which were located in such a way as to make him risk peeing on his shoes. This was quite misconceived. The idea that you can diagnose diabetes by spotting sugar marks on men’s shoes has long been discredited. In fact, the whole idea of population screening for diabetes has long been discredited, though it dies very hard. Here is the conclusion of a report by the US Preventive Services Task Force: “Screening for diabetes did not improve mortality rates after 10 years of follow-up. More evidence is needed to determine the effectiveness of treatments for screen-detected diabetes.” Er, um, yes, and you can miss out the “screen-detected” bit: we simply don’t know what we are doing when we treat most people with so called type 2 diabetes.

Lancet 18 April 2015 Vol 385
1477 The first editorial in this week’s Lancet bemoans the lack of alcohol awareness in the US. This is so true. It’s something every European must have felt while visiting the land of the free. It was not such a problem in the 18th century, when the households of Boston would consume a gallon of rum a week. Banning direct imports of rum from the West Indies sparked the War of Independence. It was nothing to do with tea: they just threw that into the sea. But by 1831, Alexis de Tocqueville reports on arrival in New York: “At first we found the absence of wine at meals a serious deprivation, and we are still baffled at the sheer amount of food that people somehow stuff down their gullets.” If only the Americans could be made more aware of wine, their obesity problem would begin to improve, and the world might become a less dangerous place, as they would take themselves less seriously.

1536 A fairly large cluster randomised trial across 168 secondary schools in Europe seems to have succeeded in reducing attempted suicide and suicidal ideation in 14-15 year olds in schools, using the Youth Aware of Mental Health Programme (YAM). Pupils of schools randomised to this intervention were only half as likely to make a suicide attempt or to have serious suicidal thoughts as those in the control arm. But the editorial on the study sounds rather cautious and weary, despite the relatively high quality of this trial and its significant result.

The BMJ 18 April 2015 Vol 350
At a time when access to seven day healthcare is a political football in the UK, The BMJ publishes a study of “the association between weekend admission to hospital and 11 hospital acquired conditions recently considered by the Centers for Medicare and Medicaid as ‘never events.'” As you can guess from the wording, the context is the US, and this study builds on work done some years ago on hospital mortality at weekends by Harlan Krumholz. It gets an excellent editorial from members of his CORE team and himself. But British readers might be a bit bemused to see this entirely US context paper following two papers about Massachusetts healthcare reform. Our own health system is not exactly without its own issues of interest at the moment.

It’s often said that drugs start off with exaggerated hopes of benefit and ignorance of harms. Actually, the opposite can sometimes be true. As a medical student, I was told that methotrexate was a potential cause of irreversible lung fibrosis. We now use methotrexate for a wider range of indications than we did then, but we don’t see many cases of MTX-related pulmonary disease, as this literature review points out. “Findings suggested that there was no increased risk of lung disease in methotrexate treated patients with non-malignant inflammatory diseases. Given the limitations of the study, however, we cannot exclude a small but clinically important risk.”

Plant of the Week: Sanguinaria canadensis “Flore pleno”

This is truly a plant of the week, because it flowers for less than seven days and then does little for the rest of the year, disappearing altogether from August to March. Its blaze is all too brief, but so spectacular that it burns itself on the mind and is eagerly looked forward to every spring.

The Canadian bloodroot is a very common woodlander down the whole of Eastern North America. Its petals are of shining white, and they can illuminate the darkest forest floor. Should you dig it up to bring to your garden, you will be caught red handed, because its broken rhizomes exude blood coloured sticky sap.

In gardening Latin, you may remember that “flore pleno” means double petalled. And in gardening English, you may remember, “double” can mean anything from a couple of small extra petals to a profuse mass of extra petals. On this garden form of the bloodroot, each flower is a ball of twenty or more fine petals of dazzling white. In sunshine these open out in the morning and close together in the late afternoon. They are held quite close to the ground, between two emerging serrated leaves of greyish green. After three or four days, the evanescent petals lie scattered on the soil and the show is over. Nothing in the rest of the season can quite match it.

• Can you remember what PCSK stands for?
• LESS IS MORE: Bisphosphonates for nursing home residents? Surgery for spinal stenosis? Screening for diabetes?
• SHARED DECISION MAKING: all the above, plus thrombolysis for acute stroke.
• PRACTICE CHANGERS: you decide.