Richard Lehman’s journal review—22 February 2016

richard_lehmanNEJM 18 Feb 2016 Vol 374
Testosterone, lust and rage
611 When the great poet WB Yeats reached the age of 67, he noticed a certain waning of his powers and decided to visit a prostitute. It does not seem to have been a very satisfactory encounter for either party (“like trying to squeeze an oyster into a slot machine,” he said). Yeats then sought the advice of Norman Haire, a hugely successful sex consultant to the rich and dotty of early 1930s London, who carried out a mysterious operation, which was probably a vasectomy combined with some kind of testosterone injection. Yeats then went on to write his Last Poems, among which is “The Spur”:

You think it horrible that lust and rage
Should dance attention upon my old age;
They were not such a plague when I was young;
What else have I to spur me into song?

Self-reported lust was an outcome measure for the latest trial of testosterone in old men, though not rage. Men aged 65 and over with low testosterone levels who were randomised to testosterone gel experienced more sexual desire and had more successful sexual activity. Their mood improved slightly on average, but not their vitality or walking distance. So should all ageing male would-be poets and lovers use testosterone? Well, I wouldn’t submit to one entry criterion for this trial, which was to have a PSA measurement. I know that as a 65 year old, my chance of having a focus of cancer in my prostate is about 80%. Measuring my PSA would make it far more likely that some urologist would go in with needles and detect it. Taking testosterone, on the other hand, would make it more likely to grow and spread, which is something you couldn’t detect in a one year trial on 790 men. Ignorance might be as much bliss as a bit more sex, though it’s hard to compare the two. All in all, I think I’ll settle for my current levels of lust and rage.

Ebola care in the US & Europe
636 During the Ebola virus disease epidemic, a total of 27 patients received care in Europe or the United States at 15 hospitals in nine countries. This retrospective tells the story. These hospitals talked to each other throughout, and together they only lost five people. The illness began with fever and fatigue and progressed to diarrhoea and then massive metabolic upheaval: hypoalbuminaemia, hyponatraemia, hypokalaemia, hypocalcaemia, and hypomagnesaemia. Renal failure, respiratory failure, and liver failure occurred in quite a few patients but their median time in hospital was just 20 days. Most of those who died did so in the first week.

Yellow belly vs pink belly
647 When I was 8, I was taken into Lincoln General Hospital with suspected appendicitis. The next morning my pain had gone but a smiley man in a dark suit came round and told me I would be having my appendix out. I never saw him before or since. A nurse then came and covered my tummy with a sharp smelling, very cold, brown liquid. “You’re a right Lincoln yellow-belly now,” she said, to my complete incomprehension. I later learnt that it was a reference to a Lincolnshire regiment in the First World War, which had refused to walk at a slow steady pace into enemy machine gun fire. But I duly went off and had my normal appendix removed through a massive incision that then became infected. Since then there have been lots of trials comparing the iodine-alcohol skin prep—which I had with chlorhexidine-alcohol—which was introduced as an antiseptic about the same time as I had my operation. Like the others, this trial on American women having caesarean sections shows that chlorhexidine results in fewer surgical site infections. This is no longer a valid subject for investigation. Iodine should be banished to the laboratory and yellow no more bellies.

Piogliazone after stroke
OL Here’s a rather strange double blinded trial: “We randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction.” Now pioglitazone decreases blood glucose, putatively by stimulating peroxisome proliferator–activated receptor γ (PPAR-γ) and increasing insulin sensitivity. So if you gave it to any group of “pre-diabetic” individuals, you would delay their crossing the arbitrary threshold into “type 2 diabetes.” And this is what happened here: there was a 3.9% reduction in the incidence of diabetes over 4.8 years, compared with placebo. Those taking pioglitazone also had an 18.5% greater chance of weight gain over 4.5kg, an 11.8% greater chance of oedema, and a 1.9% greater chance of having a major fracture. There was no difference in all cause mortality, but for a composite end point of fatal or nonfatal stroke or myocardial infarction, pioglitazone produced a 2.8% reduction. Chew these figures over. Make them into an infographic, just for an exercise. Once you have done this (and not before) you could make an offer of pioglitazone to suitable patients and see if they (not you) felt it was worthwhile in the light of their own values and preferences. Or you could take the view that since the benefits are so marginal, it would be better to wait until there has been a longer, bigger replication trial, preferably with an active comparator.

Anns Intern Med 16 Feb 2016 Vol 164
There is nothing worth reporting from JAMA this week, and the printed issue of Annals is taken up with a series of modelling papers about mammographic screening for breast cancer, concluding that it should be carried out every two years. Most of these articles are free, so if you enjoy this debate, help yourselves. I’m not going to comment. The website is more interesting:

Treat to risk & not to target
OL Although long accepted in the UK, the idea of giving statins to reduce overall cardiovascular risk rather than particular levels of cholesterol caused an uproar in 2013 when it appeared in the guidelines of the American College of Cardiology and the American Heart Association. With the arrival of a new class of powerful LDL-C lowering drugs, the PCSK9 antibodies, some have argued for a return to a target based approach. They are wrong, for reasons very nicely explained in this article by Rod Hayward and colleagues.

Trimming menisci: mostly a sham
OL One by one, big money earners for orthopaedic surgeons are being shown up as shams. “Resection of a torn meniscus has no added benefit over sham surgery to relieve knee catching or occasional locking. These findings question whether mechanical symptoms are caused by a degenerative meniscus tear and prompt caution in using patients’ self-report of these symptoms as an indication for arthroscopic partial meniscectomy.” What, no more arthroscopic washouts and trims to extract gold from knees? How else will these poor folk support their families?

