Richard Lehman’s journal review—20 March 2017

richard_lehmanNEJM  16 Mar 2017  Vol 376

Stem cells for AMD

For sufferers of age-related macular degeneration who were hoping for a stem cell cure, this week’s New England Journal brings bad news and shocking news. The bad news comes in a case report showing zero improvement after transplanting a sheet of retinal pigment epithelial cells differentiated from induced pluripotent stem cells in a patient with neovascular age-related macular degeneration. The 41 authors of this paper took the utmost care to test the material which they then implanted under the retina of one patient, after removing all neovascular membrane. At one year after surgery, the transplanted sheet remained intact, best corrected visual acuity had not improved or worsened, and cystoid macular oedema was present.

That is a great deal better than what happened to patients receiving intravitreal injections of “stem cells” derived from the patients’ own adipose tissue. The American clinics who offer this treatment perform the injections under the auspices of patient-funded, institutional review board–approved research. The research is listed on without an investigational new drug application with the FDA. Three case reports describe how the recipients became blind after the procedure.

PCSK9 inhibitorzzzzz

The future of cardiology happened at 13h00 GMT on Friday 17 March 2017. This was when the results of the FOURIER trial of evolocumab for the prevention of cardiovascular events were presented at the American College of Cardiology. The BBC immediately declared a massive breakthrough. All my American commentator friends sprang into action. In this new era, it would take, er, $2million or more to avoid one event in a high risk population over two years. The effect on all cause mortality would be, er, zero or worse. They had seen the future and it was, er, pants. Pants that cost $15,000 per person per year. As ever, I was awe-struck by the mastery of the commentaries and data synthesis produced within hours by Harlan Krumholz, Larry Husten, Gary Schwitzer, James McCormack and Vinay Prasad. By evening the future had become the familiar past. We need longer trials. We need to look at how drugs are priced. We need to look beyond lipid-lowering if we are to reduce cardiovascular disease further.

So before you all go to sleep, what were we actually looking at here? You will all, I imagine, have heard of PCSK9 inhibitors and their remarkable ability to lower low density lipid cholesterol by binding to proprotein convertase subtilisin–kexin type 9 in the liver. Three antibodies were developed to achieve this: evolocumab, alirocumab, and bococizumab. The first two are fully human antibodies and are rarely treated as foreigners by the immune system. But bococizumab is a humanized rather than a human antibody: it contains 3% of mouse material and sadly for its manufacturers, this is sufficient to induce counter-antibodies in most people. This is described in a report of the SPIRE trials, which were duly discontinued.

Evolocumab and alirocumab will continue to stumble on expensively. I imagine their main use will be to treat the severer forms of hereditary hypercholesterolaemia. Expect more hyping of the “statin intolerance” concept too, as this will create another market sector. If you want more detail, look up the superb commentaries I mentioned. And if you want a new lipid-lowering horse to put your money on, there’s now inclisiran. It’s a chemically synthesized small interfering RNA designed to target–you guessed it–PCSK9 messenger RNA. Could be transformational. Needs big phase 3 trials. Might end up costing a lot. May transform preventive cardiology. May bomb. You just never know.

JAMA  14 Mar 2017  Vol 317

Parturient montes, nascetur ridiculus mus

The FOURIER trial was a good example of massive hype and enormous effort followed by an underwhelming result. “A mountain had gone into labour and was groaning terribly. Such rumours excited great expectations all over the country. In the end, however, the mountain gave birth to a mouse,” wrote the Latin poet Phaedrus, though the story is better known from a pithy line by Horace (see heading). A mighty coalition of East Coast American institutions decided to address the mountainous issue of whether a professionally delivered intervention plus education aimed at mouse infestation might reduce asthma symptoms among mouse-sensitized children and adolescents with persistent asthma compared with education alone. The mountain groaned for five years. Mice were sacrificed, or fled in terror. But at the end of the trial, asthma symptoms did not differ between groups.

Testing fails to predict preterm birth

Spontaneous labour is preceded by shortening of the cervix and a rise in vaginal levels of fetal pronectin. So perhaps by measuring these things, one might be able to predict premature labour, ran the hypothesis. But a study of 9410 nulliparous women with singleton pregnancies showed that this combination predicted less than a quarter of preterm onset of labour, and is not fit for clinical use.

Poor anticoagulation in AF precedes stroke

A study of 94 474 North American patients with acute ischemic stroke who had a known history of atrial fibrillation shows the importance of adequate anticoagulation. 84% did not receive guideline-recommended therapeutic anticoagulation preceding the stroke. The 16% who had received adequate treatment with warfarin or DOACs had less severe strokes and lower in-hospital mortality.

JAMA Intern Med  Mar 2017 Vol 177

Kidney outcomes & BP control in non-diabetics

Here’s a meta-analysis of nine randomized clinical trials with 8127 patients and a median follow-up of 3.3 years. It aims to answer the question of whether aiming for a BP of <130/80 mm Hg (intensive control) prevents kidney disease progression better than standard control (<140/90). Every week, I look at about 20 meta-analyses, deliberately leaving aside most technical aspects and concentrating on what might be important for decision-making with patients. High blood pressure is a very common cardiorenal risk factor: end-stage renal failure is a very rare complication of high blood pressure. There is every likelihood that different BP lowering agents confer different levels of protection, and that this will differ among subgroups e.g. by ethnicity, duration, age etc. How will this review help me to reach decisions with real people, using specific drugs? Not a bit, I would suggest. It relies on surrogate end-points and compares one general strategy with another over too short a period. That’s not the fault of the authors. But it is their fault when they go on to stretch even this meagre evidence beyond anything it can support: “Targeting blood pressure below the current standard is not consistently warranted, but may benefit nonblack patients or those with heavy proteinuria.” If something hasn’t reached statistical significance, don’t make a strapline of it. It will only confuse the troops. Bury it in the conclusion, as a suggestion for further research.

