Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions.

Narrator - ?  00:11
This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show.

Dr. Sean Kane  00:32
Welcome to HelixTalk. Episode, 125 I'm your co host, Dr. Kane,

Dr. Khyati Patel  00:36
and I'm Dr. Patel, and in this episode, I'm so excited to talk about warfarin, and not just any aspect of warfarin, but kind of like the pharmacogenomics aspect, where we consider polymorphism and what kind of impact those have in our clinical recommendations. And so the title of our topic today is, let's get personal talking warfarin pharmacogenomics.

Dr. Sean Kane  01:03
So Dr. Patel, you know, we talked about DNA with our conversation with Rosalind Franklin's niece, and how it was so cool that her work way back in the early 1950s has basically led the way to what we now have as commercialization of pharmacogenomics and understanding how your genome can impact how drugs work in your body, and Warfarin is one of those drugs in the sense that now we have a lot of information about how your genetics can play a role in whether you metabolize Warfarin more or less, or are more sensitive to Warfarin or not, things like that.

Dr. Khyati Patel  01:36
Yeah, and I mean working with Warfarin in an outpatient clinic, you know, I do have first an experience of like how just managing warfarin as is with so many variable factors that could impact the outcome of therapy, it's complicated. It's not, you know, an easy answer, but then you add this polymorphism and pharmacogenomic implications, you know, on top of it, and it just becomes even more confusing. And so kind of disclaimer out here, I do the regular warfarin management, you know, in the outpatient clinic. I don't really do pharmacogenomic testing and dosing in my clinic. But with you, Dr. Kane, in our pharmacogenomics course, have been teaching this, you know, polymorphisms and how they impact drug outcome. And I teach warfarin. And so this is where the passion and the knowledge and the discussion kind of comes from.

Dr. Sean Kane  02:28
And Dr. Patel, I think it's important to note that although it's not something that's done currently in clinical practice in most scenarios, it is a thing in the sense that it is done throughout the country. And two, you know, if you think from an educator standpoint, we have to teach pharmacy students what they're going to need to know throughout their entire career, or at least set them up for that, and form the scaffolding of that. And that means that we may potentially teach topics like pharmacogenomics that are kind of on the cutting edge of what pharmacy practice may look like in 10 years, and kind of setting the stage, I think, is really important at at the level of a PharmD, so that they are ready to understand, you know, the basics, nuts and bolts of really, pharmacogenetics in general, and how to apply that to drug therapy.

Dr. Khyati Patel  03:11
Yeah. And you know, we could sit here and talk about the cost of these tests and how different institutions are weaving in these tests in their routine practice. But do know that these tests are now available on Amazon, for example, you know, and so patients may have gone out and done this 23andMe test and have like this genetic testing, you know, profiles that's personalized, and you may not have to worry about testing based on genetic information from your institutional guideline perspective. But if a patient brings in the result to you and say, Hey, like, these are my results, you know, help me. Help me, kind of guide my pharmacotherapy based on that, that's where we need to know where these concepts come from. You know, kind of adding on to what you said, Dr. Kane, so kind of to lay out that scenario for our discussion today, let's kind of start with talking about a patient. Case. We have a patient who's a 53 year old African American male who's a status post, you know, left total knee arthroplasty. Few days later, he presented to the clinic with right lower leg swelling, tenderness, some warmth, and, you know, we did at the Doppler, found that it was a DVT, very common scenario to have in patients who are status post, you know, knee or hip replacements. And there was a promotional free, you know, genetic testing going on, so a patient agreed to do it, and we found that patient had the star two allele of the two c9 gene, which is our metabolizing enzymes, and then the VKORC1 profile, which is the target protein, was 1639, GG, which is kind of like the wild type and the PCP, the doctor who you're working with is bringing these test results to you as a pharmacist, and say, Okay, what do I do with this? This, you know, provide some recommendation on the warfarin dosing. While we look at the responses from these genetic tests, it's important to kind of look at some patients factor too. So you know, pertinent past medical history for this patient include osteoarthritis, hypertension, dyslipidemia. Patient does smoke cigarette about one pack per day, and there's no previous history at BT, so this is the very first one. There are no drug allergies, and current medications are amlodipine, atorvastatin, and Tylenol is needed for the pain. So let's get started. And I think it's prudent before we dive into some of these genomics issues with warfarin, that we kind of have a background on warfarin and clotting cascade to begin with.

