[Music] hey everyone welcome back to curbside consults one of the podcast series of the New England J L medson I'm Rob one of the editorial fellows this year today I have the pleasure of interviewing Dr James dutis a professor of medicine and the David brayy Nancy Gordon chair in thromboembolic disease at McMaster University he is the first author of the American College of Chess Physicians clinical practice guideline and the peroperative management of anti-thrombotic therapy that was published in the journal chess recently Dr ducatus welcome to the show thank you very much Rob it's my pleasure to be here I'm glad to have you here to discuss this rather detailed clinical practice guideline in a quite complicated area of medicine this document covers vitamin K antagonists direct oral anti-coagulant and heprin bridging for patients with chronic atrial fibrillation mechanical heart valves or Venus thrombo embolism and anti-pla agents for mainly cardiac patients there are 43 Pico questions here with 44 guideline recommendations I wonder was this a difficult guideline to develop and how did you even start well thanks again for the opportunity to discuss the accp chest guidelines on peroperative anti-thrombotic management this was a guideline that was rather overdue because it was anchored on two previous guidelines published in 2008 and 2012 and we were delighted to be able to do this because since that last iteration we have had the direct oral anti-coagulants where Doak come onto the scene and they've become the dominant anti-coagulants in many clinical indications but we also wanted to update the literature on a variety of areas including peroperative heper and bridging and peroperative anti-l drug use so it was a nice opportunity to up at the evidence and we're delighted that it finally got published in 2022 great so I think we should probably start with some definitions uh In This Very lengthy document so we're all on the same page when we listen to the recommendations can you take us through the important terms for our listeners and any qualifying remarks sure maybe what I can do Rob is kind of provide a bit of an Insider view of how these guidelines and recommendations were developed and to allow people to understand that guideline development is a very rigorous process that has many steps that have to be adhere to but at the end of the day there's also a subjective element and there are people who are gathered to want to provide the best available recommendations but also do so in a manner in our case that's very practical so for the audience when they look at a recommendation they have to take into consideration that it was based on direct evidence but also indirect evidence in other words evidence from other areas that pertain to that general area and then thirdly there's also the interpretation of the studies the strengths and limitations finally it's really important to notice that the recommendations required a certain amount of consensus So within that process we wanted to provide recommendations About Management in various clinical domains that provide clinicians with a kind of how to approach how do you assess thromboembolic and bleeding risk how do you bridge how to you integrate VTE profilaxis and importantly how do you communicate and ensure that there is good consensus amongst the various caregivers involved in the peroperative setting and then finally to your point about definitions we also wanted to Define what are we talking about in terms of the patient groups and we focus mainly on the dominant indications for anti quagon therapy and anti therapy which are patients who have a mechanical heart valve atrial fibrillation Venus tromo embolism or coronary archery disease and of course we defined the various anti-thrombotic treatments whether they were a vitamin K antagonist a Doak or an antiplatelet agent and then in terms of the actual period of peroperative management we Define that period as starting from about 5 days before a planed Sur surgery to about 30 days after so again we're looking at planned elective surgery we did not address emergency or urgent surgery which is a very different clinical domain and was beyond the scope of these guidelines so certainly sounds like a very rigorous process and a very comprehensive guideline I think we all commend you and the panel on your effort if it's okay with you I might Focus the initial discussion on anticoagulants I think we're all trying to do our best with patients in balancing the risk of bleeding versus the risk of clot formation could you take us through the pharmacology of these drugs in relation to their clearance I think that'll help us understand the specific recommendations sure so why is an understanding of pharmacology specifically pharmacokinetics and pharmacodynamics of anti-coagulants and anti-platelets important we typically don't think about it when we're prescribing these drugs but but it is very important in a peroperative setting because we want to ensure whether we a drug is removed from the circulation that patients don't have an active anti-coagulant or anti-platelet effect for example for certain types let's say high bleed R surgery and we need to rely on the pharmacological properties because we don't often have routinely available rapid tests in all clinical situations sure you can do an INR one or two days before surgery in patients who may be on warfront to check if there's any residual effect but you may not be able to do that in all circumstances similarly we don't have a test that we can use to measure doax that is widely available and reliable and then for the antiplatelet therapy there are not really a lot of reliable and well studied tests of antiplatelet function so in the absence of these widely available tests we have to rely on both the pharmacokinetic properties and pharmacodynamic properties of these drugs have a basic understanding it's really important for peroperative management so could you give us some examples of the common drugs in terms of expected pharmacodynamics sure I'd be happy to Rob so let's consider first of all the vitamin K antagonist in North America and in many countries warrin is widely used and we know