December 16th, 2013

Selections from Richard Lehman’s Literature Review: December 16th

CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.

NEJM  12 Dec 2013  Vol 369

A Pharmacogenetic vs. a Clinical Algorithm for Warfarin Dosing (pg. 2283):  This week most of the NEJM is taken up with trials of genotyping to guide starting doses of vitamin K antagonists. Fair enough: this is a common clinical problem, and warfarin initiation is an important test case for genotyping as the gateway to personalised therapeutics. Dosing people with warfarin is currently a matter of trial and error: you grope your way forward, using lots of blood tests, and some patients end up on a dose of 1mg daily, others on a dose of 11mg, all for the same target INR. We know that a lot of this variation is governed by variants in the gene loci CYP2C9 and VKORC1. Now if genotyping can’t help in a situation as extreme as this, what use is it ever going to be as a guide to drug treatment? Here is the first trial of three: in 1015 patients during the first four weeks of newly started warfarin therapy, genotyping made absolutely no difference in achieving and maintaining the target INR.

A Randomized Trial of Genotype-Guided Dosing of Warfarin (pg. 2294): The next trial, from Europe, was smaller in size but longer in duration, and used a different genotyping platform. In 455 patients with atrial fibrillation being started on warfarin, slightly more of those in the genotyping group achieved their target INR at 12 weeks. The important outcomes—episodes of bleeding or thrombosis—were not measured in these trials.

A Randomized Trial of Genotype-Guided Dosing of Acenocoumarol and Phenprocoumon (pg. 2304): Finally, a similar trial was conducted in European countries where weirder coumarol anticoagulants are fashionable—acenocoumarol and phenprocoumon. These 548 patients fared exactly as well whether their dosing was guided by clinical factors or by genotyping. The journal runs two commentaries on these studies, one of which observes that, “The public’s expectations for pharmacogenetics may arguably be declining.” This is so true. Ever since I got my bus pass, I have used a lot of public transport, and never once have I overheard an upbeat conversation about pharmacogenetics. Neither of the articles can quite bring itself to make the final diagnosis. Yes, genotyping for vitamin K antagonist dosing may have appeared to stop breathing: yes, there is a dilated look about its pupils; no, we can’t feel a pulse; but it can’t be time to give up yet. Actually guys, if you don’t mind, I’m off for some coffee; and while I’m there I’ll fill out the death certificate.

JAMA  11 Dec 2013   Vol 310

Statin Therapy for Primary Prevention of Cardiovascular Disease (pg. 2451): Statins! For everybody who wants them, say I. You probably disagree, so read this clinical evidence synopsis about statin therapy for primary prevention of cardiovascular disease. We can agree that more evidence is needed: so once again, young research fellows, get digging in those large databases. I think the biggest question is whether the increase in “diabetes” with statins has any long term significance or is merely an artefact of the way we arbitrarily define “diabetes.”

Lancet  14 Dec 2013  Vol 382

Cangrelor: A New CHAMPION for PCI? (pg. 1981): When the Medicines Company ran its initial CHAMPION trials of cangrelor, a fast-acting intravenous platelet inhibitor, they failed to show benefit. Then earlier this year, the NEJM published the CHAMPION-PHOENIX trial which purported to show that “Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding.” But in fact it showed no such thing, because 63% of patients had received oral clopidogrel as well, as the NEJM editorial points out. Now the Lancet sees fit to publish a Medicines Company funded pooled patient data analysis from all the company’s CHAMPION trials with the conclusion that “Compared with control (clopidogrel or placebo), cangrelor reduced PCI periprocedural thrombotic complications, at the expense of increased bleeding.” So the bleeding bit is contradictory. But let’s leave the last word to the Lancet editorial entitled “Cangrelor: a new CHAMPION for percutaneous coronary intervention”, which ends “its favourable pharmacodynamic profile and effectiveness in reducing periprocedural events makes cangrelor a useful and welcome agent for interventional cardiologists and their patients.” The author then goes on to declare “I have worked as a consultant for AstraZeneca, Eli Lilly, and Sanofi, and my institution has received grant support from AstraZeneca and Boston Scientific.” So that’s all right then; his ringing endorsement of this product can’t be biased. Except that last year the Medicines Company and AstraZeneca joined forces to promote each other’s antiplatelet drugs, as reported in Forbes Weekly. How can the Lancet ignore conflicts of interest on such a scale?



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