On-X clinical study interim results

[pem]

Hi. Sorry if someone else has already posted this. I just came across some interim results (which I've been seeking) on the low-ACT U.S. clinical trial for the On-X valve:

http://www.onxlti.com/2011/04/on-x-heart-valve-proact-trial-report/

For the low-INR (1.5-2) coumadin group, they report no difference from the control group in "composite thromboembolism and hemorragic rates". I wonder why these statistics are combined and whether difference would show up if taken separately.

They do not report findings for the aspirin/plavix arm, but seem to expect similar results. Since the other arms have been going on for the same amount of time, not sure why they don't post results for those.

Anyway, it is hard to make much of what's been reported here, but it looks positive at first glance.

Best wishes

 

[pem]

I spoke with someone at On-X. They report composite values because there is not yet enough data to compare bleeding and thromboembolism separately between the study and control groups (she said if you look at the numbers individually, though not significant, you will see more TE for the study group (low INR) and more "bleed" for the control group (normal INR); but cautioned against drawing conclusions.

 

[Duff Man]

I'd like to see control vs no ACT results. I gave the article a cursory read and didn't see any mention of the results for the zero act cohort.

 

[kfay]

I have only been on coumadin a couple of times for short periods of time (and didn't have any issues with it while on it), but I don't really understand what the big deal is about reduced coumadin. You still have to take it and still have to be tested. Personally, if I had a mechanical valve, I'd rather be at a higher range to have the best chance of avoiding a stroke. As has been said on here many, many times, you can replace blood if you have a bleed, but you can't replace brain cells if you have a stroke.

Can someone please explain to me why this is so appealing?


Kim

 

[Duff Man]

less chance of a catastrophic hemorrhagic stroke or bleed elsewhere in the body with a lower INR.

In a perfect world, your valve would have hemodynamics that didn't pose a threat of TE, and your inr would be normal. But since it's not perfect and no mechanical valve even comes close, we have to increase the inr (and risks associated) to prevent TE.

 

[pem]

I have only been on coumadin a couple of times for short periods of time (and didn't have any issues with it while on it), but I don't really understand what the big deal is about reduced coumadin. You still have to take it and still have to be tested. Personally, if I had a mechanical valve, I'd rather be at a higher range to have the best chance of avoiding a stroke. As has been said on here many, many times, you can replace blood if you have a bleed, but you can't replace brain cells if you have a stroke.

Can someone please explain to me why this is so appealing?


Kim

Good question! From the reading I've done (mostly journal papers), it looks like thromboembolic events (TE) tend to be less dangerous than hemmoragic (bleeding) events. In other words, people tend to survive TE more than bleeding. I just came across this eye-opening article, which I recommend to anyone who has a mechanical aortic valve and no other TE risk factors (e.g., no atrial fibrillation). This study, conducted over several thousand subjects, concluded that current recommendations for INR are too high, the optimal INR that minimizes the combined risk of TE and bleeding for mech AV recipients with no other TE risk factors is 2.3. I think they suggest that even 2.5 doubles the bleed risk compared with 2.3. This article was among the 5 studies used to convince the FDA to allow the On-X study using a lower INR group. Here's the link:

http://eurheartj.oxfordjournals.org/content/28/20/2479.full.pdf

By the way, you actually can replace and restore lost brain function due to a phenomenon known as neural plasticity - the ability to grown new connections between neurons. This is important because we believe knowledge is encoded not directly in neurons but in the connections between them. Also, TIAs (minor strokes) can happen without people noticing them, and only find out when they show up years later on an MRI.

Best wishes,
pem

 

[pem]

I'd like to see control vs no ACT results. I gave the article a cursory read and didn't see any mention of the results for the zero act cohort.

As far as I know there is no zero ACT cohort. I think the study groups are (with treatments in parentheses): 1) Low-risk AVR (plavix + aspirin), 2) High-risk AVR (INR 1.5 - 2.0: coumadin + aspirin), 3) All MVR (INR 2.0 - 2.5: coumadin + aspirin). Each study group has its own control group, which receives standard coumadin + aspirin to keep INR in the standard 2.5 - 3.5 range.

Does that answer your question - or by "zero ACT cohort" do you mean the aspirin/plavix group? If so, the On-X rep said they don't have enough people enrolled in that study to report anything significant yet for the reasons indicated in my first posting.

Best,
pem

 

[pem]

I just came across this eye-opening article, which I recommend to anyone who has a mechanical aortic valve and no other TE risk factors (e.g., no atrial fibrillation). This study, conducted over several thousand subjects, concluded that current recommendations for INR are too high, the optimal INR that minimizes the combined risk of TE and bleeding for mech AV recipients with no other TE risk factors is 2.3. I think they suggest that even 2.5 doubles the bleed risk compared with 2.3. This article was among the 5 studies used to convince the FDA to allow the On-X study using a lower INR group. Here's the link:

http://eurheartj.oxfordjournals.org/content/28/20/2479.full.pdf

Interestingly, I came across another study that makes a similar recommendation of a narrow target INR range of 2.2-2.3 regardless of the indication for ACT. This was a Swedish study based on a huge amount of data (over 1 million people and something like 14 million INR reports) culled from medical records from Swedish INR clinics. For some reason, I think it was a women only study. The didn't determine cause of death in this study, but only ascertained the correlation between INR levels and mortality. Apparently INR levels can fluctuate naturally, so they did point out that the mortality risk was much greater with INR elevated by ACT than by natural causes.

