Richard Lehman’s journal review—29 August 2017

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM  17-24 Aug 2017  Vol 377

Pumping for cabbage

Time was when coronary artery bypass grafting (CABG) was the commonest major surgical procedure in the world. By 2002, when the Randomized On/Off Bypass (ROOBY) trial began recruiting, a strong trend was developing towards using percutaneous intervention instead, but the trial nonetheless managed to randomise 2203 men from US Veterans’ Hospitals to have CABG either using a cardiac bypass pump or off-pump. Theoretically, operating off-pump should reduce the risk of debris flying about the circulation and reaching the brain in particular, but right from the start the results of the trial favoured using a pump. At five years, this remains the case, just squeezing into the p-value significance zone, if you believe in such things. “The rate of major adverse cardiovascular events at 5 years was 31.0% in the off-pump group versus 27.1% in the on-pump group (relative risk, 1.14; 95% CI, 1.00 to 1.30; P=0.046).” Whatever the current place of bypass grafting in the treatment of ischaemic heart disease, doing it off-pump now seems to be unwarranted surgical showing off.

PCSK9 inhibitors and cognition

Hermann Ebbinghaus (1850-1909) pioneered the scientific study of memory, which is probably why his name was hijacked as the acronym of a substudy exploring the effect of evolocumab on cognitive function over a median of 19 months. Evolocumab, you may remember, is the monoclonal antibody which causes a massive drop in low-density-lipid cholesterol by binding to proprotein convertase subtilisin–kexin type 9 (PCSK9). According to what we know so far from the FOURIER trial, evolocumab produces a modest reduction in cardiovascular events when added to statin therapy in high-risk individuals. EBBINGHAUS ran parallel with FOURIER, to allay fears that tinkering so profoundly with LDL-C might be bad for the brain. So far there is no evidence of this: but 19 months is far too soon to be certain.

Tight BP control and patient reported outcomes

To me, the big question in the management of high blood pressure is how we might find the one person in a hundred who would benefit from long-term treatment and let the others go drug-free. But it’s much easier to do trials of ever-tighter control in the hope of demonstrating some marginal population benefit. The most notable in recent years was SPRINT, where the target systolic BP in the intervention group was set at 120 mm Hg or less. Conventional wisdom would predict that this could only be achieved at the expense of major adverse effects and poor adherence, but that doesn’t appear to be the case: “Satisfaction with blood-pressure care was high in both treatment groups, and we found no significant difference in adherence to blood-pressure medications… Patient-reported outcomes among participants who received intensive treatment, which targeted a systolic blood pressure of less than 120 mm Hg, were similar to those among participants who received standard treatment, including among participants with decreased physical or cognitive function.”

In a separate analysis, the cost-effectiveness of the SPRINT strategy is assessed, and here the situation is less clear: “We determined that the mean number of QALYs would be 0.27 higher among patients who received intensive control than among those who received standard control and would cost approximately $47,000 more per QALY gained if there were a reduction in adherence and treatment effects after 5 years; the cost would be approximately $28,000 more per QALY gained if the treatment effects persisted for the remaining lifetime of the patient.”

JAMA 15-22 Aug 2017  Vol 318

Does Shared Decision Making work?

On the floor beside me lie the 341 pages of the updated Cochrane Review of decision aids for people facing health treatment or screening decisions. This a magnificent compilation, which inspires an essay from one of the great leaders of the field, Victor Montori. The title is “Shared Decision Making and Improving Health Care: The Answer Is Not In.” Decision aids aimed at improving patient knowledge generally succeed in that aim. But only 10 out of the 105 trials included in the review actually tried to measure whether shared decision making had taken place. Only a small proportion of the tools examined had been adequately tested in randomized trials. But I am undeterred, because SDM tools are just adjuncts. Even SDM itself is an adjunct: it sets the moral compass for better conversations with patients, but full shared decision making on every detail of diagnosis and treatment is an ideal we more often approximate to than actually attain. Knowledge, honesty, and compassion are the real goals: we can never have enough of those.

Type 2 diabetes: too late to start being good?

Here is a successful trial of lifestyle change in type 2 diabetes dressed up as a failure. The reason is utterly boring and predictable: the outcome measure was a change in HbA1c. During a year of diet and exercise, this went from 6.65% to 6.34% in the intervention group and from 6.74% to 6.66% in the standard care group. In other words, all 93 participants who completed the trial had good glycaemic control to start with and retained it throughout. But nearly three-quarters of the intervention group were able to come off at least one drug, compared with a quarter in the standard care group. This was not a negative trial. We need longer, bigger, better ones with meaningful end-points.