for example it has a halflife of between 36 and 42 hours on the other hand in some countries for example in Europe their vitamin K antagonist is usually a cumal which is very different it has a much shorter 8 to 11h hour halflife and then there are infrequent circumstances when patients might receive fenr cuman which has a much longer half-life of 96 to 104 hours so in this situation having that knowledge of the pharmacokinetic properties in this case halflife is very important to determine how long you interrupt the drug and for the warfront of course we recommend Interruption of at least five days based on those PK principles similarly with the doax which have a halflife of about 8 to 12 hours it's also important to tailor the interruption according to that Half-Life and according to the patient's risk but the other part of the pharmocokinetic effect with doax that's really important in a peroperative setting is their onset of action a lot of clinicians may not be aware that when you take a Doak its peak anti-coagulant effect occurs one to three hours after oral intake now that may not be important when you're starting somebody on treatment for let's say atrial fibrillation but it is very important when you're resuming the doac after a surgery or procedure particularly if it's a high bleed risk because you don't want that Peak at to quag to cause bleeding and then finally when we look at the anti-platelet drugs it's very important to separate the pharmacal kinetic and pharmacodynamic effect so the half-life of aspirin or other P2 y12 Inhibitors like Cil or tagore is only a few hours but as we know in the case of aspirin cigil and prasil these are irreversible platelet Inhibitors so once they act in on the platelets their effect lasts Way Beyond their Half-Life so their pharmacodynamic effect is that they impair platelet function for the lifespan of the platelet for 7 to 10 days and it's a little bit less with tagore which has some reversibility in its antiplatelet effect so really important to have a basic understanding of the PK and PK PD properties of these drugs to allow you to use them safely and effectively per operably yeah I think that's a really good teaching point that we need to think of these drugs in a slightly different way in terms of whether we're stopping them or restarting them I think every patient is different in terms of their risk of clop formation and bleeding and the guidelines set out in table one the subgroups of patients are particular risk of thrombus formation can you tell us more about those patient populations sure now when as a clinician I'm seeing a patient for peroperative management what anchors my assessment is an empiric but patient Centric evaluation of what I think is their thromboembolic risk and what I think is their bleeding risk and the former is driven by a number of factors so whether a patient has a mechanical heart valve for example a mitro valve is higher risk than an aortic valve whether they have atrial fibrillation a very high Chads or Chads vasor is higher risk than a low Chad for and whether they have VTE a higher risk is whether they the episode occurred let's say pulmonary embolism within a month or is more remote and the bleeding risk is driven largely by the surgery or procedure not due to as much patient factors but these two elements anchor how we manage patients whether we need to interrupt anti-coagulants and if so how do we manage when do we interrupt if we interrupt a vitamin K antagonist do we need to Bridge I need to point out and this is a very important Point Rob these risk assessment formulations are empiric they have not been validated prospectively but we developed them to allow clinicians to have a starting point to assess risk for throb embolism and bleeding and they have to be used in conjunction with clinical judgment so let me give you an example of what I mean let's say I had a patient with atrial fibrillation who needed an elective surgery on a Doak and they had a Chad SW of three but let's say that Chad SW included a prior stroke that occurred peroperatively and let's say their other factor is hypertension although the risk formulation may consider those as low to moderate risk in fact you might consider that patient higher risk because they had a peroperative stroke so the table is there to provide a starting point to assess patient risk but it has to be combined with individual patient characteristics and your clinical judgment yeah I think you know applying guidelines rigidly to every patient you see is obviously not a good idea but this guideline is a very useful resource to Residents if they have questions in terms of Parry up management so I think that's a good understanding of Pati factors procedural risk metabolism of these drugs a practical example let's start with warrin I think the guideline recommends stopping for at least five days for anything other than minimal bleeding risk what do the guidelines recommend regarding vitamin K if the INR is still high pre-operatively so there still are a lot of patients who are receiving Warfare nowadays not just for mechanical hard valves but also for atrial fibrillation worldwide and it's something that we'll continue to see until they are replaced entirely by other agents in the area of Warr Interruption our recommendation is at least five days of interruption and the only caveat there is that you may require an extra day or two in selected patients let's say who have a higher Target INR if they have a mechanical heart valve or in some patients that you know because of age or other drug interactions May metabolize the warrin less quickly so once again part of that individualized management in regard to the vitamin K it might seem counterintuitive to listeners so why would you not give vitamin K if you did an INR and it was over 1.5 well the reason is that when we looked at the evidence so our recommendations are anchored on the actual evidence the data are not very good to support the use of vitamin K because these are observational studies and the efficacy to reduce the INR was not sort of robust or uniform and the other part is that patients don't routinely get inrs before a surgery and we don't