Richard Lehman’s journal review—13 August 2012

Richard LehmanJAMA  8 Aug 2012  Vol 308
575    When Stephen Lock was editor of the BMJ, he banned the expression “further research is needed” on the grounds that further research is always needed. Here is a piece by John Oiannidis which argues that further research is very often badly needed—and that it is very often instantly achievable, simply by using data that has already been collected. But to do that, researchers need to know where the data are to be found, and to have automatic access to it. The rather clunky title of this essay, “The Importance of Potential Studies That Have Not Existed and Registration of Observational Data Sets,” does little justice to a powerful discussion of issues that lie at the very heart of the coming revolution in research methodology. We are—I hope—on the verge of an era where all data from every human trial ever carried out will be available to any researcher; and more than that, an era when every clinical encounter will in principle be available for analysis after the removal of patient identifiers. As Ioannidis points out, much of this is already possible and is not being done. The “potential studies that have not existed” which he refers to are investigations that could settle contentious issues—if only people would take the trouble to look at datasets that are already in existence.

(Note for pedants: I have deliberately used “data” both as a plural and as a singular in two sentences, because this is common practice. I bet that within ten years, data will have followed “media” and become uniformly singular. Personally, I don’t like it; but that’s language for you. It’s like a bacteria. Neuter plurals counted as singular in ancient Greek.)
581    Here’s another significant insight into the enigma that is labelled “type 2 diabetes.” We all know of people who have this condition despite being of normal weight (BMI less than 25), and in fact in the five large cohorts looked at here, the proportion of subjects with normal BMI at the time of onset of diabetes varied between 9 and 21%, with a mean of 12%. The striking finding of this analysis is that these individuals have a doubling of mortality risk at 15 years compared with overweight or obese individuals with T2DM. And oddly enough, this is mainly accounted for by non-cardiovascular causes of death.

591    But now for a really puzzling observation: between 1988 and 2006, the mean level of total cholesterol in American children has declined. During this period, US kids aged between 6 and 19 have become fatter and less active. I don’t know what can account for this, and nor does the writer of the editorial that accompanies it, except to call it a reason for optimism.

NEJM  9 Aug 2012  Vol 367
495    Janus was the Roman god of doorways and transitions, famous for facing both ways at the same time. Janus kinases (JAK) are an interesting group of intracellular enzymes in the cytokine pathway, which have nearly identical phosphate-transferring domains on either side: one exhibits the kinase activity, while the other negatively regulates the kinase activity of the first. Very neat, and rather like the editor of a medical journal who faces one way and accepts papers from the pharmaceutical industry which will bring in hefty reprint revenue, and facing the other way, insists on high standards of reporting and disclosure. Let’s see how this works out with this RCT of tofacitinib, a novel oral Janus kinase (JAK) inhibitor produced by Pfizer that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. The 6-month placebo-controlled trial “was sponsored by Pfizer and was conducted in 94 centres worldwide from February 2009 through June 2010.” Pfizer gathered and analyzed the data, and “under direction from all the authors, the first draft was written by an employee of Complete Medical Communications, who was funded by Pfizer.” As a non-expert in scoring systems for RA, I can make absolutely nothing of the findings of this trial. The comparator was placebo, on the grounds that “biologic” or DMARD treatment had already failed, and by my reckoning the duration was at least five times too short to offer clear conclusions about efficacy or safety. “Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts.”

508    In a parallel trial, Pfizer tried comparing tofacitinib with adalimumab in rheumatoid patients already receiving methotrexate. This time the duration was 12 months: once again, all the authors were either Pfizer employees or had received payments from Pfizer. The two treatments turned out to be roughly equivalent in terms of clinical benefit, and adverse effects were slightly greater with tofacinitib, especially infections (two with TB). So from these two traditional, high-cost, multinational phase 3 pharma-funded trials, we can conclude that the new Pfizer drug is approximately as good as an existing agent, but with stronger signals of long-term harm. I suppose that at this point, it’s over to the FDA, the European Medicines Agency and other licensing agencies to decide whether to allow it on to the market.

542    The diagnosis of type 2 diabetes is a matter of crossing an arbitrary glycaemic threshold, which you could logically set at any point higher than about 5 mmol/L of fasting glucose. You could argue for 5.3, as the point at which “diabetic” retinopathy starts to become less rare, or 6, as the point at which glucose becomes a significant contributor to cardiovascular risk, or 7, because that marks the point at which progression to beta cell failure becomes common, or some value a bit higher, based on likelihood of benefit from glucose-lowering therapy in different subgroups. In this article, Silvio Inzucchi presents conventional arguments for the present threshold, mostly derived from UKPDS, and then extrapolates these into a rather diffuse case for universal screening at the age of 45 or thereabouts. “The identification of patients with diabetes or prediabetes by screening allows for earlier intervention, with potential reductions in future complication rates, although randomised trials are lacking to definitively show benefit.” OK: so what does that suggest? See you in ten years, when you have some evidence.

Lancet  11 Aug 2012  Vol 380
565    One way to push people over the arbitrary threshold of 7.0 mmol/L fasting glucose is to give them a thiazide diuretic: another is to give them a statin. They are then officially “diabetic,” but does that mean that they are condemned to progressive beta-cell failure? In the case of thiazides, the answer is simply no. In the case of statins, we don’t know: but we do know that the cardiovascular benefits of continuing the drug easily outweigh any negative effects from hyperglycaemia. This analysis of data from the JUPITER trial confirms that this applies across the glucose range, including people at high risk of diabetes.

