December 10th, 2012
Selections from Richard Lehman’s Literature Review: December 10th
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
NEJM 6 Dec 2012 Vol 367
Aliskiren for Type 2 Diabetes (pg. 2204): Renin starts off the renin-angiotensin-aldosterone cascade, and it was inevitable that it would become a target for pharmacological blockade; just odd that it took so long. Had ACE inhibitors and angiotensin receptor blockers and aldosterone antagonists not got there first, renin antagonists like aliskiren would undoubtedly have become first-line drugs for hypertension and heart failure. In this RCT, the drug is compared with placebo in diabetic patients with cardiovascular disease and/or renal impairment who were already on treatment with an ACEI or ARB. The initial results were good: aliskiren lowers blood pressure and reduces albuminuria. So why don’t we prescribe it for all our high-risk diabetic patients, as we do other drugs for which we have only these end-points to go by? But wait: this Novartis trial actually measured death and cardiovascular events; and by the second interim analysis, these had become significantly more frequent in the aliskiren group. Oops: if only the trial had stuck to surrogates, all would have been well. But now there will be no market for aliskiren: she arrived too late on the scene, and was too well investigated.
Lancet 8 Dec 2012 Vol 380
Monoclonal Antibody to PCSK9 in Patients with Hypercholesterolemia (pg. 1995): The Lancet seems to have adopted a policy of filling its research section with reports of phase 2 trials. This is decidedly odd, since these trials are by definition useless to practising clinicians, dealing with preliminary safety issues and dose-finding in compounds which may be years away from licensing. Take the two Amgen-funded trials in this week’s Lancet: they deal with a new monoclonal antibody AMG145 which reduces low density lipoprotein cholesterol. Of course, the drugs of choice we use when we want to reduce LDL-C are the statins, which are so cheap, safe and effective that any other intervention is going to have a very hard time finding a market. The first of these trials was conducted in 52 centres and recruited 411 participants: “For ethical reasons related to conducting a placebo-controlled study in which some patients would receive no active antihyperlipidaemia treatment, we enrolled patients with low cardiovascular risk who did not require cholesterol lowering therapy.” OK, so these people were not actually “patients” at all but healthy volunteers with highish levels of LDL-C. And sure enough, AMG145, the new antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), resulted in lowering of LDL-C and seems not to have had any adverse effects in the short term.
Monoclonal Antibody to PCSK9 Plus Statin in Patients with Hypercholesterolemia (pg. 2007): The other Amgen phase 2 trial looked at the dosing and safety of AMG145 in 631 patients with hyperlipidaemia and a fasting LDL-C level above 2.2 mmol/L despite treatment with a statin and/or ezetimibe. Again, fortnightly or monthly injections of AMG145 reduced LDL-C levels. So the paper concludes that the next requirement is “a large phase 3 clinical trial with several years of follow-up to investigate the long-term clinical efficacy and safety of AMG 145 in patients at increased risk of cardiovascular events.” Yes indeed: a trial with real end-points and an active comparator, which may with luck be completed and reported by 2020. Until then, this drug is of absolutely no interest to 99% of readers of the Lancet. So what are these lengthy reports doing in the UK’s leading medical journal? Is the reprint income they may bring from Amgen really sufficient to justify such a waste of space? Exactly what is this journal supposed to be for?
Ann Intern Med 4 Dec 2012 Vol 157
Warfarin vs. New Oral Anticoagulants for Management of AF and VTE (pg. 796): For many years now I’ve been tracking the progress towards fixed-dose anticoagulation without INR monitoring in these columns. It’s a nice idea and of course an enormous market for drug companies: there are many agents and many RCTs. I’m amazed that the authors of this systematic review of their comparative effectiveness against warfarin could narrow the field down to just six, including trials for both atrial fibrillation and venous thromboembolism. Their conclusion is prosaic and rather obvious: “Treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment.” If you have an excellent system for INR control, and patients are compliant, then the extra cost of these agents is not warranted at present. But when they come off patent, things may change, and INR testing may disappear and become one cost less for all health systems.