Richard Lehman’s journal review – 21 March 2011

Richard LehmanJAMA  16 Mar 2011  Vol 305
1119   “Chronic kidney disease is one of the most rapidly increasing chronic diseases in the United States. More than 20 million US adults have an estimated glomerular filtration rate of less than 60 mL/min/1.73m2, which represents loss of more than half of normal kidney function.” So begins the editorial which accompanies this systematic review of Serum Levels of Phosphorus, Parathyroid Hormone, and Calcium and Risks of Death and Cardiovascular Disease in Individuals With Chronic Kidney Disease. Faced with this epidemic of pseudo-“disease,” experts are convened to do something; and having convened, they have to find something to do. And, as the wise authors of this inconclusive review point out, there is nothing more dangerous than a team of experts assigned to be seen to do something: “When practice guidelines promote therapeutic strategies without sufficient evidence of effectiveness or harms, overtreatment and widespread inappropriate use of medications, services, or devices may occur. Accordingly, guidelines may recommend health interventions that do not actually improve population outcomes or the quality of care, unnecessarily increase health care expenditure, and may even harm individuals who might be expected to receive small or negligible treatment benefit.” We’ve seen it in diabetes: now we’re seeing in this new biochemical epidemic of kidney “disease.” What this study shows is that although high phosphorus levels are mildly predictive of poorer outcomes in CKD, there is not a jot of evidence that trying to lower them makes any difference.

1136  GRAVITAS is something I try to steer clear of in these reviews, but this week it is the acronym of a trial I would like to draw your attention to, partly because it shows up the limitations of platelet reactivity testing. This is not something that has caught on much in the UK, but in the US it is marketed as the answer to the problem of stent thrombosis, among other things. This was not a good trial: it was underpowered and it relied on increasing the dose of clopidogrel in patients who showed continuing high platelet reactivity following a normal dose of clopidogrel. It’s hard to judge what made the trial negative: it may have been that the test is insufficiently predictive, or that the treatment strategy was wrong. We know from basic pharmacology, and can see from this trial, that increasing the dose of clopidogrel does not result in much lowering of platelet reactivity. So it was all rather a bad idea in the first place.

NEJM  17 Mar 2011  Vol 364
1005   I like the title of this paper: Randomized Trial of Omalizumab (Anti-IgE) for Asthma in Inner City Children. It’s short and to the point, but best of all it tells you what omalizumab does. Mab means monoclonal antibody and izu means humanized: but what omal stands for is anybody’s guess. Nowadays there are mabs against pretty well every biological substance in the human body, so it’s nice to be told right away what this one is active against. But there are lots of inner city kids with IgE mediated asthma and it would also be nice to know what it costs. In the UK, the price is £256.15 per 125mg vial, meaning that the basic cost of the highest dose regimen in this 60-week trial was about £23K. Now if that cured their asthma and returned their lung function to normal, that might be a price worth paying: but in fact there was no change in lung function and merely a modest decrease in exacerbations, a bit less use of rescue steroids and a flattening of the seasonal exacerbation pattern. So if the price of omalizumab were to fall by a factor of say 20, it might be a treatment worth considering in some inner city kids with refractory asthma.

1016   Before Dr Syntax was the name of a rap singer, it was the name of a middle-aged pedant who wandered about England doing silly things and searching for a wife, in a series of caricatures by Thomas Rowlandson. This has nothing whatever to do with the SYNTAX trial: I just thought you might want to know. SYNTAX was a much more serious affair, which boosted sales of paclitaxel-eluting stents by showing that short term hard outcomes were better than coronary artery bypass grafting. This follow on study wins my approval by using instruments measuring quality of life and so approaching patient relevance: and sure enough, patients were happier and more active when not recovering from major surgery and a thoracotomy, but the difference faded after a few months and after that the two are much of a muchness. Just one more piece in the post-COURAGE landscape where the order of preference in stable angina has come full circle, with medical treatment at the top, stents second, and CABG last.

