Richard Lehman’s journal review—6 January 2014

Richard LehmanNEJM  26 Dec 2013  Vol 369
2481   There was no let up in the American journals over what they call the holiday period, and the NEJM offered a trial of a new GSK influenza vaccine to our attention on Boxing Day. It is a quadrivalent vaccine containing inactivated influenza B virus of both main lineages, and it was tested in 5168 children between the ages of 3 and 8, with hepatitis A vaccine as the control. Though my head is slightly clearer now than it was on Boxing Day, I can make nothing of this trial. Why this age group? And why was the comparator not the standard trivalent flu vaccine? Sure, the new QIV was immunogenic and had an efficacy of 74% in preventing confirmed influenza compared with nothing, but does that make it the most effective choice? Maybe the clue lies in the sentence: “The sponsor was involved in all stages of the study conduct and analysis of the data.” So, at the NEJM, 2013 ended with business as usual.

2492   Bardoxolone is the vaguely Shakespearian name for a nuclear 1 factor (erythroid-derived 2)–related factor 2 activator. But before I go any further, I will let you off the hook. Bardoxolone isn’t worth knowing about. When trialled in patients with stage 4 kidney disease, it increased cardiovascular events. So the trial was stopped.

2515   Arthroscopic partial meniscectomy is one of the most common orthopaedic procedures. But before I go any further, I’ll let you off the hook. Arthroscopic partial meniscectomy is useless. “In this trial involving patients without knee osteoarthritis, but with symptoms of a degenerative medial meniscus tear, the outcomes after arthroscopic partial meniscectomy were no better than those after a sham surgical procedure.” Now here’s a nice simple study for someone to do: plot the number of arthroscopic medial meniscectomies done in the US and UK public and private sectors over the next two years. I wouldn’t be at all surprised if the numbers hold steady, particularly in the private sector.

NEJM  2 Jan 2014  Vol 370
13   There’s scale in the pipes: call for Mr Stent the plumber. This has proved an enormously appealing idea for patients and plumbers over the last two decades, and Messrs Stent and Sons now have an annual turnover of billions. Pushing mesh into arteries is a rite of passage in many specialties, and even patients often talk of their stents with a kind of pride. A shame that most of them do nothing at all, even in coronary arteries. In renal arteries they may be universally pointless, according to this large publicly funded American trial. ” We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease.”

23   If you suffer major ischaemic damage to your left ventricle, it is quite likely to fibrose and remodel itself in such a way as to distort the mitral valve and cause what is known as “functional” mitral regurgitation. This is associated with a substantial increase in the risk of progressive heart failure and death, and it affects a lot of people—probably over two million in the US alone. The leaflets of the mitral valve remain healthy, but their alignment is wrong, so if surgical treatment is attempted, it is usually in the form of mitral valve repair rather than replacement. But that may not be as good in the long term as replacing the valve, according to the authors of a trial which randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral valve repair or chordal-sparing replacement. In the short term, clinical outcomes are identical, but in the long term, valve replacement is likely to prove more durable.

33   Left ventricular assist devices have become popular in America, where a brand leader is HeartMate II, a small axial-flow device made by Thoratec. Unfortunately there seems to have been an epidemic of pump-related thrombosis in these devices associated with high morbidity and mortality, which began abruptly in March 2011. It shows no sign of stopping.

54    “Accelerometers, cameras, global positioning systems, and other sensors were installed in the vehicles of 42 newly licensed drivers (16.3 to 17.0 years of age) and 109 adults with more driving experience.” The idea was to find out how crashes and near-crashes related to distractions such as using a cell phone, sending or receiving text messages, reaching for an object, eating, or looking at a roadside object. All these are dangerous, reaching for things being the worst. Unfortunately novice drivers tend to do these things increasingly as they gain confidence. Experienced drivers do them less, and tend to come to less harm if they do.

60   A review of the global health impact of tobacco. Here are a couple of take home messages:
“Stopping smoking works. Those who have smoked cigarettes since early adulthood but stop at 30, 40, or 50 years of age gain about 10, 9, and 6 years of life expectancy, respectively, as compared with those who continue smoking.”

