Richard Lehman’s journal review—10 March 2014

richard_lehmanNEJM  6 Mar 2014  Vol 370
901    The cat and mouse game of man versus human immunodeficiency virus has just taken a new turn. HIV kills off CD4 T cells by binding to the CCR5 receptor. Now if you could manufacture CD4 T cells without a functioning CCR5 receptor, the virus would not be able to bind to them, and might go into a sulk. You would need billions of these T lymphocytes, of course, and they might need topping up from time to time. This seems to be what happened in an experiment on 12 volunteers with HIV who stopped their antiretroviral treatment four weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified to switch off the receptor. The modified cells had an estimated mean half-life of 48 weeks. As hoped, they proved resilient against HIV: the details are complex, but this approach seems worth a lot more enquiry.

932   The observational study of outcomes following treatment of early prostate cancer in last week’s BMJ had me lamenting that there had been no watchful waiting group, and that I still didn’t have any advice for my patients, other than to avoid getting a diagnosis of localized prostate cancer. Now comes an important paper from Sweden on the results of a study in the 1990s which randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy, and followed them through to the end of 2012. I really like the way the Swedes get down to basics when describing their results: “From 10 to 18 years of follow-up, the number needed to treat to prevent one death decreased from 20 to 8 in the whole cohort, and from 8 to 4 among men younger than 65 years of age.” So the operation definitely decreases all-cause mortality, at the cost of a prevalence of erectile dysfunction of 84% in the radical-prostatectomy group at 12.4 years and 80% in the watchful waiting group; urinary leakage was reported in 41% and 11%, respectively. At last, I think, we can begin to give our patients some useful information about their options—combining this study with the lessons from last week about the comparative effectiveness of radiotherapy.

JAMA Intern Med  Mar 2014
324   There was a deathly silence when the NEJM first published the results of the ACCORD trial in June 2008. Nearly six years on, the diabetes community is still coming to terms with the demolition of its conceptual edifice based on ever tighter control of glucose and blood pressure. In the 40 months of the trial, we learn from this paper, people with longstanding diabetes in the tight BP control group showed more brain shrinkage on MRI than those on a laxer regimen. Cognitive function was the same in both groups. But these are just the sort of short-term data it’s best to ignore: we need much more than this to draw conclusions about specific treatments for type 2 diabetes. For more on that topic, read the excellent viewpoint by Kasia Lipska and Harlan Krumholz—Comparing Diabetes Medications: Where Do We Set the Bar?

336   One area of controversy I haven’t much commented on is the prescription of beta-blocking drugs prior to non-cardiac surgery. Mere GPs play little part in this saga, but out there in the exciting world of European cardiologists and surgeons, it’s been hotly debated, with accusations of needless deaths, bad trials, and non-evidence-based guidelines. To this fray, the Danes have now added some very useful observational evidence from their wonderful national registry. It seems that pre-op β-blockers only improve outcomes for two kinds of patients: those with heart failure and those who have had a recent myocardial infarction; i.e. those who should be on them anyway.

409   One of the commonest situations of risk for a drug interaction is the prescribing of antibiotics to patients on warfarin. I do it all the time, usually advising patients to reduce their warfarin dose slightly for the duration. A study from Kaiser Permanente shows that even this token effort is probably little needed. The investigators looked at over 11,000 patients with acute respiratory infections who were taking warfarin and who were or were not given antibiotics. “The proportion of patients experiencing an INR of 5.0 or more was 3.2%, 2.6%, and 1.2% for the antibiotic, sick, and stable groups, respectively…. Acute upper respiratory tract infection increases the risk of excessive anticoagulation independent of antibiotic use. Antibiotics also increase the risk; however, most patients with previously stable warfarin therapy will not experience clinically relevant increases in INR following antibiotic exposure or acute upper respiratory tract infection.”

