Richard Lehman’s journal review—23 June 2014

richard_lehmanNEJM 19 Jun 2014 Vol 370
2387  If you have a patient who is taking an opioid for chronic, non-cancer pain and gets constipated as a result, what do you do? Prescribe a laxative. Well done. And advise them that for most people with chronic pain, opioid analgesics don’t work and are best weaned off. Even better. Or else you can (perhaps, in the future) prescribe naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist. It is such a neat idea. You block the peripheral μ-opioid receptors in the colon, thus unblocking the bowel, while the brain receptors continue to respond to the opioids as before. What’s not to like? Well, the price probably. And the aforementioned fact that most people can use cheap laxatives instead, and would be better off their opioids anyway. And the fact that the evidence from the trials published here is all over the place.

For those of you who like to keep up with the ways of industry, note that “The study protocols were designed by AstraZeneca with input from the academic authors, who served as consultants to the sponsor. Study conduct, monitoring, and data analysis were performed by Quintiles, a contract research organization, under the supervision of the sponsor.” “We conducted two identical multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 studies (KODIAC-04 [study 04] and KODIAC-05 [study 05]) at 115 centers (study 04) and 142 centers (study 05) in the United States and Europe.” The participants included people on a very wide dose range of opioids, provided they had been on them for four weeks or more, and irrespective of how many laxative regimens had been tried previously (if any). The result was that the active drug group “achieved response rates that were increased by 10 to 15 percentage points, as compared with placebo.” If this drug gets FDA approval, we will know the system is bust. But then we already do.

2397  The serotonin reuptake inhibitors have been one of pharma’s greatest success stories of the last quarter century. Easy to start and hard to stop, they can be tried for almost anything that makes people feel down, and at almost any age. As a result, a large number of women become pregnant while taking an SRI. Within the Medicaid system alone, 64 389 women (6.8%) used antidepressants during the first trimester between the years 2000 and 2007. What happened to their babies? It seems that they have no significant added risk of cardiovascular abnormalities. If there are other harms, we don’t yet know.

OL  A hush falls over the great cathedral as the evening light grows dim. As if from above, unearthly music fills the incense laden air. The kneeling knights look up and lo! between the towering stone arches, a white dove sails and descends. Amid the gathering darkness, a glow shines ever brighter from the tabernacle behind the altar. Slowly the wounded king-priest raises the source of mystic light. A bionic pancreas! The true and Holy Grail! Or you may prefer this: “Here, we present the results of two 5-day trials, one involving adults and one involving adolescents [with type 1 diabetes], in which we tested an autonomous, wearable, bihormonal, bionic pancreas in two distinct outpatient settings. These studies minimally constrained patients’ behavior but allowed close observation for risk mitigation and high-density data collection.” “As compared with an insulin pump, a wearable, automated, bihormonal, bionic pancreas improved mean glycemic levels, with less frequent hypoglycemic episodes, among both adults and adolescents with type 1 diabetes mellitus.” And Sir Perceval sayde, Thanks be to God, for verraily thys is the Grail for which we have soght longe & suffred great peryll.

JAMA 18 Jun 2014 Vol 311

2387  The Lifestyle Interventions and Independence for Elders (LIFE) study would have had to have been called LIFOP in the UK, because the word “elders” to mean old people is not a usage that has spread to these parts. We reserve the term for a common roadside shrub. But LIFE is a more useful study for Britons than Americans because our oldies live longer than theirs, seeing that we have the best health system in the rich world and they have the worst. Get moving, you sedentary elders! It’s not too late to start, even if you are aged between 70 and 89. A structured, moderate-intensity physical activity programme, compared with a health education programme, reduced major mobility disability over 2.6 years among older adults at risk for disability.

2414  Geoffrey Rose said that “There is no disease that you either have or
don’t have—except perhaps sudden death or rabies. All other diseases you either have a little or a lot of.” This is true of pulmonary embolism, as I keep pointing out. It is demonstrated by this meta-analysis of “Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Haemorrhage.” “Among patients with pulmonary embolism, including those who were hemodynamically stable with right ventricular dysfunction, thrombolytic therapy was associated with lower rates of all-cause mortality and increased risks of major bleeding and ICH. However, findings may not apply to patients with pulmonary embolism who are hemodynamically stable without right ventricular dysfunction.”

Ann Intern Med 17 Jun 2014 Vol 160

836  I am an ardent believer in patient centred comparative effectiveness research, so my eye was caught by this paper describing a system to promote it for osteoarthritis in the USA, under the auspices of PCORI. When this body was set up, Republicans objected to any mention of “comparative effectiveness” so the O stands for Outcomes, which cannot include cost. I am glad to see some mission creep here—a slight access of sanity into the world’s least cost effective health system. But I am totally baffled by the methods they propose to use. “We then engaged a group of 13 stakeholders that included clinical experts and researchers in OA treatment strategies; representatives from federal and nongovernmental funding agencies, relevant professional societies, and related consumer and patient advocacy groups; and health care decision makers and policymakers. The stakeholders provided input on the draft list of evidence gaps.” Gah! The James Lind Alliance in the UK sets research priorities with two groups only: actual patients (not advocacy groups of shouty people, often paid by industry) and actual clinicians (not researchers or professional societies, often paid for by industry). That’s why I tried so hard to get PCORI to learn from the JLA. They were polite, and they even concluded it was the best model: and then they go and do this. Patients, do you think this is centred on you?

