Missed 2 days of Warfarin - Pellicle's Model??

[dick0236]

I imagine that we're all different but my first week of ACT after surgery I was a bit low taking 5 per day so I was told to take 10 for a week then retest. I thought this sounded crazy. I tested at 7.9 a week later.......

I hope you merely misunderstood their INR instructions 'cause to go to 10mg/day from 5mg/day for an INR that is "a bit low" is reckless advice and the 7.9 would be what I would expect. Always make small warfarin changes unless you have a seriously "out of whack" INR.

 

[Boomanchu]

No Dick, I might have been new to the whole ACT thing but I questioned 10mg for a week. I said that I was thinking they would have me do 7.5 rather than 5 for 3 or 4 days but was told to do the 10. When I had the 7.9 reading I was a bit nervous but was so new to ACT I just went with the flow. I'm still new to it but feel I've done enough homework to start speaking up.

 

[pellicle]

Hi
wow, sorry to hear of your GI bleed!

Now they took me to 10mg / day for 1 week and my INR was 3.6! And I have a lot of blood in my stool this morning.

that's normally not "dangerous" territory, but it is on the edge of it. Have you ever had GI bleeds before?

They want me to change to 9mg on tue and thur and remain at 10 for the rest of the week. This doesn't seem like much of a change to get me back to 2 -3 level. What level is dangerous?

well the levels where you bleed are dangerous ... I'm not entirely sure what you mean, but by levels do you mean dose levels or INR levels? I see from your BIO that you're AVR not mitral, so to me (knowing not much about your situation) there is nothing I see indicating you need to be at such a high INR.

*Have you recently been drinking lots of grapefruit juice?
*Have you taken any new medications?
*What was your dose before?
*How long have you been stable? (stable is relative if you ask me)

So to me I'd drop your dose to less than 9 for sure. I'd be dropping to 8 or maybe even 7.5 daily and monitor it daily or every 2 or three days. Do you self test? I need to know more about what your INR / Dose was before this point

I would also be monitoring your stools (as you are) and alerting your doctor to this. I know you don't want to under shoot, so to me as 10mg is producing a high INR then 7.5 should be better.

I will get the dosages for the above INR values (previous post) I just don't have the data right here.

please ... if you can get more data (like at least a month) that will be valuable.

best wishes.

 

[pellicle]

Hi

yes, I think Dicks words are spot on ... reckless ... FFS .... why do people in ACT clinics have no brain?

No Dick, I might have been new to the whole ACT thing but I questioned 10mg for a week. I said that I was thinking they would have me do 7.5 rather than 5 for 3 or 4 days but was told to do the 10. When I had the 7.9 reading I was a bit nervous but was so new to ACT I just went with the flow. I'm still new to it but feel I've done enough homework to start speaking up.

speaking up ... man I'd be raising the roof. That kind of thing borders on malpractice.

Would you mind putting numbers (INR) on that? I know that when I started I was 5mg and over a few weeks inched up to 7mg as my INR response flattened a bit (could be many factors, like surgery recovery ... drugs ...). I now stabilise on 7.25mg daily (taken as alternatign 7.5 / 7mg).

 

[Boomanchu]

I'm on 5 per day with 7.5 one day a week and hold between 2.3 and 2.5. Being mitral my target is 2.5 to 3.5 so I'm adding a second day at 7.5. I suggested that and my cardio agreed. This last visit was with my cardiologist so getting my INR read by him is always a bit more sane. Mine seems to hold so steady I don't have to worry about screwy dosage suggestions from the techs but I still look forward to home testing. I would rather ask questions on here about dosage, better to hear how it does work out rather than how it should work out. Initially I came here to find real time answers about pain levels, afib, healing time etc. My cardiologist thinks forums like this are invaluable. He says he learned what he knows at a desk and people on the forums learned what they know on an operating table.

 

[newmitral]

Hi All,

I just thought I would throw some possibly useful information into the record. It might help future members as well as answer some of the questions that have been asked recently in this thread (and others).