Dr. Sean Kane  05:44
Yeah, so in terms of the clotting cascade, you know, it's one of those figures that you probably saw way back in physiology, maybe in pathophysiology as well, basically the clotting cascade, to put it simply, as a bunch of different clotting factors coalesce into this kind of final common pathway of clotting, which means that regardless of what started the clot, it ends up that you activate clotting factor 10 into clotting factor 10 a or activated 10, and then that 10 a takes clotting factor two, also called prothrombin, converts it to thrombin, which is clotting factor two a, and clotting factor IIa is involved in the final step, which is converting fibrinogen into a fibrin‑based clot. And that fibrin is like the glue that holds together the platelets and other clotting factors that form that clot into a clot that lasts for a long period of time, as opposed to just a transient clot. So with respect to warfarin, it's relevant, because we have to know where the Warfarin is working along that pathway, which does include clotting factors II and X, and some other ones within the pathway as well.

Dr. Khyati Patel  06:49
And laying out this background Dr. Kane, it kind of drives me back to the history of warfarin. I love talking about how Warfarin was found, especially working in Wisconsin. This is like close to home back in the day, Wisconsin is a, you know, majority of farmer population and bunch of cattle were dying, you know, from hemorrhage. And they wanted to find out why are our cattle is dying. And they found out that they were eating this like spoiled silage made of sweet clover, but sweet clover has a naturally occurring chemical called coumarin. And when it's spoiling in that process, it goes from coumarin to dicoumarol. Dicoumarol is actually a potent anticoagulant, and this this reaction. It's kind of driven by this specific mold. And it was a chemist at University of Wisconsin who identified this dichumeral agent, and the synthetic form of Warfarin was then kind of derived from there. So really, the warfarin Aaron comes from the coumarin, and the war comes from Wisconsin Alumni Research Foundation. Fast forward today. We've been using this as a drug, but in back in the day when it was first found, it was actually used as rat poisoning.

Dr. Sean Kane  08:00
So the irony Dr. Patel, that you know, in the 1950s we decided to start using it on humans to thin blood, obviously lower doses than what cows were consuming. But this human product that is now a drug that is very commonly used historically, was used to kill rodents and also killed cows by accident, by eating this moldy clover, which is so interesting that that is basically the history of how that drug came about. And of course, there must be some amount of pride and kind of the Midwest and Wisconsin as well for having the name in the word Warfarin itself, which is very cool. Yeah.

Dr. Khyati Patel  08:37
And you know this, this drug, Coumadin, as it was introduced in the market in 1950s we've been using it ever since. So kind of like one of our dinosaur drugs, you know, we kind of know ins and out of Coumadin slash warfarin, which is the, you know, generic name. It's also important to kind of know some of the warfarin properties. And so those you know who are practicing, you've kind of dealt with patients being on warfarin, may know this already, but it is taken by mouth, and it's 100% bioavailable. But one of the interesting feature is that it's 99% protein bound. So that's bound to albumin. And when we look at like the further chemistry and properties of warfarin, we find that, you know, it's a it's a good mix of two different enantiomers, we have the S Warfarin and the R warfarin, and usually the s warfarin. It plays the bigger role when it comes to warfarin's anticoagulant effect. So it's about two to four times more potent than the r1 and it's responsible for up to like 70% of its anticoagulant effect.

