NEJM 8 October 2015 Vol 373
1397 Famous as a pioneer of hypertension studies, Sir George Pickering (1904-1980) was a man of forceful opinions, and used to command the attention of his hearers by gripping their arms tightly for the duration of the encounter. As I was a medical student and he was Master of my college, I endured this treatment quite frequently while others around me would unaccountably disappear. I now realise that he was probably testing an early form of ischaemic preconditioning. Limbs deprived of oxygen this way generate a magical neurohumoral response that protects all the other organs from ischaemic damage. Pickering’s views on his colleagues or life in general could easily have provoked a stroke or heart attack, but he provided complete protection through his vice like grip. But two studies in this week’s NEJM show that this protection does not extend to invasive cardiac surgery. The first trial, funded by the German Research Foundation, randomised 1403 adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anaesthesia with intravenous propofol to undergo real or sham ischaemic preconditioning. The real or sham procedure was performed after induction of anaesthesia, and the blinding protocol is an amazing demonstration of German thoroughness. But by any criterion, clinical or biochemical, there was absolutely no difference in outcomes between the groups.
1408 A 30 centre British trial used almost identical methods in 1612 patients undergoing on-pump coronary artery bypass grafting. Interestingly, these trials show there were no detectable remote organ benefits either—post-operative delirium and kidney damage were also unaffected by ischaemic preconditioning.
1418 Throughout the more than 17 years I’ve been writing these reviews, a breakthrough in the treatment of remitting-relapsing multiple sclerosis has always seemed just around the corner. The standard treatment back then was interferon beta-a1, in the form of weekly injections giving rise to flu like symptoms, without any discernible patient benefit but with a slight reduction in cumulative disability in the luckier patients. This latest trial still uses interferon as its comparator. The new agent—already tested against placebo—is called daclizumab HYP and it’s a humanized monoclonal antibody that binds to the alpha subunit (CD25) of the high-affinity interleukin-2 receptor. The HYP stands for high yield process, and fortunately does not apply to the way that this manufacturer funded trial is reported. After a maximum follow-up of 144 weeks, the benefits of the new agent are small and the investigators end their paper by stating: “The enhanced efficacy was accompanied by an increased frequency of adverse events, such that the net clinical benefit will need to be carefully considered by patients and their providers.”
1429 Have a think about this paragraph: “Systematic screening detects primary aldosteronism in 5 to 10% of all patients with hypertension and in approximately 20% of patients with treatment-resistant hypertension. A unilateral aldosterone-producing adenoma is the most common potentially curable cause of hypertension in such cases. Early detection of a unilateral aldosterone-producing adenoma is important both to maximize the likelihood of a complete cure of hypertension by means of adenoma removal and to prevent the onset of resistant hypertension and the risk of long term cardiovascular complications.” Is that important? Well, I think so. And yet adrenal adenomas are one of the commonest kinds of “incidentaloma” found on CT and MRI scans performed for other reasons, and most of them sit there doing nothing. This forbiddingly titled paper is an exploration of the circumstances under which inactive adrenal adenomas get switched on to produce floods of aldosterone. Pregnancy can be one such, and the paper consists of three case studies demonstrating the mechanism. If you must know, here is a short guide:
“The Wnt pathway, through β-catenin signaling, is critical for normal adrenocortical development and maintenance, in particular the zona glomerulosa of the cortex… Pathogenic somatic mutations of CTNNB1 have been found in 27% of adrenocortical adenomas and in 31% of adrenocortical carcinomas. Some of these mutations arise in the part of exon 3 that encodes the consensus glycogen synthase kinase 3β–casein kinase 1 (GSK-3β–CK1) phosphorylation site and therefore result in loss of phosphorylation of β-catenin. This prevents the ubiquitination of β-catenin and leads to aberrant Wnt-pathway activation… ” We’re nearly there. The three women described were found to have adenomas with the said mutations, and these adenomas were also full of hormone receptors, which reacted to the high circulating levels of human chorionic gonadotropin, luteinizing hormone, or gonadotropin-releasing hormone found in pregnancy. Hence their sudden development of hypertension and hyperaldosteronism. See, science can be fascinating and beautiful, provided you don’t have to memorise it for exams.
