Richard Lehman’s journal review—10 February 2014

richard_lehmanNEJM  6 Feb 2014  Vol 370
513   Now that I’ve moved to a policy of including online first articles in these reviews, I’m immediately confronted with a problem: I’ve already told you about most of the content of this week’s NEJM, and there isn’t much new on the website. Never mind. Here is the companion piece to the rotavirus study from last week. In that one, there wasn’t a clear signal that monovalent (as opposed to pentavalent) rotavirus vaccine was associated with a tiny risk of intussusception, but in this somewhat larger study, there is. Which is a pity.

543   I deal a lot in diarrhoea. And green mucus. Plus cloudy urine. It’s great being an out-of-hours GP in England. I think I see a lot of “community-acquired pneumonia” too, but I can’t be sure, because this American update article implies that you need to see X-ray changes to make the diagnosis, and I don’t have access to X-rays. If they have crackles, I give them amoxicillin or erythromycin and send them home. I suppose if they all died, somebody would tell me, but you can’t be sure. Now if this New England Journal update is right, I am giving them the wrong treatment: in the USA, everyone with community acquired pneumonia gets a cephalosporin or a fluoroquinolone, plus a macrolide. If I had the temerity to do that, I would be hounded out of my job for causing an epidemic of Clostridium difficile. European and American bacteriologists seem to be at complete odds with each other on this issue. British readers must on no account read this article, which is totally and utterly wrong, and will result in their personal chastisement by Dame Sally Davies for causing an outbreak of Pandemonium difficile.

559   At the opposite end of the medical spectrum from being a British GP is the acerbic American Dr Greg House (aka actor Hugh Laurie, son of an Oxford GP), whose diagnostic acumen makes up for his complete disregard for conventional ethics. A terrible role model, but he may have actually saved a life—for real. In one episode of House, the eventual diagnosis is cobalt poisoning, which causes heart failure. Ever heard of it? There are two reports of cobalt induced heart failure in this week’s journals, and in the Lancet case, it was a House watcher who made the connection between a dodgy hip replacement and the failing heart. Here in the NEJM, the diagnosis was only made after the patient had a heart transplant. There have probably already been thousands of cobalt related deaths in older patients with progressive heart failure of uncertain cause. From now on, cardiologists need to think cobalt in every heart failure patient with a metal hip prosthesis.

JAMA Intern Med  Feb 2014
213   Once again, the monthly journal floods us with an embarrassment of riches. I’m picking out this US study of transfer rates for myocardial infarct patients from non-PCI-providing hospitals to PCI-providers because (a) it shows wide and unaccountable variation in practice (b) it shows very little difference in outcomes according to rates of transfer and (c) I was at Yale when it was being done. It’s a typically high quality product from the Center for Outcomes Research and Evaluation. Conflict of interest statement: I love these guys and the work they do.

223   “The time has come,” the Walrus said,
“To talk of many things:
Of shoes—and ships—and sealing-wax—
Of cabbages—and kings—
And why the sea is boiling hot—
And whether pigs have wings.”

There was a time when CABG was king: it was the most commonly performed major operation in the developed world. Then along came stents, and percutaneous coronary intervention developed wings. Boiling hot rows have ensued between surgeons and interventional cardiologists about how to interpret the sea of evidence. But the authors of this systematic review stamp their sealing wax down firmly in favour of CABG for 3+ vessel disease: “In patients with multivessel coronary disease, compared with PCI, CABG leads to an unequivocal reduction in long-term mortality and myocardial infarctions and to reductions in repeat revascularizations, regardless of whether patients are diabetic or not.”

232   But does either of these cardiological pigs really have wings? The next systematic review looks at all randomized clinical trials of PCI and medical treatment vs MT alone for stable coronary artery disease in which stents and statins were used in more than 50% of patients. Their conclusion supports COURAGE: “In patients with stable CAD and objectively documented myocardial ischemia, PCI with MT was not associated with a reduction in death, nonfatal MI, unplanned revascularization, or angina compared with MT alone.”

