Richard Lehman’s journal review—1 February 2016

richard_lehmanNEJM 28 Jan 2016 Vol 374
Venetoclax & CLL
311 Venetoclax is a wonderful name. I shall set up a burglar alarm company in Venice so that I can see it painted on the side of gondolas: “Protect your palazzo with VENETOCLAX.” Then, when the moony silence of the Venetian night is pierced with the affrighting wail of our klaxons, I will be able to mutter contentedly, “Another one caught. Another success for Venetoclax.” I don’t know how the name venetoclax came to be attached to a new drug for resistant chronic lymphocytic leukaemia (CLL). But here it is, attacking BCL2, a protein central to the survival of CLL cells, in a phase 1 trial. Almost every patient with relapsed or refractory CLL or small lymphocytic lymphoma showed a response. I would opine that it is much too early to predict its place in the overall management of CLL, though this is a subject which I know little more about than burglar alarm selling in Venice.

Et tu, Bruton
323 Things that I do know about CLL: it affects older people, it has hitherto been hard to treat, but the emerging standard of care seems to be ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), which is slightly better than chlorambucil and costs hundreds of times as much.In this uncontrolled, phase 1–2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib.” As its name implies, acalabrutinib is also a BTK inhibitor, a me too drug which allegedly has “improved pharmacologic features, including favorable plasma exposure, rapid oral absorption, a short half-life, and the absence of irreversible targeting to alternative kinases.” So the thing to do is test it head-on with ibrutinib, to see if these differences are clinically meaningful, right? But as we’ve already seen, wrong: this was a phase 1-2 open-label trial without a comparator. Let’s hope the phase 3 trials are designed to help patients and clinicians make an informed choice.

333 BENEFIT is the name of a trial of belatacept for long term immunosuppression after renal transplantation. Given they knew it would cost a lot (£17K first year, £5K subsequently) this was quite a witty choice. Efficacy is how good a thing is at doing its job. Belatacept has good efficacy: “A 43% reduction in the risk of death or graft loss was observed for both the more intensive and the less intensive belatacept regimens as compared with the cyclosporine regimen.” Effectiveness is efficacy divided by cost difference (in principle), and ciclosporin costs 10-20 times less than belatacept. Here we get into NICE territory, and this takes us into the region of QALYs and absolute differences. Look at the Kaplan-Meier chart and you find that this impressive sounding 43% relative difference is actually quite tiny, because ciclosporin is already a pretty efficacious drug. So what’s the real numerator and denominator, and how do you make the choice? Leave it to the patient, I would say; but this is difficult terrain.

Mighty mitral surgery
344 I’m still in awe of people who open up the heart and mess with its valves. As a child I remember seeing headlines about the first successes of open heart surgery, which was regarded as a miracle at the time. When I was a medical student, there was a single chest surgeon doing it in Oxford, mostly on people with severe disease as a legacy of rheumatic fever. It was still regarded as “heroic” work, with all that implied for patient outcomes. In this trial, 251 patients had severe mitral regurgitation as a result of ischaemic damage, and their mean age was 68 (you have to go to the supplement to find their baseline characteristics—naughty). In the two years following either full mitral valve replacement or mitral valve repair, 20% of them died, in both groups. The main difference between groups was that over half of those with repair instead of replacement had regurgitation, which led to a greater incidence of acute heart failure and hospital admission.

JAMA 26 Jan 2016 Vol 315
Maternal vitamin D & wheezy kids
353 Vitamin D could be the secret of so many things. But as we test each plausible hypothesis, expectations shrink. In this week’s JAMA, there are two trials that test the idea that vitamin D supplementation during pregnancy might reduce wheezing in young children. The first one was conducted in Copenhagen, where it seems that normal practice is to give all pregnant women 400 IU/d of vitamin D3. The interventions were either placebo or an additional 2400 IU/day. “The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide confidence interval that includes a clinically important protective effect.”

The second trial was based in the US and compared a dose 4400 IU daily with 400 IU. Numbers were similar but the period of administration was a little longer. Again, the effect size was too small to reach statistical significance by three years.

“Intensive” NRT no better
371 Nicotine satisfies the craving for nicotine by binding to brain nicotine receptors. Varenicline reduces the craving for nicotine by binding to brain nicotine receptors. In this trial they compared single mode nicotine administration (a patch), dual mode nicotine (patch + lozenges, called C-NRT), and varenicline. “Among adults motivated to quit smoking, 12 weeks of open-label treatment with nicotine patch, varenicline, or C-NRT produced no significant differences in biochemically confirmed rates of smoking abstinence at 26 weeks.”

JAMA Intern Med Jan 2015 Vol 176
Patchy postal service
OL In a research setting, provision of nicotine patches in reducing doses, together with behavioural support, seems to help people stop smoking. But observational studies suggest that this may not happen in real life. A Canadian trial tested the value of mailing the patches to 500 people who smoked more than 10 cigarettes a day and wanted help in giving up, while leaving another 500 to fend for themselves. Self-reported abstinence rates were significantly higher among participants who were sent nicotine patches compared with the control group (30 day abstinence: 38 of 500 vs 15 of 499; odds ratio, 2.65). They had hoped to confirm cessation with biochemical proof from saliva, but only half the participants submitted usable samples. It was half and half between spitting for the study and spitting on it. Not very grateful, considering how much nicotine patches cost in North America.

