Richard Lehman’s journal review—30 March 2015

richard_lehmanNEJM 26 Mar 2015 Vol 372
1193 Is the NEJM preaching Socialism? “We believe that all financial incentives and logistic barriers to providing the least expensive drug, among drugs equivalent in safety and efficacy, should be eliminated so that patients may benefit fully from the results of this Diabetic Retinopathy Clinical Research Network trial as well as those from other comparative trials.”

The trial in question shows that for the treatment of early to moderate diabetic macular oedema, nine shots of bevacizumab ($50 per dose), ranibizumab ($1,200 per dose), and aflibercept ($1,950) all produce the same benefit. For the most severely affected, aflibercept improves vision slightly more. As all readers must know by now, bevacizumab does not have a licence for this indication because its manufacturers, Genentech/Roche, have not applied for one. Naturally they would rather that providers paid 24 times as much for their equivalent product, ranibizumab. I was a long-haired student in the early 1970s when Mr E Heath (Con) talked about the “unacceptable face of capitalism” while Mr H Wilson (Lab) talked of nationalizing the pharmaceutical industry to stop it profiteering at the expense of the NHS. Now my hair is nearly white and mostly gone, like my hopes.

1261 And now some more radical talk from the NEJM editorial pages: “We should do better than base clinical decisions on flawed observational studies and undersized randomized trials. It should be unacceptable to have evidence voids in areas so common and so costly (in clinical and financial terms) to the public health. We need better ways to aggregate and analyze large amounts of clinical data to better inform practice at the point of care. We also need more streamlined methods of embedding randomization into clinical activities so that the research process is facilitated rather than impeded.” These are the words of Robert Harrington but they could be those of Harlan Krumholz, or Ben Goldacre, or Paul Glasziou, or even me. They refer to the trials below.

1204 Cabbage comes in and out of favour. I personally prefer the old fashioned kinds, such as Savoy or Sweetheart, cut in strips and stir-fried in nut oil with a few chopped walnuts, perhaps some shallot and bacon. Sprinkle with balsamic vinegar. I can’t get on with Cavolo Nero which has the texture and taste of a plastic bag, however you cook it. CABG started falling out of favour with the arrival of bare metal stents and even more with the allegedly superior drug-eluting stents. Here’s the first of the two trials mentioned above. It was publicly funded in Korea and is open access. Recruitment was slow and the trial was terminated at two years. At that point, the composite end-point (grr) of death, myocardial infarction, or target-vessel revascularization had occurred in 11.0% of the patients in the PCI group and in 7.9% of those in the CABG group (absolute risk difference, 3.1 percentage points; 95% confidence interval [CI], −0.8 to 6.9; P=0.32 for noninferiority): not significant. Two years on, and the difference in favour of CABG had become just significant (CI 1.01 to 2.13; P=0.04).

1213 On to the next study, this time run by a stent manufacturer (Abbott Vascular) and behind a paywall. It’s a clinical registry study of 9223 patients with similar propensity scores who underwent PCI with everolimus-eluting stents and 9223 who underwent CABG. At nearly three years on average, the risk of death was the same. The risk of stroke was higher in the CABG group, while the risk of myocardial infarction or repeat revascularization was a bit higher in the stent group. This is the kind of study which cries out for replication by reanalysing the same individual patient dataset. Even then, propensity scoring is no substitute for true randomization. As the editorial says, these two studies take us no further forward in being able to put informed choices before patients.

JAMA 24-31 Mar 2015 Vol 313
1223 I can only apologise. This week’s JAMA is much like last week’s NEJM: it’s about curative regimens for hepatitis C, but with concurrent HIV thrown in. I could go all shouty again about pricing, but I’ve already done that for this week. If drug manufacturers want to pull in profits equal to 20 times the development and manufacturing costs of a product, there is very little anyone can do to stop them. Don’t take it from me, read the BBC article by Richard Anderson. This trial was funded by AbbeVie, and its authors boast a dizzying array of potential conflicts of interest. Ombitasvir, Paritaprevir Co-dosed With Ritonavir, Dasabuvir, and Ribavirin for Hepatitis C in Patients Co-infected With HIV-1: an open-label, randomized uncontrolled study. “We gave it to them and they mostly got better”: how delightfully retro.

1232 Ooh, and more of the same: “Virologic Response Following Combined Ledipasvir and Sofosbuvir Administration in Patients With HCV Genotype 1 and HIV Co-infection.” They even missed out the randomization. They gave it to 50 of them and they all got better bar one.

1240 Now back to that cutting edge innovation, the properly conducted randomised controlled trial. This one was initiated and funded by Micrus Endovascular, who were hoping that their cerebral artery stenting system would stop people having strokes. Their participants had all experienced a transient ischaemic attack in the preceding month and been found to have intracranial stenosis (70%-99%) involving the internal carotid, middle cerebral, intracranial vertebral, or basilar arteries. But the use of the Micrus balloon-expandable stent compared with medical therapy resulted in an increased 12-month risk of added stroke or TIA in the same territory, and increased 30-day risk of any stroke or TIA.

JAMA Int Med Mar 2015
Last week the buzzwords were deadoption and undiffusion. This week it’s deprescribing. Here are the rules according to a new paper from Australia:
(1) list all drugs the patient is taking and the reasons for each.
(2) consider overall risk of drug-induced harm.
(3) assess the current or future likely benefit potential versus the current or future harm potential of each drug.
(4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes.
(5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects.
Under (4) I’d suggest that “Agree on priorities for discontinuation with the patient” might be better.

