400 person study on lower INR (1.5-2.5) with mechanical valve

[carolinemc]

I home test. But the testing done before I home tested and the occasional test to check the accuracy of my Coaguchek was done via venous draw at the lab. It may be the if you go directly to the coumadin clinic for the test that the finger prick may be more common.

It will be interesting to see what the experience is of others on this.

My lab does the coag and rarely sends be to the basic lab. Has nothing to do with the post on a small-scale study. More studies have to be done to get doctors wo make that risk call.

 

[carolinemc]

Good research question, I live in Australia, so I can't answer that for the USA.

Mine does coag finger pricks. If it is over 4.0, then the regular lab I have to go.

 

[carolinemc]

I think that you are wise to stay above 2.0. The study that is underway references the two previous studies which looked at lower INR range, the Proact Trial and Lowering It. Proact targeted 1.5-2.0, but there was tight INR control and the average INR for the test group was 1.89, actually very close to the 2.0 mark. This suggests to me that they were cautious to stay away from the 1.5 threshold. Lowering It, which had a target range of 1.5-2.5 for the test group had an average INR of 1.94. So, both of these trials had tight control and even though there was a low threshold of 1.5, it would appear that they probably steered clear of that. It is one thing to test weekdly and have the A Team working coagulation management. In the real world, many go 4-6 weeks between INR testing and they don't always have the A Team coagulation management in play, making it even more precarious.

These studies all play games with words as well, I have noticed. They will lump all bleeds together, not separating major bleeds from minor bleeds. Then then will say, the lower INR resulted in fewer bleeding events with no increases in strokes or heart attacks. But, when you look at the actual results you find that Lowering IT had 3x as many thrombolic events in the test group as compared to the control group. How then are they able to say that the stroke events were "similar" or the same? It is because due to relatively small numbers of participants and relatively short period of study, the number of thrombolic events was 3 for the test group and 1 for the control group. It is new math to say that there was no difference, but apparently they get a pass because the two are both relatively low numbers. Increase the number of participants by 10 fold and take the study out 20 years and they will not be able to say that there was no statisical differnce when the number is something like 100 thrombolic events vs 300.

" Two moderately-sized clinical studies showed that an INR target range of 1.5-2.5 resulted in less bleeding than the usual higher target range without increasing blood clot formation or stroke in patients with a newer valve model. "

Is this true? Not really. Lowering It found 3x as many thromboembolic events in the test group with the lower INR.

" One versus three thromboembolic events occurred in the LOW-INR and CONVENTIONAL-INR, respectively, .."

https://pubmed.ncbi.nlm.nih.gov/20598989/
Look at how Proact uses new math to claim that a 60% increase in TE and thrombosis is "no different'

“…with no differences in the rates of TE and thrombosis events (2.96%/pt-yr in the test group versus 1.85%/pt-yr in the standard group, p = 0.178)”

The Prospective Randomized On-X Valve Anticoagulation Clinical Trial (PROACT): Lower is better, but is it good enough?

So, then in the new study, given the mathematical slight of hand, when referencing the two studies, they claim:

"..without increasing clot formation or stroke.."

Each have to make their own decision with the consultation of their medical team, but I would give some margin away from the 1.5 INR line.

Both studies found fewer bleeds in the lower INR group, but more strokes and heart attacks. Why not stick to the INR ranges that have the lowest events of all? Personally, I'd rather have a bleeding event than a stroke. That being said, some patients, who have issues with bleeding or are more prone to bleeding, might find that the trade off is worth it. I believe that these studies are valuable and give us important data. But, what I find troubling is that there appears to be bias in the presentation of the data favoring the sponsor of the studies economic interest in suggesting a lower INR is better. And, to be clear, the FDA in approving the lower INR for On-X, is not saying the lower INR is better. They just found that the number of events in that lower range to be reasonable.

The lab i use, does coag and if the pro time is at 4.0, the regular lab I go. They would never go by a small study.

 

[carolinemc]

I'm curious what regions/countries still do venous draws for routine INR management? My experience has always been that clinics use finger sticks.

