Richard Lehman’s journal review—27 March 2017

Richard Lehman reviews the latest research in the leading medical journals

richard_lehmanNEJM  23 Mar 2017  Vol 376
Pregabalin for sciatica
There’s nothing quite so personal as pain. If you have severe pain and take something for it and it goes away, your brain will insist that you take the same thing if it returns. This poses a number of problems for trials of pain relieving drugs. The obvious one is that pain may abate on its own: we can solve that by placebo controlled randomised trials like this one of pregabalin for acute and chronic sciatica. It shows that, overall, most sciatica resolves spontaneously, and that for the weeks during which it persists, pregabalin provides no better aggregated pain relief than placebo and causes more adverse effects. But the question still lurks: hidden in the disappointing overall figures, were there a few people for whom it worked really well? For enduring pain, the real world strategy is to try one thing, then another. The ideal trial method should therefore be a cluster of n-of-one trials. Instead, the editorial suggests a different approach, based on mechanistic biology: “This trial highlights a need in the field of pain treatment—namely, to identify biomarkers that could link the efficacy of a drug with the biologic causes of diverse types of pain.” Until that far off day, I’ll stick with just trying different things until the pain goes away.  

The more stents you put in now, the fewer you’ll put in later
Stents are so satisfying. They have won a place in our hearts. But should our hearts be stented simply because the coronary arteries look narrow? No, no, say the stenters: we are more sophisticated now, and use measures of fractional flow reserve (FFR). Does this really improve the selection of patients, or is it just a trick to keep this popular intervention common? We’ll come on to that in the next item. This trial selected people who were having heart attacks and asked if they would mind being randomised to have just their culprit artery stented or to have any other narrowed ones with reduced FFR done at the same time. The composite primary outcome lumped together death from any cause, non-fatal myocardial infarction, revascularization, and cerebrovascular events at 12 months. As you might expect, those who had more stents at the time of myocardial infarct PCI “needed” fewer later. This may be significant, inasmuch as they were truly needed, but this is hard to pick out from the summary data. And, unfortunately, the trial was underpowered to detect differences in the most important outcomes: myocardial infarction and all cause death.

Fractional flow reserve or instantaneous wave-free ratio?
“Coronary revascularization is warranted only if a patient has one or more coronary artery stenoses that are hemodynamically important. Large randomized studies have shown that fractional flow reserve (FFR) is superior to angiographic assessment for the detection of hemodynamically important coronary artery stenoses and that use of FFR to guide coronary revascularization improves clinical outcomes. FFR is measured by advancing a coronary-pressure guidewire distal to a stenotic lesion and then administering adenosine to assess the pressure gradient across the lesion during hyperemia.” There: you thought this item would be boring, and so it is, but at least you have learnt something. The trials they base this statement on are individually contestable, but never mind: FFR has become “gold standard” practice for interventional cardiology, and any other technique will have to prove “non-inferiority.” This is actually quite difficult, requiring comparative trials of sufficient size and duration to detect a difference in outcomes between two diagnostic strategies: something rarely done. The diagnostic measurement that seeks to elbow out FFR is called the instantaneous wave-free ratio (iFR), a pressure derived index of stenosis severity that is not obtained with the administration of a vasodilator. Two trials comparing these measurements were sponsored by Philips Volcano, one involving the Imperial College Trials Unit and the other the SWEDEHEART research collaboration. Both showed that iFR is equally good at lesion selection as FFR and that it is quicker and associated with fewer adverse effects. The Philips Volcano is showing smoke.

JAMA 21 Mar 2017  Vol 317
Treatment outcomes for localised prostate cancer
The first intensive work on shared decision making took place over 25 years ago and dealt with surgical options for benign prostatic hyperplasia (BPH). Nowadays BPH has slid into the background amid a PSA-driven epidemic of localised prostatic cancer. But two key outcomes described in this cohort study are the same as in that early work at Dartmouth: urinary incontinence and sexual function. In this sample, the 60% of men who opted for radical surgery were generally fitter physically and had better sexual function than those who opted for external beam radiotherapy (23%) or observation (17%). The surgical group, however, suffered the worst decline in sexual ability and an increase in urinary incontinence. This is not new news, but will help to inform the decision aids that need to be used in the future.

More fractures with warfarin?
If people taking warfarin are at greater risk of osteoporotic fractures than people taking dabigatran, that would be useful knowledge to share with patients starting anticoagulation. But we don’t know. Observational studies using propensity matching can send signals, but unless the signal is deafening, it needs confirmation by other means—ideally by a randomised controlled trial. A population wide database managed by the Hong Kong Hospital Authority sends a signal that warfarin may be associated with more osteoporotic fractures than dabigatran. There have been several RCTs comparing dabigatran with warfarin, and perhaps the full individual participant data from these could shed further light on this issue.

JAMA Intern Med  Mar 2017  Vol 177
Feeling low on 5α-reductase inhibitors
When those Dartmouth investigators looked at benign prostatic hyperplasia around 1990, they found that doctors and patients shared a common myth that BPH was a progressive process that leads to acute retention and/or renal damage. Such events may be common on urology wards but are uncommon in the population: the symptoms of BPH tend to come and go for years, causing nothing but minor inconvenience. Enter the 5α-reductase inhibitors: the pharma salesman’s dream. If your prostatic symptoms get better, it must be the pills; if they don’t, keep taking them just in case. When one drug runs out of patent, pretend a new one is better. In Ontario alone, 93 917 men aged 66 or over were started on these drugs between 2003 and 2013. Compared with matched controls, they did not commit suicide more often, but in the first 18 months they were significantly more likely to become depressed and/or to harm themselves.

