Richard Lehman’s journal review—5 October 2015

richard_lehmanNEJM 1 Oct 2015 Vol 373
1307 What will happen to all the overweight children and young adults we see around us? The honest answer is that nobody knows. There has never been such a generation before in human history, and it is entirely possible that during the next decade or two they will all be rendered thin by some miraculous new intervention. Measuring their “cardiometabolic risk factors” doesn’t really get us much further. Here is a cross-sectional analysis of data from overweight or obese children and young adults 3 to 19 years of age who were included in the US National Health and Nutrition Examination Survey from 1999 through 2012. Although there is a general association between the degree of obesity the risks of a low HDL cholesterol level, high systolic and diastolic blood pressures, and high triglyceride and glycated haemoglobin levels, it doesn’t get very strong except among the most severely obese, especially males.

1340 People smoke cigarettes for the nicotine and die from smoking because of the combustion products. So the obvious answer is to provide the nicotine without the combustion products. Yet this seems too simple a solution for various public health physicians who argue that harm reduction with e-cigarettes amounts to the perpetuation of a moral evil. I wonder how that lobby will react to this trial, which seems to stand logic on its head by providing all the combustion products but less of the nicotine. What the investigators discovered is that—over a period of six whole weeks—smokers given lower nicotine cigarettes tended to smoke fewer of them. So does this mean we can put off the day when all combustible tobacco products are simply banned? I don’t think so.

OL There was once a mammalian target-of-rapamycin (mTOR) inhibitor called sirolimus which was developed as an antifungal agent but turned out to have powerful immunomodulatory and anti-cancer effects. Others followed, and it’s now hard to remember a time when there were never any olimusses like everolimus. This drug seems to be the standard against which new drugs for renal cell carcinoma are judged. Two such are pitted against everolimus on the web pages of the NEJM. One is called nivolumab, and is a programmed death 1 (PD-1) checkpoint inhibitor. In a trial which recruited 821 patients with clear cell renal cancer, patients given nivolumab survived on average more than 5 months longer than those given everolimus. The second new drug for the condition is cabozantinib, which works by inhibiting vascular endothelial growth factor receptor (VEGFR) plus a few other things you won’t have heard of. For this trial, the given end-point is “progression-free survival” which is a dubious artificial category, but this agent also seems to have an important real survival benefit over everolimus when used in advanced kidney cancer.

JAMA Vol 314 Oct 2015
There is no printed JAMA this week, and the online articles don’t include any original research though they do include one Viewpoint piece which I thought worth commenting on. “The Next Era of Palliative Care” is an article celebrating the twentieth anniversary of the publication of the SUPPORT study. “Yet 20 years after SUPPORT, little has changed for seriously ill patients, who continue to receive poor quality, high-cost care without being informed of likely treatment outcomes so that they would be able to make decisions that reflect their values. This is not surprising, given that increases in palliative care services will never match vast and increasing palliative care needs.” So is palliative care the solution or the problem? Both, I think. To the extent that it aims to provide a patient-centred model of care with nuanced systematic elicitation of concerns and goals from the patient and carers, and skilled discussion of the process of dying, it is a model for all areas of medicine. But to the extent that it cuts itself off from the rest of medicine it is part of the problem. I don’t know if the future really lies in trying to drag palliative care professionals away from their comfort zone of cancer and a few other fairly circumscribed terminal conditions. I would rather that all physicians applied a “palliative care approach” to all patients who have life-shortening or painful conditions, and took it for granted that their main function was to elicit and respect those patients’ personal goals. But that is going to involve a transformation in lifelong learning and skill acquisition by every clinician, and a remodelling of the ways that hospitals operate.

JAMA Intern Med Oct 2015 Vol 175
OL Those reflections on palliative care derive from a long effort to promote a more effective team approach towards people dying from heart failure. The second edition of our book, Heart Failure and Palliative Care: a team approach (Radcliffe) is about to appear. For example, a high proportion of heart failure patients are depressed, for all sorts of reasons, beginning with the label itself and moving through social isolation, dependency, and all the feel-bad chemicals the body produces as its circulation grows inadequate. “Usual care” for heart failure is often maximally disruptive and minimally helpful. In this trial, enhanced usual care was compared with cognitive therapy. “A CBT intervention that targets both depression and heart failure self care is effective for depression, but not for HF self-care or physical functioning relative to enhanced UC. Additional benefits include reduced anxiety and fatigue, improved social functioning, and better health-related quality of life.” That’s terrific—so much better than some new add-on drug of marginal prognostic benefit. Wish this trial had come out in time for the book.

Lancet 3 Oct 2015 Vol 386
1353 A couple of important large individual patient data meta-analyses about breast cancer treatment appeared on the Lancet website back in July. People who do IPD analysis really command my respect. In fact I’m currently in Vienna to run a workshop at the Cochrane Colloquium to encourage more people to do this work, even though I scarcely understand how it’s actually done. Huge new databases are becoming available from the pharmaceutical industry and too few people are mining them. It’s even better when trialists in certain areas join efforts and produce ready-made data pools, like the Early Breast Cancer Trialists’ Collaborative Group. Looking at individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials, it emerges that 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with five years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. If you need more detail, the MRC has paid for you to have open access to this paper.

1353 The second analysis deals with the effect of bisphosphonates in a similar population of women with early breast cancer. Again we have the same parties to thank for discovering that adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

OL “Drug-resistant hypertension” is a really problematic diagnostic category. It probably involves a number of physiological processes, each of which may (for all we know) have different long-term consequences. For decades people in the field have concentrated on the renin-angiotensin-aldosterone pathway and sodium handling. This latest trial belongs to this tradition. Renin was measured, but aldosterone seems not to have been, despite the fact that spironolactone, an aldosterone antagonist, was the main intervention being tested. For most people classed as having drug resistant hypertension, adding in 25-50mg of spironolactone led to a useful reduction in BP, while significant hypokalaemia was rare. It was generally more effective than adding bisoprolol or doxazosin.

BMJ 3 Oct 2015 Vol 351
Another week, another dietary dogma gets binned. About 20 years ago, when I was much more credulous than I am now, I learned that men and women should take at least 1000-1200 mg/day of calcium for bone health and prevention of fractures. Pretty well everyone in a nursing home should be on calcium and vitamin D supplements. The prescription pads on which I printed thousands of items of Adcal D were all shredded long ago, and now I learn that it was all based on thin air. “Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent.

You can also look at this from the point of view of a surrogate measure, bone mineral density. It’s the same story: there is only weak evidence that increasing calcium ingestion has any effect on BMD, and it is unlikely to make any difference clinically.

Fungus of the Week: Boletus edulis

Throughout continental Europe, the boletus mushroom or cep is highly valued, but I have never seen it sold as abundantly and cheaply as in Vienna. Perhaps this is a particularly good year for the Steinpilz. It cannot be cultivated and it does not appear often in the same places, so everything depends on the efforts of gatherers who simply have to scour the neighbouring woodlands and hope for a find.

The raw flesh is crisp with a nutty flavour, which becomes more mushroomy with cooking. We have had ceps here in a number of guises, but the best dish was a very simple one of thinly sliced ones covered in parmesan cheese and heated under a grill. Just the thing after a day of gazing at Klimt and Schiele. Oh, and looking in at the Cochrane Colloquium, of course.