Richard Lehman’s journal review—8 June 2015

richard_lehmanNEJM 4 Jun 2015 Vol 372
2185 If you are the sort of exciting doctor who looks after adults with acute hypoxaemic respiratory failure, here is just the article you need. It’s a French trial comparing the effect of high-flow oxygen therapy, standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation. The three procedures did not result in significantly different intubation rates, but the patients given high-flow oxygen were twice as likely to survive to 90 days.
2197 Three trials that should have halted the overtreatment of stable type 2 diabetes appeared in the NEJM 6-7 years ago. One of them was the Veterans Affairs Diabetes Trial which showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). This paper by Rod Hayward and team reports the extended follow-up of the study participants. “After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival.” Another set of information to feed into decision aids for people with type 2 diabetes. But beware: these data apply just to this population and to the specific drugs they were given.

OL While we are on the subject of surrogate end-points, let’s look at the latest paper to appear on the NEJM website, which is the second trial to reveal a small beneficial effect of ezetimibe when added to a simvastatin 40mg, this time in patients following an acute coronary event. After seven years, the benefit is tiny but just within the limits of statistical significance, with a hazard ratio of 0.94, 95% CI 0.89-0.99. Clinically this has no meaning at all since the same degree of LDL-C lowering could have been achieved by using 40mg of atorvastatin instead of simvastatin. But the NEJM greets it with a triumphalist commentary by two staff editors entitled “Proof That Lower Is Better—LDL Cholesterol and IMPROVE-IT“, ending with “Perhaps the LDL hypothesis should now be considered the ‘LDL principle.'” Well, IMPROVE-IT is a pretty shaky pedestal on which to mount a principle. The rush to proclaim it derives, I suggest, from the pharmaceutical industry’s desperation to repeat the success of statins with new blockbuster drugs based on the surrogate measure of LDL-C lowering. And it’s interesting that the NEJM goes out of its way to support this, while it prints a series of pieces denying the pervasiveness of industry influence.

OL I’ll just pick one more paper out of the formidable list that is building up on the NEJM website. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. Now, as I pointed out a couple of weeks ago, there are a lot of zumabs out there, and elotuzumab is just the latest to be used in multiple myeloma. So the proper function of a high-ranking medical journal should be to ensure the data on this latest open-label trial are well reported and fitted into the overall context of new therapies for MM. The conclusion of the abstract makes a striking claim: “Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death.” Just how much of this paper was written by the named authors is unclear. “Professional medical writers who were paid by Bristol-Myers Squibb contributed to the preparation of the manuscript and are not listed as authors.” A Kaplan-Meier plot for progression-free survival is provided, but to find out about the claimed 30% reduction in death you have to go to the text. “Follow-up data regarding overall survival are not yet mature enough to represent in graphical form. However, there were 210 deaths (94 of 318 [30%] in the elotuzumab group vs. 116 of 317 [37%] in the control group), which represent 49% of the 427 deaths that are prespecified for the final analysis.” I read this as meaning that so far the absolute reduction in death is 7%, which doesn’t need confidence intervals because the authors (many of them unnamed) would like us to wait until a further prespecified number of people have died. And yet their abstract summary makes a claim for 30% relative reduction in death. The editor of the NEJM has warned you: don’t go by the affiliations of the authors, go by the quality of the science and the reporting. And by the way, because this was an industry-funded cancer trial it’s OK for it not to have been blinded.

JAMA 2 Jun 2015 Vol 313
2133 A German study of ischaemic preconditioning to prevent renal injury during cardiac surgery was so keen on double-blinding that it actually set up a sham procedure for cuff insufflation in patients who were already under general anaesthetic. I guess there were no conflicts of interest either because there is little money to be made from repeatedly squeezing someone’s arm to a pressure of 200mm of mercury. It’s little short of miraculous that this does indeed protect the vulnerable kidney at a time of reduced perfusion. The trial was well-conducted and is modestly reported, which also seems rather miraculous. Although the relative reduction in renal replacement therapy was 272%, it is reported as an absolute reduction of 10%. And the authors (real ones this time) don’t call for immediate clinical adoption but simply state that ” The observed reduction in the rate of acute kidney injury and the need for renal replacement warrants further investigation.”

2142 The class of antidepressants which purport to work by inhibiting serotonin reuptake are having a bad press at the moment. They are certainly of limited effect and have unpleasant withdrawal effects in many people, but fears that they may cause persistent pulmonary hypertension of the newborn if taken late in pregnancy are somewhat allayed in this study of 128 950 women who took them under Medicaid in the USA. The odds ratio for PPHN after taking SSRIs in late pregnancy is 1.28 which is lower than previous estimates and only just significant (95% CI, 1.01-1.64).

JAMA Intern Med June 2015
Obstructive sleep apnoea has a lot to do with the size and collapsibility of the upper airway. For sleeping partners, the big problem is the snoring: for those who have the condition it’s the daytime sleepiness, not to mention a more than threefold risk of cardiovascular events and stroke. Definitive treatment with continuous positive airways pressure only has a modest effect on this risk though it does have a big effect on daytime sleepiness. As for mandibular advancement devices, a small Swedish trial shows that they are probably not worthwhile even when they are adjustable and custom-made. Over four months, they did reduce recorded episodes of OSA and snoring but had no effect on daytime sleepiness and quality of life.

