Richard Lehman’s journal review—11 May 2015

richard_lehmanNEJM 7 May 2015 Vol 372
1860 This week the NEJM is offering everyone a free lunch, in the form of an open access article and editorial on the theme of “Re-interpreting Industry-Physician Relationships.” But as everyone knows, there is no such thing as a free lunch, especially when it comes to relationships between doctors and the pharmaceutical industry. So what is going on? The key lies in the word “re-interpreting.” Using two straw-man examples and one real one (Vioxx), Lisa Rosenbaum, a national correspondent for the journal, seeks to show that too many people are cognitively biased towards an “Ugly House” interpretation of the pharmaceutical industry. She intends to develop this theme in two further essays, warmly commended to our attention by her editor Jeff Drazen. The only conflicts of interest they declare are their ties to the NEJM. But that is a pretty massive conflict, isn’t it? How much of the NEJM‘s income comes from reprint sales to the pharmaceutical industry? Sorry, I didn’t catch that… commercial confidentiality?—ah, I see.

1801 Here’s a place no-one wants to be. Twenty-three weeks pregnant, and you are going into labour. They give you tocolytics, they rush around you looking determined, but your tiny blue baby is born anyway. What next? This survey of American units shows that in some of them, the baby would be swooped away for full resuscitation and intensive care; in others, not. In the first instance, the likelihood of death is 67% and in the latter it is 76%, with a 25% chance of avoiding severe impairment in the first group and an 18% chance in the second. Grim figures which get worse with each day before the 23 week mark. I don’t know how you could begin sharing a decision in this situation, but it has to be done: as the title of the (British) editorial says, this is the Elephant in the Delivery Room.

1812 Are the latest methods of pathway ablation for atrial fibrillation just fancy toys for boys? As a total ignoramus, I couldn’t possibly comment, but here is the conclusion of a trial comparing three techniques: “Among patients with persistent atrial fibrillation, we found no reduction in the rate of recurrent atrial fibrillation when either linear ablation or ablation of complex fractionated electrograms was performed in addition to pulmonary-vein isolation. (Funded by St. Jude Medical).”

OL Readers of the NEJM who are eager to follow Lisa Rosenbaum in moving beyond the “Ugly House” view of the US pharmaceutical industry had better not read a perspective piece on the website called “Progress and Hurdles for Follow-on Biologics.” It is actually pretty impossible to read, with typical sections like this: “In the interim, the FDA has required that Sandoz use the suffix “-sndz” for its version of filgrastim. This measure may help physicians and patients distinguish biosimilars, but it may also induce confusion among those expecting versions of the same product to share the same active-ingredient name, and it is not necessary for effective postapproval pharmacovigilance. For reimbursement of provider-administered biologics, payers customarily require a Healthcare Common Procedure Coding System “J code.” The Centers for Medicare and Medicaid Services is currently considering requiring unique J codes for follow-on biologics under Medicare Part B.” So drug companies hire lawyers to screw each other while everyone tries to screw the FDA and the American public, and we onlookers lose the will to live. This does not look like the House Beautiful from where I am standing.

JAMA 5 May 2015 Vol 313
1719 We all live in fear of ecology, and rightly so. In the great scheme of life we are just the latest kind of plonker to arrive, while the micro-organisms which have been here for three or more billion years just get on using us opportunistically if we provide them with a suitable environment. Ammonites, dinosaurs, and mammoths have come and gone, but bacteria remain. They have no fears and no elections. When things change, they change and persist. Clostridium difficile doesn’t have a special craving for human diarrhoea. But get rid of the competition, and it will be very happy to live in it and produce toxins to keep a good supply going. Put back in some good shit germs, and they fade. Or, as this phase 2 trial shows, you can use “good” C diff to keep “bad” C diff at bay. “Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of nontoxigenic C difficile strain M3 was well tolerated and appeared to be safe. NTCD-M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence.”