JAMA  5 Mar 2014  Vol 311
911   Seeing little in the research section of JAMA this week, I casually clicked on this personal article in their “Piece of My Mind” series. In these pieces you always run the risk of encountering slicks of sentimental gloop and thinly disguised self-congratulation, but this one is quite different. It deals with the basic question we are all asked every week, “What Would You Do, Doctor?” As would-be practitioners of shared decision-making, we usually seek ways to avoid a direct answer and reflect the question back on the patient. The author of this piece reflects on her personal experience of blurting or not blurting a direct answer. And then come the last two paragraphs: “When my husband was diagnosed with pancreatic cancer, we faced an initial onslaught of choices that I was intellectually if not emotionally well equipped to make.” Ouch. “So, as we sit in Dr K’s examination room, we hear a well-rehearsed litany of choices… I look at my husband, who appears perplexed. It’s too much for his layman’s ears, and despite the gravitas of the situation, his eyes are beginning to glaze over. I know what I would do, what I want to do. But that’s not what my husband wants to hear, what he needs to hear. I know it’s not fair and I feel sorry for Dr K, but I lean in anyway, and ask what needs to be asked: ‘What would you do, Doctor?'” This a brave and wonderful piece. We have a moral imperative to share decisions when we can, and also to bear the burden as professionals when this is the best thing to do.

919   A Swedish registry study looks at what happened to people (median age 79) admitted to hospital with myocardial infarction who were discharged with atrial fibrillation. Only 22% of them went home on warfarin. The investigators were particularly interested to see if their kidney function seemed to make any difference to outcomes. It did not: “Warfarin treatment was associated with a lower 1-year risk for the composite outcome of death, MI, and ischemic stroke without a higher risk of bleeding in consecutive acute MI patients with atrial fibrillation. This association was not related to the severity of concurrent CKD.”

Lancet  8 Mar 2014  Vol 383
871   The Lancet likes to surprise the reader from time to time. This paper, for example, does not include anyone with a (stated) medical degree amongst its 12 authors, and it deals with a topic that most Lancet readers would probably wave aside muttering “Surely this is just for nurses.” Fortunately for patients, most people with chronic venous ulcers are dealt with very well by nurses. But most trials of specific treatments are lacking in rigour, to put it mildly. This one is at least a randomised trial—as for the rest, let’s just report that the authors call it “open” and “pragmatic.” It aimed to compare the clinical effectiveness and cost-effectiveness of two-layer compression hosiery with the traditional four-layer bandage. It proved a moderately useful exercise, concluding: “Two-layer compression hosiery is a viable alternative to the four-layer bandage—it is equally as effective at healing venous leg ulcers. However, a higher rate of treatment changes in participants in the hosiery group than in the bandage group suggests that hosiery might not be suitable for all patients.”

880   By contrast, the next stocking trial includes a full 21 medical doctors amongst its Canadian authors. I read a recent tweet from a Canadian doctor saying that he likes giving talks about deep venous thrombosis because it allows him to say “phlegmasia cerulea dolens.” This trial looked at the effect of wearing compression hosiery after DVT on the subsequent development of post-thrombotic syndrome, which is not quite the same as phlegmasia cerulea dolens, but includes it (I think). Anyway, the stockings had no effect. As for phlegmasia cerulea dolens, this term does not come from ancient Greece or Rome, according to Wikipedia, but from Milwaukee. This is hard to believe, and I suspect that somewhere in De Gangraena et Sphacelo by Fabricius Hiddanus (Cologne, 1598), phlegmasia cerulea dolens may lie hidden. Learned readers may care to enlighten me if they know its true origin. Phlegmasia cerulea dolens. Painful blue oedema. Can also be spelt phlegmasia caerulea dolens. Splendid to utter it six times in a row, but not so nice to have it.

896   As usual, this week’s Lancet contains its fair share of articles on broad topics which leave one feeling vaguely concerned and helpless. There is a survey of premature deaths among people with learning disabilities, a review article on delirium in the elderly, and here is an update on autism. This is an area of ever-changing ideas and definitions: I was particularly struck to read that Hans Asperger’s 1944 case series included Fritz who “learnt to talk very early…quickly learnt to express himself in sentences and soon talked “like an adult”… lacked distance and talked without shyness even to strangers…it was impossible to teach him the polite form of address.” I suspect he would get all sorts of diagnoses today, few of them including “Asperger’s syndrome.”