“Tobacco taxes are a small percentage of overall revenue in most countries (except China), and money not spent on tobacco is spent on other taxable goods or services.”

JAMA  25 Dec 2013  Vol 310
2622   It was the morning after Howard Bauchner had been down the chimney, and we boys and girls pounced eagerly on our Christmas Day JAMA and tore off the polythene wrapper. Golly, it’s a super article on Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: a randomized clinical trial! Thank you Santa Bauchner! How could he have known that was what we really wanted? Wow, it shows that CBT plus amitryptiline works better than amitryptiline alone. Unfortunately the CBT won’t be available on the NHS until next Christmas.

2650   It’s a sad probability that for some adolescents Christmas is a high risk time for sexual abuse. This issue of JAMA contains a paper about the best way to treat the mental trauma it causes: “Adolescents girls with sexual abuse related PTSD experienced greater benefit from prolonged exposure therapy than from supportive counseling even when delivered by counselors who typically provide supportive counseling.” Prolonged exposure therapy is pretty hard work, taking a minimum of about ten one hour sessions in all, and is described in detail in the text. Maybe this too will be available through the NHS by next Christmas, but I wouldn’t count on it.

JAMA  1 Jan 2014  Vol 311
33   A double blind, placebo controlled, parallel group, randomised clinical trial in patients with Alzheimer’s disease taking an acetylcholinesterase inhibitor shows that vitamin E may slow functional decline by about 19% per year, whereas memantine does nothing. I struggle to decide whether this has any real meaning. It depends on what you are hoping to achieve, but whatever your goal, it’s fair to say that this is no leap forward. Amazing that this trial has got so much publicity.

45   Another trial shows that cooling people down on the way to hospital following cardiac arrest in the community makes no difference to outcomes.

53   Nor does mechanically assisted cardiopulmonary resuscitation for out-of-hospital cardiac arrest make any difference to short term survival or long-term neurological outcomes.

62   And for a final bit of dèja vu to start the new year, here is yet another trial showing that you can safely put transendocardial stem cells with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) into patients with ischaemic cardiomyopathy. What happens thereafter is anybody’s guess. Wake me up when there are some meaningful results.

Lancet  4 Jan 2013  Vol 383
31    In the REGARD trial, funded by ImClone Systems, patients with advanced gastric cancer given ramucirumab showed a median overall survival of 5•2 months (IQR 2•3—9•9) compared with 3•8 months (1•7—7•1) in the placebo group. The paper reports: “This drug reduced the risk of death from any cause compared with placebo and reduced risk of disease progression by half. The survival benefit with ramucirumab was consistent across almost all subgroups.” I think these sentences deserve some kind of bad taste prize for trial reporting. Remember that all the participants died within a median of less than six months, and both groups within about six weeks of each other. As they faced death, they volunteered to try out a new drug for the benefit of others (and for this company in particular) and they do not deserve to be insulted with this kind of pharmababble.

40   A serogroup A meningococcal polysaccharide—tetanus toxoid conjugate vaccine (PsA—TT, MenAfriVac) was licensed in India as recently as 2009, and was recently used in a meningitis epidemic in three regions of Chad. It is set to make a tremendous difference throughout the African meningitis belt: “The incidence of meningitis during the 2012 meningitis season in these three regions was 2•48 per 100 000 (57 cases in the 2•3 million population), whereas in regions without mass vaccination, incidence was 43•8 per 100 000 (3809 cases per 8•7 million population), a 94% difference in crude incidence (p<0•0001), and an incidence rate ratio of 0•096 (95% CI 0•046—0•198). Despite enhanced surveillance, no case of serogroup A meningococcal meningitis was reported in the three vaccinated regions.”

94   The best thing in the journal this week is a paper on global health from Julio Frenk and two colleagues. Here is a sample: ” it is necessary to move beyond reductionist definitions and to reconceptualise global health to reflect two key notions. First, global health should not be viewed as foreign health, but rather as the health of the global population. Second, global health should be understood not as a manifestation of dependence, but rather as the product of health interdependence, a process that has arisen in parallel with economic and geopolitical interdependence.” As you groansomely return to the frustrations of the British health system, deliberately mangled wherever you turn, lift your head and look round. The world as a whole is becoming a better, kinder place: keep true to your values: our self-destructive insular madness cannot go on if you refuse to be part of it.

