Richard Lehman’s journal review—18 August 2014

richard_lehmanNEJM 14 August 2014 Vol 371
601  The usual wisdom about sodium chloride is that the more you take, the higher your blood pressure and hence your cardiovascular risk. We’ll begin, like the NEJM, with the PURE study. This was a massive undertaking. They recruited 102 216 adults from 18 countries and measured their 24 hour sodium and potassium excretion, using a single fasting morning urine specimen, and their blood pressure by using an automated device. In an ideal world, they would have carried on doing this every week for a month or two, but hey, this is still better than anyone has managed before now. Using these single point in time measurements, they found that people with elevated blood pressure seemed to be more sensitive to the effects of the cations sodium and potassium. Higher sodium raised their blood pressure more, and higher potassium lowered it more, than in individuals with normal blood pressure. In fact, if sodium is a cation, potassium should be called a dogion. And what I have described as effects are in fact associations: we cannot really know if they are causal.

612  But now comes the bombshell. In the PURE study, there was no simple linear relationship between sodium intake and the composite outcome of death and major cardiovascular events, over a mean follow-up period of 3.7 years. Quite the contrary, there was a sort of elongated U-shape distribution. The U begins high and is then splayed out: people who excreted less than 3 grams of salt daily were at much the highest risk of death and cardiovascular events. The lowest risk lay between 3 g and 5 g, with a slow and rather flat rise thereafter. On this evidence, trying to achieve a salt intake under 3 g is a bad idea, which will do you more harm than eating as much salt as you like. Moreover, if you eat plenty of potassium as well, you will have plenty of dogion to counter the cation. The true Mediterranean diet wins again. Eat salad and tomatoes with your anchovies, drink wine with your briny olives, sprinkle coarse salt on your grilled fish, lay it on a bed of cucumber, and follow it with ripe figs and apricots. Live long and live happily.

624  It was rather witty, if slightly unkind, of the NEJM to follow these PURE papers with a massive modelling study built on the assumption that sodium increases cardiovascular risk in linear fashion, mediated by blood pressure. Dariush Mozaffarian and his immensely hardworking team must be biting their lips, having trawled through all the data they could find about sodium excretion in 66 countries. They used a reference standard of 2 g sodium a day, assuming this was the point of optimal consumption and lowest risk. But from PURE, we now know it is associated with a higher cardiovascular risk than 13 grams a day. So they should now go through all their data again, having adjusted their statistical software to the observational curves of the PURE study. Even so, I would question the value of modelling studies on this scale: the human race is a complex thing to study, and all models need to be taken with a pinch of salt.

646  I glanced at the NEJM‘s latest Clinical Practice review about obsessive-compulsive disorder to see if I had missed any recent developments. When I took my psychiatry exam at medical school exactly 40 years ago, I was asked about treatments for OCD and I replied behavioural therapy and/or clomipramine. This produced a purr of assent and swift progress to the next question. Today I learn that the treatment of OCD consists of behavioural therapy and/or a SSRI antidepressant, although the reviewer mentions that none of these has been shown to be more effective than clomipramine (which is, in fact, itself mainly an SSRI). Being really more of a dog than a cat, I woof my assent.

JAMA 13 August 2014 Vol 312
593  A few weeks ago, I suggested that people with hepatitis C should travel to the moon, because I had heard that treatments for it were affordable there. Alas, this is no joke. Two potentially curative polymerase inhibitor regimens are now available. In the USA, the price of sofosbuvir is essentially $1000 per pill, or $84 000 for a standard 12 week course. In the UK, the same course can be had for $54 000, and in Egypt it is rumoured to be available at $900. So perhaps travel to the Nile rather than the moon. But the current global system of drug pricing is clearly loony.

606  I approve of colorectal cancer screening, which is why I have just thrown away the faecal occult blood testing kit sent to me by the NHS screening programme. If you want to detect colorectal cancer, just go in there and look for it. I happen to have had a colonoscopy in the last ten years. The best compromise is probably to offer everybody one-time flexible sigmoidoscopy. This avoids the cost and danger of universal colonoscopy, while detecting the majority of cancers. The Norwegian study here is the fourth to show that this strategy reduces colorectal cancer mortality by 20-30% in the screened population.

623  I realize that you may not be a methodology dork, dear reader, but the occurrence of the name Doug Altman in the authorship of any paper should make you sit up and take notice, even if it has a title like “Association Between Analytic Strategy and Estimates of Treatment Outcomes in Meta-analyses.” Doug does not put his name on anything that is not important and clearly written. Just consider how this affects your practice. If you like to know what you are doing to your patients every day, you should seek out all the information you can about the harms and benefits of the treatments you use. I know we are amazingly bad at doing this, but that shouldn’t stop us trying. For this, we need well extracted information from reliably conducted studies, which give information about the outcomes that interest us and our patients. Meta-analyses are supposed to provide this. But if the meta-analysts pick the wrong studies and the wrong end points, and report them badly, then we are no further forward. We just give up and do what we always did, printing out the prescription, while giving some excuse to the patient as to why we think they should take the stuff. Or worse still, we will be fooled into believing our own bad practice.