JAMA  5 Feb 2014  Vol 311
479   Most of this week’s JAMA is about high blood pressure. As we all know, long term BP and stroke risk show a nice linear relationship: and most of us in medicine, myself included, find comfort in simple things. It follows that a lot of patients who present with stroke also present with high blood pressure, and the temptation is to get it down as fast as possible. This idea was tested in 2038 patients admitted to Chinese hospitals: “Among patients with acute ischemic stroke, blood pressure reduction with antihypertensive medications, compared with the absence of hypertensive medication, did not reduce the likelihood of death and major disability at 14 days or hospital discharge.” BP lowering is a long-term strategy to prevent a second event, not an immediate necessity.

490   Blood pressure is an actual thing, but individual blood pressure measurements are a surrogate for what happens over decades within the circulation. Coronary artery calcium is also something real, but is just a distant surrogate for the thing that matters, which is unstable atheroma in the blood vessels supplying the myocardium. Marry up the two and you have a happy pair of surrogate parents: but what for? The trouble with blood pressure research is that it needs a decade or more to provide real knowledge about outcomes. This study identifies five trajectories of BP in younger adults, and links the higher ones with “subclinical atherosclerosis,” meaning a higher coronary calcium score. We get the drift: but how does this help us manage individual, perfectly asymptomatic, real people?

OL   There are plenty of Viewpoints for you to access free on the JAMA website, of which I shall just pick out two. The first is written by the amazing medical student Nick Downing, who thereby adds to his tally of top-ranking journal articles: a typically lucid dissection of the FDA’s decision to ban a personal genome product, co-written with Joe Ross. The second caught my eye because of the word “morcellation.” Apparently this has been around since 1993, when the first laparoscopic morcellators appeared. “The electric morcellator is an instrument that shaves or cores tissue into long strips for removal through laparoscopic ports of less than 2 cm. Initially used for uterine extraction, the morcellator has been used for removal of leiomyomata, kidneys, and spleens.” The problem is that it can spray bits of all these, and now stands accused of having seeded a uterine leiomyosarcoma around the abdominal cavity; this looked like a fibroid but turned out not to be. There is quite a list of other nasty morcells which may have caused harm to patients.

Lancet  8 Feb 2014  Vol 383
515   I’m normally reliably rude about pharma funded phase 2 trials published in The Lancet, but in the case of this one, we may be witnessing a breakthrough in the treatment of an important infection. “These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin.” Gilead, the manufacturer, is already releasing sofosbuvir at a knock down price ($2K per 24 week course) in poorer countries, so let’s hope the pricing of ledipasvir follows suit. If genotype-1 hepatitis C is now curable, we need to provide a cure for everybody.

524   Cervical cytology crept upon the world with no assessment of its effectiveness or efficacy, as Archie Cochrane pointed out in his 1973 classic, Effectiveness and Efficiency. It has probably saved many lives, but it is enormously inaccurate and resource intensive. Now at last there is a real prospect of it being superseded by screening for human papillomavirus. Investigators have now looked in detail at the long-term results of four large European trials comparing HPV based screening with conventional cytology. Their conclusion is that “HPV based screening provides 60—70% greater protection against invasive cervical carcinomas compared with cytology. Data of large scale randomised trials support initiation of HPV based screening from age 30 years and extension of screening intervals to at least 5 years.” Bring it on now.

533   Here’s a phase 3 trial, designed, run, and written up by ACACIA, manufacturers of pimavanserin, a selective serotonin 5-HT2A inverse agonist. Leaving aside what an “inverse agonist” might mean, the trial recruited 199 patients from 52 centres with Parkinson’s disease related psychosis. The duration of the trial was six weeks, of which two consisted of a washout period, and the comparator was placebo. So after dropouts (some due to new psychosis in the pimvanserin group), the trial assessed the drug in 89 patients for four weeks. In most patients, this drug appeared to provide some benefit compared with placebo and did not worsen motor symptoms in the short term. That’s it. I suppose that ACACIA hope this will suffice for the regulatory agencies to allow pimavanserin out on the market for this rather uncommon condition, and that indication-creep will then set in. It has happened before, which is why we are currently saddled with the most awful bunch of inadequately tested psychotropic drugs.