Lancet 21 Jun 2014 Vol 383

2127  I don’t often have to help women make finely balanced decisions about breast cancer treatment, but quite a few people are in that difficult position. So heartfelt thanks to the Early Breast Cancer Trialists’ Collaborative Group. They have gone through the individual patient data from 8135 participants in 22 trials and their conclusion is: “After mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes in these trials even when systemic therapy was given. For today’s women, who in many countries are at lower risk of recurrence, absolute gains might be smaller but proportional gains might be larger because of more effective radiotherapy.”

2136  A novel rotavirus proves successful in India. What’s so special about that? There are already two licensed oral rotavirus vaccines—RotaTeq (Merck) and Rotarix (GlaxoSmithKline)—and this one is no more effective. But it is much more affordable, and it exemplifies a new way of making cheap products locally to transform health outcomes. As a commentary article explains, the vaccine was not the product of a major multinational manufacturer, but rather the result of work by Team Science, based in India. I love the notion of Team Science as a way to bypass the commercial model that denies so many effective treatments to those who most need them. And thank you too, Bill Gates, for helping to fund this effort. How many of you non-Microsoft users have written to Apple asking what they are doing for the world with all their profits?

The BMJ 21 Jun 2014 Vol 348

Here is a truly important study that needs to be mulled over. In a Danish group of 6000 people at high risk of cardiovascular disease, “After five years of counselling a significant effect on lifestyle was seen, with a substantial reduction in the prevalence of smoking, improved dietary habits, sustained physical activity (among men), and a decrease in binge drinking. Furthermore, a significant improvement in self reported mental health and sustained self reported physical health occurred. These findings indicate that counselling promotes beneficial changes at the individual level for at least a limited period of time.” But this intervention had no effect on ischaemic heart disease, stroke, or mortality at the population level after 10 years. The individuals benefited, but the “population” did not. Does this negate the value of the intervention? I think not, but then I am not a public health physician.

In 2003 and 2004, the FDA announced concerns about suicidality following initiation of serotonin reuptake inhibitors in teenagers. Subsequently, there was a 30% drop in SRI use by teenagers, and an increase in self-poisoning with psychotropic drugs. A so-called “quasi-experimental study” concludes: “Safety warnings about antidepressants and widespread media coverage decreased antidepressant use, and there were simultaneous increases in suicide attempts among young people.” No,no,no. There was no experiment, quasi or otherwise. Post hoc, propter hoc? Maybe. And actually the number of completed suicides did not change. “It is essential to monitor and reduce possible unintended consequences of FDA warnings and media reporting,” the authors conclude. I have absolutely no idea what they are talking about.

High levels of vitamin D in every country are strongly associated with longevity, or, to put it the other way round, low levels are associated with all-cause and cause-specific mortality. Post hoc, propter hoc? We just don’t know. These are observational data, and like proper scientists, the authors conclude that ” Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.” Just nipping off to take mine, though.

It would be wrong to puff my own work, so please ignore a piece called “The medical reformation” in this week’s print issue of The BMJ. Go rather to Trisha Greenhalgh’s masterly essay on the challenges to evidence based medicine, to which I contributed a few ideas but almost no words. In fact, it will take at least 100 further articles to address the challenges to EBM. I am just in the process of thinking what these should be.

Plant of the Week: Sambucus nigra “Black Lace”

After my remark about elders and the LIFE study, I thought I would pause to praise this excellent and ubiquitous new ornamental shrub.

Before the Romans, the only elders to be found in Britain were tribal elders. Although these formed quite effective and well armed networks, they were no match for the elderberry loving Roman legions. Everywhere the invading soldiers marched, they infested the land with fruit bearing, shrubby trees such as mulberries and elders. No doubt they used them to concoct hot, Ribena-like drinks to keep out the cold in dismal postings such as Hadrian’s Wall, or on Druid-killing sprees in Wales.

My Polish parents would gather elderberries for the same reason, and it was only when I grew up that I discovered that much nicer drinks can be made from the flowers rather than the fruit. To do this, however, involves the copious use of lemons, which were unknown in Poland during the war years.

To gardeners, elders are best known as tree-weeds, growing rapidly from seeds in bird droppings unless immediately uprooted. For garden ornament, there have been purple leaved clones in circulation for decades, but this newcomer is much the best. It has nearly black, deeply cut leaves, and abundant large umbels of pale pinky flowers. And it is extremely vigorous, although it can be cut back hard each winter.

You can pay money for this plant if you are really in a hurry, or else you can ask someone for a branch or two in the winter. Simply stuck in the ground, these strike root at once and may even flower the same season.