Hi Iwfal, Thank you sharing the healthy and important pro vs con perspective.
1) with regard to hemorrhage in Jelis, this has certainly been mentioned at Clinical meetings over the years when Jelis data are reviewed and presented. The mentioned areas of hemorrhage in the Jelis paper include: cerebral, fundal, epistaxis and subcutaneous. It was the first mentioned which caused me reason to pause as it sounded somewhat similar to Statins which we know do decrease ischemic stroke on the one hand and yet have been associated with increasing intra- cerebral hemorrhage on the other.
The paper by Tanaka et al ( Stroke, 2008, 39, 2052-2058) in a Jelis Sub-analysis, observed a significant reduction of recurrent stroke in the the Secondary Population.
Stroke in the Primary Arm 1.3% (-EPA) and 1.5% (+EPA) HR 1.08; CI 0.95-1.22.
Stroke in the Secondary Arm 10.5 % (-EPA) and 6.8% (+EPA) HR 0.80 CI 0.64-0.997. No significant intergroup differences in Cerebral hemorrhage was observed. As R-It resembles more the Secondary population of Jelis, I believe that this is an important paper and point to include in your comments to make it more comprehensive.
It does not diminish your comment about significant observation of hemorrhage with V - I believe that the relevance of this may correspond to what many of us observe in clinical practice, namely subcutaneous manifestations such as bruising - as this is the most common in this category expressed by patients. I am of the opinion that increase in hemorrhage in the V Arm will in all likelihood be reported when R-It is finally published but I think of the more superficial variety while CVE may well show reduction not only in MI but also in Stroke.
2) with regard to mortality decrease, I do agree with you this is a greater hurdle to overcome. However, this is not new in the Lipid space. Statins have been notoriously inconsistent in Mortality benefit. Even the newest PCSK9 inhibitor add on to Statins in Fourier showed only a modest reduction in MACE with mortality leaning on the other side with a HR of 1.05.
You correctly quoted All cause death in Jelis 2.8 vs 3.1% HR 1.09 CI 0.92-1.28.
If one looks at Secondary Prevention in Jelis ( in my opinion somewhat closer to the R-It population) the HR of Coronary Death was 0.87 with a wide CI of 0.46-1.64. At least Coronary Death in Jelis Sec prevention Arm was on the favorable side. I do think that Mortality benefit may be a huge hurdle for V to overcome in R-It. If MACE and several SEs are significant I think that will be of huge clinical benefit without Mortality benefit, as most of us know how challenging such a hurdle is when adding an agent on top of Statins. This may well be more robust than adding Zetia (RRR 8%) or a PCSK9 (RRR 15%) on top of a Statin - and if the RRR exceeds 15%, V certainly will be occupying the value of an add on to Statins never seen before. If the Diabetes subgroup exceeds this, that will capture yet another clinical important clinical indication. Now if Mortality benefit is also observed, well then we all surely will be waking up to Breaking News not only locally but globally.
AI
