Fluctuating INR.

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Pineapplehead

New member
Joined
Jul 21, 2024
Messages
2
Location
Montreal
I’m a 25-year-old woman who recently joined the club. I had BAV with AR and AS and had my valve replaced with a St. Jude’s mechanical valve on June 13th this year. I’m on acenocoumarol (Acitrom) and know that INR levels can fluctuate during the first few months. For the past four weeks, my INR has been stable, ranging between 2.2 and 2.6, with a consistent dosage of 4-4-3. However, my recent test came back with an INR of 1.5, down from 2.2 last week. My doctor said it’s not a major concern, increased my dosage to 4-4-5, and asked me to test again in 10 days.
I’ve been eating a variety of foods and haven’t had any alcohol, and I don’t think I’ve consumed any significant amounts of vitamin K.
Is there something I might be missing?


Thank you !
 

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I don't completely understand the doctor's rationale for the higher dose every three days. The 4 4 5 that he suggested may be enough to bump the INR up, but, personally, I would be much more comfortable with an INR that's closer to 3 - especially if I just had the valve implanted.

If your doctor wants a faster boost, why not 5-4-4? This should increase the INR faster than 4-4-5 - but, still, this variable dosing thing confuses me.

Maybe he should have you on a consistent dose of 4 mg EVERY day and see how this works.

As you noted, the INR will fluctuate post-op, so what you take in three months may not be what you're taking now. What's most important is that your INR not drop below 2 (or so) during (or after, FWIW) this healing period, and if it does, that you bring your INR back in range fairly quickly. I'm not suggesting any large dose, or major changes from your then current dose - slow adjustments make management much easier than a large dose that throws all the calculations off.
 
Is there something I might be missing?
Warfarin works that way from time to time. As you continue to heal from your surgery and become more active you will find your Warfarin needs will change and a +/- .7 INR change is not that unusual......but it normally does trigger a dosing change. I understand that the valve manufacturer is not concerned about the low INR......but it "freaks out" those of us who have older mechanical valves. I would trust your doc in increasing your dose slowly as your range is very narrow.....2.2-2.6.
 
Hi and welcome

... I’m on acenocoumarol (Acitrom)
really ... in Canada? That's interesting and weird. If you were in (say) the 3rd world, India or Eastern block Europe (stick Spain in there for the time being) I'd expect Acitrom but Canada?

Who prescribed that? I didn't even know it was available there.

This isn't just trivial its actually a core issue. You see, of the three anticoagulants, this has the shortest half life and results in the highest volatility within the patient

Some notes:
Acenocoumarol (sintrom, acitrom ) is an alternative to warfarin it is called​
fluindione (mainly France and Africa) Link: https://en.wikipedia.org/wiki/Acenocoumarol
Elimination half-life 8 to 11 hours​
Phenprocoumon (germany)​
Elimination half-life 6–7 days​
Warfarin (most common)​
Elimination half-life 1 week (active half-life is 20-60 hours)​
[my note: weird notation of "active half life"]​
its worth noting that 20 - 60 hour range (so between a day and three days).

This variation in half life has significant effects on how to manage the drug and how it responds to "oops, I forgot my dose"

Basically with Acitrom your INR will be 1 again after 30 hours, with warfarin or Phenprocoumon you've got time to just retake and not fluff things up wildly.

Acitrom is so sensitive to INR changes I've discovered (in working with others) that 12 hours difference in when you measure vs when you take shows a difference in INR. So this means:
  • if you take your pill at 7am and test at 9am vs 5pm you'll see INR difference (I've seen 2.7 vs 1.8)
  • if you take at 8pm the same sort of problem emerges