Dr. Sean Kane  09:38
From a kinetic standpoint, it has a pretty long half life, 36 to 42 hours. We'll call it a day and a half half life. But because of how it works, and we'll talk about that in a second, its therapeutic effects actually last a little bit longer than that, so they go out to three to four days in terms of the therapeutic effect of a single dose of warfarin. Most people are familiar with this, but we check INR. And INR tells us how anticoagulated a patient is on warfarin, and the INR goal for a patient is going to depend on the indication. Most typically, it's between two and three. But for certain patients, primarily those with mechanical heart valves, it may be two and a half to three and a half. And what's so interesting about the INR is that INR on warfarin can be impacted by literally hundreds of things. So Dr, tell what are some things that come to your mind when you think about what can make your INR go up or down, and someone who's taking warfarin?

Dr. Khyati Patel  10:29
I mean, where do we start? Right? There's, there's just so many different factors. You know, just yesterday, I told a patient that if you sneeze, maybe your INR will change, and it's not literally that would happen. But if somebody has a cold, or they are, you know, have some viral or bacterial infection going on that could possibly change the INR. But besides that, you know that that's part of committing diseases. What's going on with the patient? You know what drugs, other drugs patients taking, including over the counter, medications, what are the food interactions, some of the lifestyle factors, such as use of alcohol, smoking, how much exercise does a person perform? Impacts it too. We kind of talked about how it's protein bound. So any any kind of changes in the albumin content as patients age or they're having some, you know, liver disease that could also change the way the warfarin would impact INR. And then, last, but not the least, the purpose of this discussion is genetic polymorphisms do impact Warfarin in terms you know, if it's as we know, narrow therapeutic window means, if the INR is lower, that means patients have more tendency to clot, and if the INR is higher, patients have more tendency to bleed. And so it's, it's important to maintain the INRS within the goals that you know you mentioned Dr. Kane for depending on the indications.

Dr. Sean Kane  11:51
So obviously bleeding is the thing that we worry about, and the risk of therapeutic failure, so a clot returning or getting worse. But there's also some kind of, I would say, weird or strange, but rare side effects, so skin necrosis and purple toe syndrome. These are the two really, really rare, like less than point 1% incidence rates, but it's one of those, like board questions and things like that that you may see with warfarin. And these are basically issues of kind of circulation, where blood circulation to tissues, especially like fatty tissues or your literally, your toe ends up causing some some problems kind of beyond the scope of the podcast, but for sure, those that are taking NAPLEX or sitting for a board exam in the future, skin necrosis and purple toe syndrome are the zebras of the warfarin side effect profile that everyone should be aware of.

Dr. Khyati Patel  12:40
Definitely a good point, kind of going back to the layout you had provided Dr. Kane about the coagulation cascade and where exactly Warfarin works. So Warfarin is a vitamin K antagonist, and in the entire scheme of our coagulation cascade, there are a few factors that are dependent on vitamin K for their action. And these are factors II, VII, IX, and X, and then the two naturally occurring anticoagulants, such as protein s and protein C, these factors have to be activated in order for them to do their job, and the activation is pretty much an addition of a carboxyl group on their glutamic acid residue. Now this reaction is not happening by itself. It's kind of like a coupled reaction. So in order for that reaction to happen, another reaction has to happen, and that reaction is oxidation of vitamin K. So your active Vitamin K is then converted into inactive vitamin K by this enzyme called vitamin K, epoxide reductase, complex one, and this vitamin k has to be reduced in order for it to be reactivated. So it's kind of going into this recycling process. Warfarin comes in and prevents this reduction. And basically, you know, reactivation of vitamin K, and it blocks the vitamin K epoxide reductase enzyme, which is kind of responsible for this reaction. This is exactly where warfarin works.

Dr. Sean Kane  14:15
Dr. Patel. What's so interesting about this is that this is a completely unique mechanism compared to all of our other anticoagulants in the market. So, you know, we have our direct anticoagulants that directly bind to a clotting factor and inactivate a specific or several clotting factors. We have our kind of indirect anticoagulants that use things like antithrombin three. Heparin would be an example of this, where they kind of have a wingman protein that helps them with anticoagulation. In this case, Warfarin actually is not interacting with any of the clotting factors itself. What it's doing is it's interacting with an enzyme involved in Vitamin K recycling, and that Vitamin K is responsible for helping with the formation of these vitamin K. Independent clotting factors. So really we're we're turning off the faucet of making more clotting factors, as opposed to going out and blocking clotting factors that already exist in the body. And that's one of the reasons why Warfarin takes so long to kick in, is that we have to wait for kind of those clotting factors to be recycled out of the body as we are turning off the production or the faucet of those clotting factors.

