Richard Lehman’s journal review—20 January 2014

Richard LehmanNEJM  16 Jan 2014  Vol 370
201    Developing and marketing a new drug is a tricky business, but it can be a very lucrative one. AiCuris is a company I hadn’t heard of before, but it seems to specialize in antiviral drugs. For such a company, herpes simplex 2 infection presents a huge market opportunity: people with genital herpes have moderately effective drugs to use for flare-ups, but they would all like to think there is a cure on the horizon. This trial of a new helicase-primase inhibitor, pritelivir, “was designed as a randomized, parallel, double-blind, placebo-controlled study by investigators at the University of Washington and by the sponsor, AiCuris.” It is a nice piece of investigational science which tells us a lot about the daily shedding pattern of HSV-2 but nothing about the clinical utility of pritelivir. “Pritelivir reduced the rates of genital HSV shedding and days with lesions in a dose-dependent manner in otherwise healthy men and women with genital herpes.” A nice thing to have the NEJM say about your drug: but what else might it do these otherwise healthy men and women when taken long-term; and how does it compare with, say, daily aciclovir? Does this reduction in shedding actually have any clinical significance? At what point should the FDA release it for use on the general population? What should the end points be, and what should be the duration of the next trial? I think these issues should be a matter of public debate, and not a matter for AiCuris to decide. Same with all new drugs. It is we who will be using them, we who will pay for them, and we who stand to be harmed by them.

233    I am confused by the occasional glimpses that I get into the epidemiology of type 2 diabetes, and if I ever got the time I’d like to look in detail at the types of evidence and what they show. This latest lot of data come from those two famous cohort studies, the Nurses’ Health Study (all female, all nurses) and the Health Professionals Follow-up Study (all male, mostly doctors): no gender stereotyping there, then. In 2012, a study of several different and smaller cohorts published in JAMA showed lower mortality in people who were obese at the time of diabetes diagnosis; but in these much bigger cohorts, no such relationship is found in people who developed diabetes under the age of 65. Up to this threshold, the more obese you are, the higher your risk of (a) getting diabetes and (b) dying prematurely. I’ll leave you to do your own delving.

JAMA  15 Jan 2014  Vol 311
252   The huge VISTA-16 trial was designed by Anthera Pharmaceuticals to showcase its new antiplatelet agent, varespladib. 5145 patients were recruited from 362 academic centres around the world, and received either varespladib or placebo within 96 hours of an acute coronary event. Towards the end of the second year, the trial was stopped because the difference in coronary events, stroke and cardiovascular mortality was moving significantly in favour of placebo. That’s not fair. “Varespladib methyl is a nonspecific pan-sPLA2 inhibitor with favorable effects on atherosclerotic lesions in animal studies. Initial studies demonstrated that varespladib reduced levels of sPLA2-IIA by more than 90%, in addition to lowering low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) in patients with stable coronary disease and ACS.” So what does this tell us, folks? Never rely on animal models and surrogate markers.

263   I’ll put in a shout here for the primary care department at Oxford University, which ran the FACS trial. A team headed by David Mant supported a surgical principal investigator to study the effect of scheduled blood measurement of carcinoembryonic antigen (CEA) and computed tomography (CT) as follow-up to detect recurrent colorectal cancer treatable with curative intent. This is a really useful study to guide the follow-up of patients who have undergone bowel cancer surgery with apparent success. “Intensive imaging or CEA screening each provided an increased rate of surgical treatment of recurrence with curative intent compared with minimal follow-up; there was no advantage in combining CEA and CT. If there is a survival advantage to any strategy, it is likely to be small.”

271   My take on coronary calcium scoring is simple: if you are worried enough to think about it, just swallow a statin every night and take more exercise. But like the medieval theologians who supposedly argued about how many angels could fit on the end of a pin, the coronary artery calcium scorers have taken to arguing about how thick the calcium needs to be. Bizarrely, the thinner the calcium, the more dangerous it seems to be. You can read the full paper for nothing. But you’d be better off going for a walk and eating an orange.

279   This British study looks at a set of individuals who are genetically programmed to run at a higher “normal” level of blood glucose than the rest of us, because they carry heterozygous, inactivating glucokinase (GCK) mutations. They run at a mean HbA1c of 6.9% and provide an interesting insight into the long-term significance of high sugar in isolation: “Despite a median duration of 48.6 years of hyperglycemia, patients with a GCK mutation had low prevalence of microvascular and macrovascular complications.” By contrast, a cohort of similar age who had developed type 2 diabetes of youth had a horrific rate of macrovascular and microvascular complications. There is so much more to “type 2 diabetes” than sugar.

