Richard Lehman’s journal review—31 May 2016

richard_lehmanNEJM 26 May 2016 Vol 374
An end to oncology drug madness?
2001 “Seamless Oncology-Drug Development” is a viewpoint piece about the research and regulatory changes that have allegedly been driven by a desire for “early access to transformative new anticancer drugs.” To my simple way of thinking, this would mean first showing that the new drug was transformative, through large double-blinded randomised controlled trials demonstrating a sizeable survival benefit. Secondly, in order to achieve “early access,” the drug would then be immediately available to all patients, and charged at production cost to the health provider. Thirdly, further trials would be conducted using it earlier in the disease process, compared to existing standard treatment. These processes would be overseen and subsidised by governments who cared about the fate of their citizens with cancer and the sustainability of their health systems.
But the exact opposite is happening. This article offers some solutions, but is not nearly radical enough. It talks about “drugs with unprecedented levels of efficacy,” when these are still about one in 50 among the $10K per month duds, which are regularly touted in the leading journals. If you want a sane running commentary on this, follow @VinayPrasad82 and @oncology_bg on Twitter. I find the current situation beyond bewildering.

What do you mean by Asians and non-inferior?
OL While still bewildered, I tried to understand the conclusion of this alteplase dosing trial called ENCHANTED. It is described as a trial involving “predominantly Asian patients with acute ischemic stroke. [It] did not show the noninferiority of low dose alteplase to standard dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low dose alteplase.” Now if you look at the map, Asia is a big place. British “Asians” from the Indian subcontinent are genetically distinct from the mostly Chinese “Asians” in this trial, but both groups are highly heterogeneous within themselves. It’s high time we dropped this sloppy designation from the academic medical literature. It’s also time we dropped the silly term “non-inferior.” If you look at the actual outcomes of the trial, the two dosages achieve results which are indistinguishable for clinical purposes. But the upper bound of the confidence interval for outcomes after the lower dose exceeded an arbitrary prespecified level: it was 1.25 and not 1.14. So by a sleight of curious pedantry the higher dose wins, even for the “Asian” subgroup. If you don’t get this, neither do I.

Early or delayed renal dialysis for ICU patients?
OL Intensive care units and renal dialysis suites are really not places where I am your best guide. I’ve peeped behind their curtains a few times over the years to visit the odd patient, but how decisions are made is a complete mystery to me. But here’s a French trial whose conclusion I can easily understand: “In a trial involving critically ill patients with severe acute kidney injury, we found no significant difference with regard to mortality between an early and a delayed strategy for the initiation of renal-replacement therapy. A delayed strategy averted the need for renal-replacement therapy in an appreciable number of patients.”

JAMA 24/31 May 2016 Vol 315
Coiled & waiting to damage the bronchi
2178 Here’s a déjà vu moment for those who’ve been paying attention to these reviews. I hope that means all of you, children. Do you remember a trial of endobronchial coils for emphysema a few months ago? They caused all sorts of problems: pneumonia, pneumothorax, device migration, and bleeding. It was the same in this manufacturer funded, multicentre trial in 315 people with severe lung hyperinflation and homogeneous or heterogeneous emphysema. “Major complications occurred in 34.8% of coil participants vs 19.1% of usual care (P=.002).” This should be the end of endobronchial coils as far as I can see. They should be banned before any more patients are harmed.

Confounded salt, again
2200 The journals seem to be full of observational association studies at present. In recent weeks we’ve had worship, potatoes, leisure time exercise, and this week it’s salt. It seems unlikely that we’re going to get through the summer without mindfulness and chocolate. This study takes a population with “chronic kidney disease”—i.e. an estimated glomerular filtration rate of 20-70 (!). Words cannot do this justice. But at least the salt measurement makes sense: the cumulative mean of urinary sodium excretion from three 24 hour urinary measurements and calibrated to sex specific mean 24 hour urinary creatinine excretion. The curves would suggest that people with a sodium output (=intake) of more than 4.5g daily get the most cardiovascular events. The mean was 3.7g in the whole group. “Participants with higher calibrated 24 hour urinary sodium excretion were more likely to be male, white, and current smokers; report a history of hypertension, diabetes, hypercholesterolemia, and CVD; and take antihypertensive medications.” The investigators tried to adjust for all these factors individually, as far as that is possible. But my point would be that it isn’t really possible, or relevant. No one in the real world is surprised to learn that fat, smoking, white men tend to eat salty food and have heart attacks: what would really be surprising is if someone found a way to get them to eat less salt and proved that this altered their outcomes.