Here's the link for the Swedish study:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC131183/pdf/1073.pdf

There is an interesting graph that shows that outside the narrow recommended range of 2.2-2.3 the risks increase a bit faster on the low end of INR than on the high end, so from a practical standpoint, if one wanted to adhere to the recommendations of this study, I think the idea would be to aim for the 2.2-2.3 range erring slightly on the high side. To be clear, I am not recommending that anyone change their INR behavior; but I think it is worthwhile to read studies like this and discuss them with your physician.

 

[bdryer]

Hi Kim

The appeal to maintain a lower INR for me as well as for other athletes, especially those of us who may be subjected to an impact, is hemorrhaging.

One of my prime reasons for pursuing and accepting nothing less then the On-X AV, was the success of the early proact study where an INR of 1.5 to 2.0 is maintained.

When you cycle thousands of KM's per year and ski close to 100 days a year, it's inevitable you are going to get slammed and their is nothing you can do about it. The more you participate the higher the odds are of you going down. Hence we really want to avoid hemorrhaging.

You are correct that it would indeed be devastating to have a stroke cause one over compensated to avoid hemorrhaging. It's the game we chose to play. With frequent testing, [especially home testing] we can better walk the high wire and live to do it another day.

 

[normofthenorth]

I spoke with someone at On-X. They report composite values because there is not yet enough data to compare bleeding and thromboembolism separately between the study and control groups (she said if you look at the numbers individually, though not significant, you will see more TE for the study group (low INR) and more "bleed" for the control group (normal INR); but cautioned against drawing conclusions.

I don't see why we should hesitate in "drawing conclusions", when all the evidence from all the previous studies since the beginning of studies, would lead us to expect exactly those results -- more TE for the study group (low INR) and more "bleed" for the control group (normal INR)!!

 

[normofthenorth]

I have only been on coumadin a couple of times for short periods of time (and didn't have any issues with it while on it), but I don't really understand what the big deal is about reduced coumadin. You still have to take it and still have to be tested. Personally, if I had a mechanical valve, I'd rather be at a higher range to have the best chance of avoiding a stroke. As has been said on here many, many times, you can replace blood if you have a bleed, but you can't replace brain cells if you have a stroke.

Can someone please explain to me why this is so appealing?


Kim

If the bleeding is from (say) a cerebral aneurysm or a concussion, then the pressure within the skull can destroy a LOT of brain cells (and is the leading cause of death from intracranial bleeding), unless it's relieved quickly -- either by clotting or by somebody drilling a hole in your skull to relieve the pressure and save your life. That's one of many reasons why high INRs are bad for longevity, and lower ones would be better, if it weren't for the serious risks of higher ThromboEmbolism, e.g., from a mechanical valve or other risk-makers like A-fib or recent MV repair, etc. There are also some other reasons to wish for lower INR that don't directly affect mortality -- like ACT's effect on bruising, nosebleeds and similar nuisances, and the advisability of doing certain fun (but high-impact) activities. Some people find those nuisances virtually non-existent, while others are significantly bothered by them.

 

[Lynlw]

There are other articles that have a little more info http://www.theheart.org/article/1211373.do

All 185 patients in the high-risk arm received an On-X valve as a replacement for a defective aortic valve and were considered to have a high potential for thrombotic or bleeding events. All patients were maintained with standard anticoagulation therapy for the first three months after surgery and then randomized into the low-anticoagulant group or the control group. The low-anticoagulant group was switched to a daily dose of either 81 or 325 mg of aspirin plus warfarin to achieve an INR target of 1.5 to 2.0. Patients randomized to the control group continued with standard anticoagulation therapy—aspirin and warfarin to achieve an INR of 2.0 to 3.5 throughout the trial, the target set in the ACC/AHA guidelines for treatment of patients with a replacement aortic valve. The average follow-up so far is about 16 months, with a total of 247 patient-years of data collected. Eventually, the investigators expect to collect 6000 patient-years of data.

During the study period, five low-anticoagulant and four control patients died. The low-anticoagulant group had 2.5 bleeding events per patient-year, vs 4.4 per patient year in the control group, but the stroke rate was 1.3% per patient-year in the low-anticoagulant group vs 0.4% per patient-year in the control group. For the combined end point of stroke and thrombotic and bleeding events, the rates were 3.8% per patient-year in the low-anticoagulant group and 4.9% per patient-year in the control group."

Too me it doesn't look much different that the stats you see for the other mech valves, especially in the control group, even tho they all home test and went by INRs, which kind of makes sense since the first South African study compared 3 valves and for the most part the results were about the same no matter which valve the people had

Altho it would he helpful to know what the 9 people died from in the time frame -since that seems a little high for a year an 1/2 AVe, post op considerring these were pretty healthy people to be able to be in the trial. and would be good to know how bad the results are from the clots or bleeds or where they were (brain, GI, cut), but ii guess that will come out when the trial is over.