Lancet  18 Jan 2014  Vol 383
219   This trial of cognitive behavioural therapy for “health anxiety” was an enormous undertaking: “Of 28 991 patients screened, 444 were randomly assigned to receive either adapted cognitive behaviour therapy (CBT-HA group, 219 participants) or standard care (standard care group, 225).” The screened patients were attending cardiology, endocrine, gastroenterology, and respiratory medicine clinics in six English general hospitals. Those who were allocated CBT received a mean of six sessions and their improvement was measured as 2•98 points greater than in those in the standard care group. Without examining the score in detail, the reader really has no idea what this means. But only 13.9% of the CBT patients attained “normal” levels of health anxiety, whatever they may be. I am lost. Perhaps this is a good use of CBT, perhaps it isn’t. Maybe we should go about reducing British health anxiety in other ways—for example, by shutting down certain newspapers.

226   A cluster randomised trial of using the Liverpool Care Pathway for patients at the end of life in Italian hospitals produces no clear result. The accompanying editorial looks at the whole sorry process of incentivizing and then abandoning the LCP in UK hospitals: “The goal of any national policy initiative is to improve health outcomes. A decade after widespread uptake, which part of government should take responsibility for the widespread policy imperatives informed by the results from studies of LCP: politicians, bureaucrats, clinician advisers, or all three groups? The results of the only adequately powered study of LCP so far have not shown clinically meaningful differences for patients—the ultimate measure of useful health policy. Looking to the future, there is a need for government and other funders to be far more willing to fund research into health services that can inform policy and for many more senior clinicians to contribute to shaping national clinical policies.” Oh wow: you mean an NHS run by responsible adults and not for the sake of political soundbites? I rub my eyes.

257   The Lancet‘s invaluable series on research waste draws to a close with two papers, one on unpublished research and the other on incomplete or uninterpretable research reporting. Wonderful stuff which combines the insights of many of those I admire most. In an accompanying editorial, two of The Lancet‘s editors come close to confessing that they are part of the problem, running a “luxury journal” which perpetuates the current absurd model of career advancement through selective publication in prestige journals. “On the basis of the evidence we present in this Series, a far broader question should be posed: how should the entire scientific enterprise change to produce reliable and accessible evidence that addresses the challenges faced by society and the individuals who make up those societies?” In the next few weeks, a new group will start seeking answers to this question—the Campaign for Real Evidence Based Medicine. Watch this space.

BMJ  18 Jan 2014  Vol 347
You have to be very old to remember the fibre needle. It was used to play shellac discs revolving at 78rpm on machines which produced sound by mechanical amplification. I am reminded of them by this systematic review of dietary fibre intake and cardiovascular disease. As far as I am concerned, this is just another case of medieval theologians counting angels on the head of a fibre needle. In the real world, we eat food, not fibre. Things that we know are good for the heart, like fresh fruit and vegetables, happen to contain a lot of cellulose. This counts as insoluble fibre—or is it soluble?—who cares. If you want the theology, turn to an editorial which worries about people not eating enough brown rice. If you want a life, go for a walk and eat an orange. Play some 78s. Drink wine. Eat fish. Dig the garden, using plenty of fibre as compost, because this is the best way for fibre to help your heart.

The Clinical Practice Research Dataset is a wonderful resource, but it has produced some distinctly odd and sometimes contradictory analyses. Case-control studies based on the CPRD need to be taken with a pinch of salt. This one appears to show that sodium-containing formulations of drugs increase mortality in those who take them. How you can adjust for all other variables escapes me.

If you don’t even know the number-needed-to-treat for an intervention, versus the number-needed-to-harm, how can you possibly share decision making with your patient? But knowledge of the NNT and NNH is only the first step towards proper decision making, because these figures do not apply to the individual in front of you, but are simply an aggregate from trial populations. And how reliable is this information anyway? A study of systematic reviews about harms from treatment reports that, “Systematic reviews compound the poor reporting of harms data in primary studies by failing to report on harms or doing so inadequately. Improving reporting of adverse events in systematic reviews is an important step towards a balanced assessment of an intervention.” We cannot share decisions properly without better evidence. We need a Campaign for Real EBM centred on what will help us to inform people properly about what we propose to do to them.

There are two really useful therapeutic reviews this week: one on supporting smoking cessation and the other on neuropathic pain. Perhaps one can learn from the other. For smoking cessation, adding one intervention to another does not improve results, but increases adverse effects. For neuropathic pain, we need to ask whether most patients really benefit from carrying on with a cocktail of all the drugs anybody anywhere has thought of giving them. It seems to me that for many the treatment burden exceeds the value of the treatment.

Plant of the Week: Gardenia jasminoides

There is no scent quite to equal that of a gardenia, which used to be a popular buttonhole flower or house plant. You can still buy small pots of gardenia from Ikea and other places, though they have mostly given place to scentless orchids with long-lasting gaudy flowers.

New Zealand is a great place to enjoy gardenias, where the equable climate allows them to flower for most of the year. They are plants for shade rather than full sunshine. Last year we nearly bought an allegedly hardy gardenia for our garden—the variety known as “Kleim’s Hardy.” It would have been a good time to try it, given the mildness of this year’s winter. Generally speaking these evergreen shrubs classed as “hardy zone 8” invariably die in a cold winter when young, but sometimes survive if they have had a year or two to establish.

In the meantime, enjoying the gardenia smell might require another trip to Ikea for a house plant. Could anything possibly be worth the agony?