JAMA Intern Med May 2016 Vol 176
CBT for menopausal insomnia
OL MsFLASH is a trial acronym—I just wanted you to know that. There could be misunderstandings. In the US, ladies of a certain age experience flashes, while their British sisters content themselves with flushes. The intervention in this trial had no effect on flashes or flushes, but it did help to combat insomnia in women aged 40-65 with vasomotor symptoms. It consisted of six telephone calls delivering cognitive behavioural therapy over eight weeks, compared with general menopause advice.

Opioids for low back pain
OL Low back pain is one of the commonest reasons for people to take long term analgesic drugs. This systematic review looks at what we know about the role of opioids. “For people with chronic low back pain who tolerate the medicine, opioid analgesics provide modest short term pain relief but the effect is not likely to be clinically important within guideline recommended doses. Evidence on long term efficacy is lacking. The efficacy of opioid analgesics in acute low back pain is unknown.” Thousands of North Americans are dying from overdoses of prescribed opioids, especially oxycodone. A recent Lancet review suggested that diclofenac 150mg daily is more effective. But that could kill more thousands from cardiovascular disease. And we know that paracetamol is useless for chronic back pain. So where do we go from here?

Lancet 28 May 2016 Vol 387
Finding a market for rituximab
OL Follow-up studies and systematic reviews confirm that patients with rheumatoid arthritis no longer need fear long term joint damage provided they are treated early with three conventional cheap drugs and are able to tolerate them. So where does that leave all the far from cheap rheumatoid drugs that have been produced over the past 15 years or so? Answer: in a fight for a much smaller market. Here’s Roche’s attempt to join it, with help from Arthritis Research UK and 35 rheumatology departments in the UK—just about all that there are. They ran an open label trial comparing the efficacy and cost of their drug, rituximab, with two tumour necrosis factor (TNF) blocking agents, etanercept and adalimumab. “Interpretation: Initial treatment with rituximab is non-inferior to initial TNF inhibitor treatment in patients seropositive for rheumatoid arthritis and naive to treatment with biologicals, and is cost saving over 12 months.” The premises of this study and the economic analysis in particular are subject to scathing analysis in the accompanying editorial, “Drivers of costly treatment strategies in rheumatoid arthritis.” It’s worth reading as a caveat for all effectiveness asserting articles based on official price levels.

QOF & mortality
OL Payment by performance in British general practice was a massively expensive experiment set up in 2004. It was watched attentively by the world, and has been copied in one or two countries. Every study of it has shown essentially the same thing. Incentivised by the money, most general practices hit the specified (arbitrary, surrogate) targets almost immediately. Then they showed a levelling off, and there followed several years of gaming where the government thought of increasingly difficult targets in order to suppress GP income as a proportion of total NHS spend. GPs found themselves working harder for less money, while their professional values were ignored in favour of increasingly dubious targets for treating largely asymptomatic people. Doctors who could retire left, while others reduced their working hours. Nobody wanted to enter general practice and vacancies became impossible to fill. So much for the effect on doctors and the NHS. And what was the effect on patients, as judged by mortality in the key areas of the quality and outcomes framework (QOF)? Well, nothing, according to this study.

How many pinches of salt?
OL The salt “controversy” is gradually resolving itself, and this study takes us a long way towards the point where everybody should agree on the basic facts. However, I’m not holding my breath. A great many people have waxed highly self-important in the cause of salt reduction. Here’s a pooled analysis of sodium excretion in 133 118 individuals (63 559 with hypertension and 69 559 without hypertension) with a median age of 55 years. The graph is quite familiar to those who have been following the subject for the past two years. Salt intake below 3g per day is associated with a dramatic increase in death and cardiovascular disease events. For normotensive individuals, there is a very small and gradual increase above 8g. For individuals with high blood pressure, the increase starts around 6g. The idea that there is a linear relationship between salt intake and blood pressure, and that this transmits directly into adverse cardiovascular events, is outdated and untenable.
The Lancet should make this paper and Eoin O’Brien’s terrific editorial open access, because everybody needs to read them.

