Richard Lehman’s journal review—9 March 2015

richard_lehmanNEJM 5 Mar 2015 Vol 372
893 “A Precious Jewel—The Role of General Practice in the English NHS” is an essay by Martin Marshall from University College, London. It is open access, and the best summary I have read of the plight of general practice after the maulings of the last few years. Without being polemical, Marshall makes it very clear that all the elements which patients want, and which should shape the medicine of the future, are already present in UK general practice, but are being rendered ever less possible to deliver.

905 “Cleaner Air, Bigger Lungs” is the title of the editorial that accompanies a longitudinal study of air pollution and pulmonary function in three cohorts of kids living in Southern California between 1994 and 2011. That sums it up nicely: “We have shown that improved air quality in southern California is associated with statistically and clinically significant improvements in childhood lung-function growth. The pollutants we found to be associated with lung-function growth—nitrogen dioxide, PM2.5, and PM10—are products of primary fuel combustion and are likely to be at increased levels in most urban environments. These pollutants were among those effectively reduced through targeted policy strategies.”

914 By the time you get down to E on a list, interest starts to fade. Vitamin E and hepatitis E are the also-rans of medicine; like minor sports for bored men on Sunday afternoons. Not so, however, if you are a pregnant woman with hep E in Bangladesh. They “estimated the incidence of hepatitis E in areas in which HEV genotype 1 is endemic to be 3.3 million cases per year, resulting in 70,000 deaths and 3000 stillbirths. This may be an underestimation, because a recent study suggests that, in Bangladesh alone, hepatitis E is responsible for more than 1000 deaths per year among pregnant women.” The other 3 genotypes are less aggressive but widely distributed and sporadically very harmful. GlaxoSmithKline and Xiamen Innovax Biotech developed a recombinant hep E genotype 1 vaccine called Hecolin which has been used in China since 2012. Here’s a study that shows that 3 doses provide lasting immunity for 4.5 years, with a vaccine efficacy estimated at 87%.

JAMA 3 Mar 2015 Vol 313
905 Among the books which Osler suggested that every doctor should read is Don Quixote. I ardently agree. The middle-aged Don had his head turned by the Arthurian tales of knight errantry which were immensely popular at the time, and he decided to become a knight errant in his own right. He set out with Sancho Panza to wander the earth righting every supposed wrong he encountered. I am blissfully rereading Cervantes at present, and then came across this Canadian study which seeks to help homeless people with mental health problems. Like the poor knight, it is entirely provider-centred and led astray by its own language: “Importance Scattered-site housing with Intensive Case Management (ICM) may be an appropriate and less-costly option for homeless adults with mental illness who do not require the treatment intensity of Assertive Community Treatment… Conclusions and Relevance: Among homeless adults with mental illness in 4 Canadian cities, scattered site housing with ICM services compared with usual access to existing housing and community services resulted in increased housing stability over 24 months, but did not improve generic quality of life.” These people’s lives are dominated by disorientation, fear, cold, heat, shit, hunger, insults and random acts of kindness, all of which form the incomparably rich substrate of Don Quixote. It is human life as it always was and still is for millions of people: even some Canadians.

916 A French study (PremedX) questions the ritual of premedication before elective surgery. The agent was lorazepam at a dose of 2.5mg: a fair old clobber for most people. But “compared with placebo or no premedication (it) did not improve the self-reported patient experience the day after surgery, but was associated with modestly prolonged time to extubation and a lower rate of early cognitive recovery.”

926 “The Natural History of Benign Thyroid Nodules.” We now know an awful lot about these, thanks to guidelines which demand that they be followed up with annual ultrasound and rebiopsy if there are signs of enlargement. Eight academic units in Italy collected a series of 153 patients (174 nodules) whose nodules showed significant growth. Two of these became cancerous, compared with three cancers which developed de novo or in nodules which did not grow. I know these figures don’t make sense on their own: if this is your kind of topic you need to dig into the full paper and the accompanying editorial, which draws out the main lessons, including the fact that a lot of the Italian cohort were iodine deficient.

JAMA Intern Med Mar 2015
OL “Do carry on Rx to reduce SBP below 130 in nursing home pts @JAMAInternalMed if you want to kill them” I wrote on Twitter a couple of weeks ago. This week it will have to be “Do carry on Rx to reduce SBP below 130 in cognitively impaired elderly @JAMAInternalMed if you want to worsen their dementia.” This study was conducted over a three-and-a-half year period in two Italian memory clinics. Low daytime systolic blood pressure was independently associated with a greater progression of cognitive decline in older patients with dementia and mild cognitive impairment among those treated with blood pressure lowering medication – as most of them were.

The Lancet 7 Mar 2015 Vol 385
857 Roflumilast is an oral phosphodiesterase 4 inhibitor which Takeda put on sale about 5 years ago at a fairly moderate price—a bit over £1 daily—to reduce exacerbations in chronic obstructive pulmonary disease. Now COPD is a drug manufacturer’s dream—it is very common, and whatever you do, it gets worse, so doctors are always keen to try out new drugs in the hope of some marginal benefit. If you can demonstrate that your product reduces exacerbations, it’s win-win: neither the doctor nor the patient can possibly know if it is working, but will carry on with it just in case. The regulatory bodies, particularly NICE, weren’t convinced that roflumilast had a sound enough evidence base. Since trials of new drugs are almost never done except by their manufacturers, it fell to Takeda to design, conduct, analyze and write up another trial of their product. They enrolled 1945 patients with severe chronic obstructive pulmonary disease from 203 centres in 21 countries. Fewer than 10 patients per centre for a common condition? Standard practice as we know. The final hurdle is to get a study like this past the eagle-eyed editors of a major journal which derives a substantial income from reprint sales.

Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy, even in combination with tiotropium.”

What does “our findings suggest” really mean? It’s a real struggle to work this one out. “The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13•2% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0•805 vs placebo 0•927; rate ratio [RR] 0•868 [95% CI 0•753–1•002], p=0•0529), and 14•2% lower according to a predefined sensitivity analysis using negative binomial regression (0•823 vs 0•959; 0•858 [0•740–0•995], p=0•0424).” I read this as saying that the alleged benefit of roflumilast is either just non-significant statistically or just significant: clinically, the meaning of 13% fewer exacerbations is uncertain as “The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1•8%) deaths occurred in the roflumilast group compared with 18 (1•9%) in the placebo group.” On such quibbles do sales of billions of dollars depend. No need for robust regulation, independently designed and conducted trials, and journals with no financial interest in publishing saleable studies. The present system is perfect for providing what it provides.

867 Having gone on at length about that paper, I could go on at much greater length about elevated blood pressure and its treatments from the differing perspectives of the population and the individual. Say that (like me) you are a bit fatter than you should be and have a slightly elevated blood pressure. What does the massive database held by the Blood Pressure Lowering Treatment Trialists’ Collaboration have to say about the best drugs for you/me to take? “We found little evidence that selection of a particular class of blood pressure-lowering drug will lead to substantially different outcomes for individuals who are obese compared with those who are lean.

875 Pyogenic vertebral osteomyelitis is a pretty uncommon condition but one that needs spotting early and treating “aggressively” with appropriate antibiotics. If I had it I wouldn’t quibble about what “aggressive” meant: enough to ensure a cure would be sufficient. Standard practice is 12 weeks on a cocktail of oral fluoroquinolone plus rifampicin. In this open-label, non-inferiority, randomised controlled trial, they enrolled patients aged 18 years or older with microbiologically confirmed pyogenic vertebral osteomyelitis and typical radiological features from 71 medical care centres across France. Patients were randomly assigned to either 6 weeks or 12 weeks of antibiotic treatment. Cure rates at one year were the same.

The BMJ 7 Mar 2015 Vol 350
How much “overdiagnosis” should we accept in a cancer screening programme? I have read a lot of the literature, scanned the trials as they have appeared, and wrestled with the subject for at least 15 years—and I couldn’t give you a straight answer. Indeed I would be sceptical of anyone who tried. In this online survey, women were presented with scenarios on breast and bowel cancer, men with scenarios on prostate and bowel cancer. Respondents ranged from 0% to 100% in the level of overdetection they would find acceptable, with medians ranging from 113 to 313 cases of overdetection per 1000 people screened. I’m not even sure that it is possible to produce decision aids that would genuinely achieve informed choice in the majority of the population: but it is worth trying.

As for what constitutes “overdiagnosis” in different contexts, there is a good analysis piece based on the excellent conference last September.

Trials and systematic reviews: I know these subjects put a lot of clinicians off, and I sustain a faint hope that my readership includes a lot of clinicians. Guys: you need to be interested, because it is by means of this information that you treat patients. Individuals. Maybe you switch off because you realize that trials only give summary data about recruited populations, not individuals, and these summary data are prone to manipulation and selective reporting. Good—I’m with you on that. The “evidence” in evidence based medicine is the evidence that is there, not the evidence that should be there. But how are we ever going to change that? Two ways: by doing different, quicker, bigger, smarter research; and by making better use of the data about individuals that currently lies hidden. Beate Wieseler is head of Department of Drug Assessment in Germany’s equivalent of NICE, and she and her team report on the quality of the dossiers provided to them. “Conventional, publicly available sources provide insufficient information on new drugs, especially on patient relevant outcomes in approved subpopulations.

Beate is a great advocate of open trial databases and meta-analysis of individual patient data. I just don’t see that there’s any excuse for meta-analyses which ignore the availability of IPD—and which don’t attempt to get to IPD from databases which are currently hidden from view. But in case this sounds over-zealous and geeky I will simply commend to your attention this survey by various forward-looking Cochranites, which concludes that “systematic reviews and meta-analyses based on IPD are being under-utilised. Guideline developers should routinely seek good quality and up to date IPD meta-analyses to inform guidelines.”

And now for the Quality and Outcomes Framework in UK general practice. I have already used a naughty word once in this review, so in the interests of family reading I will make no comment on QOF. “All-cause and cause-specific mortality rates declined over the study period. Higher mortality was associated with greater area deprivation, urban location, and higher proportion of a non-white population. In general, there was no significant relationship between practice performance on quality indicators included in the QOF and all-cause or cause-specific mortality rates in the practice locality.”

Plant of the Week: Abeliophyllum distychum

Every couple of years I mention this little shrub, but my influence is clearly insufficient because it has not yet reached the “widely available” category in The Plant Finder. Yet there is nothing quite like it for gratification at this time of year, when its little white flowers, tinged with pink, cover the stems and exhale a perfume like honey mixed with Dove soap. It’s as hardy and easy as forsythia, and just as free-flowering, but the colour is much better, and of course it wins outright for its scent.

The rest of the year it’s a bit straggly and non-descript, but you can cut it back hard after flowering and it keep it from looking as messy as forsythia. A one-trick pony, then, but what a welcome trick it is to have abundant scented blossom before anything else in the garden.