Richard Lehman’s journal review—4 June 2018

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM 31 May 2018

FAME-2: PCI guided by FFR

An air of gloom and perplexity lay over the city of Kardiograd, as Stentov paced his about his factories. They had once throbbed to the sound of drugs being hammered into tiny pieces of mesh, but were now half-empty. Business had slumped to a mere 5 billion roubles a year: how can a man live on such a sum? His erstwhile friends Darrel Francevski and Ivan Mandrolov no longer visited him for tea, and in the last month alone, he had to lay off five liveried footmen.

“Courage!” muttered Stentov to himself, but then remembered that COURAGE had begun all his woes. After that trial, his cardiologist friends still put his stents into everyone they found to have narrowed coronaries, but they wore a guilty air and hid in doorways when his carriage approached.

Darrel Francevski tried to help him by saying he would show that although the narrowing itself might not matter, surely the amount of blood going through it must. They would call it the “fractional flow reserve” (FFR) and do a trial. The physicians of Kardiograd breathed sighs of relief, and took to doffing their hats to Stentov once more. Surely, thought Stentov, my profits will go into orbit again.

But alas, ORBITA simply showed that COURAGE was right. The f. flow reserve didn’t make any f. difference. F stands for fractional, you will remember, though when Stentov next met Darrel he seemed to forget this. But Darrel, who is a jovial man, simply laughed and put his arm round Stentov’s shoulders. “You’ve had a good innings” he said, referring to some incomprehensible English ball game. Stentov pushed him towards the door and slammed it behind him.

“I cannot let that man have the last word!” shouted Stentov to the empty room, so loudly that it shattered one of his priceless Ming vases.

But some weeks later, a flunkey appeared with a copy of the New England Journal of Medicine, carefully ironed and on a silver tray. “This may be of interest to you, sir” the servant ventured. “Read me the bit that matters, then” replied Stentov testily. “In patients with stable coronary artery disease, an initial FFR-guided PCI strategy was associated with a significantly lower rate of the primary composite end point of death, myocardial infarction, or urgent revascularization at 5 years than medical therapy alone,” read the footman. “So my FAME is restored!” cried Stentov. “What else does it say?”

“Well, sir, it goes on to point out that patients without haemodynamically significant stenoses had a favourable long-term outcome with medical therapy alone. And if I may say so, sir, there were no differences in death or infarction, just in needing to have a stent put in later. And also, I’m not entirely sure the figures…”

“Oh shut up man, and get on with your work. If I can make enough money, who needs fame too.”

Darrel Francevski is Darrel Francis, and Ivan Mandrolov is John Mandrola. You will learn far more about cardiology from their tweets and blogs than you ever could from me.

Family support on the unbearable ICU

The PARTNER trial examined the effect of helping families whose relatives were critically ill on intensive care units. It’s an uncommon and admirable example of a multicentre, stepped-wedge, cluster-randomized trial of a complex intervention to support people in an agonizingly stressful situation. The patients stood a 40% risk of death or severe permanent disability, and the family members might at any time have to make surrogate decisions about them. The intervention was grounded in the theory of cognitive–emotional decision making, which suggests that medical decisions are influenced by both the affective and the cognitive challenges of making consequential health decisions. It did not significantly affect the surrogates’ burden of psychological symptoms, because nothing probably could. But the surrogates’ ratings of the quality of communication and the patient- and family-centeredness of care were better with the intervention than with usual care; and the length of stay in the ICU was shorter.

