Richard Lehman’s journal review—4 August 2014

richard_lehmanNEJM 31 July 2014 Vol 371
397  Set aside half an hour to enjoy this week’s New England Journal. The key articles are all about malaria, and they are free. You might expect an account of The Origins of Anti-Malarial Drug Resistance to be both boring and depressing, but this one by Randall Packard is neither. It is beautifully written and I found it quite exhilarating. The key to eliminating drug resistance in malaria is quite simple: improve the living and working conditions of gem miners in the Pailin province of Cambodia. For decades, men from surrounding countries have flocked to these mines to earn a few months of money by digging for long hours, surrounded by water filled shafts and sleeping outside by night. When they get a fever, they pay half their earnings to get subtherapeutic doses of artemisinins. They are the breeding ground of resistant malaria and take it back to their homes across South East Asia. I’m struck by the parallel with Rudolf Virchow’s miners in his famous Report on the Typhus Epidemic in Upper Silesia (1848), where he states that the outbreak could not be solved by treating individual patients with drugs or with minor changes in food, housing, or clothing laws, but only through radical action to promote the advancement of an entire population, which could only be achieved by “full and unlimited democracy” and “education, freedom, and prosperity.”

403  In the meantime, there have to be technical fixes of course. These are relatively simple to devise, given the physiological differences between human beings and malaria parasites. Novartis has just come up with one called spiroindolone KAE609 or cipargamin, and within a few hours it cleared parasitemia in adults with uncomplicated P. vivax or P. falciparum malaria. It will need to be used with a mixture of care and militancy. The human race has already squandered good opportunities to get rid of malaria. The problem is not to devise new drugs, but to devise new ways of delivering social justice in an age of greed. Selling cipargamin to the gem miners of Pailin to make Novartis richer is just going to drive the problem through another cycle. We need to heed Virchow, who went slightly mad thinking about these things. He opposed the germ theory of disease because he saw it as a distraction from the need to improve social conditions: he hated Darwinism for the same reason. Eliminating malaria is a challenge to the human race to work in self interested harmony.

411  Next, to a classic of British epidemiology, which deserves a place alongside John Snow‘s astonishing investigation of the Southwark and Vauxhall Waterworks Company and the London cholera outbreak of 1849. Snow trudged the streets of London, ascertaining each case and the supplier of water to each household, at a time when the germ theory of disease was still widely derided. This later gave rise to the term “shoe leather epidemiology.” The many authors of “Spread of Artemisinin Resistance in Plasmodium falciparum Malaria,” by contrast, performed their heroic feat of clinical investigation not by shoe leather, but by arduous teamwork across 15 sites in 10 countries: seven in Asia and three in Africa. They used an in-vivo assay of artemisinin resistance: “Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral blood samples were measured every 6 hours, and the parasite clearance half-lives were determined.” Golly, this is worthy of Manson himself. And to top it all, they used this to create a map that rivals Snow’s Broad Street classic. The parasite clearance time following artesunate is directly proportionate to the closeness of the site to the Pailin gem mines of Cambodia. Remove the pump handle! Close the mines!

474  But this is not the message of the rather gloomy editorial, which seems to think that resistance is inevitable. A rare hopeful note is struck when the author says: “Fortunately, scientists in academia and pharmaceutical companies have learned from this lack of preparation, and despite the current success of artemisinin-based combination therapies, an active program of development of antimalarial drugs has been sustained during the past two decades.” But I’m with Virchow and Snow on this. Close the mines until everyone is properly housed and there is no standing water. Set up free clinics with proper testing and effective doses for everyone. Artemisinins remain perfectly effective drugs when properly used, even in Cambodia. They just take seven hours to clear the parasites, rather than two. This is a problem about humans, not plasmodia.

JAMA Intern Med August 2014
OL  Once more it is time to praise Joe Ross. He has two articles waiting to see print in JAMA Internal. The first one tracks the continuing use of ezetimibe in the United States following the ENHANCE trial, which demonstrated that ezetimibe use lowered cholesterol levels, but did not slow the progression of atherosclerosis. He and his team looked at the records of 10 597 296 continuously eligible adults in the USA, and found that nearly three years after ezetimibe had been shown to do nothing, 186 272 of them were still ezetimibe users, i.e. 1.8% of the total adult population.

His second shorter paper looks at how many of the pivotal trials that led to FDA approval of new agents have been published in peer reviewed biomedical journals. They all should be, of course, together with full de-identified data so we can all see whether these new treatments really work. But 14% are not even published in summary form.

OL  “UK declares war on antimicrobial resistance” is the depressing headline in this week’s Lancet.