JAMA 6 October 2015 Vol 314
1346 I was taught in the days of maximally invasive surgery when the saying ran, “big mistakes are made through small holes.” And—whisper it not to the robots—big mistakes can still be made through small holes. It all depends on the procedure and the skill of the operator. Laparoscopic surgery has made some amazing advances and has cut admission times dramatically, but it still needs to be assessed on a condition by condition basis, and JAMA this week takes a cool look at how it compares with open surgery for rectal cancer. Answer: not too well. A total of 486 patients from the US and Canada with clinical stage II or III rectal cancer within 12 cm of the anal verge were randomised after completion of neoadjuvant therapy to laparoscopic or open resection. Laparoscopic resection took a little longer and did not result in a shorter hospital stay. The prespecified primary outcome measure—a composite of pathological criteria for complete excision—was a bit worse in the laparoscopy group. We’ll find out about the recurrence and survival outcomes in a few years’ time.
1356 At the same time, a very similar trial was going on in other former British colonies. Twenty six accredited surgeons from 24 sites in Australia and New Zealand randomised 475 patients with T1-T3 rectal adenocarcinoma less than 15 cm from the anal verge to open or laparoscopically assisted surgery. The results mirror those of the North American trial. As for silly acronyms, I slightly prefer ALaCaRT to ACOSOG Z6051.
JAMA Intern Med October 2015
The Greek tragedians explored the consequences of moral imperatives clashing with human inadequacies, and I feel that this is often what happens with shared decision making in medicine. Every day, distressed people come to see us, and within 10 minutes we are supposed to explore their distress and offer the means of relieving it. The easiest route is often to diagnose “depression” and either pass them over to someone else to deal with it or offer them a drug labelled as an antidepressant. Actually, I don’t think this should ever happen: always first offer understanding, assurance that the distress will get better, the promise of support, and another appointment in the very near future. In the meantime, give them Robert Burton’s advice from The Anatomy of Melancholy: “be not solitary, be not idle.” (see Chris Dowrick’s book Beyond Depression). But at some point thereafter, you may decide to offer an antidepressant drug. The evidence base for these—and especially for comparisons between them—is wretchedly inadequate, as you can discover in Peter Gøtzsche’s new book Deadly Psychiatry and Organised Denial. So how can you actually achieve an informed choice with the patient in front of you? I have to say that I think it’s impossible, given the inadequacy of the evidence. When I tried to create an Option Grid for this, I gave up after months of effort; and long ago, I tried about six of these drugs before I found one that “worked.” Its main effect was to make me feel worse when I came off it. However, the choice may have to be made, faut de mieux. Here is a trial of a Depression Medication Choice (DMC) encounter decision aid conducted by my friends and heroes at the Mayo Clinic. “The DMC decision aid helped primary care clinicians and patients with moderate to severe depression select antidepressants together, improving the decision making process without extending the visit. On the other hand, DMC had no discernible effect on medication adherence or depression outcomes. By translating comparative effectiveness into patient centered care, use of DMC improved the quality of primary care for patients with depression.”
Lancet 10 October 2015 Vol 386
1447 The first research article in this week’s Lancet is about a Chinese paradox. “Chinese men now smoke more than a third of the world’s cigarettes, following a large increase in urban then rural usage. Conversely, Chinese women now smoke far less than in previous generations.” Given the political system of China, it would seem a small matter to abolish the cultivation of tobacco and the sale of combustible tobacco products. If this does not happen, the authors of this study predict that the annual number of deaths in China that are caused by tobacco will rise from about 1 million in 2010 to 2 million in 2030 and 3 million in 2050. I suppose that an alternative solution would be for Chinese women to follow the example of Lysistrata in the play by Aristophanes and go on a sex strike, refusing the advances of all men who smoke.