When I first got my mechanical valve, it took me a long time to get my INR in range, and it took a larger than typical dose of warfarin to do it.
I was curious to see what the typical warfarin maintenance dose actually was, and where my dose (12.5/day) fell in the distribution. The only paper I could find at the time that had this information was this one:

http://www.futuremedicine.com/doi/ab...7410541.4.1.11

" Individualizing warfarin therapy"
by Kristen K Reynolds, Roland Valdes Jr, Bronwyn R Hartung & Mark W Linder

At the time, I was able to download a free PDF copy of the full paper, but it now appears to be behind a payment firewall.

Figure 2 of this paper (shown below) gives the weekly dose distributions from the authors' study of maintenance dose within their sample population.

Figure is at: https://drive.google.com/file/d/0B_A...Qjg/view?pli=1 in case it doesn't embed properly in this post.

(Sorry, please use above link to view the figure. I get a "not authorized" error when trying to embed the image)

As you can see, the typical ACT patient seems to average about 5 mg/day which is 35 mg/week.
At 12.5 mg/day (87.5 mg/week) I am off the scale on this chart. So, my own particular maintenance is clearly a 3-sigma case on the high side of daily dose. Nevertheless, this is not any cause for concern. It takes what it takes, and the important measurement is not how much warfarin you take, but rather your INR as a result. At 12.5 mg/day I'm far from setting any records, but clearly anything over 10mg/day would be considered a high dose per this chart.

The paper does make a few interesting points that are a bit technical, but important to note.

1. Our individual response to warfarin is determined primarily by genetics, more so than by age, body weight/size or exercise/activity, although those are also contributing factors.

2. The mechanism that comes into play when you are first adapting to the warfarin and building to a stable blood concentration is controlled by a different genetic factor than the one driving the short-term vitamin-k antagonism process. This explains why it can take some people many days, or even weeks to climb to their final stable warfarin range, while others achieve stability after only a few days. FYI, it took me about three weeks to get into range taking my maintenance dose of warfarin after I had to bridge from some surgery. It also took several weeks to get into range initially.


The short-term INR response to missing a dose (or 2) can be very quick, and much different from the longer term stabilization time - depending on your particular genetic makeup. In my search for a simple dose-to-INR model, I was unable to find a simple 3rd order equation that matched my own short-term INR response to missing a dose (or 2) and subsequent recovery by taking my normal dose (or more).
I concluded that the mechanisms involved are more complex than a simple curve-fitting model can accurately predict.

I did, however, stumble upon this article:

http://www.biomedcentral.com/1472-6947/15/7

"A Bayesian decision support tool for efficient
dose individualization of warfarin in adults and
children"

with available Java application for download that implements the set of differential equations described in the paper.
I plan to give that model a try and see if I can find coefficients that will allow me to more accurately match my own particular metabolism's response and model/predict the optimal recovery from any future faux-pas in my ACT.

 

[pellicle]

Hi there ... really great post, thanks for all the refs

Figure 2 of this paper (shown below) gives the weekly dose distributions from the authors' study of maintenance dose within their sample population.

Figure is at: https://drive.google.com/file/d/0B_A...Qjg/view?pli=1 in case it doesn't embed properly in this post.

looking at that chart (reproduced below) I see that I'm also skewed to the RHS of that bell.

yet at about 7mg per day I'd say that I'm right in the middle of what I see reported here for maintaining an INR of about 2.5 (I realise you maintain 3.5) and not skewed off to the sides.

So that leaves me to wonder about:
* what their target INR was
* how wide their sample reference was.

I guess what I'm saying is:
* the chart is from old data which I would question
* I don't think your 2 standard deviations away from the norm dose for your INR target.

of course there are now well understood genetic differences (that can be tested for) to determine INR.