The BMJ 29 May 2016 Vol 353
Left to their own devices
Here’s a paper that bears the name of Lord Darzi, so it’s now official: you can put anything you like into human beings. Looking at 218 trials, his team identified a multitude of new medical devices in clinical studies, almost half of which received regulatory clearance or approval. Actually clearance or approval preceded the studies in 43% of cases. The paper deals mostly with approval by the US Food and Drug Administration via the 510(k) process. But in the UK too, selling such products is much more important than knowing what they do to people. All Academic Health Science Networks have the fast tracking of new technologies as a priority, using the NHS as a test bed and source of revenue for UK PLC. The National Institute for Health and Care Excellence is under pressure to make the process even less rigorous than it is at present. You couldn’t make it up. This is supposed to be democracy in action, safeguarding its citizens.

Late death after sepsis
An overwhelming inflammatory response to infection causing hypotension and organ failure is a signal that either the infection is very nasty or that something is not right with the body’s defences. This study shows that over a fifth of patients aged 65 or over who survive hospital admission for sepsis die sooner than they should. I don’t have anything to do with such poorly patients these days, but if I did, I might start by looking at their adrenal function a few weeks after recovery.

We don’t need scores of scores
The Dutch authors of this paper found 363 cardiovascular risk prediction models, most of them based on European populations. Not only is that an absurd number, but they have obsolescence built in. Cardiovascular disease has fallen by 70% across Europe over 30 years, but in a very uneven way. Does living in Lithuania count as a risk factor? Observationally, that’s more dangerous than smoking 60 cigarettes a day in Oxfordshire. Yet we’re supposed to choose one of these prediction scores to help healthy people decide about statins, exercise, diet, weight loss, and diabetes treatments. The fact is that the same general rules will work for most people at any level of risk, and the best we can do is match a very rough ballpark estimate with personal habits and preferences.

Plant of the Week: Clematis montana “Broughton Star”

For six weeks beginning in the middle of May, sunny days in Britain are a beauty emergency. If you don’t get out and look at great gardens during these weeks, the chance will be gone for another year. And if one day is sunny, there is no possible way to know if any more will be.

Two days have just gone by when it was a rapturous pleasure just to drive through the lanes of the North Cotswolds. Each village sported handsome horse chestnut trees in full flower, wisteria growing against honeyed stone or red brick, and massed montana clematis flower covering thatched roofs, walls, trees, and hedgerows.

It really doesn’t matter which of these spring flowering clematis you grow. They are hardy, vigorous, and wilt-proof, and they come in a variety of whites and pinks. Some have an overpowering scent of dusty vanilla sugar or marshmallows. “Broughton Star” is more moderately fragrant, with lovely cut purply foliage and clear pink double flowers. Look around and see if you can find room for it to cover some part of your house or garden each spring.

Editor’s note: When it was first published, this blog contained a paragraph on this study in JAMA. This parargraph was framed around a misinterpretation of the findings of that study and so was removed on the evening of 31 May 2016.

  • George

    Why do we talk about salt and hypertension without controlling for hyperinsulinaemia? The low insulin fasting state induces natriuremia, consistently elevated insulin levels can result in retention of both sodium and fluid. Essential hypertension is associated with increased insulin resistance and decreased insulin clearance (this is the title of a paper). The kind of food associated with insulin resistance in the Western(ised) world, and the kind of food eaten round the clock so there’s no low insulin fasting state, is famously as salty as it is starchy, oily, and sweet.
    Persons who go on very low carbohydrate diets, often with the goal of reversing conditions associated with insulin resistance, not excluding hypertension, are likely to find, firstly that they can lose a deal of “water weight” quickly, secondly that natriuremia can increase to the point where they need to supplement salt to keep body and soul together.
    So what would happen if, say, fasting insulin or C-peptide was also being measured in one of these giant salt surveys? I’d like to see this happen, because it might well explain a large proportion of the correlations.

  • Charlie Tomson

    Re:Early or delayed renal dialysis: the German study did NOT show the same thing; rather, it showed the opposite, in a group of patients with ‘earlier’ acute kidney injury, and concluded ‘Among critically ill patients with AKI, early RRT compared with delayed initiation reduced mortality over the first 90 days. So the jury is still very much out on this topic.