On-X CE-mark and (unfortunately) 1.5

[ElectLive]

Hello all. Well...my "attendance" has been very poor the last year or so, so unfortunately have not seen much of the recent conversations. But after taking a quick look, it appears no one has brought this up here yet, so let me try to do my best in limited time:

http://www.onxlti.com/x-life-technologies-reports-ce-mark-approval/
http://www.onxlti.com/wp/wp-content/uploads/2014/01/OnXLTI-Product-Profile.pdf

So, as you can see, On-X has achieved a pretty sizable milestone in the last week...CE-mark (Europe) approval for the reduced anticoagulation regimen that was studied in certain aortic valve patients as part of the ongoing PROACT trial. First things first, this is only approved in the applicable countries in Europe...FDA review is still ongoing here in the US. Second, this is not for mitral valve patients. Third, it is less than clear in those publications, but what was actually submitted for approval was an INR range of 1.5 to 2.0, not a fixed 1.5. Finally, it remains to be seen what the corresponding consensus guidelines experts in Europe have to say about this...approval is one thing, recommended typical practice is often quite another, or at least until further evidence is accrued (PROACT is after all not yet complete). In any case, this is obviously still a pretty big deal, newsworthy if nothing else.

Now, on to the opinion part of my post... :wink2: Ok, I have called into question some of the marketing efforts of On-X more than a few times here before. It certainly does go with the territory it seems, and they are certainly not alone. However, it really drives me crazy that they have not just the audacity, but I would go so far as to say foolish disregard for patient safety awareness to rename/rebrand and advertise their valve as follows:

The On-X Plus 1.5 (tm) Aortic Heart Valve : The first and only mechanical heart valve that can be safely managed at a therapeutic INR of 1.5, a near-normal level.

Yikes! :eek2: I've gone over the PROACT data several times before, and will not do that in detail again here. But here is one of the threads: http://www.valvereplacement.org/forums/showthread.php?41634-Latest-on-ProAct-for-Reduced-Anticoagulation-with-On-X-valve. A few key points from one of the data sources: The average INR range of the test group was actually 1.89, obviously much closer to 2.0 than 1.5 and the "overs" were also much more pronounced than the "unders". In fact, the true range studied probably more closely resembled 1.5 to 2.5 than it did 1.5 to 2.0. Also, the average INR range of the test group who had major bleeding events was actually 3.5 while the average INR range of the test group who had stroke events was actually 1.6.

So, I tell you what, CE-mark approval or not, I think it is outlandish for On-X to say in big bold letters that their valve can be safely managed at an INR of 1.5...made worse by the fact that they are renaming the valve to emphasize the point even further. That is simply not what PROACT has proven. It has proven that bleeding complications can be reduced, with a possible net benefit in composite (stroke and bleeding) endpoints. But obviously that is not what they are advertising...I guess not how you sell things. :rolleyes2: Thoughts?

 

[RobThatsMe]

I have an On-X aortic valve, and I look at it this way.
I shall take a wait and see attitude on this lower INR approval data above.
I have had a mechanical aortic valve since March of 2000, and feel very comfortable managing my INR between 2.5 and 3.5
There have been no issues to date monitoring my INR within this range,
and really see no reason to, "Up My Game", ( I hate that commercial!), and manage my INR in the lower ranges of 1.5 - 2.0

I do hope that the On-X company has a well founded patient sampling to justify the 1.5 claim, or else sometime in the future they will have multiple patient lawsuit "claims" in their laps.

Just my 2 cents on this..

Rob

 

[T in YVR]

Why don't you email On-X and raise your concerns and see what they say? I have emailed them in the past with questions etc, and they were very responsive. I am sure this type of concern would warrant a response....and if you do so, and you get a reply, you should post it here and share! I would be interested to hear what they have to say.

T

 

[clay_from_nj]

Ten years ago, research suggested that you could "up your game" (INR 1.5-2.5) with an ATS valve.

 

[Heart Of The Sunrise]

I agree with RobThatsMe: Accept that my cardio has me 2.0 to 2.5. No issues. I am usually 2.4 , 2.5, 2.6.

 

[pellicle]

Ten years ago, research suggested that you could "up your game" (INR 1.5-2.5) with an ATS valve.

clay, you are the man when it comes to the research!

Hats off!

 

[ElectLive]

...my cardio has me 2.0 to 2.5. No issues...

My guess would be that many cardios might take this approach, even should full approval continue into the US, then beyond. Sure, the number 1.5 for On-X is likely to sell more valves, but a meaningful interpretation of the available data would make a number like 2.2 for instance probably a much more reasonable number. In other words, still attempting to reduce bleeding events, but not veering too far over in terms of stroke risk. The interesting point of course is that On-X is somewhat playing the "how low can you go" game and looking at composite rates...meaning stroke and bleeding treated as equals from an evaluation standpoint. Most long term mechanical valve members here seem to more do the opposite...tending to err more on the side of bleeding versus stroke, for obvious reasons.