To understand this perhaps this helps

Anticoagulants with vitamin K antagonism include the coumarin derivatives acenocoumarol, phenprocoumon, warfarin and the indanediones, fluindione and phenindione. Most VKA are completely absorbed following oral administration and bound to albumin in the plasma by more than 95%.​
The elimination half-life is 24 hours for acencoumarol (including its metabolites), 36 hours for warfarin and 150 hours for phenprocoumon.​
The half-lives of the clotting factors range between 8–72 hours.​
Consequently, it takes several days for the inhibitory effect on the synthesis of the coagulation factors to result in reduced concentrations in the liver. [personal note: I'm sus on the several days and lack of understanding about time to reach steady state] . Coumarin derivatives are metabolized in the liver and excreted by the kidneys. They are particularly susceptible to interactions with other drugs that are able to compete with them for plasma protein binding, alter their metabolism in the liver, or inhibit or stimulate synthesis of the clotting factors.​

please observe my [personal notes] .. there's a lot in the above 3 paragraphs and it deserves a question answer all on its own. However it all depends on the amount and depth that you want to understand this in... I'm that guy who dives deep.

and know that INR levels can fluctuate during the first few months.
INR always fluctuates, but its actually well documented that after the first weeks or months you will have a decreased sensitivity to warfarin. This article from 2010 seems not to have yet reached the medical commuinty 14 years later:

Decreasing warfarin sensitivity during the first three months after heart valve surgery: implications for dosing
K Meijer 1, Y-K Kim, S Schulman

However, my recent test came back with an INR of 1.5, down from 2.2 last week.

assuming that you are being tested at the same time, and taking at the same time then perhaps its time to simply "increase your dose" as noted above.

My doctor said it’s not a major concern, increased my dosage to 4-4-5, and asked me to test again in 10 days.
as you can see from the above details about half life this strategy of "averaging the doses" is not appropriate with Acitrom

I’ve been eating a variety of foods and haven’t had any alcohol, and I don’t think I’ve consumed any significant amounts of vitamin K.
good ... a healthy balanced diet is fantastic.

Is there something I might be missing?

Hopefully I've filled in what's missing. Feel free to ask anything to clarify anything I've said.

To describe me a bit, I read this recently and thought it applies to my whole life:

Signal Developer Explains Why Early Encrypted Messaging Tools Flopped


Marlinspike brought up Pretty Good Privacy (PGP), a set of encryption tools first shipped in 1991. PGP was many people’s first experience with encrypted messaging—and their last for years after butting heads with its arcane user experience.
“We would teach people how to run a PGP keyserver,” he reminisced, chuckling. “We'll just hang out over dinner and sign keys or whatever.”
Alas, people were willing to do no such thing: “We were just wrong.”

AKA they were idiots*


So short answer summary:
  • INR is the only thing that matters, dose as needed for INR nothing more, nothing less
  • Do not adjust for food unless that's going to become your whole new normal
  • beware of dosing and testing times with Acitrom

PM me if you want to converse

Best Wishes


PS: * idiot defined
Pirsig’s mechanic is, in the original sense of the term, an idiot. Indeed, he exemplifies the truth about idiocy, which is that it is at once an ethical and a cognitive failure. The Greek idios means “private,” and an idiōtēs means a private person, as opposed to a person in their public role—for example, that of motorcycle mechanic.
Pirsig’s mechanic is idiotic because he fails to grasp his public role, which entails, or should, a relation of active concern to others, and to the machine. He is not involved. It is not his problem. Because he is an idiot.
This still comes across in the related English words “idiomatic” and “idiosyncratic,” which similarly suggest self-enclosure. For example, when a foreigner asks him for directions, the idiot will reply idiomatically, rather than refer to a shared coordinate system. He also lacks the attentive openness that seeks things out in the shared world, as when Pirsig’s mechanic “barely listened to the piston slap before saying, ‘Oh yeah. Tappets.’”
At bottom, the idiot is a solipsist
 
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sorry, but for a starter I value higher independent studies, not studies by the makers (which may well have biased)
This:
https://www.acitrom.com/acitrom_vs_warfarin_comparative_studies.html

isn't a study list, its just a cherry picking

There is one study referenced but it does not really say anything in detail about methods, operational guidelines nor metrics, for the first statements, indeed its perhaps the most information detail poor "study" I've ever seen. For instance this assertion

Since warfarin with its longer half-life is believed to provide a stable international normalized ratio (INR) compared to shorter acting drugs, studies were carried out to compare the stability of INR with warfarin and acenocoumarol.

makes a valid question ... but:

One study found that acenocoumarol and warfarin are comparable in terms of stability of prothrombin time (PT) indicating that the longer half-life of warfarin is not of great clinical significance.

ok, how compareable? How does that indicate it is not of clinical significance when (for instance) patient behaviour and irregular taking would be of greater significance, as would the competency of the clinic. I saw no evidence presented on the study of the half life.