Dr. Khyati Patel  15:20
Yeah, definitely a very cool mechanism. And the VKORC1, which is the vitamin K epoxide reductase complex 1. It's the it's the protein or the target. That's important to know when we are talking about polymorphisms in a little bit. Another target of this polymorphisms is it's located within the process of Warfarin metabolism. Warfarin usually gets metabolized using this p4 50 family enzymes, and it leads to hydroxylated metabolites of the warfarin and these enzymes, majority of these enzymes are the two c9 2c 19, one, a, two and three, a, four, two c9 actually has been the principal enzyme that we know that's responsible for metabolizing this s enantiomer, the isomer, and that's that's the more potent one when it comes to anticoagulant effect. So CYP2C9 is the one to remember for warfarin metabolism, and the main enzyme involved. A minor route of warfarin metabolism is via reductase enzymes leading to warfarin alcohols. And Warfarin alcohols usually don't tend to have much anticoagulant activity.

Dr. Sean Kane  16:36
So to kind of piggyback on that, Dr. Patel, you mentioned that two c9 is the main way that Warfarin gets inactivated in the body. And that's actually, as you mentioned, one of the main things that we look at when it comes to pharmacogenomics of warfarin. So if you think about it, this is an enzyme that gets rid of warfarin. So we need to know, are there polymorphisms that make this enzyme Superman, where it chews up Warfarin better, or does it make it weaker, or a loss of function allele where two c9 doesn't work as well in the body. So what are typical things that we see with two c9 in human beings? In terms of polymorphisms?

Dr. Khyati Patel  17:08
Dr. Kane, believe it or not, there's 50 some variants of two c9 genes are known to the genetic world. If you were to say that, and not all of these impact. You know the way Warfarin works, per se, but when we look at all these different variants, the star two and star three variants are of the most interest to us, because these are the loss of function and the alleles that would result into higher bleeding, longer time to get to the stable INRS, perhaps even longer than two to four weeks in the dosing process. And these patients require smaller doses to reach the INR. So you know, you do a higher dose and their their tendency to bleed, can increase the star two and start three. Variant, however specific to certain patient population. So these are found mainly in a European, Caucasian patients. So frequency is about seven to 11% and then these are actually virtually absent in our Asian patient population, from the, you know, the available information we have.

Dr. Sean Kane  18:17
And then, as I understand it, there's actually a set of alleles that are more commonly seen in African American patients, and this would be things like star 568, and 11. These are also reduced to function alleles, and kind of Historically, most of the pharmacogenomic testing was done in Caucasian so we kind of didn't appreciate the importance of this, especially in an African American patient population. But now that we have a little bit more data, we know, and we'll talk about this later, that if you are considering genomic testing on someone who's African American, you kind of need to test for these things, because it's predominant enough and it would change the clinical picture enough that it's a big deal for that patient population. Yeah.

Dr. Khyati Patel  18:55
So as we keep some of these important variants in mind, it's also important to keep in mind what patient populations they're affecting and and also know that not all genetic tests test for all of these variants. So if you have a particular patient in front of you, you need to know, you know and you're trying to utilize genetic testing, you need to know what type of test to use, because not all tests test for all of these variants.

Dr. Sean Kane  19:21
So another common thing that we think about with Warfarin is that V, core c1, protein. This is the target protein of warfarin. This is the enzyme responsible for recycling vitamin K that Warfarin blocks. So there's actually a single nucleotide polymorphism. So Dr. Patel, can you tell us more about how we describe this particular polymorphism? Yes.