BMJ  8 Mar 2014  Vol 348
A few months ago, I attended a meeting in which the Chief Medical Officer, Professor Dame Sally Davies, accused most of the audience of being too fat. I looked around me and concluded that she needed new glasses: I was one of only about five overweight people in a room of a hundred or more. But to persons of a public health persuasion, everybody is a sinner needing to be saved. But oh how few repent! And of these, how few are saved! Pregnant women in Adelaide who were found to have a BMI between 25 and 29 were randomised to usual care or an intervention that included a combination of dietary, exercise, and behavioural strategies delivered by a research dietician and trained research assistants. There were no differences in maternal pregnancy and birth outcomes between the two treatment groups.

Go as far as you can from Adelaide and you’ll find yourself in Norway, where public healthists also fret about the best diet for pregnant women, this time with a view to preventing preterm delivery. In this happy land, the “traditional” diet consists of fish and potatoes. Yum. Then there is a “prudent diet,” which includes “vegetables, fruits, oils, water as beverage, whole grain cereals, fibre rich bread.” And then, alas, there is a diet which includes “salty and sweet snacks, white bread, desserts and processed meat products.” Naturally, the sinful sausage-eating snackers fare worst in the premature babes league. But at least the authors have the sense to say “this study cannot establish causality” and “our results indicate that increasing the intake of foods associated with a prudent dietary pattern is more important than totally excluding processed food, fast food, junk food, and snacks.”

The use of chemotherapy in terminally ill cancer patients in the last months of life was associated with an increased risk of undergoing cardiopulmonary resuscitation, mechanical ventilation or both and of dying in an intensive care unit.” Where? America, of course. I fear I’m beginning to sound like Nigel Farage, but I remember the days when BMJ stood for British Medical Journal. Seriously, I think if the journal is going to publish this kind of study, it should always include a comparison with the situation in the UK and the rest of Europe. That would be useful on both sides of the water.

Coeliac disease is now a very common diagnosis, and I share a tiny bit of the blame because I encouraged Harold Hin to do the first case-finding study in UK primary care using endomysial antibody testing. I usually admire the BMJ‘s Clinical Reviews, but I found this one a bit dogmatic. It deals with some of the important issues, such as the variable reliability of some serological tests, but avoids what seems to me the central question: if people feel no better on a gluten-free diet, does it make any difference to any significant outcome if they stop it? Clinic doctors don’t see these patients, because they stop coming to clinics. And when a new test increases the prevalence of a condition one-hundredfold (from 1 in 10,000 to 1 in 100), then it becomes a new disease, and all previous literature about it becomes obsolete. I suspect that a lot of today’s “coeliac patients” get little benefit from diagnosis and treatment, especially if they were asymptomatic and detected by screening.

A splendid editorial has just appeared on the BMJ website dealing with the astonishing disparity between the early open trials of the Medtronic Symplicity renal denervation device, and the subsequent properly conducted randomized Symplicity 3 trial. You’ll remember that I was hoodwinked by the hype which surrounded the publication of the long-term follow up of the original Symplicity 1/2 trial in the Lancet three weeks ago, showing a 30mm Hg drop in systolic BP maintained into the third year. The Symplicity 3 trial of the same device subsequently failed to meet its prestated end-point of a 10mm Hg drop. This should already have been known to the Lancet, as it had been announced by Medtronic on the 9th January. It’s a startling illustration of the need for randomized, properly blinded trials of medical devices. And it’s scary to think how few of those there have been—of devices currently used by millions of people.

Plant of the Week: Lonicera fragrantissima

It’s a little known gardening fact that in a good year in England you can enjoy the smell of honeysuckle every month of the year. For the winter months, you would depend heavily on this species and its close relatives, such as standishii, and hybrid children such as x purpusii. And then there is the rare and excellent ramosissima with leaves that open purple. By fiddling about with different clones of these, you might achieve true round-the-year loniceric bliss before you (or they) died.

I would go for this one, which deserves its description. Fragrantissima it will certainly be, but you can never tell when. In some cold winters it has flowered as early as December, whereas in this mild winter it is at its best now. Maybe it should be renamed paradoxissima.

But certainly not Phlegmasia cerulea dolens.