In other studies investigating the use of acenocoumarol and warfarin in atrial fibrillation, it has been seen that the stability of anticoagulant action of acenocoumarol was better than warfarin.

So I tracked down that study
https://pubmed.ncbi.nlm.nih.gov/15724697/

Hungarian ... yep

Objective: The aim of this SPORTIF-III substudy was to compare acenocoumarol (A) with warfarin (W) in the same group of 74 patients, with chronic atrial fibrillation who started with W and then changed to A.​

not a bad design, but 74 patients is small

Methods: We compared prospectively a 3 months period on W with a 3 months period on A.​

Short ....

Results: The mean number of INR measurements per patient was 5.7 +/- 1.2 and 5.4 +/- 1.6 resp (NS).​

so, over 3 months (13 weeks) they took 5.7 measurements ?? Is this a joke? How does this even clarify stability?


The mean percentage of INR-s in the therapeutic range of 2-3 was 49 +/- 22.6% for W​

that's pretty low
and 56 +/- 26.8% for A (p < 0.05),​
that's better but still pretty low as far as bench marks go. I'm going to go out on a limb and say the clinicians managing this were inexperienced in managing warfarin as I've had >95% inside theraptuic range on weekly measurements for the last 13 years.


the percentage of subtherapeutic values were not different, the supratherapeutic values however occurred more frequently on W (28 +/- 20%) than on A (19 +/- 19%), p < 0,001.​
that's pretty bad ... I'd rather be over 3 than under 2 for two weeks between tests

There was a good correlation between A and W doses (r = 0.65, p < 0.001), the mean W dose was 5.03 +/- 1.99 mg, the mean A dose was 2.5 +/- 1.3 mg, the W/A dose ratio was computed to be 2.18 +/- 0.78.​

what is the significance of this? No, really ... it's just "excipient" to the argument

this graph tells us very little, except to support their assertion *but without any basis, information"

1723374123442.png


they write:

There was a good correlation between acenocoumarol and warfarin doses (r = 0.65, p < 0.001), the mean warfarin dose was 5.03 ± 1.99 mg, the mean acenocoumarol dose was 2.5 ± 1.3 mg, the warfarin to acenocoumarol dose ratio was computed to be 2.18 ± 0.78.

which is nice to know, but really, what does that even matter? Dose to INR is unimportant and irrelevant, INR consistency is.

This is fully consistent with the usual arguments I read from places like Hungary that try to make arguments as to why their "different choice" is better.

Here's my view:
Acenocoumarol is easier to manage for a clinician because it has a lower half life, you just make sure the patient takes the drug and you don't measure too often because you may find out they spend way more time out of therapeutic range (under it) than you thought. You don't need to worry about stopping and starging ACTherapy because you just stop and it stops. Warfarin takes a little longer to clear (the values given are typically overblown) so you need 2 or 3 days to be at INR ~ 1 for a procedure. It takes a little longer to resume to therapeutic levels too, but then I've not tested "starting" durations (because daily INR's weren't taken for the patient I was working with).

But what would I know?

Don't believe me, don't trust me; instead examine the data, the arguments and the evidence. Claims require evidence, there was little evidence given in that.

Best Wishes
 
I’m from India but currently living in Montreal (had surgery in India). Thank you for your detailed answer and I realized from your information that I might be testing too late. I take my medication at 6 p.m. and currently test my INR the next day around 10-11 a.m. I am still using lab testing.When do people usually test ?
 
I do an INR test every Friday, if I'm 2.5 to 3 then I do it again the following Friday, if it's 2 to 2.5 I do another test on Monday.
I'm rarely below 2.5 and I always make a prediction before the test based on what I've eaten and drunk. That's how I try to understand what I overdid and educate myself on nutrition.
After years I can say that I know what to expect before the test
 
I do an INR test every Friday, if I'm 2.5 to 3 then I do it again the following Friday, if it's 2 to 2.5 I do another test on Monday.
I'm rarely below 2.5 and I always make a prediction before the test based on what I've eaten and drunk. That's how I try to understand what I overdid and educate myself on nutrition.
After years I can say that I know what to expect before the test
Warfarin or Acitrom?
 