1027   I’ve just been reading the chapter in James Le Fanu’s book The Rise and Fall of Modern Medicine (1999) where he describes the awful fate of children undergoing experimental treatments for acute lymphoblastic leukaemia between the first attempts at chemotherapy in 1945 and the final discovery of a complex curative regimen in 1971. The battle against cancer is a horrible, ditch-by-ditch, bayonet-in-the-guts affair; no sudden breakthroughs or Daily Mail style victories. In adult acute myeloid leukaemia, you currently have a choice between a dose of cytarabine that might not induce remission, or a high dose that would make you want to die: this study shows that it is possible to identify an intermediate dose that gives maximum benefit with fewest adverse effects.

1037   I’m trying to do some speed learning on outcomes research, and this paper is a nice example. The outcome is death in hospital, which you would think was about the easiest thing there is to measure, though recent UK studies have shown bizarre differences according to methodology. The object of study is the level of nursing cover. Like previous cross-sectional studies, this retrospective observational study shows that when target nursing levels are not met, more patients die. What else might we want to know? Well, I for one would like to know how these shortages affected the professional values and job satisfaction of the nurses, and above all I would like to hear the experiences of the patients and their bereaved families. We need a science of kindness which is value centred, to run in tandem with good quantitative data gathering. The real job of medicine is to marry the two.

1046   Multiple myeloma is on the cusp of becoming a curable disease: it already is in a substantial percentage of younger patients who are suitable for autologous bone marrow transplantation following remission inducing treatment. But for most of us in general practice it still means the elderly patient waiting out the five years between diagnosis and an unpleasant death. This comprehensive update has less hope to offer such patients, who at present tend to be given bortezomib and/or lenalidomide towards the end of their disease process rather than initially as part of an attempt at cure. With these drugs, and especially with thalidomide, be on the lookout for peripheral neuropathy. Perhaps the most difficult group of all are those who have been told they have “smouldering myeloma.” They know they may be progressing to a painful and fatal disease, but at present we know of nothing that will stop it. I am all for openness with patients, but I wonder if this is a burden of disclosure that we should sometimes spare them.

Lancet  19 Mar 2011  Vol 377
977   It is a brave man who can make a joke of his faecal incontinence, like a friend of mine, known to many of you, who tells a wonderful tale about indelible brown marks on a borrowed towel – then when he confessed to the owner, they turned out to be old ironing burns. But for many people, this is no laughing matter, and not something they can even bear to tell a doctor about. So full marks to The Lancet for giving top billing to this trial of perianal injections of dextranomer in stabilised hyaluronic acid for treatment of faecal incontinence. Also full marks to the triallists for designing a randomised trial with sham injections. But in this journal, you have to watch out. The summary ends: ” Interpretation: Anal injection of NASHA Dx is an effective treatment for faecal incontinence.” Then: “Funding: Q-Med AB.” Naturally, this company manufactures NASHA Dx and is keen to stress its safety and effectiveness, although previous studies of perianal injections have been summarised by Cochrane as inconclusive. As so often, you have to go to the editorial to get a proper analysis. This one is excellent: after pointing out the shortcomings in the documentation of outcomes before and after the procedure, it concludes: “So, although Graf and colleagues’ study might change the conclusion of an updated Cochrane review on the subject, should it change clinical practice? Maybe, but until we ask patients what they think, we cannot be sure whether a statistically significant result will actually change peoples’ lives.” Amen.

1011    Tonight I shall be going off to do an out-of-hours primary care shift. Half the patients will be febrile children and one of these will probably make me feel slightly scared, though I have been seeing febrile children for 35 years. To seem competent, I will have to write down their heart rate and respiratory rate though in former life I rarely bothered to do that: I thought a general impression was good enough. But a team of Oxford colleagues has shown that these things matter, even to experienced doctors: here they give the normal ranges based on a systematic review of observational studies. Even better is their succinct paper with Anthony Harnden in this month’s  BJGP on the early signs of meningococcal disease, which deserves universal circulation.

1019   Ah, here comes another seminar on Alzheimer’s disease to disturb the afternoon nap time of my retirement. It is rather good. It tells me that 70% of the risk of Alzheimer’s is genetic, and I take comfort that all my ancestors were of unimpaired intellect in their old age, though decidedly odd. I’ve never smoked. I will move swiftly past any disclosures about alcohol and physical exercise. Zzzz. Now where was I?