Lastly I really liked that last link with Bayesian probability techniques. Much better than the usual stochastic approach

http://en.wikipedia.org/wiki/Bayesian_probability

I hope you're doing well

I'm actually doing another test on myself after missing my dose on Wednesday (douh >.< ) and my INR dropped from 2.7 on Sat (and it was 2.7 the Sat before) to 1.8 by Thursday night when I realised that Wed's pill was still in the box.

I recently read some interesting points about coagulation levels which I'd been meaning to post, so now seems a good time.


Firstly as observations from the GELIA study the researchers made this observation:

As > 90% of INR measurements during the entire follow-up period were within the therapeutic range of INR 2.0 to 4.5, which is the lowest erratic INR ever published

really ... that's the lowest variation they've ever seen published ... well no bloody wonder people have complications ... my INR is 91% inside 2 to 3 ...

Then in the LOWERING IT study (where they found that for all modern bileaflet valves) INR of lower levels such as 1.5 - 2 were attainable "without any increase of thromboembolic complications."
They observed:

Thrombosis and thromboembolism risks
are greater with any mechanical valves in the mitral than the aortic
position, and, therefore, higher INR levels (2.5 to 3.5) are generally
recommended for mechanical mitral valve prostheses [9,10]. These
recommendations must be read with the knowledge that several biases
in published investigations actually prevent any firm conclusion. The
most common are: study cohort including patients implanted with
different generation devices, non-randomised series without controls,
lack of stratification for additional risk factors associated with the type
and location of prosthetic valves, concomitant antiplatelet therapy.

{my underline and emphasis}
which is interesting

 

[pellicle]

Hi Newmitral

nice post, very informative.

I'd wonder about that graph though as my experience here is many of us seem to have reported around the 7mg (49mg a week) and that chart puts me off to the right hand side of the hump

given you are in a higher target range(3.5 vs 2.5) I think your 12mg is less of an outlier than just a bit further to the right than the median. I'd wonder about who their group was.

I was reading an analysis of a study called LOWERING IT and they made this comment about older data and older viewpoints.

Evidence and Lack of Evidence of Current Recommendations on Anticoagulation

The common prescription policy for patients with mechanical
valve replacement declares a therapeutic range from INR 2.5 to 4.5.
This large range includes a zone of higher risk for bleedings, beginning
from INR 3.5. After mechanical Aortic Valve Replacement (AVR), the
goal of oral anticoagulant therapy is usually to achieve an International
Normalized Ratio (INR) of 2.5 to 3.5 for the first 3 months after surgery
and 2.0 to 3.0 beyond that time [3,4]. Low-dose aspirin (75 to 100 mg
per day) is also indicated in addition to Warfarin [3,4,9,10]. At that
level of anticoagulation, the risk of significant haemorrhage appears
to be 1% to 2% per year [4]. Thrombosis and thromboembolism risks
are greater with any mechanical valves in the mitral than the aortic
position, and, therefore, higher INR levels (2.5 to 3.5) are generally
recommended for mechanical mitral valve prostheses [9,10]. These
recommendations must be read with the knowledge that several biases
in published investigations actually prevent any firm conclusion. The
most common are: study cohort including patients implanted with
different generation devices, non-randomised series without controls,
lack of stratification for additional risk factors associated with the type
and location of prosthetic valves, concomitant antiplatelet therapy.

 

[pellicle]

I thought I'd put in this quote out of reply but thought it was interesting:

The LOWERING-IT study was a prospective, open-label, singlecentre
randomized controlled trial that compared the thromboembolic
and bleeding events between two different anticoagulation intensity
levels in low-risk patients undergoing a single aortic mechanical
replacement. The two anticoagulation intensity levels were the low
anticoagulation intensity, with a range INR of 1.5 to 2.5 (LOW-INR
group), and the currently recommended intensity, with the standard
range INR of 2.0 to 3.0 (CONVENTIONAL-INR group).