1465 Another toxic habit that you might think the Chinese government could address is the use of drugs that harm the kidneys. It seems that virtually anything can be bought from Chinese pharmacies, including traditional herbal products that often contain nephrotoxic plant substances and pharmaceutical products like NSAIDs, which can be used under a variety of labels and at any dose the purchaser decides. Small wonder, then, that acute kidney injury is a growing problem in China and that over 70% of patients give a history of possible toxic drug ingestion. This is twice or more than the proportion in other countries.
1493 The development of the Chinese health system will affect the lives of 1.4 billion people already born, and many more yet unborn. It would be wonderful if China could learn to avoid the mistakes of others and create an equitable, affordable health system based on localism and primary care. Meanwhile, Harlan Krumholz, America’s leading outcomes researcher and much else besides, is helping China to create a self-learning health system. With Chinese colleagues who have co-created a cardiovascular outcomes network, he discusses the prospects of extending their methods to the whole health system.
The BMJ 10 October 2015 Vol 351
Survival of breast cancer is improving all the time. Women with cancers of 1cm or less at diagnosis in the Netherlands have an identical survival rate to those without breast cancer. In fact, the Dutch statistics can be used by those on either side of the mammography screening debate, although on this occasion The BMJ chooses to run an editorial using them in support of screening.
An alternative argument would attribute all the progress to adjuvant treatment, with screening detecting only a few “real” cancers and diluting the statistics with a large number of cancers that would never progress. But however you wish to play the figures in that debate, they bring very good news.
With colonic cancer there is better evidence that screening reduces mortality, although this applies only to endoscopy. In the 27 European Union member states, colorectal cancer mortality fell by 13.0% in men and 27.0% in women between 1989 and 2011, compared with corresponding reductions of 39.8% and 38.8% in the United States. But European countries outside the EU, and on its eastern fringes, fared much less well. It isn’t at all clear whether these disparities will get narrower in the foreseeable future.
We are still fumbling our way towards an understanding of the best way to handle polypharmacy in older patients with comorbidities. Mary Tinetti and colleagues provide some evidence with an analysis of the Medicare Current Beneficiary Survey cohort, a nationally representative sample of Americans aged 65 years or more. For example, β blockers, calcium channel blockers, RAS blockers, and statins were associated with reduced mortality when prescribed to people who had conditions for which they were indicated in guidelines. But, of course, the limitation of this kind of evidence is that these were not a randomised sample. Poorlier patients may have been unable to continue these drugs. Drugs which appeared to have no mortality benefit were metformin, clopidogrel, and serotonin reuptake inhibitors. This tells us a little, but not enough.
Ten Commandments for Patient Centred Treatment
Back in January 2012, I finished my weekly blog with John Yudkin’s original 10 Commandments for the New Therapeutics. Ever since then a group of us have been trying to finesse and develop them for different audiences. As some of you may have seen, they have now appeared in the British Journal of General Practice in a version aimed mainly at general practitioners in the UK. John Yudkin kindly gave me lead authorship, although the original idea and much of the substance is his. The full version is open access and here’s what you get on the basic tablets of stone:
1. Thou shalt have no aim except to help patients, according to the goals they wish to achieve
2. Thou shalt always seek knowledge of the benefits, harms, and costs of treatment, and share this knowledge at all times
3. Thou shalt, if all else fails or if the evidence is lacking, happily consider watchful waiting as an appropriate course of action
4. Thou shalt honour balanced sources of knowledge, but thou shalt keep thyself from all who may seek to deceive thee
5. Thou shalt treat according to level of risk and not to level of risk factor
6. Thou shalt not bow down to treatment targets designed by committees, for these are but graven images
7. Honour thy older patients, for although they often have the highest risk, they may also have the highest risk of harm from treatment
8. Thou shalt stop any treatment that is not of clear benefit and regularly reassess the need for all treatments and tests
9. Thou shalt diligently try to find the best treatment for the individual, because different treatments work for different people
10. Thou shalt seek to use as few drugs as possible
It’s all available on a Creative Commons licence so you are free to copy, re-use, and tweak provided you give due attribution to the authors and the BJGP.