Ann Intern Med 29 May 2018

Preference sensitive lung cancer screening
The deepest underlying problem in talking about screening is the conflict between the individual and society. This is felt most acutely in a fully shared health service like the NHS, but it arises in all systems where insurance spreads the risk of health care. It’s very hard to democratize this: the nearest we have got is the method of citizens’ juries, which for the time being remain very rare events. Here’s a thought-provoking paper which looks at the issue from the standpoint of the individual. It is based on data from two large trials of screening for lung cancer in high-risk individuals, mapped on to what is known from other sources about people’s ranges of preference according to risk. The conclusion is that for higher-risk eligible persons with longer life expectancy (roughly 50% of the study population), the benefits of LDCT screening overcame even highly negative views about screening and its downsides. But these “persons” were a simulation. Nobody does modelling studies better than Rod Hayward’s team, but it would now be nice to go out and get some real-life data on this important issue, covering all forms of cancer screening.

The Lancet 2 Jun 2018

Guselkumab for psoriatic arthritis
I don’t know about you, but it’s taken me a long time to get my head round the so-called “biologics” that rheumatologists have been using for the last 15 years or so. Psoriatic arthritis is relatively uncommon, but can be nasty. Nowadays it can be controlled using TNFα blockers (of which there are lots, including bupropion and LSD, would you believe), plus ustekinumab, secukinumab, ixekizumab, abatacept, apremilast and tofacitinib. But, argue the authors of this Janssen-funded study, “an unmet need exists for new single-drug therapies, with robust efficacy and acceptable safety, to treat all psoriatic arthritis disease manifestations.” Well, that would certainly make life nice and simple, but will Janssen’s novel anti-interleukin 23p19 antibody, guselkumab, fit the bill and spare us having to remember all the others? It will take an awfully long time to tell: this trial used a complex design simply to get itself in contention. It tells us virtually nothing about how guselkumab might fit into the broader scheme of things. If you want to read about how this currently stands, there are a couple of helpful review articles: one about the pathogenesis of psoriatic arthritis and the other about current clinical management.

Hip arthroscopy for impingement syndrome
What a relief to turn from another drug-company trial in a crowded small market to a publicly funded trial in the NHS. Even better, it was done by orthopaedic surgeons. These guys have become my research heroes over the 20 years I’ve been writing these reviews. The orthopaedic trials I’ve read have almost all been about what is best for patients, not how to sell the latest product. This trial compared the clinical effectiveness of hip arthroscopy with best conservative care. No devices were harmed in the making of this trial, because none were used, unless you count a hip arthroscope. That went in to half the hips randomised: the others got “personalised hip therapy”. The patients all had femoroacetabular impingement syndrome, a relatively common non-arthritic cause of hip pain in young adults caused by symptomatic premature contact between the proximal femur and acetabular rim during hip motion. I’m not clear what actually took place in the arthroscoped group: “shape abnormalities and consequent labral and cartilage pathology were treated” in accordance with the Most Worshipful Craft and Mystery of Orthopaedics. At 12 months, these patients had better outcomes than those assigned to the Most Worshipful Craft and Mystery of Physiotherapy.

Albumin for liver ascites
There have been disputes for decades about human albumin as a treatment for the ascites of advanced liver disease. The introduction to this trial contains a lengthy paragraph about hypoalbuminaemia, plasma colloid-osmotic pressure, fluid partition between plasma and the interstitial space, peripheral arterial vasodilation, and regulation of endothelial function and inflammatory or immune responses. All of which could provide a rationale for either using or withholding albumin for cirrhotic ascites. As somebody said, there is a perfect physiological rationale for every treatment that works, and also for every treatment that doesn’t work. For the ANSWER, we can go to an Italian trial which randomised 431 patients with cirrhosis and uncomplicated ascites who were also receiving furosemide and spironolactone. 18-month mortality was lower in the group who also received intravenous infusions of human albumin.

The BMJ 2 Jun 2018

Alcohol and cardiovascular events—again
Alcohol intake was inversely associated with non-fatal CHD risk but positively associated with the risk of different stroke subtypes.” We’ve been reading this conclusion for about three decades now. The merit of this latest study is its EPIC scale both in numbers (32,549) and thoroughness (looking at lifelong consumption, examining individual records, analyzing by subtypes of alcoholic drink and subtypes of stroke). Forced to drink very rarely for the rest of my life, I shall confine myself to an annual sip or two of Meursault-Génèvrieres and the third growth of the Château Latour estates.

