Richard Lehman’s journal review—23 January 2017

richard_lehmanNEJM  19 Jan 2017  Vol 376
Transmission of drug resistant TB
Tuberculosis in Europe used to be known as the White Death, and that is the title of the best book about its history. But in parts of South Africa extensively drug resistant (XDR) tuberculosis might be called the New Black Death, because there it kills an increasing number of people who are almost invariably poor and black. It’s unusual to see a paper like this one in the NEJM, dealing with a disease (I almost wrote “health issue”; bah) among disadvantaged people in a remote country. Three quarters of the 404 patients from KwaZulu-Natal Province had HIV and over half of them carried the same strain of XDR-TB. The rest mostly fell into small clusters of 30 other different TB genotypes, and complex evidence points to person to person transmission as the most important factor.

Doctor, why am I so fat?
Ah, I’m glad you asked me. I’ve been puzzling about this for so long that I’ve become fat myself. A review article tries to sum up what we know about the “Mechanisms, Pathophysiology, and Management of Obesity.” Here’s a key paragraph: “Genes and environment interact in a complex system that regulates energy balance, linked physiological processes, and weight. Two sets of neurons in the hypothalamic arcuate nucleus that are inhibited or excited by circulating neuropeptide hormones control energy balance by regulating food intake and energy expenditure. Short term and long term energy balance is controlled through a coordinated network of central mechanisms and peripheral signals that arise from the microbiome and cells within adipose tissue, stomach, pancreas, and other organs. Brain regions outside the hypothalamus contribute to energy-balance regulation through sensory-signal input, cognitive processes, the hedonic effects of food consumption, memory, and attention.” So it’s dead simple, really.

JAMA  17 Jan 2017  Vol 317
Sharing decisions about osteoporosis
Osteoporosis is a good example of a long term risk factor that requires informed decision making. I would even take that further and say that it requires informed consent for treatment. Hip fracture in older people carries a bad prognosis for continued mobility and independent life. Women with low bone mineral density are especially susceptible. But every one of them must have the chance to decide for herself. This viewpoint article is sensible in its approach to risk evaluation and lists all the essentials of an adequate dialogue with people who are at risk. The problem is that to do it properly would require two visits of about 30 minutes each for the millions of asymptomatic but at risk individuals—just as for statins. For long term preventive treatment, shared decision making is not just desirable, it is a human right. But it requires careful framing and individualisation, and how can we make this feasible in an already overburdened health system? I don’t have the answer, but I’d suggest that it would be a good area for the National Institute for Health and Care Excellence and the chief medical officer to look at.

When asthma diagnosis goes puff
Speaking of mandatory informed consent for long term treatment, how about asthma? Now I’ll go even further and suggest that we demand informed consent before putting anyone on the disease register. Asthma has been a bugbear of mine throughout my clinical life. I saw waves of overdiagnosis and overtreatment crash through British primary care from the late 1980s onwards, each wave encouraged by pharmaceutical capture of the nursing workforce. New drug delivery systems, free peak flow meters, prevention, monitoring, clinics: to what end? Just more and more people on asthma registers. And once there, always there. Here is a sobering study, which undertook full clinical investigation of 701 Canadian adults who had been given a diagnosis of asthma in the previous five years. Twelve had a different and serious diagnosis. And fully a third of them had no evidence of asthma at all when their treatment was withdrawn.

Diabetes the killer in China
At least “diabetes” has some kind of biochemical threshold, though you may remember a pretty damning systematic review two weeks ago, which showed how such thresholds vary arbitrarily and overlap but little. We badly need to sort out what really lurks under the label of “type 2 diabetes,” but there’s no doubt that at a population level it’s associated with a lot of morbidity and premature mortality. China is blessed with the finest and most varied cuisine in the world and has hundreds of millions of urban dwellers who can now afford to eat it. How they will be affected by the increasing prevalence of T2DM is examined in a study of 512 869 adults aged 30 to 79 from 10 provinces in China. People in rural areas had the lowest rates of diabetes, but if they got it, they did worse than those in urban areas. Everywhere the presence of diabetes was associated with higher death rates from cardiovascular disease and a range of cancers.

JAMA Intern Med  Jan 2017  Vol 177
Conflicts of interest in guidelines and Twitter
O what a tangled web we weave/ When pharma money we receive. There is a bumper crop of papers in this week’s journals about conflicts of interest, as they are known in polite company. One deals with submissions to a consultation about the prescribing of opioids for non-cancer pain. Most submissions supported a restrictive prescribing policy, including some that came from organisations that accept funding from opioid manufacturers. On the other hand, those who objected to the policy were more likely to have received such money. The point of the research letter is that none of them declared these ties.
It was the same when a different set of researchers looked at haematologist-oncologists who use Twitter. It wasn’t so much that they discovered a conspiracy to promote expensive new drugs: it was just that nearly three quarters had received “general payments” averaging about $1600 from pharma and research support of around $10K. At present there’s no easy way to flag this up. It seems embedded in the culture, and it’s by no means just an American phenomenon.