BMJ  19 Mar 2011  Vol 342
637   I am seized with generalised anxiety disorder whenever I think about psychiatric drugs. Most of the time we really do not know what we are doing. In my experience, the most effective drug for GAD is lorazepam, but that leads to dependency: instead we are urged to prescribe SRIs like fluoxetine (top in this meta-analysis) which also lead to dependency, though for some reason nobody is allowed to say so. From the perspective of my desk, looking at the distraught patient wanting something to help, and the clock behind telling me that the ten minutes are up, these drugs were a godsend; but by gad I now wonder if I was really doing anybody much good.

638   We wear out; our telomeres shorten; man that is born of woman hath but a short time to live; all flesh is grass; so teach us to number our days, that we may apply our hearts to wisdom. One way to number your days is to consider how much knee and hip osteoarthritis you have: this population based cohort study from Somerset and Avon finds that people with walking disability die sooner, mainly from cardiovascular causes. Obesity was protective in this group. The paper and editorial speculate that there are genetic factors at work here, which is a pretty safe bet: but don’t forget the help these patients get from us doctors too, bumping them off with long term NSAIDs, many of which carry a higher CV risk than smoking. Let us apply our hearts to wisdom and avoid any but naproxen and ibuprofen.

650 And now back to psychiatric drugs. When the phenothiazine antipsychotics arrived in the 1950s, they emptied whole lunatic asylums smelling of chloral and urine. They remain good drugs, marred by their extrapyramidal side-effects. Then came the so-called atypical antipsychotic drugs which swapped these adverse effects for metabolic effects which we are only now reaping the full force of: obesity, diabetes, and cardiovascular disease. It’s a poor exchange, especially as they are generally much more expensive and no more effective. This review of them shows how little science there is in this area: the final quotation from NICE says it all: “choosing the most appropriate drug and formulation for an individual may be more important than the drug group.” In other words, keeping trying until something seems to work.

Arch Int Med  14 Mar 2011  Vol 171
384   The epidemiology of heart failure is hard to decipher, not least because a lot of people still confuse HF with left systolic dysfunction. If you look at heart failure as a whole – i.e. including the 50% with a normal ejection fraction – then you find that most people who develop it have had high blood pressure at some stage in their lives. By the time the breathless old lady comes along to you with a massive pulse pressure (say 188/80), it is probably too late to do anything useful. If you send her for echo, she will have a normal ejection fraction, but she has irreversibly stiffened capacitance arteries and you will spend the next few months making her fall over by trying to reduce her systolic pressure. This Bayesian network meta-analysis of antihypertensive treatment and the development of heart failure in hypertension identifies the best drugs to prevent HF, given earlier in life – and lo and behold they are diuretics, ACE inhibitors and ARBs.

404   I have spent the last two years railing in public against the “one size fits all” approach to type 2 diabetes which we are encouraged to adopt in UK general practice by the QOF payment scheme, so I was mildly thrilled to spot this paper based on a UK study, which promises to stratify cardiovascular risk in diabetic men by age and duration of diabetes. But the paper is almost unreadable: instead of describing a continuum, it cuts up the data to fit, or fail to fit, a “previous MI” model of comparison. I sent it to two eminent American physicians who replied: “One day we will realize that all of us, including clinicians and patients, can think in shades of grey. That we do not need a single threshold to make decisions. That medicine is hard, but that we are ready to work with the challenge,” and “We pull the smartest people into medicine and then something happens that they can no longer do anything that requires more than counting on their fingers.”
Plant of the Week: Narcissus pseudonarcissus

I make no apology for celebrating this plant every year around this time. The native daffodil is simply a joy, and if you can make the pilgrimage to Newent and its surrounding woods and fields, where it grows wild by the million, you will realise that no hybrid can match it.

This should not, of course, put you off buying and planting all the hybrids you can. I like the big ones with pink trumpets: you may like ones that resemble scrambled eggs with blood. I don’t care; I can look away: be happy, it’s Spring!