Ann Intern Med 2 Jun 2015 Vol 162
765 “Screening for diabetes did not improve mortality rates after 10 years of follow-up. More evidence is needed to determine the effectiveness of treatments for screen-detected diabetes.” This is the conclusion of a systematic review for the U.S. Preventive Services Task Force on screening for type 2 diabetes mellitus, and is in line with the definitive UK randomized trial carried out by Simon Griffin. It also accords with the fact that we know very little about the long term effects of glucose-lowering therapies. You can read this thorough review in full, since it is open access.

Lancet 6 Jun 2015 Vol 380
2255 In the last couple of years, David Cameron has got passionate about dementia. Now a passionate Cameron is not just an embarrassing sight but often portends harm. For a while, GPs were given £50 per person diagnosed with dementia. There is still a push for “case-finding” which seems oddly like the screening which is no longer being pushed. So what then? Referral to an overbooked memory clinic followed by unnecessary drugs or a pat on the head? Nobody really knows. A Finnish randomized trial tried out a comprehensive intervention for people with mild cognitive impairment which was arduously invasive in the domains of diet, physical exercise, and cognitive training. These elderly Finns certainly had plenty to do through the long winter nights. As a result they fared better than the control group, especially for processing speed, and least for memory. Since the government is calling for £30 billion in NHS savings, the way forward is clear: send all elderly people with cognitive impairment to Finland.

2264 Statins are wonderful drugs which have saved millions of lives. Statins are potentially harmful drugs which are taken by millions of people who will never benefit from them. Both these statements are true. You don’t have to take sides in the “statin wars,” and it helps nobody if you adduce all the evidence you can for one statement or the other, and then shout boo from the top of your preferred heap. And genetics is not going to come to the rescue with a definitive map of everybody’s cardiovascular future written in DNA. But it may help to advise individuals of their ball-park risk reduction from taking a statin. A look at genetic variants among participants in the major statin trials finds that there were: “greater absolute risk reductions in those individuals in higher genetic risk categories (p=0•0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT.”

2280 So are we creeping towards a future where everyone will be genotyped before being given any drug? I guess this is now just a decade or three away, once it becomes affordable on a population level. You will of course remember the ENGAGE AF-TIMI 48 trial. It was a randomised, double-blind trial in which patients with atrial fibrillation were assigned to warfarin or one of two doses of edoxaban. Looking at the trial data, investigators now find that the CYP2C9 and VKORC1 genotypes identify patients who are more likely to experience early bleeding with warfarin and who derive a greater early safety benefit from edoxaban compared with warfarin. There you are.

BMJ 6 Jun 2015 Vol 350
Varenicline is probably the best oral agent for helping people to overcome nicotine addiction, though the much cheaper parent agent cytisine may be just as good. These drugs are partial agonists of the nicotinic acetylcholine receptor, simultaneously relieving withdrawal symptoms and decreasing rewards from smoking. From the start there have been reports that they may mess with your brain in less welcome ways. Between 22 November 2006 and 31 December 2009, 43 861 women and 25 896 men were treated with varenicline in Sweden. This excellent analysis compared the risk of suicidal behaviours, criminal offending, psychiatric disorders, transport accidents, and traffic related offences for each individual during the period they took varenicline and the rest of that three year period. They found no increase except a small one for exacerbation of pre-existing psychiatric conditions.

In an analysis piece, the Cochrane Collaboration comes under fire from within its own ranks, both for what it has never attempted to do and for what it does imperfectly. It’s actually a very incomplete catalogue and the solutions it proposes are also imperfect. But I must declare an interest: I am now luckily a part of Cochrane UK for half a day a week. And I’m a signatory to a letter responding to this analysis, which will soon be on the BMJ Rapid Response site. So I will say no more about it. But I’d like to draw your attention to the fabulous blogs that are put out by Sarah Chapman on our Evidently Cochrane website. The latest is about food allergy and intolerance, written by a 13 year old who shows more understanding than most health professionals I’ve encountered.

Plant of the Week: Paeonia “Tria”

This peony tree with abundant soft yellow flowers held above cut foliage is simply the most breathtakingly beautiful plant you can grow in our climate. It is the culmination of about 1500 years of refinement in peony cultivation, first in China, then in Japan, then in France and the USA. You can trace the various stages in the development of the yellow peony tree in just one compartment of Hidcote garden in the Cotswolds, though you are just too late to do it this year. And they do not have Tria. In fact hardly anybody does: the Plant Finder lists just one UK supplier.

I think we owe it to friends and posterity to take root cuttings from our four year old plant when winter comes. It is growing rampantly in a dry clay spot we used to call “the killing bed.” It is very hardy and will grow in US zones 4-8. The dry twisted sticks produce beautiful purple brown leaves in March, which gradually turn into a dome of green as the flower buds open. It is supposed to flower successionally over some weeks, but this year ours has produced nearly all its blooms at once. They nestle in loveliness just above the leaves. As the evening light fades, they take on a special radiance,” Like golden lamps in a green night,” as Andrew Marvell wrote long ago of another wonderful plant (Bermudas 1653).