Dialysis dilemmas
OL “Observational studies examining the association between the timing of initiation of dialysis and subsequent outcomes have contradictory findings. Most studies have reported higher mortality when dialysis is started earlier in the course of CKD or at a higher estimated glomerular filtration rate . . . Other studies, however, have reported no difference or improved survival when dialysis is started earlier in the course of CKD.” Renal medicine is a black box to me. I couldn’t begin to discuss it with patients. So who actually does the discussing, and how well is it done? This landmark qualitative study addresses these questions unsparingly. It is open access and needs to be read by everyone interested in shared decision making as well as by all renal physicians. I’ll quote at length:
“The timing of initiation of dialysis reflected the complex interplay of at least three interrelated and dynamic processes. The first was physician practices, which ranged from practices intended to prepare patients for dialysis to those intended to forestall the need for dialysis by managing the signs and symptoms of uremia with medical interventions. The second process was sources of momentum. Initiation of dialysis was often precipitated by clinical events involving acute illness or medical procedures. In these settings, the imperative to treat often seemed to override patient choice. The third process was patient-physician dynamics. Interactions between patients and physicians were sometimes adversarial, and physician recommendations to initiate dialysis sometimes seemed to conflict with patient priorities.”
It does not sound good. A couple of weeks ago in the NEJM, Terri Fried wrote that “The greater the uncertainty surrounding the options and the greater the clinician’s ambivalence about the ‘right’ choice, the greater the likelihood that the patient will be asked to make the decision.” That isn’t what this real life study reveals, but it’s equally undesirable. Shared decision making with vulnerable patients in the context of organ failure needs a lot of honest thought before we can implement humane and realistic solutions. This is a great mapping paper and it reveals an ugly landscape. Now we need some well designed research on solutions—in heart failure and advanced respiratory disease, as well as end-stage renal failure.

Lancet 30 Jan 2016 Vol 387
High BP: Two systematic reviews
435 Every generalist doctor has to make decisions about lowering blood pressure. Every good doctor wants to share those decisions with the symptomless individuals who may be expected to take tablets for the rest of their lives. The Lancet now has two systematic reviews on this issue, one on its website from 23 December 2015, which I commented on in my first blog of the year, and this one which first appeared on 7 November and now appears in print. The message (and some of the authorship) of both these reviews is the same: BP lowering below a systolic of 140 mm Hg will yield population reductions in cardiovascular events, death, and renal failure. I don’t propose to compare the two or repeat my previous comments. I just long for the day when reviews like this come with infographics, which tell clinicians what the estimated lifetime benefits are for people with particular aggregated risk, or better still, for clusters of risk. Until then, we are just treating the herd to make population statistics look better.

Gnomes, genes, & futility
433 Most of the articles on the Lancet website are currently about genomics. They don’t make very happy reading. In case you have wearied of my curmudgeonly comments on this vast area of medical endeavour and spending, just read a nice short letter on the subject from Australia, including these sentences: “A broad, genomic, health risk factor modification approach to major complex diseases has not yet proven to be effective. An alternative strategy is needed to deliver on the promise of personalised medicine . . . Genomic medicine achieved its initial success with its application to serious diseases caused by highly penetrant alleles.” I’ll leave it at that for now.

The BMJ 30 Jan 2016 Vol 352
Falls hope fails
I am constantly struck by the lack of evidence for all sorts of well intentioned things we do to improve patient care and safety. This article tells us that there are 250 000 falls in British hospitals each year, resulting in over 1000 fractures. “The 6-PACK programme is a targeted, nurse led, multifactorial falls prevention programme designed specifically for acute hospitals. It includes a nine item fall risk tool and six interventions. The components of the 6-PACK programme were selected on the basis of best available evidence at the time of development, expert opinion, and best practice guideline recommendations.” It is eminently practical and sensible and was implemented by Australian nurses, noted for their similar qualities. But when 16 medical and eight surgical wards were randomised to 6-Pack or usual care, it made no difference to falls and injuries.

Deadly psychiatry
For over a year, I’ve been meaning to order and read Peter Gøtzsche’s Deadly Psychiatry and Organised Denial. One of the great things about Peter is that he is willing to commit to hard work as well as often outspoken advocacy. He has long promoted the cause of individual participant data meta-analysis, as well as attacking the misrepresentation of harms and benefits for psychotropic drugs. Here his team look at all the clinical study reports they can get access to so as to ascertain the true risk of suicide and aggression in people taking a range of non-tricyclic antidepressants, based on clinical study reports. For adults, there is no signal for added risk, but for children and adolescents the risk of suicidality and aggression is doubled. Yet some fuzziness remains, which can only be dispersed by making the full individual data available.

Plant of the Week: Chaenomeles speciosa “Kinshiden”

The prolonged mildness of this British winter means that various specks of colour are appearing in urban gardens where by rights there should be none for another two months. On closer inspection, many of these are the emerging flowers of Japanese quince bushes.

These are the easiest of small shrubs and come in a range of flower colours, almost all of them delightful. Any branch stuck in the ground will yield a new plant, though it may be a slow process. Watch out for the stout thorns though. In good soil Japanese quinces can grow over 2m high and need to be kept in check. More often they settle for less and are often grown as wall shrubs, where their tendency to untidiness can actually make them quite picturesque. The traditional waxy red flowered ones can look magical against weathered stone walls, as visitors to Magdalen College, Oxford will recollect.

Kinshiden is a new one from Japan with double flowers of white and pale yellow. We already have a red quince and a few apple-blossom quinces (Moerloosei) but I’ll definitely buy this one if I come across it. Once the flowers have finished their weeks of loveliness, the shiny leaves are attractive, and then in autumn you can collect the fragrant hard fruit and make quince jelly. Not the original, true quince jelly made from the fruit of Cydonia oblonga, but just as delicious.