Dr. Khyati Patel  19:40
So verbalizing it, it sounds a little bit confusing, but basically, this polymorphism that's more of an interest is replacement of the G nucleotide with an A nucleotide in the star two haplotype of the recourse b1 and that means that you would. You would see a test result of a patient having the single polymorphism of 1639, A, A, and these patients would require lower Warfarin dose to reach the therapeutic target. So kind of like, similar to your two c9, star two, Star Three, they don't need much higher dose. And if higher doses are given, they might be at a higher risk for bleeding.

Dr. Sean Kane  20:23
Then we also have kind of the Superman version of V core c1 which is a star three or star four haplotype, which means that these patients Warfarin doesn't work as well against that V core c1 enzyme, it doesn't bind as potently, and these patients actually need higher doses of Warfarin in order to have the same therapeutic effect. So mostly with two, c9 we saw loss of function where patients are more sensitive to warfarin. But with V core, c1 it can go either way, based on the polymorphism, you may be more sensitive or less sensitive to warfarin.

Dr. Khyati Patel  20:52
Yeah, and it's important to know most of the genetic tests kind of look for that G to the a replacement, the single polymorphism, the Star Three, Star four haplotypes, which require higher Warfarin dose, are not also commonly included in most genetic tests out there. And then, you know, there's a few more polymorphisms that affect warfarin, but the third important ones that clinically mean something when it comes to dosing is in the CYP4F2 enzyme. This is a vitamin K oxidase. Vitamin K oxidase basically help remove the excess vitamin K build up from the vitamin K cycle. So basically, there is not enough vitamin K in the cycle. That means the vitamin K dependent factors don't do their job. And so where does this matter? The variant of this particular CYP4F2 enzyme is in that Star Three allele, and again, it's going to kind of work as a Superman like you analyzed Dr. Kane. It's going to require more Warfarin dose, relatively compared to somebody who doesn't have this variant. Patients with this variant will require about eight to 11% higher doses. The grand scheme of things you may not even notice, but those who requiring higher doses, as is this could be a pretty good increase in their baseline dose.

Dr. Sean Kane  22:19
So what are the more commonly commercially available polymorphism tests that we can actually conduct in a normal clinical practice? Yeah, as

Dr. Khyati Patel  22:28
I mentioned, Dr. Kane, most of these tests available commercially would test for the two, c9, and we course even polymorphism. So many examples are out there. Trigen Corporation, Warfarin genotyping, there's a kit out there, you know, there is an infinity Warfarin assay by autogenomics. There's like, five or six different ones out there. When it comes to utilization of this test, it really depends on, you know, market availability, as well as how, you know, affordable these tests are. Surely you're not going to find patients going out and finding this like clinically available test to get tested prior to starting warfarin, so you may see its utility based on what's the quote, unquote formulary or institutional decisions from the P&T committee. But but more kind of like the patient side of the test they may come with, are going to be 23andme for example, you know, those are kind of like online, available tests, and those are like pan tasks. They're not specific to warfarin. They test for everything.

Dr. Sean Kane  23:37
So then you know, the logical question, Dr. Patel is, so what if you know that a patient has a two c9, star two allele, you might know that they're more sensitive to warfarin, but that alone may not be helpful in knowing you know how much less Warfarin do you give them, or other clinical factors that you may take into account. So hopefully, there are some clinical tools out there that could kind of take these genomic tests in combination with other factors that we know are associated with Warfarin sensitivity, and kind of bundle it up so that a practicing clinician then can come up with a single starting dose or a dose titration for a patient based on all of these factors. Because, you know, obviously, we're not using just the genomic test in a box. For example, if a patient is on amiodarone, we have to take that into account too, not just their genetics.