BMJ   4 Jan 2014  Vol 348
When I first started writing these reviews in 1998, coronary artery stents were quite a new thing: there were even radioactive stents on the market, but they didn’t last long when it was found that they caused arterial wall fibrosis. So how did they get on the market in the first place? Simply because regulatory control of medical device marketing was farcically lax then, and it hasn’t changed much since. I’ve recently heard a medical device manufacturer say quite openly that products simply can’t be subjected to lifetime safety testing because their business cycle simply couldn’t be run that way. New must always be pushed as better, until someone comes along and proves otherwise, at which point you take stock of the profits and move on.

This is not just the industry position: it also just about sums up the regulatory position for anything from absorbent dressings to left ventricular assist devices. This week’s BMJ has two large systematic reviews of coronary stents: one is a comprehensive network meta-analysis comparing durable polymer stents with biodegradable stents, and the other is “mixed treatment comparison meta-analysis” which also includes bare metal stents. Confused already? This is not entirely accidental: it is in the interests of device manufacturers to sow confusion as they go along. And since they pay for nearly all the trials, they can choose their case-mix and their comparators. What they will never tell you is what happens years down the line.

I genuinely admire these gigantic efforts: the first paper looks at data from 60 trials and the second looks at 126. What really puzzles me is that they both combine results from trials in acute coronary syndromes, for which there is a good evidence for PCI including stenting, and trials in stable coronary disease, where stenting is grossly overused and problems of case-mix become insuperable. Both articles plump for certain products as the safest, but I simply don’t believe that you can do that given the nature, duration, and quality of the data available.

Atenolol was the wonder drug of the mid1980s, if your memory goes back that far. Even humble young GPs such as myself got word of ISIS-1 and duly prescribed it for all our post infarct patients, unless they have something called asthma. This was the era when there was much confusion between “asthma,” “chronic bronchitis,” and the new kid on the block, “chronic obstructive airways disease,” which shortly after morphed into COPD. Here is a study of British primary and secondary care databases which shows that only 39% of patients with COPD are prescribed a beta-blocker after MI in hospital, and that those who do receive one are twice as likely to be alive at three years. This is dire. Practice changed in the USA from 2001 onwards, after a paper in JACC by Krumholz and colleagues, and now 90% of COPD patients there receive beta-blockers after MI. It’s crazy that the message still hasn’t got through in Britain.

Three classes of cardioprotective drugs have come under a cloud for inducing “diabetes:” β-blockers, thiazides, and statins. The NAVIGATOR study was a study of the effect of nateglinide and valsartan on 9306 subjects with impaired glucose tolerance, who were prescribed other drugs at the discretion of their doctors. So they form a high risk cohort for observing the effects of other medications as well as the effects of those they were randomised to receive as part of the trial. I am uneasy about the biases that creep in here, but let that be. “New diabetes” was a fasting glucose of 7mmol/L or above. Beta-blockers did not increase its occurrence but “diuretics” (presumably mostly thiazides) and statins did, by about a third. To discuss the relevance or otherwise of this would take too long here, so if you are interested I will point you to my recent exchange of views with a young American diabetologist on CardioExchange.

Plant of the Week: Helleborus foetidus

The stinking hellebore is a native plant of Oxfordshire with green flowers in early spring. The flowers can occasionally have an attractive scent, but the leaves always have a sharp, repellent smell. As I drove from village to north Cotswold village this weekend, tending to a few splendidly ancient human inhabitants on the verge of extinction, I was surprised to note large roadside hellebore in full green flower. It was a welcome sight, not normally to be seen until the start of March.

I guess such hellebores have grown here since the glaciers retreated after the last Ice Age. They are poisonous in all their parts, and their bright green flowers and dark cut leaves would have carried a menacing symbolism for generations of local hill people. You can imagine hellebore folklore going back even beyond the ancient Celtic tribes who created the barrows and the stone circles which lie scattered on these hills. “Arr, they be ‘ellebores, and no good never came of them green uns,” they would have muttered in their best Maglemosian dialect, “And while you’re here, doctor, would you like a cup of tea?”