Richard Lehman’s journal review—3 February 2014

richard_lehmanNEJM  30 Jan 2014  Vol 370
There is very little in the print journals this week, and JAMA is taking a week out, so this seems like a good opportunity to switch over to including online first papers (marked OL) in these weekly reviews. I’ve threatened to do this before but never properly crossed the threshold. It introduces a certain complexity but offers you a few bits of fresher produce.

403   The Hebrew Bible contains some very odd books, notably the wildly erotic Song of Songs, and the book called Koheleth (the Gatherer) which says that life is essentially meaningless. Despite this grossly unorthodox position, Koheleth was kept in the Christian Bible (as Ecclesiastes) when that reached its present form in the fourth century. In these reviews, I try not to sound too much like the Gatherer (or Preacher), though there are a lot of topics which make me feel like him. “I have seen all the works that are done under the sun, and behold, all is vanity and vexation of spirit. That which is crooked cannot be made straight: and that which is wanting cannot be numbered… For in much wisdom is much grief: and he that increaseth knowledge increaseth sorrow.” Increased knowledge about childhood obesity in the USA increaseth sorrow. Most of it is fixed below the age of six. It gets more prevalent as you sink down the social scale until you get to rock bottom and hunger sets in. The Land of the Free is full of noble rhetoric and cheap food full of sugar and fat. Nobody seems to have the political will to do anything meaningful about it. All is vanity and vexation of spirit.

412   “In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12 month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of −2.0 or less at the lumbar spine, total hip, or femoral neck and −3.5 or more at each of the three sites).” Oh great. Another phase 2 study of a pricey monoclonal antibody to address the “epidemic of osteoporosis,” i.e. a pharma-driven epidemic of overdiagnosis in older women. With a nice surrogate end point: bone mineral density, which bears an oblique relationship to fracture risk. And, in a market crowded with competing cheap agents, a placebo comparator. Hail romosozumab! “In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma)” All is vanity and vexation of spirit, saith the Preacher.

433   The Preacher has an ambivalent relationship to biomarkers. A lot of them are jut vanity and vexation of spirit, but there are one or two—cardiac troponins being a prime example—that are of huge clinical value and redefine an entire condition, albeit at the potential expense of overdiagnosis. Systemic sclerosis is many thousands of times less common than myocardial infarction, but it is a very nasty disease without a diagnostic or prognostic marker. So full marks to the Dutch team who through proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. This study shows that careful and arduous science can bring real progress in medicine: “Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension.”

OL   The editor of the NEJM, Jeff Drazen, has sat on the fence for two years on the question of open data from interventional trials, but he now solicits your views on how long investigators should be allowed to hang on to their full datasets. Ah, but don’t send your views to him: you are advised to submit them instead to the Institute of Medicine feedback process, and await their considered verdict some time next year. Drazen obviously finds the fence quite a comfortable sitting place.

OL   And now for Idelalisib. Idly spit labials and split sibillants with lisping siblings. You may or may not want to master this word. It denotes an orally-available last-ditch drug for relapsed indolent lymphoma or relapsed chronic lymphatic leukemia, featuring in two trials funded by Gilead Pharmaceuticals. “Wall Street Salivates” was the headline when these appeared. This is not a side-effect mentioned in these single-arm studies. And is a drug that might make billions for Gilead good news for health systems and for people dying from these diseases? All is vanity: we need a new model for developing affordable cancer drugs, saith the Preacher.

OL   When the latest rotavirus vaccines (RV1 and RV5) underwent their first large scale trials, everyone was keeping a careful lookout for an increase in intussusception, which had led to the withdrawal of previous vaccines. The all-clear was sounded cautiously, and millions of American babies received the vaccine, saving many hospital admissions and possibly a few deaths. This study looks at 507,874 first doses and 1,277,556 total doses of RV5 and 53,638 first doses and 103,098 total doses of RV1. So was that all-clear justified? Sort of: “RV5 was associated with approximately 1.5 (95% CI, 0.2 to 3.2) excess cases of intussusception per 100,000 recipients of the first dose. The secondary analysis of RV1 suggested a potential risk, although the study of RV1 was underpowered. These risks must be considered in light of the demonstrated benefits of rotavirus vaccination.”

