Richard Lehman’s journal review—15 February 2016

richard_lehmanNEJM  11 Feb 2016  Vol 374

The decline of Alzheimer’s

523    Let’s start off on a happy note, and think about dementia. On Saturday morning the BBC News website ran a story about a new molecule tested on worms in Cambridge that could block the deterioration of brain cells. So there is hope. For the worms of Cambridge, if not for BBC journalists. And there is indeed hope for us all, according to a survey of 5205 persons 60 years of age or older followed up for three decades or more. “Among participants in the Framingham Heart Study, the incidence of dementia has declined over the course of three decades. The factors contributing to this decline have not been completely identified.” So the coming epidemic of dementia may not really happen at all, on the scale forecast by single-issue lobbyists, regardless of any British breakthroughs which may happen in the coming days, weeks, or worms.

Outpacing the evidence

533   Cardiac pacemaker technology is now very effective and reliable, barring the odd problem with the implanted battery site or breakage of the leads. So where might there be a gap in the market? The Micra transcatheter pacemaker, a single-chamber ventricular pacemaker made by Medtronic, is self-contained in a hermetically enclosed capsule with a volume of 0.8 cm3, a length of 25.9 mm, an outer diameter of 6.7 mm, and a weight of 2.0 g. It can be placed in the right ventricle and left to get on with it. Now pretend you are in charge of a large health organisation such as the NHS and you are being asked to purchase these devices. The performance figures look fine at first glance, but right near the end of the paper you come across the following: “The primary limitation of our study is the lack of comparison with a randomized control group. Instead, we compared the outcomes in our patients against separately defined performance criteria for safety and efficacy, and in a post hoc analysis we compared them with outcomes in a group of control patients. Additional limitations were that the follow-up data were limited to six months and that implantation experience was limited to the 94 physicians who performed the implantations.” This is honest, but damning. I think if you had responsibility for patients and for a limited budget, you could only respond, “Well, do another study, and make it randomised this time. And run it till the devices stop working and describe what happens then.”

Nearly there with polio

501   There were just 72 reported cases of wild poliomyelitis in the world in 2015, all of them in Pakistan and Afghanistan. Type 2 wild poliovirus, one of three strains responsible for centuries of human paralysis and disfigurement, has been eradicated. It is almost time to rejoice, but this free Perspective piece describes the difficult end-game which must be got right before we can break open the champagne. Oral vaccines containing attenuated live type 2 virus need to be withdrawn because they are causing harm, while better vaccines against type 1 and 3 need to be deployed universally until these strains also die out.

Nowhere near there with Zika

OL   The virus of the moment is of course Zika. You will all have read a lot about it, perhaps more than I have. But you may still want to read the short open access editorial on the NEJM website which lists the problems we have yet to overcome in understanding how the virus may be linked with microcephaly, and how we may be able to distinguish between active Zika infection and infection with other flaviviruses.

There’s an article in The Lancet about the WHO response to these issues.

JAMA  9 Feb 2016  Vol 315

Behave yourself with antibiotics

562    Antibiotic prescribing for respiratory tract infections in primary care: I’ve covered this so many times I’m losing the will to live. This study comes from the USA, where antibiotic prescribing for RTI is higher than in the UK and the proportion of resistant organisms is very much higher. A cluster randomised trial included 47 practices on both coasts of America, and used three behavioural interventions of proven value: 1. suggested alternatives presented electronic order sets suggesting nonantibiotic treatments; 2. accountable justification prompted clinicians to enter free-text justifications for prescribing antibiotics into patients’ electronic health records 3. peer comparison sent emails to clinicians that compared their antibiotic prescribing rates with those of “top performers” (those with the lowest inappropriate prescribing rates). All of them worked.

Stroke disappointments

571   I haven’t commented quite so often on specialised rehabilitation programmes for stroke, but I’ve read Cochrane reviews of several, and they generally report little or no difference from usual care. Sadly, that’s the outcome of this trial comparing the efficacy of a structured, task-oriented motor training program vs usual occupational therapy during stroke rehabilitation for upper limb motor deficits.

JAMA Intern Med  Feb 2016  Vol 176

A short sermon

OL   Oh dear, another negative study of telemonitoring to reduce readmissions for heart failure. I can feel a sermon coming on. Several sermons, actually. Enough to fill the whole of Lent with righteous gloom. First of all, how do you find out what patients living and dying with heart failure experience, and what drives them or their loved ones to call for an ambulance? Do you begin by measuring their sodium and BNP and weight and 6 minute walking distance? No, you spend an hour with each of them listening carefully to what they tell you, asking questions as needed. This is called qualitative research, about which The BMJ authors’ site has this to say: “Although we appreciate that qualitative studies can yield very interesting insights and questions, they don’t provide firm answers and hence have limited potential to improve doctors’ decisions. Our data show that most of the qualitative research we have published is rarely downloaded, shared, cited, or picked up in other ways by readers. Moreover, we’re increasingly prioritising papers that will be relevant to our wide international audience… and a lot of qualitative work tends to be very specific to its own setting.” Back in 2002, when The BMJ had a different policy, a paper appeared by Scott Murray and colleagues, based on 219 repeated qualitative interviews of 40 patients dying of lung cancer or heart failure and all those involved in their care. Whenever I have presented their findings in the UK or the USA, coupled with clips from the website, audiences have gasped in recognition and pondered why such experiences are still so common. Nothing like this 360-degree longitudinal qualitative research has appeared again in a high impact factor journal, but such journals have repeatedly published negative studies of expensive complex top-down monitoring interventions for heart failure. Cardiologists seem trapped in a belief system that if only patients will comply, decompensation in heart failure can be tracked in advance and prevented by timely adjustments in treatment. This has a mechanistic rationale of course. But it fails the test of real life, for reasons that lie with doctors as well as the limits of pharmacotherapy and the instinctive reactions of frightened sick patients. That may be one reason that value-exploring research is ” rarely downloaded, shared, cited, or picked up in other ways by readers” of The BMJ, and why so much futile research on complex interventions continues to be done.