Lancet 28 Mar 2015
1183 Recent years have seen a number of trials showing that a “restrictive” policy of blood transfusion results in short-term outcomes as good or better than a “liberal” policy. It has even been suggested that blood transfusion might be toxic to the immune system and cause long-term harm. But in the FOCUS trial, follow up at a median of 3.1 years shows that long-term mortality did not differ significantly between the liberal transfusion strategy (432 deaths) and the restrictive transfusion strategy (409 deaths) (hazard ratio 1•09 [95% CI 0•95–1•25]; p=0•21).
Lift ye then your voices;
swell the mighty flood;
louder still and louder
praise the precious blood.
(last verse of Viva! viva Gesu!, a rather nasty hymn for Holy Week).

1198 When this trial first appeared on the Lancet website, I remember thinking what a crazy little thing it is. It’s a phase 2 study of AF-219, an anti-tussive drug, which inhibits P2X3. The AF stands for Afferent Pharmaceuticals, who believe that P2X3 receptors on the afferent vagal nerve could mediate sensitisation of the cough reflex, leading to chronic cough. They recruited 36 Mancunians with a cough that had lasted more than eight weeks and gave 24 of them their new drug, and placebo to the rest. All of the active group developed taste disturbances, which led six to pull out. Those who continued also experienced a 75% diminution in their cough. ” Interpretation: P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives.” Well, if you don’t mind swapping your irritating cough for an irritating taste.

1206 This week’s massive cancer survey looks at survival rates in England and Wales from 1971- 2011. It is pretty good news. Overall survival at ten years from diagnosis now matches the figure for overall survival at one year in 1971. There’s a wealth of intriguing detail and you can pick through it for yourself because this an open access article.

1219 In 2008, NICE advised the cessation of antibiotic prophylaxis before dental treatment in people at risk of infective endocarditis, except in the highest risk category. I remember thinking at the time that they were sticking their necks out a bit; the best way to test this strategy would have been to randomize by counties or countries within the UK and see what trends developed. A rise in the level of IE would be presumptive evidence that this strategy was unwise. And so it has proved: the incidence graph looking back shows a kink upwards from 2008.” Although our data do not establish a causal association, prescriptions of antibiotic prophylaxis have fallen substantially and the incidence of infective endocarditis has increased significantly in England since introduction of the 2008 NICE guidelines.”

BMJ 28 Mar 2015 Vol 350

Two hundred years ago, the standard advice of a London physician to a rich patient would have been: “stop drinking port, eat vegetables, and get out of London.” This was good counsel then, and it is even better since the invention of the internal combustion engine. Two studies this week attempt to quantify the harms of motor exhaust and fine particulate air pollution. The first, surprisingly, examines its link with anxiety, using data from the Nurses’ Health Study. From this painstaking analysis, you will find that the closer they lived to a busy road many years ago, the more they tended to self-report anxiety now. Now if you extrapolate from a cohort of American nurses to the general population, you may be inclined to believe this shows that particulate air pollution causes anxiety. Or maybe it’s the cars or the neighbourhood or the bigger hospitals they work in. Or it could just be that anxious nurses like to live in busy places.

Somewhat better evidence links short term exposure to air pollution with acute stroke. There is a massive literature: out of 2748 articles, 103 satisfied the inclusion criteria for this meta-analysis, and its conclusions are based on a total of 6.2 million events across 28 countries. The bad gases are carbon monoxide, sulfur dioxide, and nitrogen dioxide, and particulate matter also looks like a culprit for bringing on stroke, both at <2.5 µm or <10 µm diameter. My lord, should you wish to be spared a stroke, you must avoid port wine, eat vegetables, and take exercise henceforth in your country estates. My fee will be 100 guineas.

Varenicline is quite effective at helping people to overcome nicotine addiction, but a year or two after its introduction, reports began to circulate about its potential for inducing depression and suicidal behaviour. This meta-analysis should lay these fears to rest, though that is a tall order, now that the dog has a bad name. Varenicline can lead to bad dreams and sleep disturbance, but the investigators found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression, or death.

Fish of the Week: Scomber scombrus

I was moved to celebrate the mackerel this week by reading a passage in Thomas Gray, A Biography by R W Ketton-Cremer (1955) which casually alludes to “the death of the Master of Magdalene, his old acquaintance Dr Chapman, after consuming five large mackerel and a turbot.”

I hold the turbot blameless in this. Nobody has died from a surfeit of this excellent fish, though I have attempted it several times.

The five large mackerel, however, cannot be so lightly exonerated. In the eighteenth century, mackerel would arrive at the landbound colleges of Oxford and Cambridge after two or three days’ travel, and then be stored in the cellars of the Hall. There they would give out a faint green glow as they decomposed. We know this from a pamphlet written in the following century by John Newman, who was railing against Oxford University reforms proposed by the Master of my own college, Pembroke. “As a stinking mackerel gives forth light to its cellar, so Pembroke College in its decay presumes to enlighten the University”—or something similar. We have not forgiven him to this day.

As the luminous mackerel proceeds to rot, its proteins degenerate and form scombrotoxins, and these can produce rapid death by histamine poisoning. It is easy to see how five large college-stored mackerel might have seen off poor Dr Chapman. He probably disguised their taste with chilli vinegar, which was very popular at the time. And who can blame him for then turning to turbot?

These days most colleges in Oxford and Cambridge have adopted the refrigerator, but that does not prevent them from serving bad fish. Why, I had some there just the other day.