1728 I would like to help Lisa Rosenbaum in her quest to help you reinterpret industry-physician relationships, so I am taking the unusual step of quoting the following from the latest trial report of a hepatitis C antiviral drug combination, funded by Bristol-Myers Squibb:
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Poordad reported having received grants and personal fees from Bristol-Myers Squibb, Gilead, AbbVie, Janssen, Merck, Novartis, and Salix and grants from Idenix, Theravance, and Achillion. Dr Sievert reported having received grants and personal fees from Bristol-Myers Squibb and personal fees from Merck, AbbVie, Gilead, and Roche. Dr Mollison reported having received personal fees from Bristol-Myers Squibb. Dr Bräu reported having received grants from Bristol-Myers Squibb, Gilead, AbbVie, and Vertex. Dr Levin reported having received personal fees or other support from Merck, Gilead, Bristol-Myers Squibb, and Janssen. Dr Sepe reported having received grants and personal fees from and having served on a speakers’ bureau for Gilead and AbbVie. Dr Lee reported having received grants and personal fees from Bristol-Myers Squibb, AbbVie, Achillion, Boehringer Ingelheim, Debio, GlaxoSmithKline, Gilead, Janssen, Genentech-Roche, Merck, Novartis, and Vertex. Dr Conway reported having received grants and personal fees from Vertex Pharmaceuticals, Merck, Boehringer Ingelheim, and Janssen Pharmaceuticals and grants from AbbVie and Gilead Sciences. Dr Pol reported having received research funding from Bristol-Myers Squibb, Gilead, Roche, and Merck Sharp & Dohme and serving as a speaker and board member for Bristol-Myers Squibb, GlaxoSmithKline, Boehringer Ingelheim, Janssen, Gilead, Roche, Merck, Sanofi, Novartis, Vertex Pharmaceuticals, and AbbVie. Dr Boyer reported having received personal fees from Merck Sharp & Dohme, Janssen, Gilead, AbbVie, and Bristol-Myers Squibb. Dr Bronowicki reported having received grants and personal fees from Bristol-Myers Squibb and personal fees from Merck Sharp & Dohme, AbbVie, Gilead, Novartis, Roche, and Boehringer Ingelheim. Dr Jacobson reported having received grants and personal fees from Bristol-Myers Squibb, AbbVie, Achillion, Boehringer Ingelheim, Gilead, Genentech, Merck, Janssen, and Vertex Pharmaceuticals, personal fees from Idenix, and grants from Novartis; having served as a consultant and advisor for Bristol-Myers Squibb, AbbVie, Achillion, Boehringer Ingelheim, Gilead, Genentech, Merck, Janssen, Vertex Pharmaceuticals, and Idenix; and having served on a speakers’ bureau for Bristol-Myers Squibb, Gilead, Idenix, and Vertex Pharmaceuticals. Dr Muir reported having received grants from Bristol-Myers Squibb and Roche; grants and personal fees from AbbVie, Achillion, Bristol-Myers Squibb, Gilead, and Merck; and personal fees from Theravance. Dr Reddy reported having received personal fees from Genentech-Roche, Vertex, and Novartis; grants and personal fees from Merck, Janssen, Gilead, Bristol-Myers Squibb, and AbbVie; and grants from Ikaria. Dr Tam reported having received grants from Bristol-Myers Squibb. Dr de Lédinghen reported having received personal fees from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck. Dr Sulkowski reported having received grants and personal fees from Bristol-Myers Squibb, AbbVie, Gilead, Janssen, and Merck and personal fees from Achillion. Ms Boparai and Drs McPhee, Hughes, Swenson, and Yin reported being employees of Bristol-Myers Squibb. No other disclosures were reported.

1736 The point I’m making is that this is perfectly normal. In fact Bristol-Myers Squibb is taking the moral high ground in the hepatitis C drug wars. While its competitors are happy to charge $84-95K for a curative course of their drugs, the company is entering into talks with health authorities in numerous countries and generic drug makers to make their product more affordable. I’m all for this kind of “moral competition” between pharma companies, which we’ve seen in data sharing as well. It helps to alleviate the worst excesses of predatory capitalism, and it eventually worked with drugs for HIV. But the system remains keenly predatory in most areas, as evidenced by drugs for multiple sclerosis, where prices for products in the USA have risen 5-7 times above general drug price inflation despite dubious efficacy and falling production costs. And it is crazy that drug producers continue to design, conduct, and analyze all the key trials of their own products.

JAMA Intern Med May 2015
OL A major breakthrough in stroke prevention for patients with atrial fibrillation is closure of the left atrial appendage, the place where clot forms before it shoots into the brain. The Lariat device has received US Food and Drug Administration (FDA) 510(k) clearance for soft-tissue approximation and is being widely used off-label for left atrial appendage (LAA) exclusion. But a study based on published reports comes up with some worrying findings: “In the FDA MAUDE database, there were 35 unique reports of adverse events with use of the Lariat device. Among these, we identified 5 adverse event reports that noted pericardial effusion and death and an additional 23 reported urgent cardiac surgery without mention of death.”

