HDL a negative risk factor? or cholesterol efflux??

This comment was sent to me by Elizabeth Russo, who worked on a formal evaluation of Entresto (the name of the combo drug valsartan/sacubitril) for the non-profit ICER (Institute for Clinical and Economic Review, at http://icer-review.org/ ):

[for my blog, see: http://gmodestmedblogs.blogspot.com/2016/05/heart-failure-guidelines-new-meds.html ]

Controversies and Uncertainties 

Criticisms of Entresto center on the PARADIGM-HF trial having compared the combination neprilysin inhibitor and ARB valsartan to the ACE inhibitor enalapril rather than to valsartan alone. Another critique relates to the fact that the pivotal trial was conducted only among patients who tolerated a “run-in” phase of treatment with enalapril followed by treatment with Entresto. There is also concern that neprilysin inhibition itself can potentiate angioedema. In fact, more patients in the treatment arm developed angioedema than did in the enalapril arm of the PARADIGM-HF trial (0.5% versus 0.2%). Further, investigators in the PARADIGM-HF trial gave patients in the control arm 10mg twice daily dosing of enalapril rather than 20mg twice daily dosing, which is the maximum (and goal) dose. Neprilysin inhibition is an emerging practice, which means there is limited experience using drugs like sacubitril long-term, and the long-term risks that might be associated with it are unknown. There is a theoretical risk that neprilysin inhibition might potentiate dementia from accumulation of amyloid plaques in the brain. FDA has required Entresto’s manufacturer to conduct a multi-center, randomized, double-blind, active-controlled trial to examine its effects compared to valsartan on cognitive function in patients with CHF and preserved ejection fraction. The argument for proceeding with drug approval before cognitive function studies are complete is that average life expectancy in patients with CHF is much shorter than the amount of time it usually takes to develop dementia.

Summary 

We judge there to be moderate certainty of an incremental to substantial net benefit for Entresto compared to standard of care with ACE inhibitor treatment in patients with Class II-IV CHF and reduced ejection fraction. There is moderate certainty because the PARADIGM-HF trial was a large, good quality study in which Entresto produced significant reductions in cardiovascular and all-cause mortality as well as in heart failure specific hospitalization and ED visits in comparison to an agent that itself has demonstrated clinical benefits in these domains. Some uncertainties remain, however, including the relative contribution of sacubitril versus valsartan to these results, the expected tolerability of Entresto, its clinical performance in real-world practice, and its potential for harm in certain patient subgroups. Given the entire body of evidence, our rating of comparative clinical effectiveness using the ICER Evidence Rating framework is B+ (“Incremental or better”).

So, somewhat similar criticisms to the below, but

--it certainly would have been much better to compare valsartan/sacubitril to valsartan, and the dose of valsartan in valsartan/sacubitril is the max dose, whereas enalapril is 20mg/d vs the max of 40/d [there are suggestions that ACE-I may be more potent than ARBs overall for HFrEF, though there have not been actual head-to-head studies that I have seen. Nonetheless, a cleaner/clearer study would have been as ICER suggests]

--the issue they raise of ??dementia/accumulation of amyloid is really concerning. And really brings up the issue here and with many studies of newer drugs: they affect/disrupt many bodily processes (which arguably have evolved over millennia and many/most have survived evolutionarily for a reason). And, again, studies which show positive results are often stopped early, as with PARADIGM-HF, which disproportionately showcase the benefits (which is why they are stopped early), yet understate the risks (which may take longer to manifest themselves)

Thanks for the info, Elizabeth (and I do welcome comments on the blogs)