572   I tried counting the authors of this celebrated mendelian randomisation study of plasma high density lipoprotein cholesterol and myocardial infarction, but I had to give up due to vertigo. There must be about 120. If you believe them, there is no likelihood of any causal link between HDL-C levels and protection from MI. If you don’t believe them, you can start all over again: perform two mendelian randomisation analyses. First, use as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and test this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, use as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and test this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, also test a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.

581   You’ll note that the preceding study did confirm that LDL-C is causal in adverse cardiovascular events; and only LDL-lowering strategy that we know to prevent CV events is statin therapy. Now there are three camps where statins are concerned: the “put them in the water supply” camp at one extreme, and the “treat to target” camp at the other, and half way between the “treat to risk” camp. This meta-analysis of individual data from 27 randomised trials confirms that statins lower cardiovascular risk at all levels, with the most pronounced effect of course at the top of the risk scale. Some friends of mine would argue that statins taken from the age of say 16 would prevent atheroma altogether; others among my friends rail at the mass medication of society and seem to wish that statins had never been invented; I myself think they should be offered to everyone above some arbitrary age, say 50. In their editorial, Shah Ebrahim and Juan Casas appear to agree, though their last paragraph does offer the tempting alternative of moving to Mauritius.

591    The management of “hypertension” in primary care is one of the most boring jobs we do, and I fear we don’t do it very well. Most of the individuals who trudge regularly into our surgeries every six months gain no benefit whatsoever from the drugs we give them—the number needed to prevent one stroke is typically 100-400—and most of the time we don’t even measure their BP adequately anyway. We medicate the herd for small benefit, while often struggling with the patients at highest risk. Fortunately most of the drugs we use are cheap and safe, but the market is so huge that drug companies continue to develop new drugs which might work for some subgroups of patients with resistant hypertension. This review usefully lists them, but the real revolution is likely to come from a different direction—devices and procedures which permanently reset the sympathetic nervous system. In ten years’ time, I wouldn’t be surprised to see renal sympathetic denervation becoming a routine procedure: or will it be continuous carotid stimulation?

BMJ  11 Aug 2012  Vol 345
In theory, annual screening for chlamydia in the whole population at the ages of greatest prevalence ought to reduce the disease burden. This Dutch trial shows that it doesn’t, because so few invitations for screening get taken up by 16-29 year olds.

In laboratory tests of platelet function, proton pump inhibitors cancel out the effect of clopidogrel because they inhibit the P450 2C19 enzyme. So if you look at a cohort of people who are taking clopidogrel (with aspirin) you might expect to find a higher rate of coronary events in those who are also taking a PPI. And in fact, as this study from the UK GP Research Database shows, there is a 30% or so higher risk in this group, if you look at the cohort as a whole. In fact there is an even higher risk difference in non-vascular death, which begins to make you wonder whether there is something else going on in these people who are taking PPIs. Maybe the groups are not comparable: and the cunning authors then go on to test this hypothesis by looking at them within individual differences in CV outcomes during periods on and off PPI treatment. Here the effect direction is reversed. This is intriguing, and probably means that most people can take clopidogrel and PPIs together with impunity: but there are some loose ends here. Somebody needs to repeat this exercise using another database, looking more precisely at the individual clinical reasons for co-treatment with PPIs, aspirin and clopidogrel.

The most important contribution to this week’s BMJ is undoubtedly an analysis by Donald Light and Joel Lexchin of the truth behind the “innovation crisis” in the pharmaceutical industry. They demonstrate that it is a widely touted myth, aimed at putting pressure on regulatory agencies to help the poor ailing industry by setting a lower bar for licensing new products. In fact only one in ten products has any added clinical value, whereas the FDA is currently granting “priority status” to 44% of new drugs. The remaining 90% simply drive up health costs without adding benefit, and most industry effort is put into developing such me-too drugs. And this is a highly successful business model: pharmaceutical R&D budgets rose by $34.2bn between 1995 and 2010, while profits rose by $200bn.  The pharmaceutical industry could innovate if it had the incentives to, and indeed does do so one time in ten: but most of the time it is creaming off easy money from health systems that can ill afford it.

Plant of the Week: Clematis “Arabella
We went shopping for late-flowering clematis at Wisley last week. The prices are outrageous, but there is a display of different clematis varieties stretching 100 meters or so, all well grown and most of them in flower. So we filled a trolley and trundled to the pay station, trying not to look at the till receipt afterwards.

This “herbaceous” clematis really stands no chance in our garden, where the soil is more or less entirely composed of clematis wilt spores. That’s why we normally only try to grow varieties of montana  or viticella which are largely wilt resistant. We have already killed at least one of Arabella’s parents, C durandii, and perhaps her lovely pale soft blue-grey flowers will never be seen again once we have placed her carefully amongst our slugs and spores. At the moment these subtle blooms are giving us pleasure as she stands in her pot, wafting a subtle fragrance. Soon she will go to meet her doom, optimistically placed among the large herbaceous plants she is meant to straggle through in years to come.