Ann Intern Med 5 May 2015 Vol 162
601 I don’t know if anyone in the UK uses low-molecular-weight heparin for women with unexplained recurrent pregnancy loss, but a new trial from Germany and Austria shows that it makes no difference to outcomes when given up to 24 weeks into gestation.

610 Just to remind you of the “obesity paradox” in type 2 diabetes, as observed in over 10,000 citizens of East Yorkshire with T2DM but no initial cardiovascular disease. Over 10 years, “overweight or obese patients (BMI >25 kg/m2) had a higher rate of cardiac events (such as the acute coronary syndrome and heart failure) than those of normal weight (BMI, 18.5 to 24.9 kg/m2). However, being overweight (BMI, 25 to 29.9 kg/m2) was associated with a lower mortality risk, whereas obese patients (BMI >30 kg/m2) had a mortality risk similar to that of normal-weight persons. Patients with low body weight had the worst prognosis.”

630 Many systematic reviews I read seem just to be going through the motions, but that would be an unfair description for this one which deals with stool transplants for the eradication of recurrent Clostridium difficile infection. This is a hot topic—or a very cool one, if you count the frozen pellet method—and I hope one form or other of this treatment will be universally used in the future. Some doubt remains about the best method of administration but there seems little doubt about its effectiveness and safety, though most trials are a bit crap in design and reporting (as almost always).

Lancet 9 May 2015 Vol 385
1843 “We conclude that maintenance treatment with capecitabine and bevacizumab until disease progression, after initial treatment with six cycles of CAPOX-B, can be considered standard in first-line treatment of metastatic colorectal cancer,” say the authors of this report of an open-label trial funded by Roche and Sanofi-Aventis. I am baffled. If you look at the Kaplan-Meier curve for survival, it makes no significant difference at any point. It does make some temporary difference to evidence of relapse, at the cost of one quarter of patients getting a nasty skin condition affecting their hands and feet.

1853 There’s more special pleading based on “progression-free survival” with a last-ditch drug for relapsed Hodgkin’s lymphoma, called brentuximab vedotin, which costs £2,500 per vial. Again The Lancet allows the pharma-funded authors to hype up its benefits: “This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation.” Facts: it caused a peripheral sensory neuropathy in more than half the patients, neutropenia in 35%, and “At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group.” No-one is going to persuade me that the present House of Cancer Drugs is anything but Ugly, however much whitewash journal editors allow authors to daub on it.

1902 “A retrospective and prospective analysis of the west African Ebola virus disease epidemic: robust national health systems at the foundation and an empowered WHO at the apex.” This sounds wonderful: am I dreaming? No, but the authors are. They are pointing out how things should be, not how they exist. The Ebola outbreak revealed the worst about some aspects of human nature and culture, and some of the best. Now it seems to be over, I’m happy to salute The Lancet for encouraging the latter.

BMJ 9 May 2015 Vol 350
My thirty-odd years of general practice in an Oxfordshire town were punctuated with occasional diagnoses of malaria, mostly in our close-knit Pakistani community. I was very fond of them, as they seemed of me, and they would occasionally confess that they didn’t bother with antimalarials when making trips to their families back home. That meant doing blood films if they got a fever, and the occasional discovery of Plasmodium vivax parasitaemia. This UK survey covers 27 years and confirms that P vivax is clustered in South Asian communities (note for US readers: that usually means the Indian subcontinent in British parlance) and that it is never fatal under the age of 50 in Britain. Although the peak time for travel to Pakistan and India is in the first three months of the year, the peak incidence of P vivax malaria here is between April and September. And there is a curious variation in latency of infection (the time it takes for hypnozoites to wake up and circulate)—a median 37 days April to September versus 143 days October to March. This is a really interesting paper, worth a full read.

After all the Ugly House stuff about rip-off pharmaceuticals I’ve had to report this and every week, it’s great to see a Dutch trial which shows that: “A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients.” Cost of etanercept: £200 per week. Cost of adalimumab: £350+ every one or two weeks. Hallelujomab.

Plant of the Week: Zaluzianskya ovata

I was charmed by a pot of this plant in a nursery which called it “night-scented stock” and promised that it would have evergreen leaves, abundant flowers and a lovely scent in the evenings. It does indeed have all these things.

It is a South African plant of about 15cm across at its largest, and like most plants from the area it likes wet summers and dry winters. So don’t depend on its surviving the British winter without special precautions.

So far we have been utterly charmed by its unusual daisy flowers, bright white when unfurled slowly during the day, but backed with dark red. Steal out as night falls. The scent is indescribable.