JUST MY THOUGHTS..
Since the people with the lower INR (and aspirin like it seems all patients took) had higher rates of TE, obviously there is NO way of knowing IF the person did not agree to be in the trial, IF they might have avoided having the TE, but it is a reminder TO ME that IF you are considerring taking place in a trial, make sure you really consider what the outcomes could be IF they don't go as well as they hope. Be sure that if it is something like this, that MAY increase your rates of having a stroke, or whatever the trial is trying to improve, it is something you and your loved ones are willing to gamble on, especially in a trial like this that even If you have the best results possible there doesn't seem to be a huge advantage to you personally ..in this case as Kim pointed out, even IF you can take a lower amount of Coumadin you still need to have the testing, watch your dose and everything else that people don't really like that much about coumadin.

We've taken part in a few trials or experimental procedures not even in trials, but the benefit/risks ratio to us was a little better, (IMO) IF the theory helped Justin might have avoided some surgery but If it didn't work he wouldn't have ended up any worse off than he already was, just would have needed a surgery that we were hoping to avoid.
I know for this trial specifically there has been a few people deciding wether to sign up or not..(especially since they do things like provide a free monitor etc) even tho people mention you MIGHT increase your odd of having a stroke, sometimes I get the impression people don't really believe it will happen to them, or downplay the risks thinking IF it is in a trial it MUST be pretty safe.

 

[pem]

Lyn and Norm,

Lots of great points - really well taken. I am grateful that this forum exists and that strong critical thinkers like you participate actively. It's a real benefit to all of us. Thank you!

I thought I would report on some new findings. I've now had a chance to talk at some length with folks from both On-X and ATS and also to read some more papers.

One concern that I've had is that most of the studies are sponsored by valve manufacturers and, therefore, unavoidably biased. No one disputes this. But the ATS rep pointed out that while it is difficult to make apples-to-apples comparisons from longitudinal studies, there are some studies that have to follow stringent FDA guidelines. There are two documents of interest that must be provided to the FDA for every valve and are carefully reviewed and, I believe, adhere to stringent methodological constraints. These documents are the IFU (Information For Use) and the SSE (Summary of Safety and Effectiveness). Both are available from the FDA for any approved medical device including all artificial heart valves. While these documents may not contain all relevant data or longitudinal data, they do provide a relatively unbiased way to make an apples-to-apples comparison between two valves.

For the ATS open-pivot bileaflet valve, the FDA link is:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=p990046

For the On-X valve, the FDA link is:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=p000037

And the page from which you can search for data on other valves, just by entering the valve name in the "Search medical devices" box is:
http://www.fda.gov/MedicalDevices/default.htm

By the way, just to follow up on my earlier posting about the paper I read, which suggests a target INR of 2.3 to best balance risk of bleed with risk of stroke, I read another related study. This other study was a Swedish study in which millions of medical records from Swedish INR clinics were analyzed. I think about 14 million INR reports were analyzed. Most of the people were on ACT for atrial fibrillation, but a significant percentage (about 14% if I remember right) had mechanical heart valves. I think this study was only for women (why?) and the mean age was about 70 years old. They also concluded that a narrow range of 2.2-2.3 was optimal for survivability. It looked like the drop-off was more precipitous on the lower side of the INR, but only a little. This would suggest erring slightly on the higher side of that range. But in discussing these findings with the ATS rep, he reminded me that this is an age-related function. That is, the minimum for combined stroke/bleed risk will be lower as we age. So perhaps for 70 year-olds, whose vascular system may be more prone to bleeding, it is best to stay on the lower INR range, whereas younger vascular systems may tolerate better a higher INR and benefit more from avoiding TE without greater risk of bleed. In any case, for myself (a 40-year-old), I have not read anything to justify maintaining an INR higher than about 2.5 if I get a mech valve and end up without Afib. Obviously, if my cardiologist pushes back on this, I will listen.

Another interesting finding for me, from the Swedish study, is that INR levels can fluctuate naturally for a variety of reasons. In their correlational study, they found that bleed risks were much more strongly associated with INR levels that were artificially increased than INR levels that increased for natural reasons. Interesting! Also, in a similar vein (no pun intended), the ATS rep reported anecdotally that ACT-related events tend to occur more as a consequence of fluctuating INR levels than stable INR levels, even when those stable levels are high. This seems to suggest that the body can perhaps adapt to a range of INR levels, but needs time to do so. That's just my own conjecture.

Thanks for the ongoing discourse.
pem

 

[pem]

I don't see why we should hesitate in "drawing conclusions", when all the evidence from all the previous studies since the beginning of studies, would lead us to expect exactly those results -- more TE for the study group (low INR) and more "bleed" for the control group (normal INR)!!

I think what she meant (and I'm just interpreting here) is that with the On-X valve, we might hope for lower TE in the study group because of the purported benefits of the On-X design and materials - and perhaps these early results don't bear that out. So I think she may be saying, don't jump to the conclusion that On-X valves are just as thrombolitic as other valves.

On the other hand, your point, if it was intended rhetorically, is well taken