Dr. Khyati Patel  24:26
You're absolutely right. Dr. Kane, you know, like we said earlier, these genetic test results or having these polymorphism just adds to the confusion of dosing warfarin, as is among all other factors that patients may have so in the world of AIS and believe in the live in the world of algorithms, there are people out there who've created these algorithms, either they're like spreadsheets based, or they're online algorithms. And these algorithms kind of combine results from polymorphisms and include other patients. Two factors to give you that initial starting dose. So one good example is international Warfarin pharmacogenetics consortium, the iwpc calculator. It's basically a Excel spreadsheet. It asks you to input things like patients, you know, age, sex, race, their smoking status, you know, some interacting drug, as you mentioned, amiodarone statin, if they're on phenotype. And then what type of genetic variants are we talking about in terms of CYP2C9 and the VKORC1 gene. Warfarindosing.com is pretty good. It incorporates both the iwpc as well as gage algorithm. And this gage algorithm additionally will allow you to input results from CYP4F2 and GGCX genotyping, if those test results are available, so kind of one step further from the iwpc calculator. And you know, once we got to know about Warfarin polymorphisms, there was an FDA mandate for the warfarin label to be updated, quote, unquote, committed label to be updated, to have a nice table based on genetic testing as to what should be the patient's starting dose if they have certain genetic tests positive or negative, depending on that, there are a few studies done that compares Whether we dose it based on warfarin label. The genetic table in the warfarin label versus these algorithm, there's not a robust data, but based on few studies we have available, it's advocating for the use of these algorithm based dosing, rather than just going off of the warfarin labels.

Dr. Sean Kane  26:39
So we'll certainly have you know, I WPC and Warfarin dosing.com, LinkedIn. Show Notes, this is episode 125, so if you go to HelixTalk.com you can see links to those resources as well. But Dr. Patel, really, you know, globally, the kind of million dollar question here is okay? So even if we could predict that a patient needs two and a half instead of five milligrams of warfarin, on initiation of warfarin. Does that result in better clinical outcomes? So what kind of data do we have to support the practice of using a pharmacogenomic based approach to warfarin dosing?

Dr. Khyati Patel  27:13
Yeah, and you know, that's the buzz of the town. Dr. Kane. You know the literature that's available, it's not very concrete. It's more of like an equivocal in nature, because as as we know, this is kind of still a new concept, or more studies being done. You know, a few years ago, we didn't even have African American patient in some of these studies. So all the data we had available was in the European ancestry. Until much later, more studies, more inclusive studies were done. So now we have data from, you know, more diverse patient population, but the 2017 CPIC guidelines, and CPIC stands for the clinical pharmacogenetics Implementation Consortium guideline update came out. Their very first guideline was available in 2011 and in this 2017 or 2016 depending on what you read on their title, included some new data from the studies in it. We were kind of trying to summarize what those studies were and what they showed. The first study was the EU impact, and as the name says, EU, these were looking at genetic based dosing versus standard dosing in European patients, again, not including our Asian or African American patients. And what they found that pharmacogenetic algorithm based dosing was actually better than standard dosing in terms of reaching to the stable dose, reaching better time and therapeutic range, and not having so many Supra therapeutic INRS that were above four, which could lead to, you know, bleeding outcomes and such.

Dr. Sean Kane  28:47
You know, another article that's mentioned is the COAG trial. And basically, with this particular trial, they they suggested that there was no difference in many different outcomes related to INRS and having a stable dose. But the problem with that study is that about a quarter of the patients were of African ancestry. And the problem with that is, as we talked about earlier, as more data came out, and we studied those with African descent in more detail, we came to appreciate that there are certain polymorphisms, especially with two, c9, so star 568, and 11. Those polymorphisms are loss of function alleles, and if you don't test for it, then you won't know that they have it. And then obviously your trial looking at pharmacogenomics with Warfarin is not going to be as robust. So in this particular trial, the COAG trial, a quarter of them were from African ancestry. They didn't look at these polymorphisms that are more common in those with African ancestry, so they didn't show a difference in terms of pharmacogenetic testing. But I think it's reasonable to say that they didn't have all the information that they needed to have in order to have a robust study to look at that question.