The Lancet 18 Mar 2017 Vol 389

Our statin war correspondent writes

I know some people like to watch a good fight, but for me the statin wars between The Lancet and The BMJ, seemed endlessly tiresome and pointless. Even now, the two central lessons don’t seem to have emerged clearly: firstly, taking a statin is an individual choice, not a herd intervention; and secondly, the effect is not a herd effect at all but accrues maximally to a few individuals while leaving most with no benefit at all. But in this overheated argument, the issue has been depicted as a moral crusade to make people take pills for their own good and tell them that any adverse effects they experience must be in their imagination. Many months after The Lancet published a review by Rory Collins, which was to settle the matter, the journal publishes responses from dissenters, including the BMJ authors whose article triggered the war and Fiona Godlee who stood by them. She writes: “So despite Horton and Collins and colleagues wanting to shut down the discussion and award themselves the final word, the debate about statins in primary prevention is alive and kicking. It is a debate that needs to be resolved as thoughtfully, objectively, and openly as possible, and not by eminence-based narrative reviews, however extensive, based on meta-analysis of data that only Collins, his fellow trialists, and industry sponsors have seen. This absence of independence and transparency is not unusual in medicine—indeed it is sadly still very much the norm.” Bravissima! And praise to The Lancet for printing this. Can we look forward to calm and good sense from now on?

Hip screws i’FAITH

The Lancet has published a study comparing two kinds of screw fixation for hip fractures. Hip fractures are common and often presage immobility and death in old people, so a good treatment is of interest to all of us. The FAITH trial concludes that “in terms of reoperation rates the sliding hip screw shows no advantage, but some groups of patients (smokers and those with displaced or base of neck fractures) might do better with a sliding hip screw than with cancellous screws.” Useful knowledge.

BLISTERingly good

If you ever get the chance to hear Hywel Williams talk about his work, don’t miss it. He talks a wonderful talk, but he walks an even more wonderful walk. The BLISTER trial is a classic example from his Centre of Evidence Based Dermatology in Nottingham. Bullous pemphigoid is a distressingly itchy auto-immune skin disease of older people, whose incidence has doubled in the last decade and now stands somewhere between 14 and 42 new patients per million inhabitants of the UK and Europe. Too rare and too cheaply treated to be of any interest to the pharmaceutical industry: but Hywel and his colleagues did a systematic review and found that there was no clear evidence to choose between treatment with oral steroids or tetracyclines. They talked to patients; they collected a group of colleagues from across the UK to conduct a trial, and they found funding from a non-pharma source. This is what they always do. Go thou, dear reader, and do likewise. Oh, and what did they find? That starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. Truly useful knowledge. Go forth, dear reader, and discover something of your own that really benefits patients.

The BMJ 18 Mar 2017 Vol 356

Hot fresh microbiome

A single-author review from the USA sets out to describe how our understanding of our microbial communities (microbiota) has developed over recent years. “Perhaps the most radical change is the realization that most of the microbes that inhabit our body supply crucial ecosystem services that benefit the entire host-microbe system. These services include the production of important resources, bioconversion of nutrients, and protection against pathogenic microbes.” I like this analogy between the microbiome and a service industry. It can work both ways. This article, though long and occasionally hard to penetrate, is good reading for a rainy afternoon. It ends on a note of American optimism. “The insights gained through the study of our indigenous microbiota are leading the way to a better understanding of the mechanisms by which microbes can maintain health and trigger disease. With this greater understanding it is hoped that we will be in a position to develop new ways to prevent and treat a wide range of diseases and to foster health by tending to our microbial symbionts.” Little cuties. Now please wash your hands.

Plant of the Week: Forsythia suspensa var sieboldii

I’m all for people growing the plants they enjoy, but I suspect that most of the shouty yellow forsythias that appear at this time of year are not there for pleasure but are just mistakes which nobody has thought to correct. Our neighbour planted one in a prominent spot near our common drive a few years ago. In the interests of internecine tranquillity, I said nothing and raised not an eyebrow in his direction. Fortunately he is a man of order and soon tired of its wild and straggling habit: an inoffensive little barberry now marks the place where once it blazed bad yellow at the March winds.

The forsythias which clash inexcusably with the early cherry and magnolia trees are usually of the intermedia group, but from time to time I catch sight of paler forsythias which make me want to stop the car and admire them, perhaps also surreptitiously helping myself to a branch while nobody is looking. What stops me doing this is the fact that we don’t have any room for another large straggling shrub. If we had, I would probably go for F suspensa var sieboldii, placed on a bank, though I may be relying too much on book descriptions and Google images. “Introduced c.1857. This unique Forsythia is distinguished by its arching, rambling, lax habit; its pleasing, light yellow flowers are borne all along the vigorous new shoots as well as on the old twigs; it is by far the most desirable for cutting for the house,” wrote Graham Stuart Thomas (1992), who was never wrong.

Correction: The item “Testing fails to predict preterm birth” previously referred to cervical “lengthening” preceding premature labour. This should have been “cervical shortening.” It was corrected on 24 March 2017. 

  • kidmugsy

    “We need to look beyond lipid-lowering”: I doubt it. You probably need to bin lipid-lowering altogether as being based on a false hypothesis.

    “if we are to reduce cardiovascular disease further”: I very much doubt that ‘we’ have lowered CVD. It gives every appearance of having been a epidemic that is coming to an end, presumably as resistance to the causative micro-organisms increases. It might well be worth trying to identify them, though, rather than just inferring their role.