After my AVR, I went to a coumadin clinic for about a year before switching to home testing. They always used a finger stick and portable device. That was 16 years ago. Since then, occasionally, I had my INR tested at several different clinics. They all used a Coaguchek device.

The only times, I had INR tested via lab was when I specifically asked for it to be added as part of my annual physical where they were drawing blood anyway for lipid and other typical tests as part of the physical.

It depends on the hospital standards. I switched to a teaching school who uses coag and regular lab if the INR is above 4.0.

 

[henkac]

Is this true? Not really. Lowering It found 3x as many thromboembolic events in the test group with the lower INR.

" One versus three thromboembolic events occurred in the LOW-INR and CONVENTIONAL-INR, respectively, .."

It's actually the other way around. They had 1 TE in the Low-INR and 3 in the standard.

 

[pellicle]

It's actually the other way around. They had 1 TE in the Low-INR and 3 in the standard.

which is actually curious because one would expect more strokes at lower INR than higher. To my mind however the study is a bit vexed in both the duration and control of INR and as such proves very little.

Interestingly we see as many or more On-X patients complaining of stroke or TIA here than we do even good old ball blood smashers

Yet what I also see is:

which is more TE and thrombosis in the Test Group

 

[henkac]

Yes. It tells us this is probably a bit more complex than we would wish it to be. We'de probably need to look at more individual factors on all of the patients to know what's really going on.

You can also find in the study that both group have a couple of patient years below INR 1.5. I can't find if any of them are mong the TEs. Not a wild guess some are. But I don't know.

And even if the patients had help tp manage INR, none of the groups where close to being on range above 90%,as you guys are.

 

[pellicle]

We'de probably need to look at more individual factors on all of the patients to know what's really going on.

Indeed, a point I often make

 

[Timmay]

... Interestingly we see as many or more On-X patients complaining of stroke or TIA here than we do even good old ball blood smashers ...

One reason might be that the On-X valve is being used almost exclusively a lot of the major heart surgery centers. Examples: My hospital (Washington D.C. Hospital, MedStar) will install an On-X. I don't even know if they install other mechanical valves . Not mentioned or discussed. And I didn't know any better to ask. The On-X was recommended by my surgeon (for the good or the bad ). There are other major centers that are the same like the Franciscan Health Heart Valve Center.

I am very curious as to the number of On-X aortic valves installed in the past 2 years as compared to the St. Jude's here in the states. Not sure if that data is even available .

FWIW, ball smashers are only being used by angry spouses at this point right? (relax everyone, just a joke!).

 

[Protimenow]

It looks as if the reps (recently called 'detail' people) took the administrators at these hospitals, or the cardio chiefs, on enough junkets, sponsored enough dinners or vacations to push the advantages of On-X, and did whatever was necessary to convince the powers that be at the institutions that On-X was the only valve to use.

They probably also painted the horrors of having an INR above 2.

Most patients would trust the recommendations of their surgeon. They would go with the On-X - especially if they aren't offered a choice.

The clinics will keep their INRs below 2, although there is no reason that 2.5 shouldn't be a more realistic target.

Morbidity and mortality for these poor trusting souls will increase. Eventually, the medical centers offering no option besides On-X may actually re-evaluate their position or, at least, for god's sake, increase the minimum INR for these patients.

 

[tom in MO]

It looks as if the reps (recently called 'detail' people) took the administrators at these hospitals, or the cardio chiefs, on enough junkets, sponsored enough dinners or vacations to push the advantages of On-X, and did whatever was necessary to convince the powers that be at the institutions that On-X was the only valve to use.

They probably also painted the horrors of having an INR above 2.

Most patients would trust the recommendations of their surgeon. They would go with the On-X - especially if they aren't offered a choice.

The clinics will keep their INRs below 2, although there is no reason that 2.5 shouldn't be a more realistic target.

Morbidity and mortality for these poor trusting souls will increase. Eventually, the medical centers offering no option besides On-X may actually re-evaluate their position or, at least, for god's sake, increase the minimum INR for these patients.