Vague recommendations for cancer follow-up
“OK, we’ve treated your cancer: see a doctor you’ve never met before at the end of a busy outpatient clinic and have some tests every six or 12 or 24 months, just in case it comes back.” I’ve always had mixed feelings about this ingrained ritual, and so it seems have those who are appointed to guide us. This study looks at 41 guidelines on surveillance after treatment for nine common cancers, published between 1 January 2010 and 1 March 2016. European guidelines trump American for containing ambiguous recommendations: 100% vs 68%. But given the general lack of evidence, that probably just means that the American ones have a 32% higher level of meaningless certainty.

Sudden inspections improve patient survival?
Two more journals to go, and I’m already worn out from too many observational studies. You may already have heard of this one. In the US, hospitals receive unannounced visits from The Joint Committee (TJC) lasting several days, during which they have to prove compliance with best practice. No doubt everyone scrambles to show that they are present and doing everything by the book. A large survey shows a just detectable improvement in patient survival during these inspections, especially in teaching hospitals. Then the cats depart and the mice do play—as usual.

The Lancet  25 Mar 2017  Vol 389
Cardiovascular disease and the noble savage
“Trope” is an annoying word introduced by literary academics to describe a recurring image or concept, such as people living happily in the wild. The noble savage trope appears in various guises from the earliest literature (Sumer, 3000 BC) to the present: we love to think that in some age or in some place, humans might live long healthy lives in perfect harmony with Nature. Sadly, we never have and never will, although we might do much better if we tried a bit harder. The Tsimane who live in the Bolivian Amazon practice a mixture of hunting, gathering, fishing, and farming. Although they show a high burden of chronic inflammation as shown by elevated C-reactive protein levels, they have the lowest reported levels of coronary artery disease of any population recorded to date, as assessed by coronary artery calcium scoring. “These findings suggest that coronary atherosclerosis can be avoided in most people by achieving a lifetime with very low LDL, low blood pressure, low glucose, normal body mass index, no smoking, and plenty of physical activity.”

The BMJ  25 Mar 2017  Vol 356
Blessed are the cheese eaters?
All who have watched The Life of Brian treasure the Sermon on the Mount scene where an educated onlooker hears “Blessed are the cheesemakers” and murmurs, “Of course, not to be taken literally. All manufacturers of dairy products are equally blessed.” But does this blessing extend to a reduction in blood pressure? There may be millions, nay billions, of people around the world who could be misinterpreting Brian’s beatitude and consuming dairy products in the hope of avoiding hypertension. But this review of the randomised trials (yes, there are eight!) plus Mendelian randomised studies reaches a sad conclusion: “The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.”

HERDOO2, how do you do
HERDOO2 stands for Hyperpigmentation, Edema (sic), or Redness in either leg; D-dimer level ≥250 μg/L; Obesity with body mass index ≥30; or Older age, ≥65 years. The English version would be HORDOO2, with the O in oedema, but I don’t see it catching on. As you may have guessed, it is a decision rule for when you can safely discontinue anticoagulants after short term treatment for unprovoked venous thromboembolism in women without other risk factors. It was assessed in a prospective cohort study involving 44 secondary or tertiary care centres in seven countries. “Women with a first unprovoked VTE event and none or one of the HERDOO2 criteria have a low risk of recurrent VTE and can safely discontinue anticoagulants after completing short term treatment.” Short term here meant five to 12 months.

Wine that makes glad the heart of men
Ah, another observational study to end the week’s tally. This one is huge and sophisticated, and attempts to address the link between alcohol consumption and 12 common symptomatic manifestations of cardiovascular disease, including chronic stable angina, unstable angina, acute myocardial infarction, unheralded coronary heart disease death, heart failure, sudden coronary death/cardiac arrest, transient ischaemic attack, ischaemic stroke, intracerebral and subarachnoid haemorrhage, peripheral arterial disease, and abdominal aortic aneurysm. It is based on data from nearly two million people, using inputs from the Clinical Practice Research Datalink, married up with other large UK databases. Data about endpoints is therefore probably reasonably complete. But as someone who used to enter data into the CPRD, I wouldn’t vouch at all for the GP data about alcohol consumption. Most of it will be what patients wanted their doctors to believe. There’s the usual signal here of a threshold above which alcohol intake ceases to show any association with reduced CVD and starts to show an association with increased risk, not just for ischaemic disease and stroke but also for heart failure. But I’d suggest that whether you believe this or not, other factors should determine how much wine you have with your cheese.

Plant question of the week: Is there a really blue aubretia?
I’ve been looking hard this year for a really clear blue aubretia. The ones that flower on our local town and village walls at this time of year all seem to have a mauve or magenta mixture in their blue, unless they happen to be white. Same with the ones in pots at markets and garden centres. They may have blue in their names, but they just aren’t true blue.

The internet and written descriptions are no good either. They just tell lies, in words or pictures. A variety called ” Cascade Blue” is a good campanula blue in one photo and muddy mauve in another. “Kitty Blue” is just purple. So is “Blue Beauty.”

This ghastly situation should have been remedied long ago, by traditional hybridisation and selection or by genetic engineering. If anyone possesses a good clear blue aubretia, could I please have a bit? I will travel far.