I do an INR test every Friday, if I'm 2.5 to 3 then I do it again the following Friday, if it's 2 to 2.5 I do another test on Monday.
I'm rarely below 2.5 and I always make a prediction before the test based on what I've eaten and drunk. That's how I try to understand what I overdid and educate myself on nutrition.
After years I can say that I know what to expect before the test
I see this was probably a reply to @Pineapplehead , not me. I can see why you couldn't quote-reply that
 
Good Morning


1723407413219.png


I can only speculate on how you made the "reply" process nested like this, so I'll just say
  1. click reply,
  2. then type under what is there
if you are using a phone then you need to be adroit with your fingers on that ******** media.

So, I copied and pasted as quote what you wrote so I can engage with it.
I’m from India but currently living in Montreal (had surgery in India).
that makes sense....

Thank you for your detailed answer and I realized from your information that I might be testing too late.

Its tricky because the INR will vary during the day quite substantially. I'd set up a pattern (which is what worked for the Indians I have been helping) where you take in the AM and test around 7pm ... that gives a nice reliable pattern.
The alternative is to choose to test at the same time as you take (thus giving 24 hours) ... try both and see which one gives a more amenable result (not too high, not too low, but just right).
Its best if you write down the times and test in one planned operation where you choose your taking time based on your personal convenience (myself that's 7pm) then test:
  • early morning
  • lunch
  • bed time
there is none of this bull5hit with Warfarin (and its longer half life).

I take my medication at 6 p.m. and currently test my INR the next day around 10-11 a.m. I am still using lab testing.

Well since you're using lab testing (far from ideal, as you can see above the convenience and knowledge possible from self testing) you may be stuck with changing your taking times. Indeed one of the indian persons problmes came exactly from changing testing time from the morning (on the way to work) ot the evening (on the way home). Another was "changed lab" (solved by going back to the same lab.

I don't trust labs ... basically I don't trust anything without evidence

When do people usually test ?
most here are on warfarin, where such things don't make much difference (because of that half life).

HTH
 

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After years I can say that I know what to expect before the test
this is pretty usual ... I can say that I did a quick audit this morning and that the worst performers were those shackled with Acitrom, not least because of the usual miserable choices given them in pill sizing options. They were however in the high 80% (and I only have two current people in that data set)
For Warfarin I get the following
number​
in range​
1​
100​
2​
97​
3​
98​
4​
85​
5​
94​
6​
99​
7​
97​
8​
95​
9​
93​

So I'm still going to say:
  1. the clinical management in that Acitrom trial from Hungary is miserable and like most clinicians in my experience need a) much better coaching and perhaps b) struggle with non-compliant users (I know that all too well)
  2. warfarin shapes up pretty well with all the advantages you'd expect from a longer half life stability when monitored closely (and the monitoring closely is the best way to accurately know how long you're in rance.
I've personally supervised dozens of people with daily testing (yes, daily) and seen what sort of INR volatility you get. To make a clear example of why "the only way to know is to know" : if you test once per year and get 2.5 on that test is that representative of the whole year?

Too many people fall prey to the notion that I'm super stable (good for you) so therefor everyone must be the same ... sorry but that's just not true.

Until some studies are done on Acitrom with good data and good patient compliance I'm remaining in the position of "it is inferior and people shouldn't be on it if long term stability is a priority"

Best Wishes
 
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If I'm 2.2 and I don't eat vegetables the next day I'm close to 2.5, if I'm 3.2 and I eat a big salad the next day I'm 2.5 - 2.7.
Because here in Greece, the strips covered by the public health insurance cost me 0.42 euros each, so it is not a problem to take frequent measurements if it is necessary.
In any case, I have found a way to be 2.2 to 3.0 every Friday morning that I measure and to measure in between if that is required.
The cost of sintrom is 1.70 for 20 pills and they last me for a month.
An earlier study
https://pubmed.ncbi.nlm.nih.gov/9869157/
 

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