That's an overly dark and incorrect assessment. Valve manufacturers have to report adverse events to the FDA along with routine assessments of performance. If "morbidity and mortality" have increased the world's regulatory authorities wouldn't have approved the valve and if it increased after approval, they'd yank the valve.

Do you really think On-X employees would risk patient health for "junkets, sponsored dinners or vacations?" Real life is not a Law and Order episode.

 

[henkac]

It looks as if the reps (recently called 'detail' people) took the administrators at these hospitals, or the cardio chiefs, on enough junkets, sponsored enough dinners or vacations to push the advantages of On-X, and did whatever was necessary to convince the powers that be at the institutions that On-X was the only valve to use.

They probably also painted the horrors of having an INR above 2.

Most patients would trust the recommendations of their surgeon. They would go with the On-X - especially if they aren't offered a choice.

The clinics will keep their INRs below 2, although there is no reason that 2.5 shouldn't be a more realistic target.

Morbidity and mortality for these poor trusting souls will increase. Eventually, the medical centers offering no option besides On-X may actually re-evaluate their position or, at least, for god's sake, increase the minimum INR for these patients.

This is actually numbers from the Lowering IT - study from 2010. No On-X there.

 

[Protimenow]

That's an overly dark and incorrect assessment. Valve manufacturers have to report adverse events to the FDA along with routine assessments of performance. If "morbidity and mortality" have increased the world's regulatory authorities wouldn't have approved the valve and if it increased after approval, they'd yank the valve.

Do you really think On-X employees would risk patient health for "junkets, sponsored dinners or vacations?" Real life is not a Law and Order episode.

They would if they drink the Kool-Ade. They only represent what THEY are told by the manufacturer/marketing department.
What other reason would there be for medical centers NOT offering patients a choice?

I'm not sure that reports to the FDA would be presented in such a way to trigger red flags. 'Hey, this person needed a heart valve. He got one, and had a blood clot. Obviously, he couldn't have been maintaining his INR or he wouldn't have had a problem.' It might be hard for the FDA to connect the dots between low INR and excess deaths.

 

[vitdoc]

That's an overly dark and incorrect assessment. Valve manufacturers have to report adverse events to the FDA along with routine assessments of performance. If "morbidity and mortality" have increased the world's regulatory authorities wouldn't have approved the valve and if it increased after approval, they'd yank the valve.

Do you really think On-X employees would risk patient health for "junkets, sponsored dinners or vacations?" Real life is not a Law and Order episode.

I am not sure that this is an accurate statement. Once these devices are out in the real world the reporting on problems becomes much less stringent. Having a stroke with a mechanical valve is a known complication and would not necessarily trigger a report to the FDA.

Usually the device manufacturers will negotiate pricing with the hospital or hospital system for the best deals on the devices. If the surgeons don't complain too much these have now become often corporate decisions. As far as the corporate world is concerned if the device is FDA approved it is OK. What levels of anticoagulation have nothing to do with these corporate decisions.

Basically if you are more worried about bleeding go low on your INR. If you are more worried about strokes go higher. Personally I am more worried about strokes so an INR of 2 or less makes me nervous.
In all the studies I have seen with low INRs the stroke rates are higher with the low INR patients. This absurd statistic of combined stroke+bleeding which usually looks favorable for the low INR group is a dumb statistic. The effects of strokes and bleeding usually are quite different.

Ultimately I don't think the people working for these companies are inherently evil but they have their biases and the bottom line is they have to sell these devices to survive.

Doctors are also inundated by these "detail" people who push their products. Doctors are not all knowing and don't have the time to research ever little detail. So they can be influenced by these detail people.

I as a physician have always been leery of what I hear from them when they come to my office. But they clearly have influence or the drug/device companies would not continue to employ them.

 

[pellicle]

Having a stroke with a mechanical valve is a known complication and would not necessarily trigger a report to the FDA.

agreed ... and were I a conspiracy minded person I'd say that On-X knew that well when engaging in the design of the study for lower INR.

I have observed in the past that the rate of incidence in which would make the risk of an incident high is about 3.8 years ... Given that 26 events per patient year is given in "the dutch study" as it is called by one member

would suggest an even on average of 3.76 years were you to maintain an INR in the 1.5~1.9 range.