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

... this low-intensity anticoagulation strategy is associated with a significant reduction
of the average hemorrhagic events when compared to conventional therapy (INR of 2.0 to 3.0), without any increase of thromboembolic complication.Interestingly, this trial included different types of bileaflet prostheses highlighting the low-thrombogenicity of these devices

As described in the LOWERING-IT trial, a target INR 1.5 to 2.5 was prescribed. Selected young women achieving this target INR with a warfarin daily dose lower than 5 mg were preferentially offered a third generation mechanical device. When pregnant, such women were kept on the same low-dose sodium warfarin anticoagulation throughout
all pregnancy with a weekly INR estimation and joint cardiologic and obstetric monthly evaluations. Cesarean delivery was scheduled before the end of the 37th gestational week. Warfarin therapy was discontinued only 2 days before section and restarted 1 day after surgery. As recently reported, no maternal nor foetal complications were detected in sixteen
pregnancies managed by this anticoagulation protocol

 

[pellicle]

actually I'm also in the midst of another self (accidental) experiment.

I discovered on Thursday evening last week that I'd forgotten my Wednesday dose. I immediately took INR (Thursday evening) and it was down to 1.8 My INR was 2.7 on the Saturday morning before (when I usually take my INR) and had been 2.7 the Saturday before (unusual for me to have exactly the same number between readings). I was 2.0 this Saturday just gone so it had moved back to there within the times I expect.

 

[newmitral]

Hi Pellicle,

I'd wonder about that graph though as my experience here is many of us seem to have reported around the 7mg (49mg a week) and that chart puts me off to the right hand side of the hump

Many other papers I found indicated that the average daily maintenance dose was around 5mg/day, with typical ranges of 2 to 10 mg. One other paper:

www.bloodjournal.org/content/106/7/2329.full.pdf

"The impact of CYP2C9 and VKORC1 genetic polymorphism and patient
characteristics upon warfarin dose requirements"

had a boxplot (figure 1) showing the distribution of warfarin dose by CYP2C9 and VKORC1 genotype.

This figure shows the same values for warfarin maintenance dose range indicated in the first paper I referenced above. So, I tend to believe the data from those studies.

If you have access to other published scholarly articles that have plots of maintenance dose distributions, preferably similar to the style in the "Individualizing Warfarin Therapy" article, I would be grateful if you could post references to them - especially if the download of the full article is free. I would love to see a similar plot for a population of valve-replacement patients, particularly one broken down by aortic vs mitral with the different target ranges.

I do believe both those referenced studies were for INR target of 2.5 (range 2.0-3.0).

given you are in a higher target range(3.5 vs 2.5) I think your 12mg is less of an outlier than just a bit further to the right than the median.

Just for the record, my target INR is 3.0, not 3.5. I can say from experience that if I were to shoot for a target of 2.5 instead of my current 3.0, it would only drop my daily dose to about 11.5 to 12.0, not a big difference from the 12.5 to 13.0 I'm currently taking.

But, we are all different, and it takes what it takes to stay in range. The important value is the achieved INR, not the dose required to get there.

 

[pellicle]

Hi

Many other papers I found indicated that the average daily maintenance dose was around 5mg/day, with typical ranges of 2 to 10 mg. One other paper:

putting you not far outside that ...

This figure shows the same values for warfarin maintenance dose range indicated in the first paper I referenced above. So, I tend to believe the data from those studies.

I don't disbelieve that either. I'm not sure what it is you are demonstrating here ...

If you have access to other published scholarly articles that have plots of maintenance dose distributions
...
But, we are all different, and it takes what it takes to stay in range. The important value is the achieved INR, not the dose required to get there.

exactly correct and I have not said otherwise. If your concern is that I don't think that 12mg daily is way outside the curve then I apologise, but to me I still feel that 12 isn't so much more than the 10 you indicated above as being typical ranges.

I did not claim to have any special data requiring backup by scholarly article, indeed all I said was

my experience here is many of us seem to have reported around the 7mg

I'm sorry you seem to have been offended by that

Thanks for the other references, they were interesting reading too.