JAMA Intern Med August 2014 Vol 174
OL  It is most regrettable that the leading journals have taken to publishing interesting papers during the month of August. Just when you think you can catch up with long neglected projects while everybody is away, or do a bit in the garden, along comes a whole batch of papers that really call for mental involvement. Here, on top of the NEJM salt papers, is a pretty amazing study from the Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease (CLARIFY) registry. Do I really want to spend a sleepy summer afternoon going through this for your benefit? No, but I will; and then I intend to take a week’s break. The really startling finding here is that if you have known coronary disease accompanied by silent myocardial ischaemia, your outlook is actually better than if you have coronary disease without silent ischaemia. You can understand why these silently ischaemic people do better than those with overt angina, but it’s more difficult to understand why they do better than others with coronary disease and no reduction in perfusion. Perhaps it’s to do with ischaemic preconditioning. This was a complex cohort on a lot of preventive medication, so if you really want to make deductions, you too will have to sacrifice part of a summer’s day.

OL  A more straightforward paper. Some observational studies have claimed that bisphosphonates may help to prevent postmenopausal breast cancer. But if you look at the randomized controlled trials of alendronate or zoledronic acid in this population, you don’t find any decrease in the risk of invasive postmenopausal breast cancer.

OL  And if you look for folate deficiency in the US population, where flour is fortified with folic acid, you are incredibly unlikely to find it. A total of 84 187 serum folate levels were measured in 77 627 individuals over an eleven year period at a large academic medical centre in Boston, Massachusetts. A mere 47 showed deficiency (0.056%). I wonder what the UK figures in a similar centre would be like. (P.S. In the United States, Medicare pays $20 for every folate test you send to the lab: the cost of the test to you is $2, but if you charge the patient you ask for $128.)

Lancet 16 August 2014 Vol 384
583  Here is a heart failure trial, which illustrates everything that’s wrong with heart failure trials: and yet I quite like it. “The funder assisted in study design, data collection, data analysis, and preparing this report. They had no role in data interpretation.” Given the first sentence, can you believe the second? The funder, Biotronik SE & Co. KG. was of course testing its own product—a telemonitor implanted within a Lumax dual-chamber implantable cardioverter-defibrillators or cardiac resynchronization therapy device. The mean age of the participants was at least 10 years younger than the average patient with heart failure, and the unwieldy composite end point was all-cause death, overnight hospital admission for heart failure, change in New York Heart Association class, and change in patient global self-assessment. Half of the patients were blinded, but the assessors were not. What’s not to hate? And yet the results are important and believable. Ignore the messy composite end point: the fact is that 10 versus 27 patients died during follow-up of one year. And this was achieved with minimal effort: these devices didn’t go off all the time, creating anxiety and work for everybody. On average, patients in the active group only received two phone calls during the study. So having devices that report events is probably genuinely useful for preventing serious tachyarrhythmias, pacing malfunction, and inappropriate shock therapy, and can halve mortality. It’s good to know there are replication studies underway, as Martin Cowie’s sensible editorial describes.

591  “Blood pressure lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data.” I rubbed my eyes. Grails don’t come much holier than this. For 10 years, we’ve realised that statin treatment is not about lipids, but about cardiovascular risk reduction. And yet we’ve gone on treating “hypertension” as if it was a disease in itself. I had almost given up hope that hypertensionologists would realize that the numbers needed to treat to prevent events in people with elevated BP depended on their total cardiovascular risk. And here it is, nicely illustrated in a meta-analysis of 11 randomized trials. “These results support the use of predicted baseline cardiovascular disease risk equations to inform blood pressure lowering treatment decisions.” As people with high blood pressure constitute the largest group of symptomless attenders in primary care, this will require little short of a revolution. Bring it on. I look forward to the day when nobody takes blood pressure lowering medication without a reasonable idea of the benefit (or harm) it may bring for them personally. This could be the most important paper for general practice to come out in the last 10 years.

599  Now that I have a small job with the UK Cochrane collaboration, I read more meta-analyses than I have hot dinners, by a factor of about ten. Mission fatigue can creep in, but here is another meta-analysis that restores the will to fight. Bivalirudin costs several hundred times as much as heparin. But it is widely used in patients undergoing percutaneous coronary intervention (PCI). Randomized trials have failed to show a significant difference between the two. But if you combine data from all of them, you discover a higher rate of myocardial infarction and stent thrombosis in patients given bivalirudin. In most situations, this is not offset by the slightly lower risk of bleeding. The older, much cheaper, drug is simply better.

OL  Lurking on the Lancet website is the 13 year follow-up from the European Randomised Study of Screening for Prostate Cancer (ERSPC). The absolute risk reduction of death from prostate cancer at 13 years was 0.11 for every 1000 person-years or 1.28 for every 1000 men randomised, which is equivalent to one prostate cancer death averted for every 781. “Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of population based screening.” I won’t comment further, because much of what I want to say has been better said by Laura Newman in her blog. PSA is not fit for screening.

The BMJ 16 August 2014 Vol 349
I think the new “The” that has been added to BMJ stands for Transatlantic Health Esoterica. In this week’s research section, you can read about the rise in obstetric acute renal failure in Canada and the use of tranexamic acid in major joint operations in the United States.

The British Medical bit consists of a study of the impact of centralising acute stroke services in English metropolitan areas on mortality and length of hospital stay. This is a before and after study in London and Manchester. Make what you will of it: the differences are small and might have happened anyway. The authors use it to support centralization. Why am I not surprised?

Plant of the Week: Salicornia europea

This coming week, I shall be taking a short holiday to gather sampkin in Anglesey. Sampkin is the North Welsh version of the word samphire, given to a number of edible annual plants that grow on our shores. I think the one that grows on Red Wharf beach is the one I’ve named here, but I’m not sure. It is delicious and juicy, without the stale bitterness of the imported samphire now sold in supermarkets.

I also hope to gather early season fungi in the woods of North Wales. It will be cold and rainy enough.

And there will be no reviews next week. They will resume thereafter, except in the case of death from fungus poisoning.