BMJ  8 Feb 2014  Vol 348
Most people agree that patients should be given full information about the treatment they receive, and the opportunity to share in decision making as far as they can or wish. On this basis, “shared decision making” is a basic human right, and as health professionals we have a duty to see that it happens. So far the audience nods and hopes. Then it comes to the detail, and the squirming starts. Personally, I have every sympathy with the squirmers, because in most contexts, we lack the skills, the time, and the tools to make “SDM” a reality. I think it is going to be many years yet before we are able to have truly informed and equal dialogue with patients. And we simply cannot predict what the consequences will be. The first in-depth roll-out of SDM happened in Dartmouth College (USA) over 20 years ago, and it was found that men with prostate-related symptoms who were given full information about their options often declined surgery: hence the cost of prostate treatment in that area fell. Enthusiasts have extrapolated this and other evidence to sell SDM as a method of cost saving in overprovided health systems. But it’s good to see this systematic review from Dartmouth redressing the balance, by showing that evidence for this is simply not good enough to make any predictions one way or the other about the effect of decision sharing on system costs. We need to do it because it is the right thing to do, not because it helps to contain costs.

If you suffer nightmares of being woken in the middle to the night to hold a retractor while getting soaked in blood, departing at dawn with a dead patient on the table, it’s probably because you were once a house surgeon who assisted at the repair of a ruptured aortic aneurysm. This condition still carries a mortality of between 35-40%, as shown in this important British IMPROVE trial of endovascular versus open repair for AAA. The result was a draw, though the accompanying editorial predicts a gradual move towards the endovascular technique. At least that way the houseman’s white boots are less likely to fill up with blood.

Looking after patients with end stage respiratory disease can be difficult and distressing. Palliative care involves the use of opioids and benzodiazepines, but many doctors worry that these may hasten death by causing respiratory depression. This is true of high doses only: a Swedish study shows that “lower dose opioids are not associated with increased admissions or deaths in patients with COPD and might be safe for symptom reduction in severe respiratory disease.”

Never mind the cobalt: how long is my new hip going to last, doctor? A Nordic database study concludes: “The survival of cemented implants for total hip replacement was higher than that of uncemented implants in patients aged 65 years or older. The increased use of uncemented implants in this age group is not supported by these data.” So a properly informed patient would probably opt for the more expensive prosthesis. Shared decision making can increase costs but improve the outcomes that matter to the patient. Which is why it is a good and necessary thing.

Plant of the Week: Sarcococca hookeriana var. digyna

The sarcococca or “Christmas box” family of shrubs contains a member called “humilis,” and they are all rather humble looking, with evergreen leaves and little tufts of flower in the middle of winter. This one has sharp ended leaves of deep olive green and its flower tufts are wonderfully scented of honey. Its stems are red and it usually stops short of a metre in height, though there is a new variety—which I haven’t seen—called “Purple Stem” which is alleged to grow a bit higher.

This is an imperturbable little plant which is easy to propagate. Years ago I planted a few of them down our lane in the hope that they would lighten the gloom of February with a pervasive smell of honey. But this year has been too windy for that to happen. You have to stoop close to enjoy them.

  • George

    That the HCV trial included people with cirrhosis makes it a bit special. I have, or rather had (touch wood) geno 3 and was in a trial of Sofosbuvir and GS-5186 (another Gilead drug). By the end of the trial, virus was undetectable, ALT and AST were 18, and, the best part, fibroscan score had dropped from 7.4 to 5.5.
    The only side effect was a somewhat inflamed throat followed by some respiratory infection over the first month (the treatment was only 8 weeks), after that I felt fine. I didn’t need Ribavirin (trial participants randomised to take Ribavirin did seem to have a hard time). I have a bit of follow-up yet before I can be officially cleared, but the odds look good. The best part may be that if this type of treatment doesn’t take the first time, there is probably little harm in trying it again; and that certainly wasn’t the case with interferon/Ribavirin.
    I’m a Pharma sceptic, never felt like trying interferon, but this treatment is indeed very likely to prove a breakthrough, and it’s great news that Gilead are licensing it to generic manufacturers.
    The hope is now that the technology used to identify these drugs will also work when applied to other viruses. A cure for HBV, or HIV, or HSV? We live in interesting times.