Let us now sing Hymn number 292, “Through the night of doubt and sorrow Onward goes the pilgrim band.”

Lancet  13 Feb 2016  Vol 387

Tight fitting lithium genes

OL   The printed Lancet is badly out of sync with its website. I will do my humble best to catch up, though the mere sight of the author list for “Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study” is enough to make me flinch. This huge German-based partnership of gene gnomes has tried to find the exact locus that explains the varying response that people with bipolar disorder have to lithium therapy. They believe they may have succeeded: “The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.” Actually this is the fourth genome-wide association study of lithium response to be published, and each of them has come up with a different answer. We must stand by in humble admiration, monitoring our patients and awaiting important steps forward in the clinical management of bipolar disorder.

Biodegradable fashions

OL   Models have swanked down the catwalks of Paris and Milan in dresses made out of biodegradables, and in outfits made of cobalt and chrome alloy (probably). It is the same in the fashion world of cardiology. Normal people can get bored with this quite quickly. In this meta-analysis, bioresorbable vascular scaffolds did not lead to different rates of composite patient-oriented and device-oriented adverse events at one year follow-up compared with cobalt-chromium everolimus-eluting stents.

Fingolimod failure

OL    For nearly two decades, I’ve been commenting on trials of drugs for relapsing-remitting multiple sclerosis, though I’m left with no idea about a clear winner. The Moving Finger writes; and, having writ, moves on. I know I have written about fingolimod, because I remember calling it thingumybob. Beyond that, I remember nothing. It has some effect on relapsing MS, attributed to its effect on the sphingosine 1-phosphate (S1P) receptor. But primary progressive multiple sclerosis is a different and altogether nastier condition, and this trial shows that fingolimod makes no difference to progression. Nor does anything yet discovered.

BMJ   13 Feb 2016  Vol 352

Atypical glandular: what’s that doc?

Among the various worrying things that can appear on cervical screening reports there is “some atypical glandular cells seen: suggest referral.” A population-wide study from Sweden gives some statistics on what this means in terms of cancer risk: “The prevalence of cervical cancer was 1.4% for women with AGC, which was lower than for women with HSIL (2.5%) but higher than for women with LSIL (0.2%); adenocarcinoma accounted for 73.2% of the prevalent cases associated with AGC.” But wait: that was prevalence. What about subsequent cancers—incidence? Here’s the scary bit: “The incidence rate of adenocarcinoma was 61 times higher than for women with normal results on cytology in the first screening round after AGC, and remained nine times higher for up to 15.5 years.” But that’s just a relative figure. You can go to the text for the absolute figures, but overall you’re better off going to the commentary. But oops, that’s behind a paywall.

Now here’s a couple of questions: would you have found this paper more useful if it contained some infographics you could share with patients?

Would it have had more impact for you if you could click on a video link of patients being told about atypical glandular cells on their smear and showing how they went through their subsequent treatment?

Just asking. I know some of this sounds dangerously qualitative.

RCT results v population results

Randomized controlled trials are tedious to conduct, tedious to get funded, and often tedious to read. The commonest criticism is that they don’t reflect real-life populations. So now that we can collect data from whole real-life populations, why don’t we drop RCTs? This needs an hour’s worth of EBM seminar time to discuss, and here’s the paper the class needs to read, comparing estimated treatment effects for mortality between observational studies using routinely collected health data (RCD) and subsequent evidence from randomized controlled trials on the same clinical question. “Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials … Studies of routinely collected health data could give different answers from subsequent randomized controlled trials on the same clinical questions, and may substantially overestimate treatment effects. Caution is needed to prevent misguided clinical decision making.”

Plant of the Week: Teucrium fruticans 

There’s never been quite so flowery a winter as this one in England. That doesn’t stop February being a tiresome, unnecessary, and malevolent month, but it does remind one that from now on things are going to get better and better.

Despite some recent frosts, our teucrium has decided it’s time to produce lots of lovely blue flowers among its tousled silver foliage. These look more like the blooms of late summer, and rightly so, since the teucrium will flower then too. The foliage will look just the same but emit wafts of aromatic fragrance.

So here is a plant for all seasons. Once it is in full growth, treat it with great severity to stop it becoming a sprawling mess. If you want new plants, just stick the branches in the ground. It is probably best kept disciplined against a warm wall.