Ann Intern Med  21 Jan 2014  Vol 160
111   I keep mentioning implantable cardioverter defibrillators in these reviews, partly because they keep coming up in the literature, but also because I am worried by them. I will spare you the detail of this systematic review of ICD effectiveness for primary prevention of sudden cardiac death across subgroups by sex, age, New York Heart Association class, left ventricular ejection fraction, heart failure, left bundle branch block, QRS interval, time since myocardial infarction, blood urea nitrogen level, and diabetes: but the bottom line is that for none of these groups taken alone can it be shown that ICDs are of any benefit at all. It is only if you aggregate them that you can show an effect. This tells you two things: that their benefit is very small, and that you cannot predict if implanting an ICD is going to help the patient in front of you. So it seems to me that these devices should be reserved for the tiny minority of patients who have a strong theoretical preference for being kept alive at any cost rather than running a risk of dying suddenly and painlessly.

At present, more than 100,00 ICDs are fitted to American patients every year. You can read about dying with one in situ in a commentary from JAMA Intern Med.

JAMA Intern Med  Jan 2014  Vol 174
I am belatedly bringing you a couple of items which appeared in the paper monthly three weeks ago, together with a couple posted on the website since then. From now on, I hope to keep a weekly flow. I find this the most challenging of the journals to review, because its papers tend to reflect the real priorities and uncertainties of clinical care, and its commentaries tend to be thoughtful pieces written by committed clinicians. All that can be hard to boil down into a few sentences.

70   In the UK, the standard drug for preventing alcohol withdrawal symptoms is the old-fashioned benzodiazepine, chlordiazepoxide. I haven’t needed to take any myself yet but I get the impression it is fairly effective. From a trial in 150 people described here, it seems that gabapentin might be a useful alternative for acute withdrawal, and given regularly at 1800mg daily it might be more appropriate for preventing a relapse and encouraging harm reduction.

90   A study of FDA drug approvals in 2008 nicely complements the Yale study that subsequently appeared in JAMA itself. Thomas Moore and Curt Furberg find that “for new drugs approved by the FDA in 2008, those that received expedited review were approved more rapidly than those that received standard review. However, considerably fewer patients were studied prior to approval, and many safety questions remained unanswered. By 2013, many postmarketing studies had not been completed.” An associated commentary asks, “Can Expedited FDA Drug Approval Without Expedited Follow-up Be Trusted?” But the real question should be “Should People be Exposed to Drugs with Unknown Harms and Benefits?” because all this “post-marketing” stuff is really human experimentation without informed consent; and it isn’t even mandatory to do it properly.

OL  I’ve never really had time for meditation as a deliberate activity, though I guess we all meditate when we are in the bath, or walking, or sitting through a boring lecture. Does this do us good? I’ve no idea. This meta-analysis looks at “meditation” as a generic intervention for anxiety, depression, or pain and finds that it has a slight benefit. I suspect very few people who advocate meditation will have any truck with this sort of lump-’em-together review. Isn’t meditation just part of a transformation of life and a reordering of consciousness that most of us feel drawn to but never really achieve? For me, meditation is easily induced by plainchant, or the prolonged alap of an extended raga, but I fear I shall never be a monk or an Indian musician. Yeats, though he was tone-deaf, was fascinated by these states. Of dancers, he wrote “They know not what they know/ But know not grief.”

OT   When you start somebody on medication for “hypertension,” do you calculate their overall cardiovascular risk and explain the benefit of treatment in absolute terms such as a number-needed-to treat? Of course not, because even if you wanted to, you wouldn’t be able to find a suitable tool and you might lose QOF points. That’s how good we are at being patient-centred doctors. And if that’s awful, turn to the domain of “chronic kidney disease,” as Ken Covinsky and colleagues do in this analysis. Even if you can extrapolate accurately from the clinical trials to the elderly patient in front of you (which, by the way, you can’t), you would find NNTs in excess of 100 for any treatment you might give them in order to prevent end-stage renal failure, unless they are on the brink of it already. This is where tunnel-vision interpretations of “evidence-based” medicine have got us.