advocate for that because there are a number of studies that forego doing an INR the day of the surgery as long as you have that at least 5day window of warer interruption and rates of major bleeding are quite low so it doesn't appear to affect clinically meaningful outcomes the other part was a practical part that we mentioned that vitamin K may not be easily available in an oral form it sometimes can be given intravenously which we don't want to recommend routinely and may lead to warrin reinitiation resistance so for those reasons we did not recommend the routine administration of vitamin K for more patients who had a higher INR over 1.5 of course this does not exclude you doing that if let's say a patient unexpectedly has an INR of let's say two or two and a half of course you're going to give vitamin K to allow that surgery to proceed within the next day or so you mentioned prosthetic valves at the start of your answer I think a lot of people would like to hear from you given the recommendation in the guideline about mechanical valves and maybe you could tell us a bit about the thinking behind that sure and this is one of the controversial areas that might raise a bit of eyebrows among readers or listeners and in our guideline recommendations we actually suggest against bridging in patients with atrial fibrillation this is a moderate strength of evidence also a against bridging in patients with Venus thrombo embolism and perhaps unexpectedly in patients with a mechanical heart valve of course all of whom these three groups would be receiving Warr but we go on to say the following so we're starting out with the premise that the default should be not to Bridge and the rationale for that is if you look at the totality of evidence whether it is in any of these three groups but particularly in patients with atrial fibrillation we found that the evidence does not support bridging as a way of mitigating against the risk of peroperative arterial thromboembolism but there is consistant evidence that it increases the risk for bleeding you don't want to have bleeding peroperatively because that in turn may lead to further delay in resumption of anti-coagulation which will have the undesired effect of exposing those patients to an increased risk of stroke and other thrombo embolism so we're starting with that premise that the default is don't bridge but we go on to provide additional recommendations that you can Bridge patients who are deemed at high risk so that's when you can apply the thromboembolic risk table to identify who might be some of these patients so patients with a mechanical heart valve in the mitro position that have at least one risk factor which is pretty well all mechanical mitro valve patients patients who have a very high Chads score or Chad's vas score patients who have had a recent within 3 months episode of Venus tromo embolism those are patients that we actually advocate in favor of bridging although that is a kind of conditional recommendation based on very weak evidence and then we also go on to say as I alluded to earlier Rob that clinical judgment plays a role so just because somebody falls into that low-risk category by the table doesn't mean you canot consider them at higher risk based on individualized factors so yes we're advocating against bridging but with important caveats and qualifiers right so again kind of reemphasizing taking the clinical context into account when interpreting these guidelines you also make recommendations for more minor procedures like Dental minor skin surgeries icds and colonoscopies can you tell us about the rec recomendations for those procedures sure and these are procedures that are very common you know we're dealing with clinicians who have to advise either Health Care Professionals whether they're dentists B surgeons or dermatologists but there's also increase in use of pacemakers and icds over the last one to two decades and there's actually some very good literature now that is supporting the continuation of anti-coagulants particularly vitamin K antagonist around Pacemaker and ICD implantation and that's why there we had a a strong recommendation in favor of continuation versus Interruption Andor Bridging the evidence is not as robust in patients having other minor procedures either Dental eye or skin but there are weaker recommendations conditional recommendations again to continue anti-coagulants in minor procedures and we try to Define these once again having said that not all dental procedures are the same and having a tooth extraction may not be the same risk in all patients so you have to take that into consideration and this is where we come back to the point I made earlier in our kind of Preamble about the importance of communication among healthc care providers it's a very multi-directional communication pathway and you want to talk to the dentist and say what's the patient like in terms of their bleeding risk and let's not forget the patient perspective are they concerned about bleeding it may not be clinically important but it sure may be important to the patient so these factors have to be taken into consideration but overall we're advocating continuing anti-coagulants in a number of procedures and as regard to colonoscopies we're also advocating their avoidance of bridging once again and also caution that colonos opies can be very different it could be something screening but versus somebody who you know has a history of popse and will need a polypectomy which itself is a high bleed risk procedure so general concepts combined with individualized patient Centric management when bridging Protocols are used are there any recommendations in the guidelines in terms of depending on what Hein you're using when to start and stop peroperatively yes there are Rob so bridging anticoagulation isn't used as much nowadays as it was 15 20 years ago but it still has a role and we do provide kind of a how to bridge if you are going to do it in terms of when to administer bridging therapy preoperatively what dose to use for example we recommend to use half the total daily dose the day before the surgery in the morning so to allow that anti-coagulant effect to be eliminated at