Lancet  21 Jan 2017  Vol 389
Mask or tube for baby anaesthesia?
Although Oxford was the first university to have a chair of anaesthetics, I encountered very few anaesthetists during my time at its medical school. I got the general impression that their main job was to get a tube securely down the trachea and then sit among vague hissing sounds for the duration of the operation, occasionally offering opinions about political figures and holiday destinations. But when giving anaesthesia to babies for short procedures, the tube seems to be inferior to the mask, according to a randomised trial in Western Australia. It was stopped early when it became clear that for infants under a year old having minor operations, endotracheal tubes were associated with more respiratory complications than laryngeal mask airways.

PROMIS of fewer and better prostate biopsies
Imagine that you suspect cancer in a breast, but you don’t know where it is. Nor is it entirely clear where the breast itself is. You can only feel it via an orifice, and this kind of breast is about the size of a walnut. All you can do is point a biopsy needle up the orifice and try to sample as much of the breast as you can. Moreover, most will have some cancer in them, but only a few cancers will progress. Enough: you get my point. Men have prostate glands that lie deeply hidden. Unlocking their mysteries has hitherto meant using a biochemical test with terrible predictive characteristics followed by multiple biopsies in unspeakable places. The PROMIS trial used multi-parametric magnetic resonance imaging (MP-MRI) to help locate clinically significant cancers in men with elevated prostate specific antigen. It was a complex study, but the bottom line (if I may put it that way) is that about 27% fewer men will need to have biopsy needles introduced through their bottoms.

The BMJ  21 Jan 2017  Vol 356
Positive RCTs and sponsorship
Here’s the third (and best) “conflict of interest” paper to appear in the main journals this week. The object is to investigate how the financial ties of the principal investigator (PI) might affect the chance of a positive result in a randomised trial. So this is primarily about people, not companies. In fact, this is an artificial distinction because all principal investigators who run trials for industry have a vested interest in producing positive results, even if their financial ties are entirely institutional rather than personal. Getting new funding will expand their unit and pay their staff. In fact, this study of 195 trials found that 58% of PIs do have personal as well institutional ties with industry: honoraria, shares, speaker’s fees, travel expenses, and so forth. And the study concludes that financial ties of principal investigators were independently associated with positive clinical trial results. Financial bias on such a scale shows that a whole new system for independently testing new interventions is required.

RAS inhibitors and the non-failing heart
Since the introduction of angiotensin converting enzyme inhibitors in the 1980s, an urban myth has grown up that all renin angiotensin system inhibitors (RASi) are somehow good for the heart and the kidneys. Here’s a big systematic review and meta-analysis that looks at the totality of evidence. These agents are OK, but have no special magic. “In patients with stable coronary artery disease without heart failure, RASi reduced cardiovascular events and death only when compared with placebo but not when compared with active controls. Even among placebo controlled trials in this study, the benefit of RASi was mainly seen in trials with higher control event rates but not in those with lower control event rates. Evidence does not support a preferred status of RASi over other active controls.”

Predicting osteoporotic fractures
QFracture, FRAX, and Garvan: do you use any of these? They are the leading brands of open access fracture prediction scores based on patient characteristics alone. They have undergone a lot of separate validation studies, but this study was the first to compare their real life performance over five years in a single population of a million people in Israel. Garvan came third. Both QFracture and FRAX had high discriminatory power for hip fracture prediction, with QFracture performing slightly better. FRAX is slightly easier to use.

Patient voices and guidelines
So once again you’ve followed me on a winding path through the week’s evidence. Like me, you’ll have forgotten most of it in a few hours or days. However, clever elves will be getting to work right away on the quantitative studies, and eventually some of their data might influence the creation of clinical guidelines. And people are gradually realising that guidelines themselves should not be the final product: patients and health professionals need tools to help them share decision making, meaning that the real point of evidence synthesis is to produce good, simple, interactive tools for use in clinical dialogue. But then another problem arises: people are all different. There may be clusters of preference, but there is rarely a single right answer for everybody. And to understand why, we need the insights of qualitative study. I have belaboured The BMJ about this many times, with little effect. But here at last is a very good BMJ analysis piece making the point clearly and trenchantly. “Clinical guidelines and quality standards might stress the need for decision making to be shared, but it is the synthesis of qualitative evidence that details what this negotiation should involve for any particular condition and its treatment. By accessing and using evidence on patients’ anxieties, beliefs, and preferences, which can be highly condition specific, recommendations in clinical guidelines can be tailored and enhanced.”

Plant of the Week: Cortaderia selloana
Looking over the frosted lawn with sun breaking through the morning mist, I do wish I could see a spectral mass of pampas grass at the end of the garden. There is nothing more beautiful on a day like this. Those stately wands with their great tufts of white or pinkish cream, standing still amid the ice and fog, or moving almost imperceptibly. Those great spears of leaf, elegantly folded and covered with rime.

But to grow this plant, you need a big garden. It demands a lot of space, and a vista to admire it from. Without these, you shouldn’t think of owning one. It will quickly outstay its welcome, and then you will cut your arms on its leaves and hurt your back trying to dig out its deep tangled roots. If you attempt to burn it in situ, it will flourish as never before. Pampas grass is best admired in parks or other peoples’ gardens.

  • Ronald Hirsch, MD

    Perhaps there needs to be informed consent for BMD testing itself. There is an epidemic of testing in healthy, low risk women from menopause to age 65 who then are “diagnosed” with osteopenia or osteoporosis and often get placed on medications.