Lancet  1 Feb 2014  Vol 383
413   Strictly for Stent War enthusiasts and pharma-watchers only: “Third generation zotarolimus eluting and everolimus eluting stents in all comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single blind, multicentre, non inferiority trial.” “Both stents were similarly efficacious and safe, and provided excellent clinical outcomes, especially in view of the large number of patients who presented with acute myocardial infarctions.” It’s beyond parody. Is this an academic paper or an advertisement?  Do I need to tell you that his trial was sponsored by the makers of the two stents?

OL   This study appeared on The Lancet website on 9 December 2013. It uses data from 22 European cohort studies to examine the association between natural cause mortality and long term exposure to several air pollutants, and I’m pointing you to it now because it relates to two studies that appear in the BMJ this week. You don’t need to live in Beijing for air pollution to cut your life short: “Long term exposure to fine particulate air pollution was associated with natural cause mortality, even within concentration ranges well below the present European annual mean limit value.”

OL   Wanted: a pharma-sponsored trial that doesn’t push a pharmaceutical intervention. Found: an analysis of NAVIGATOR that dwells on the dose related benefits of daily activity in individuals at high cardiovascular risk. Thank you, Novartis. See, I can be nice to a drug company.

OL   What happens to people in South Africa who have extensively drug-resistant tuberculosis (XDR-TB) once they have left hospital? An intensive cohort follow-up study of 107 patients found that within five years, three-quarters of them had died, irrespective of HIV status. How much XDR-TB they had passed on to others is not known, nor how they spent their last days. This hardly bears thinking about.

OL   “We used data from national registries on consecutive patients registered between 2004 and 2010 in all hospitals providing care for acute coronary syndrome in Sweden and the UK. The primary outcome was all cause mortality 30 days after admission.” I really wouldn’t have predicted the result of this comparison: 30-day mortality was 7•6% (95% CI 7•4—7•7) in Sweden and 10•5% (10•4—10•6) in the UK. One factor driving this may be the finding that “in Sweden, compared with the UK, there was earlier and more extensive uptake of primary percutaneous coronary intervention (59% vs 22%) and more frequent use of β blockers at discharge (89% vs 78%).” If a country with such a scattered population as Sweden can achieve such a good rate of primary PCI, what excuse do we have in the UK?

OL   And yes, I can’t fail to mention the Cambridge peanut allergy trial in this quick catch-up of Lancet online articles. Most kids with peanut allergy can be safely desensitized with tiny incremental doses of peanut. But, as the investigators warn, do not try this at home.

BMJ  1 Feb 2014  Vol 348
An article about air pollution in Beijing expresses the harm as years of life lost (YLL), but the message tends to get lost in a heavy smog of data. The European cohort study known as the ESCAPE project is a little less foggy but essentially repeats the message of the earlier Lancet study in finding that levels of pollution below those normally considered harmful are associated with an increase in coronary events.

If you are a woman with a history of CIN3 on any smear during your life, your risk of cervical or vaginal cancer rises steeply with age. This is dramatically demonstrated in Figure 1 of this whole-population Swedish analysis. For these women, gynaecological vigilance can’t ever be relaxed.

Plant of the Week: Mahonia japonica

This can be a great brute of an evergreen shrub, covering 3 or 4 metres in every direction. Or you can keep it genteel with the greatest of ease by cutting it back anywhere during the first half of the growing season. It will flourish anywhere, in dry shade or in full sunshine, in bad soil or good, and you will adore it winter for its great spikes of soft yellow flowers, carrying a heavy scent of lemon and lily-of-the-valley.

Just be slightly careful though if you have no eye protection, because as you bend forward to enjoy its fabulous perfume, you may impale your cornea on a spike from its prickly leaves. They look quite handsome and innocent but they can be quite malicious. Otherwise this is a garden plant which comes close to attaining perfection in every department.