BNP-guided heart failure treatment

“Brain” natriuretic peptide was discovered as a cardiac hormone in the early 1990s, and I latched on to it at once. Here was the very voice of the ventricles: ever changing, always saying something. But over years of measuring it in primary care (via research studies), I learnt that in all this chatter there is much more noise than signal. I am amazed at how long it has taken the cardiology community to realize this. Here is the latest attempt at using BNP to guide therapy in systolic heart failure. It adds 894 patients to the 3660 already assessed in the 18 randomised trials included in a recent Cochrane Review.

This latest US trial was discontinued for futility.”In high-risk patients with HFrEF, a strategy of NT-proBNP–guided therapy was not more effective than a usual care strategy in improving outcomes.” There is no longer absence of evidence for BNP-guided heart failure treatment: there is evidence of absence. Don’t do it. It doesn’t work.

JAMA Int Med Aug 2017

Continuing to Share Medicine

The “Sharing Medicine” series in JAMA IM was to have been my envoi to the world, but it looks as if I’m going to have to bumble on a bit longer. Here is the final article of the series, written with Louise Locock and Ron Epstein.

I hope to write quite a lot more about the Shared Understanding of Medicine over the next three years, and I hope lots of you will do the same. I’m delighted that others are continuing the theme in JAMA IM, as in this piece about Sharing and Healing Through Storytelling in Medicine.

Informed consent for trials of antibiotics

Peter Doshi looked at 78 trials of 17 antibiotics to see how well the trialists explained concepts such as noninferiority and “clinically acceptable” inferiority to trial participants. Here is what he and his colleagues discovered:

Question  How often is the study purpose explained to potential participants in randomized clinical trials of antibiotics?

Findings  In this cross-sectional analysis of trial documents submitted to regulators, no informed consent forms consistently conveyed the primary hypothesis of the study.

Meaning  Patients enrolling in antibiotic clinical trials are not accurately informed of study purpose, raising fundamental questions of the ethics of consent in antibiotic drug trials.

The Lancet Aug 2017  Vol 390

Is late-life dependency increasing?

Andrew Dilnot on the “burden of the ageing population” is always refreshing. “Life is getting longer. Death is not defeated, but it takes longer to win than it used to. The increases seen for most people in life expectancy are surely a matter for great rejoicing.” Here he is commenting on a study of changes in dependency between 1991 and 2011 in three English counties. “On average older men now spend 2·4 years and women 3·0 years with substantial care needs, and most will live in the community.” As this prospect steals upon me, my rejoicing gets ever less.

Pembrolizumab v ipilimumab for melanoma

It’s several years now since the unthinkable happened: a few patients with metastatic melanoma showed complete remission with treatment, and continued disease-free thereafter. I think the agent was ipilimumab, an antibody directed at the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathway. Antibodies of this type are called checkpoint inhibitors, and pembrolizumab is another one, working on a somewhat different T-cell pathway. The makers of pembrolizumab, Merck, are very keen to claim that it is better than ipilimumab. The pre-specified primary endpoint for their head-on trial was overall survival, defined as the time from randomisation to death from any cause. But they have submitted their report to The Lancet before median survival was established for either pembrolizumab dosage group. It seems very likely that pembro is the better drug, but a little more patience would not have come amiss.

Plant of the Week: Cimicifuga racemosa “Atropurpurea”

The official botanical name for this handsome late-flowering plant is now Actaea simplex but I prefer the old name which means “flea-ridder” in Latin. In English it has long been known as bugbane or just baneberry.

The word “bane” used to carry mighty power, but now barely survives in vestiges such as “he’s the bane of my life” or “she’s the bane of every new junior doctor on the ward”. Our local town is named after Bana, a sixth-century Anglo-Saxon warrior whose name is simply translated as murderer. They were fond of names like that round here: other local settlements are named for “Grim” and “Adder”, nice Saxon boys who were handy with an axe.

The flea-murderer has fragrant spikes of white flower above nearly black cut leaves: choose your plant carefully to make sure they are really dark and dramatic. The delicate flowers go on to form indelicate berries which can poison people as well as fleas. It’s a dramatic plant of late summer, but the bane of any child-friendly garden.