October 6th, 2014
Selections from Richard Lehman’s Literature Review: October 6th
CardioExchange is pleased to reprint this selection 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.
JAMA Intern Med October 2014
Medical Device Safety and Effectiveness (OL): I sounded off about the state of medical device control in both Europe and the US a couple of weeks ago. It’s so farcically inadequate you may want to look away. But for the brave, here are some articles brought to you by the editor of JAMA Intern Med, who is an author on one* of them:
Lack of Publicly Available Scientific Evidence on the Safety and Effectiveness of Implanted Medical Devices (free online)
*Assessing the Safety and Effectiveness of Devices After US Food and Drug Administration Approval: FDA Mandated Postapproval Studies
The Food and Drug Administration’s Unique Device Identification System: Better Postmarket Data on the Safety and Effectiveness of Medical Devices
Improving Medical Device Regulation: A Work in Progress (free online)
Lancet 4 October 2014 Vol 384
Familial Hypercholesterolemia: Moving swiftly past the printed Lancet for this week, which is unusually free of interest, we turn to the website and its latest editorial, with the title “Familial hypercholesterolaemia: PCSK9 inhibitors are coming.” Yes, indeed they are, but when should we let them arrive? When they have shown short term safety and good evidence of lowering LDL cholesterol? Or when they have shown long term safety and effectiveness in reducing actual cardiovascular events? Guess what, the two trials on the Lancet website only provide evidence about the first.
PCSK9 Inhibition with Evolocumab (AMG 145) in Heterozygous Familial Hypercholesterolemia (RUTHERFORD-2) OL: Heterozygous familial hypercholesterolaemia is the commonest dominantly inherited metabolic disorder in humans, affecting about one person in 250. That’s a market of three million people in the US and Europe. But I don’t think that’s the main reason why at least three drug companies are scrambling to produce monoclonal antibodies to treat it. Beyond these individuals lies the immense market for cholesterol lowering agents to reduce cardiovascular risk in the general population. Evolocumab seems to be ahead from the starting block. It binds to proprotein convertase subtilisin/kexin type 9 (PCSK9) which, as you probably know, directs the low density lipoprotein cholesterol receptor to lysosomal degradation, inhibiting its recycling to the hepatocyte surface and thus catabolism of plasma LDL. The evolocumab trials take their names from great physicists who were active 100 years ago. These are given in capitals, as if they were acronyms, but they are nowhere explained in the text. Perhaps just as well. RUTHERFORD-2, a randomised, double blind, placebo controlled trial, examined the effect of evolocumab in people with heterozygous hypercholesterolaemia, and it yielded a rapid 60% reduction in LDL cholesterol with no more adverse effects than placebo.
Inhibition of PCSK9 with Evolocumab in Homozygous Familial Hypercholesterolemia (TESLA Part B) (OL): It’s tougher work, however, using this strategy in people who carry paired genes which give them very high levels of LDL cholesterol. These rare unfortunates (one in 300 000) have homozygous familial hypercholesterolaemia. The TESLA part B trial used a relatively high dose of evolocumab and succeeded in lowering LDL cholesterol by 31% on average at 12 weeks in 33 individuals. But don’t think you have heard the last of this. Soon you will be reading trials of alirocumab and bococizumab, which are also antibodies to PCSK9. One day they could all become Bigbizumab.
The BMJ 4 October 2014 Vol 349
As with the Lancet, so with The BMJ. Let’s go straight to the website. Here are two important papers that refute ideas which I have tended to support. Great. That is what science is all about.
Effects of a Patient Oriented Decision Aid for Prioritizing Treatment Goals in Diabetes (OL): I have argued that our goal in diabetes should be to help people choose which outcomes matter most to them and let their treatment be guided by that. Researchers tried this out in 18 general practices in the north of the Netherlands. The intervention comprised a decision aid for people with diabetes, with individually tailored risk information and treatment options for multiple risk factors. Result: “We found no evidence that the patient oriented treatment decision aid improves patient empowerment by an important amount. The aid was not used to its full extent in a substantial number of participants.” That’s truly disappointing, but it is somewhat similar to Victor Montori’s experience with his own excellent decision aid developed at the Mayo Clinic some years ago. The problem seems to me that we are trying for too much culture change too quickly. That, and the fact that it is pretty impossible to know from the limited evidence we have which drugs for diabetes do what.
Industry Sponsorship Bias in Research Findings (OL): I was immersed in statins for several months this year until I began to drown. With these drugs too, the evidence about adverse effects and benefits is extraordinarily hard to convey in simple terms. Some of my friends take the view that these pills are being foisted on people by big pharma, who have exaggerated their benefits and played down their harms. I don’t believe the first part of that, and I believe that most of the “harms” are small and entirely reversible. But I was open to the suggestion that at least some of the company funded trials might have contained an element of oversell. Now Huseyin Naci and colleagues have done a superb systematic review and network meta-analysis, which reaches the following conclusion: “Our analysis shows that the findings obtained from industry sponsored statin trials seem similar in magnitude as those in non-industry sources. There are actual differences in the effectiveness of individual statins at various doses that explain previously observed discrepancies between industry and non-industry sponsored trials.” Splendid: industry deserves praise where it has acted honourably and provided us with sound knowledge about a genuinely life saving class of drugs.