So recalling again from this analysis: The mean follow-up was 3.8 years

Would seem quite a coincidence wouldn't it.

Must be an accident.

 

[vitdoc]

My practice is involved with a large number of drug studies on eye drugs for various retinal conditions. When these studies are initiated a lot of thought goes into trying to design the study as likely to work as possible. Recently one of the drug companies had a failed study. They analyzed the study and decided that the way it was set up allowed the study to fail. So feeling confident that their product would ultimately pass muster they set up another study done slightly differently which they hope will succeed. This INR stuff is a lot like that. Concoct weird statistics (adding bleeding+stroke) showing they are "superior" in one group and getting the FDA to OK this device. Also I think there is a trend for the FDA to OK things that possibly in the past would not be OKed. For example one of the drugs for Alzheimers was authorized even though it did not show direct clinical efficacy for Alzheimers. It only showed a marker being altered. Somewhat like the defense industry in the US there is a revolving door between government and industry in other departments like the FDA. So there may be conflicts of interest in making these decisions.

 

[pellicle]

...So there may be conflicts of interest in making these decisions.

maybe even disclosed ;-)

 

[Chuck C]

It's actually the other way around. They had 1 TE in the Low-INR and 3 in the standard.

Can you please link your source? Perhaps you are citing a different study.

In my original post above, I linked the data from the PROACT Trial, as well as the source.

Here it is again.

“…with no differences in the rates of TE and thrombosis events (2.96%/pt-yr in the test group versus 1.85%/pt-yr in the standard group, p = 0.178)"

See Table one from the link below and Pellicle has also given a snapshop the same Table 1 as see above.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472691/

 

[henkac]

Given that 26 events per patient year is given in "the dutch study" as it is called by one member

You mean 26 events per 100 patient years, right? If you refer to "The dutch study". Or am I missing something?

Also note: out of the 38 total bleeding events, 11 is "Nonfatal bleeding in skin and muscles". They adopted the event labeling from an even older study and "Nonfatal bleeding in skin and muscles" could be something major, but could just as well be someone visiting the hospital due to a badly sprained ankle or muscle strain. We dont know, but concidering it to be 29% of all events it's something we don't see much of in other stories.

Also "The dutch study" is made on a much older population.

We should also consider the study method. "The dutch study" is a prospective study, with no randomized control group wich gives us quite alot data, but not that much to interpet it with.

We know there were 2 events in the total 7.5 patient years st INR 1,5-1,9. If study was 3.5 years. 2 patients is probably 100% of the patiens in the 1,5-1,9 grouop = all of the data behind the 26.6 events/ 100 p. years. No information on what happend but based on everything else we know, 100% of patients on 1,5-1.9 do not have events. Those 2 making out 100% of that number do not reflect a normal warfarin population.

Not saying there's not things to learn from the dutch study. But it's different from both the Lowering IT and Proact in so many ways I find it a bit hard to use it against them. Not saying those two are perfect. They have weaknesses as well. But we have to compare apples to apples and pears to pears.

Hope I'm not coming out as a basher here. I just enjoy growing in knowledge by good old (greek) putting science up against science discussions.

 

[Protimenow]

I'm with Vitdoc here - I am much more concerned with strokes (from an INR that is too low) than I am about an INR that is a bit high. I may be a bit more careful to avoid situations where I might get bruised, or small or large cuts if my INR is above 4.0 or so.

I had a TIA (stroke) in 2011 or 2012 because I relied on a Hemosense meter that was giving me a 2.6 reading. The hospital showed INR of 1.7. I don't know how long my INR was that low.

This is one of the reasons that I've been rethinking the Coag-Sense - for me, the results are usually lower than those for the CoaguChek XS. If the Coag-Sense says my INR is 2 or below, I can react by slightly increasing my dose.

My concern is that a 2.0 reported on a CoaguChek XS MIGHT be lower than that.

I finally got a standing order for blood draws. I'll restart some comparisons between the meters and the lab, and see what the three tell me (and I'll probably give the lab results the most value, unless they return ridiculous results (which has happened in the past)).