Lyme-lit reassurance
Rummaging in the insect drawers of the Natural Science Museum in South Kensington about 20 years ago, a curator found an immense collection of ticks collected from British wild animals in the late nineteenth century. Under the microscope, a large number of them carried the Borrelia spp of Lyme disease. In fact Lyme disease is not uncommon in Europe, as this study from Denmark shows. But even in those with a positive Borrelia burgdorferi intrathecal antibody test and a clinical diagnosis of Lyme borreliosis, it seems relatively benign. There is an association with non-melanoma skin cancers (probably mediated by time outdoors) and some blood malignancies, but a verified diagnosis of Lyme neuroborreliosis had no substantial effect on long term survival, health, or educational/social functioning in Danes.

FDA and safety follow-up

Here is a great paper (COI warning: written by friends) showing that while the US Food and Drug Administration has increasingly approved new drugs and biologics on the basis of shorter, smaller, and fewer trials in the last decade, this has not been accompanied by any balancing improvement in the quality of post-marketing studies. On the contrary, it is often impossible to tell what is actually going on in a large proportion of these: of 110 clinical trials, 38 (34.5%), 44 (40.0%), 62 (56.4%), 66 (60.0%), and 98 (89.1%) did not report enough information to establish use of randomization, comparator type, allocation, outcome, and number of patients to be enrolled, respectively. And about a quarter of them never get published.

Plants of the Week: Hardy blue geraniums

The English Spring reaches peak lushness around now, and this is about the best English Spring ever—certainly the warmest May since records began. Thunderstorms have kept the soil moist and well supplied with nitrogen. I doubt whether there are better places to be on earth just now than rural Oxfordshire.

This is also peak geranium week. The hardy geraniums provide flowers from April onwards but the greatest number of delectable garden species and varieties are to be seen just now. So are the wildings, most notably G pratensis which begins to form large areas of diffuse blue on our grassy roadside verges. It is surely no crime to stop by and carefully lift a plant or two with the best flowers—either a dark pure blue or a pale striated form. There will be hundreds more around it.

Once established in your garden, these meadow geraniums will become welcome weeds with tough, easily divisible roots and innumerable daughter plants from seed.

But there are many other blue geraniums to be had just now. G magnificum is a classic with excellent leaves and abundant flowers, able to tough it out on shady dry banks or in full sunshine. Left alone, it flowers for about 2-3 weeks and then grows straggly. Remember to cut it back very hard in mid-July for tidiness and to encourage another display in late August. Its hybrid with G renardii, “Philippe Vapelle”, has prettier rounded leaves and flowers a little earlier, but is much less tough and sports a washier blue.

For all-season value, there is nothing to compare with the 1950s hybrid “Johnson’s Blue”. It will hide in the skirts of any shrub or spill over any edge that is spillworthy and give you lovely mid-blue flowers from early May to November. Later-flowering forms which are full of merit are G.wallichianum “Buxton’s Variety” and the recent stellar hybrid with discreetly patterned leaves, “Rozeanne”, covered in blue flowers with purple veining from August till the first frosts.

You need all of these. And then you need to divide them and give them to friends.

Could you write a weekly journal review?

Richard Lehman will be retiring from writing his weekly reviews in the Summer 2018. We are looking for someone to replace Richard and write a weekly journal review. We are interested in candidates with excellent knowledge of research and critical appraisal, and an understanding of how research impacts on clinical practice.

We are particularly interested in candidates who have clinical experience and an excellent standard of English. You must be motivated, creative, and able to write the weekly reviews to a tight deadline every week.

This freelance position offers a salary per column.

Please apply with a CV and covering letter and an example of how you would write a research review.

Please send applications to: Juliet Dobson, Digital content editor, The