Dr. Khyati Patel  29:53
Yeah, and for that same reason, Dr. Kane, you know, they found African American patients who were. Dosed using these algorithms without sufficient you know, Star 568, and 11 allele information had more Supra therapeutic INR. So that kind of confirmed the importance of testing for these additional alleles, the two c9 alleles in African American patients. And then last, but not the least, the newest trial was the gift trial, and this was a trial that looked at outcomes that were beyond some of these surrogate outcomes of, you know, time and therapeutic range. You know, INR is above certain range and whatnot. These looked at endpoints such as, you know, symptomatic or asymptomatic VTE, major bleeding, INR above four, and actually death as well. So these, these were like clinical endpoint looking type of trials, again, comparing genetic algorithm based dosing to standard clinical dosing. Patient population, however, wasn't a robust patient population. This was like orthopedic patients who would have VTE post‑operative after a procedure. And what they found is there was 27% reduction in this composite clinical outcome for those who got doses based on genetic algorithm versus standard dosing, which is pretty decent outcome when you look at you know clinically, although this algorithm, again, did not include testing for the African American ancestry specific alleles like the 568, and 11.

Dr. Sean Kane  31:28
So you know, these three trials have played a huge role in the newest CPIC guidelines related to Warfarin pharmacogenomic testing. So Dr. tell maybe we can just walk through that algorithm very briefly, knowing that we'll have a link in our show notes for any listeners that want to dive deeper into it. But the first question is, do you have genetic testing available? If you don't, then obviously you dose it clinically as you normally would. So assuming that you have genetic testing available to you, what is the next question you need to ask as part of their kind of flow sheet?

Dr. Khyati Patel  32:00
Yeah, you need, you need to, like, ask the patient of their ancestry. So these are, like, self identified ancestry, whether they're non African American. So like, your Caucasian, Asian patient versus African American, and if they're, you know, if they say that they're Caucasian or Asian patients, then you utilize the results of this at CYP2C9 and VKORC1, and then dose these patients based on the genetic algorithms we have available, such as Warfarin dosing.com, or iwpc algorithm, if the patients do identify with African ancestry. The further question we want to ask is, do they have the additional two c9 alleles that matter in these patients, the star five, star six, Star eight and star 11. And if they do, then we should go ahead and calculate their dose based on the pharmacogenetic algorithms in general. However, if they have any of these polymorphisms, positive, the 568, and 11, just knowing from the get go that these these patients would need about 15 to 30% decrease dose than your patients who don't have these variants present. Yeah.

Dr. Sean Kane  33:16
So basically, if you can't test for these alleles that are more common in those with African descent, then you you really shouldn't bother doing it, period. So I think that's a really important point to drive home. Is that even if you had genetic testing available at your facility, if you're treating someone of African descent and you don't have these alleles, 568, or 11, for two, c9, the recommendation is that you don't proceed with pharmacogenetic testing and evaluation, because you're you have a high likelihood of not capturing these alleles and potentially overdosing the patient, because you can't appreciate if they have this loss of function allele or not, right?

Dr. Khyati Patel  33:52
And in that case, you know, these patients would be dosed with your, you know, either institutional or chest based clinical guidelines.

Dr. Sean Kane  34:00
So you know, Dr. toe, you kind of mentioned at the beginning, and I agree with you at my site as well. We don't do genetic testing commonly to help assist with warfarin dosing. But I think most people in the pharmacy realm think that as technology improves, as cost gets lower, that this will eventually become more of a thing. So what are some things that you think have to play a role in either mandating that this becomes a standard of care or a more common thing that happens when initiating Warfarin in a patient.

Dr. Khyati Patel  34:31
Yeah, as I said, the data is pretty equivocal. You know, you look at some studies that will tell you don't, don't, don't, don't, doze based on these results, but then some studies will say, Yeah, dose it based on genetic results. And I think what we need is more robust data looking at the outcomes that really matter, looking at outcomes such as, are we preventing deaths? Are we preventing a clot? Are you preventing a symptomatic vte, like the last trial? Did? We just don't have enough data there. And I think having that would. Probably instill more confidence in using genetic testing for the dosing.