However, as I mentioned in that other thread, when pressed on this issue, the lead investigator admitted that for him the true benefit of PROACT has more to do with trying to better identify the "sweet spot" (optimal INR range) where the inverse event curves intersect, so not just targeting the lowest possible point in other words. FWIW...the PROACT curves they've shown were certainly not very detailed, but the sweet spot looked pretty close to 2.1. But that's again assuming bleeding and stroke as true equals. Also assuming 200 patients is enough for meaningful data, but that's another discusion!

In any case, it seems pretty likely, and I would guess, that neither the lead investigator, nor most cardiologists, would recommend 1.5 as a safe INR target. The On-X marketing team of course does so without reservation...hence my reaction. Now, perhaps as the lower limit of a range similar to the ATS study (1.5 to 2.5), though, maybe cardiologists will...that remains to be seen. It will probably be a tough medical decision, though. Despite the "statistically insignificant" difference in stroke at the study range, there were actually more events, more so seen in TIA's. Of course, lost in all of this is the fact that some patients just need the freedom (and reassurance) to reduce INR from "industry standard" either temporarily or long-term due to other conditions or procedures, and PROACT should be really really good news in that regard.

P.S. T in YVR - You know, despite appearances here otherwise, my mother is the reactionary letter writer in the family, not me! :wink2: But I'll certainly let you know if I change my mind and/or find the time to do so then get a response...thanks for the idea. Actually, what I'd really like to do is have a long conversation with the lead investigator. Lucky for me he's right down the road, partner of and second in command to my surgeon. But, quite honestly, I'm hoping to not have to talk to any surgeons for a while longer... :rolleyes2:

 

[Lynlw]

I've had similar thoughts about ON-X marketing and claims, in general and especially when it comes to the PROACT trial.

First I believe (IMO) that with all the talk when discussing valve choice of some day lower INR, that many people probably think there were hundreds or thousands of patients who took part in the trials and have years worth of data showing how "SAFE" this valve is in lower INRs. MY guess is many patients and even medical staff would probably be surprised to know that the "high risk group", in the lower INR arms of the trial is only less than 400 people TOTAL and HALF of that 400 (185 patients) are in the 1.5 -2.0 arm the other half of that 400 (190) are in the normal control INR 2-3. arm. and of those 375 people the amount of time they have their valve and were part of the trial is only about 4 years , many less than that.. which is important to remember when reading how many people have major bleeds, clots strokes, in that time frame. when you see that of the 190 patients control 13 had major bleeds or 8 of 185 test patients had major bleeds,
or in the lower INR there were 4 CVA(stroke) and 5 TIA compared to only 1 CVA and 2 TIAs in the controls normal 2.0-3 INR group.
TO ME at least that would give me pause even tho they say it isnt significant. It doesnt look much different than the "lower INR more clots, higher INR more bleeds" it always been

Too be fair I have to say that they started out with 435 patients total, however EVERYONE in the trial had to be on normal 2-3 INR for the first 3 months, (Do they mention that in the ON-X 1.5?) which is the higher risk time for any valve, and then after the 90 days, 60 people were removed from the trial during that first 90 days, for various reasons, including didn't have surgery or got another valve or they had a major event (10) or died (8).
Since these 60 patients weren't randomized, none of their "events" counted, as far as Events for the "test" lower 1.5-2 patients or control 2-3 INR 375 people still qualified 90 days later and they were then randomized to the 2 arms

The numbers above are from this report
http://my.americanheart.org/idc/gro...p/@scon/documents/downloadable/ucm_425310.pdf
that has alot of graphs etc.
there are updated numbers at

http://aats.org/annualmeeting/Program-Books/2013/1.cgi

that hopefully I can copy the chart from it has 22 major bleeds for the 2-3 INR compared to 9 in the lower INR, but 5 strokes in the lower INR compared to 3 in the normal control group. I havent seen a break down of where the major bleeds are, so don't know how many were internal bleeds or hemorrhagic strokes.

Adverse Event Control N (%/ptyr) Treatment N (%/ptyr) Rate Ratio Confidence Limits p-value
Major Bleed 22 (3.26) 9 (1.48) 0.46 0.21-0.99 0.047
Minor Bleed 23 (3.41) 8 (1.32) 0.39 0.17-0.87 0.021
Total Bleed 45 (6.66) 17 (2.80) 0.42 0.24-0.73 0.002
Stroke 3 (0.44) 5 (0.82) 1.86 0.44-7.77 0.397
TIA 5 (0.74) 7 (1.15) 1.56 0.49-4.91 0.448
Neurological Events 8 (1.18) 12 (1.98) 1.67 0.68-4.09 0.261
Overall Mortality 9 (1.33) 10 (1.65) 1.24 0.50-3.04 0.6
.

Now remember these are patients who had the newest "safest' valves AND home test, and probably working closely with top doctors, so it might be surprising to see that they were in range 70% for the control and 68% for test subject and its surprising to me how different these stats are to what is often quoted as how low clotss and bleeds are IF you home test etc

. BUT even 435 (total before they randomized into the 2 arms and dropped 60 patients) is still a really small group of patients and less than 200 for the lower INR, to bet someone I love's life on.especially since you still need to test and other things some people don"t like about Coumadin,
Especially compared to something like 60,000 patients allready received TAVI valves and many people still consider THAT number of patients a pipe dream.as far as taking into consideration when making a valve choice TODAY.