JAMA Int Med Feb 2016
“Hospice” in the USA
OL “Hospice visits in the last two days of life by professional staff vary by race, hospice program, and geographic region of the country. Visits were less likely when the Medicare beneficiary was black, dying on a Sunday, and receiving care in a nursing home.” At first sight, this looks rather damning, but there is a clue in the last bit. Many of the patients were in a nursing home, not a hospice: “hospice visits” in the US are actually out-of-hospice visits by palliative care staff. We are two great nations divided by a common language. And I do wish we could get rid of the word “hospice” altogether: it carries an unmistakable whiff of medieval incense and the Crusades, and in the UK many of them bear the names of Christian saints. No wonder you hardly ever see a Muslim patient in a hospice; and I know many atheists who view them with suspicion.

Put a geriatrician in charge
OL I think that geriatricians do the hardest job in medicine and I badly want them to succeed. But by definition, the soil that they till is poor, and few crops can be expected. Here’s a trial from the Netherlands showing that “A systematic comprehensive geriatric assessment, followed by the transitional care bridge program, showed no effect on activities of daily living functioning in acutely hospitalized older patients (after discharge).” So does that represent success or failure? Failure for the bridge programme, undoubtedly, but perhaps another example of usual geriatric care being already as good as it can get.

Lancet 20 Feb 2016 Vol 387
Balloons through the cervix
OL “What you need is a nice ripe cervix, my dear, so I can either give you a pill or we can put a little balloon in it to help things along.” I’m not sure how you say that in Dutch, but the women of the Netherlands in this trial agreed to be randomly assigned to one method or the other. “A well-powered randomised controlled trial to directly compare oral misoprostol with Foley catheter alone for induction of labour has never been done; therefore, we did a multicentre randomised controlled trial on the subject.” And for these women with an “unfavourable” cervix at term, the two methods produced identical results.

CFS & mortality
OL Having chronic fatigue syndrome will not hasten your death, but it may lead you to take matters into your own hands. This is the conclusion of a study based on a database of 2147 cases of CFS, and although it may be the best so far, it seems a little small to be definitive. This is shown by the 95% confidence interval range for suicide compared with the matched general population: SMR 6.85, 95% CI 2.22–15.98. In other words, people with chronic fatigue may be anything between twice and sixteen times more likely to kill themselves. For other causes of death, the added risk with CFS does not reach statistical significance.

The BMJ 20 Feb 2016 Vol 352
Incretin mimetics and cancer
After a long period when there were only two oral drug classes to reduce glucose in type 2 diabetes, a whole lot of new ones came along. Unfortunately, the trials simply showed how good they were at reducing blood sugar over a year or two, and little else. Some of the latest depend on mimicking the incretin pathway: these are the dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists. Short term safety in the trials looked good, but then reports came in suggesting they might be linked with an increased risk of pancreatic cancer. Here’s a massive study combining the health records from six participating sites in Canada, the United States, and the United Kingdom to see if there is any evidence of an excess of pancreatic cancer so far in those taking the new drugs compared with old fashioned sulfonylureas. Fortunately, there is not.

DPP-4 inhibitors & heart failure
The situation isn’t quite so clear with the above mentioned dipeptidyl peptidase-4 (DPP-4) inhibitors and the long term risk of heart failure. This review looks at several sources of published evidence: randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors with a variety of comparators. There is a signal that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use. This deserves active surveillance, I think.

Academic laggards
The medical students of Yale who fall into the hands of Harlan Krumholz and Joe Ross are truly fortunate, but they won’t find themselves with time on their hands. The ones on this paper (now mostly resident doctors) did an enormous literature search for trials with a primary completion date between October 2007 and September 2010 conducted primarily at medical centres across the US, yielding a study cohort of 4347 trials across 51 academic institutions. They then tracked when and where these trials had been published within two years of completion. About 60% of them had not appeared within two years. From academic units who had used human subjects. In 2016 and under the noses of ethics committees and heads of department.

Not another sermon
The BMJ has published some really good “quantitative” research this week, but its most accessed paper by far is the open letter from Trisha Greenhalgh and 75 other academics questioning its stance on qualitative research. As I quoted in last week’s blog, the current wording on The BMJ website doesn’t absolutely rule it out, but it certainly doesn’t make it welcome either. I won’t mount the pulpit for another Lenten sermon this week, but I’d just like to ask these questions in case The BMJ is right and there are lots of readers who think that qualitative research is too squidgy and unrelated to clinical practice. For all I know there may be thousands, but if so they are keeping remarkably silent in the rapid responses:
• In relation to the first paper, would you find it of interest to know how decisions about using incretin mimetics and other drugs without long term evidence are shared with people who have diabetes, and how much they want to be involved?
• In relation to the second paper, might you be interested in what people understand by “heart failure” and how they react to uncertainty when a drug might carry a risk for it?
• Given that most academic authors don’t seem to have got round to publishing their results within two years, would it be of interest to read about their avowed reasons and the reactions of departmental heads and ethics overseers?

Just wondering. I have dear friends on both sides of this argument, but to me the answer is perfectly clear: these (and a thousand similar) are important questions, and The BMJ should welcome articles that answer them.

Plants of the Week: a Spring Symphony

On a sunny bank in the grounds of Wroxton Abbey, we saw the following flowering in a symphony of green, white, and yellow: snowdrops, aconites, primroses, celandines, and daffodils. Never before, and perhaps never again. A sight to fill the soul with delight and hope.

I was going to use this as an excuse to go on about Schumann’s Spring Symphony and its interpretation by Wilhelm Furtwängler, but you will be relieved to see that I have run out of space.