Dr. Sean Kane  35:05
I think too, you know, genetic testing in general is not incredibly common, and I think that as it becomes more commonplace in general, things like warfarin, clopidogrel or Plavix, other areas are more likely to pick it up as well, potentially also, like you mentioned with something like 23andme where you kind of pan test, where you get all sorts of genetic information, and maybe you're doing it for one particular question, but once you do it, once for a patient, you have their genetic tests forever. So you know, if I got tested five years ago for something unrelated to warfarin, if I still have that testing data available five years later, you could potentially use that testing data to help dose my warfarin, even though that's not why you got the genetic test in the first place. So potentially that's another avenue for this to become more commonplace.

Dr. Khyati Patel  35:52
I think, Dr. Kane, what you just said last is very important, as these commercialized tests targeted for patients become available and they go out and do these tests and kind of bring it to the doctors and providers and say, hey, please those you know utilize this information. I think that's another way of kind of saying we can afford some of these genetic testing and personalize the medicine.

Dr. Sean Kane  36:15
So Doctor, why don't we go back to that patient case. So this was the patient who was African American who had a new knee replacement, and now they have a lower extremity DVT, and we're starting Warfarin on them, and we have this free genomic testing available to us, and we're deciding, what do we do with it, right?

Dr. Khyati Patel  36:35
So if you recall for our patient, the patient had the two c9, star two allele. This allele is significant. However, we need to keep in mind that because this patient is African American, there are other CYP2C9 variants that we need to consider, such as Star five, star six, eight and 11, and that information was not available from this particular genetic test. And the VKORC1 gene for this patient was wild type, meaning that it didn't have any implications on warfarin dosing. And so, as we kind of discussed from the CPI, C 2017, guidelines, you know, for African ancestry patient, this test in itself, what we have in front of us doesn't provide a complete picture. And so because this star 568, and 11 information is not available, the recommendation is that we dose this particular patient based on clinical algorithm and not genetic algorithm. If we were to do it on genetic algorithm, we probably will put patient at a disadvantage of more bleeding events. And that was, you know, available from data available from the COAG trial. And you know that those 27% of African American patients. So if you apply that clinical dosing, you know, normally for your ortho patients, we usually start out with a little bit of a higher dose of five milligrams daily, and then test it within two to three days. And obviously for having the first vte, the goal INR would be two to three so that would be our target goal, and our adjustment of the warfarin dose will be based on that goal.

Dr. Sean Kane  38:15
Perfect, you know, just to kind of wrap things up, some key concepts here. So Dr. tell one thing that is always important with all of pharmacogenomics is that we take the entire patient picture in mind, not just their genetic profile. So we think about with Warfarin a variety of different interactions, like drug and food interactions, lifestyle, things like that, in addition to the genetic information that we have

Dr. Khyati Patel  38:38
right and the genetic polymorphisms that are more pertinent to warfarin, as we know now, are in the metabolizing enzyme CYP2C9, the target protein VKORC1, and the vitamin K oxidase CYP4F2, which could alter the warfarin response in patients who have these variants positive.

Dr. Sean Kane  39:00
Another key concept is that, for the most part, most of the data is kind of plus or minus in terms of pharmacogenomic testing of the data that we do have, it would appear, like in the gift trial, that there may be benefit to kind of an algorithm based approach, but I would say that most people are waiting for a little bit more data to have more concrete clinical outcomes and a more robust patient population to make this a more common almost standard of care for warfarin dosing.

Dr. Khyati Patel  39:27
And then know that the data we have available, we want to make sure we apply it properly to patient you know that in front of us. So some of these polymorphism are specific to different ancestry, and not all commercially available tests would have the results for these polymorphisms, and so guidelines such as the CPIC provide further insight on how we apply the test results to a particular patient's Warfarin dose. Perfect.

Dr. Sean Kane  39:56
Well. Dr. Patel, always a pleasure for the listeners, if you want to see show notes. And links to some of the resources that we talked about today. Go to HelixTalk.com episode 125 we're on Twitter at HelixTalk, and we love, love the five star reviews in iTunes. So keep those coming. So with that, I'm Dr. Kane

Dr. Khyati Patel  40:13
and I'm Dr. Patel, and it's pleasures of his mind, Dr. Kane and to the audience, study hard.

Narrator - Dr. Abel  40:19
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Narrator - ?  40:30
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