The cudgel will fall on British GPs, who already have one of the most rational and parsimonious records of antibiotic prescribing in the world. To put this in perspective, it’s salutary to have a look at a report on antibiotic prescribing for community acquired pneumonia (CAP) in the USA between 1998 and 2009. American guidelines recommend a macrolide or doxycycline for previously healthy ambulatory patients with CAP. Fluoroquinolone monotherapy or a β-lactam–macrolide combination are recommended for patients with comorbid conditions, or risk factors for drug resistant Streptococcus pneumoniae infection. If we followed these guidelines here we would risk getting struck off. This little paper deplores the fact that American community doctors still prescribe old fashioned beta-lactam antibiotics for 18% of their chest infection patients. We prescribe nothing else, unless they are allergic to them. And we in Oxfordshire have just received a circular chiding us for prescribing too much co-amoxiclav instead of plain amoxicillin. When the UK declares war on antibiotic resistance, I suspect that the world will laugh, and go on doing exactly what it likes. Which is a pity, because it is outside—and not within these islands—that the problem is serious.

Lancet 2 August 2014 Vol 384
403  What do you know about ledipasvir–sofosbuvir? Something to do with hepatitis C? Well done. A cure, in fact, as I said when the trial appeared in the NEJM last May, and as I happily restate today. Some have rightly complained that the trial was more like an observational study of different combinations than a proper RCT, and with that I also happily concur. Happily because the results were so positive that there was no need for a proper RCT. And now we have another cure for hepatitis C, simeprevir once daily with peginterferon alfa 2a, judging by two genuine RCTs in this week’s Lancet. Worldwide, an estimated 170-200 million people have chronic hepatitis C virus infection, and 30% of all cases of cirrhosis, 25% of hepatocellular carcinomas, and over 350 000 deaths per year are attributable to this infection. Now we can be sure that all these people can be cured. But hardly any of them will be, until these drugs become affordable. Hepatitis C has become a problem about humans, not about viruses.

The BMJ 2 August 2014 Vol 349
A common complaint about meta-analyses is that they lump together apples and oranges. This one adds lychees, pineapples, melons, and persimmons, to name but a few. Plus, in aggregate and separately, spinach, peas, broccoli, lettuce, pak choi, sorrel, and carrots. In fact, this meta-analysis is singularly uninterested in what the intervention actually is. Nothing is named. Anything that counts as a fruit or a vegetable in the literature gets in. It is interested in a heap of statistics that can increase its odds ratio of getting published by The BMJ, and these are derived from 16 cohort studies, which try to quantify the consumption of fruit and vegetables in relation to the incidence of cardiovascular disease and cancer. It confirms—insofar as it can—that eating 4.3 portions of “fruit and vegetables” is associated with a reduced risk of dying from cardiovascular disease or cancer. Beyond that, you’re just eating them as food.

If you have a closed, displaced, intra-articular fracture of your heel bone in the UK, a surgeon will go in and try to put the bits together in the hope of a better long term result. But this hope is vain, according to this trial of conservative management versus open reduction and fixation, conducted in 22 British tertiary referral centres. “Operative treatment compared with non-operative care showed no symptomatic or functional advantage after two years in patients with typical displaced intra-articular fractures of the calcaneus, and the risk of complications was higher after surgery. Based on these findings, operative treatment by open reduction and internal fixation is not recommended for these fractures.” When orthopaedic surgeons conduct randomised trials to question their own standard practice, let nobody disparage the progress of evidence based medicine.

You are promised CME points if you trudge your way through this week’s Clinical Review about non-alcoholic fatty liver disease (NAFLD). Its prevalence worldwide is thought to be approximately 20% in the general population, and up to 70% in patients with type 2 diabetes mellitus. It is a new disease to monger, and nothing more, since the way to get your liver less fat is the same as to get any part of you less fat. Druin Burch has caricatured it as being the same as fatty elbow disease, and he has just written a thoughtful editorial on the subject for PLOS Medicine. This will not get you any CME points, but it will give you the pleasure of some well written, good sense on NAFLD and its partner in disease-mongerist crime: “chronic kidney disease”.

Plant of the Week: Clematis viticella “Kermesina”

Now that most of the horizontal spaces in our garden have been filled, we have become great buyers of clematis. This is perilous work. Just getting them home undamaged is a challenge. Then there is the problem of labelling. Half the clematis we have bought seem to be mislabelled. Clematis: an essential guide by Ruth and Jonathan Gooch costs £25, but is what it says on the cover: essential if you want to know what you’ve really got.

Next you must dig a hole as they advise, next to a shrub or tree. Most wall grown clematis are a straggly abomination. Make the hole deep, fill it with a few stones at the bottom for drainage, throw in some bone meal, mix some earth with dungy compost, put in the clematis so that first nodes on the stem are covered, add more soil and firm it up, water well, and you’re off. The wise gardener now forgets his/her clematis. If it lives, it is a delightful surprise. If it dies, well, you had forgotten it ever existed.

Our soil consists of one mass of clematis wilt spores, mixed generously with slugs. But the wilt fungus will rarely attack clematides of the species montana or viticella. So we avoid all the blowsy, large flowered mid-season varieties which are wilt-prone. This leaves us with a gap in mid-May to mid-July, but the garden is looking great then anyway. It’s about now that we are reminded of all the late flowering viticella varieties we’ve planted over the years. Just now the most splendid of them is the rich red “Kermesina,” catching the sun in the branches of a tall apple tree, which was grown by one of our little ones 20 years ago from the pip of a “Golden Delicious” apple she had shared with her grandmother.