the time of the surgery and we also advise staggered resumption of bridging post-operatively particularly for high bleeding resurgery so that you don't start for 48 to 72 hours and we also look at it as in a nuanced way for example I alluded earlier to a distinction between bridging which we Define as a therapeutic dose Lin Heparin or unfractionated Hein regimen and a lowd do regimen that is used predominantly for the prevention of Venus thromboembolism whether whereas bridging that I just referred to is designed to prevent arterial thrombo embolism so we talk about how can you integrate VT prophylaxis for the first two or three days after a surgery before you start their Bonafide bridging two to three days later so all of these kind of how to messages are Incorporated in this guideline and we hope it can be used at the point of care to help clinicians so i' briefly like to also discuss doax obviously far more commonly used now can you give us some recommendations from the guideline regarding Doak Interruption peroperatively sure so with the DOA and I'm referring to four agents a pixan the botran a doxan and river oxan and although they are slightly different we try to provide recommendations for each Doak but there's commonalities and the commonalities are anchored on the fact that all of these have a elimination halflife of between eight and 12 hours one exception is patients who are taking de botran and have impaired Ral function because the botran unlike the other doax is cleared predominantly by the kidney they the interruption interval that is required is longer but for most situations we recommend it's a weak or conditional recommendation because there aren't a lot of high quality RCT data to interrupt for one to two days before the surgery procedure and to resume similarly within one to two days or longer depending on the bleeding risk so here with Doak management is really really important to identify what you think the bleeding risk for the patient is and one area that the secondary of controversy that may come up Rob it has to do with patients who are receiving neuraxial so referring to spinal or epidural anesthesia or procedures for pain management like a lumbar block that sort of thing the reason it's controversial is because there are a number of anesthesia societies for example the American Society of regional anesthesia that generally recommend longer intervals of doac interruption prior to neuraxial or other high bleeding risk surgeries or procedures whereas we recomend only a two-day Interruption interval for those patients so why do we think two days is sufficient well first of all we have a fair bit of data on two days of interruption of a doax let's say somebody's having a procedure on a Friday and then their last dose of the doac will be on the Tuesday so nothing on Wednesday nothing on the Thursday so we have a lot of data on that kind of interruption interval whereas we don't have very much if any clinical data on longer intervals of interruption and what that means in terms of bleeding risk and thr embolic risk the second point is that we also have data that shows if you interrupt for about for two days then the residual antiquin effect when it's measured in almost all cases is less than 50 nanograms per ml which is considered by many but not by all a safe level to proceed with any kind of surgery including neuraxial anesthesia and then the third rationale for a two-day interval is that actually when you look at the time interval so let's say you're having surgery on the Friday at noon and you take your last dose of your Doak on the Tuesday at supper time well that's actually about a 60 to 68 hour interval between the last dose and the time of surgery that's five elimination half-lies the Doak so we're achieving the aim of allowing an elimination of that Doak with a two-day interval Interruption but it still remains an area of controversy I think it's something that I think we need to discuss with our anesthesia and other surgical colleagues I think that's a great tour through managing anti-coagulation in the peroperative period I think we should also discuss antiplatelet agents that are covered in this guideline particularly that difficult circumstance that we come across with recent PCI and Cary stem placement can you tell us a little bit again about the pharmacology of these agents sure so the three main areas that we cover with respect to anti-platelets management are patients who are having non-cardiac surgery coronary artery bypass surgery and then patients who as you just referred to Rob who have a coronary stent implanted and typically are receiving dual anti therapy with aspirin and a P2 12 inhibitor which is usually either cigil tagore or less commonly prasil and here it's really important to understand the pharmacodynamics because most of these drugs are irreversibly affect platelet function so if you give somebody a dose of any of these drugs those platelets will be inhibited for the duration of that platelet lifespan which is 7 to 10 days and that's why for circumstances when we want to recommend in uption of these agents which we do do in the guidelines the interruption interval is 7 to 10 days for many of these drugs a little bit less for tagore because it has an element of reversibility in terms of the platelet inhibition so that's the pharmacodynamic effect sort of what it does and then as I alluded to earlier in the podcast the phac kinetic effect is very different because the halflife is only a few hours so that part is not so important here it's more pharmacodynamic effect but back to the situation with the patient with PCI and a stent this is a really complex situation and unfortunately we don't have a lot of good data to direct our recommendations so the recommendations we do have are conditional or weak recommendations but the first is of course that we want to advise clinicians to delay the surgery if it's possible beyond at least a 1 to three month period and sometimes that may not be feasible so so if it's not feasible or not clinically acceptable for example somebody with a neoplasm in whom there's a need to reect it urgently or promptly then we do recommend a management where the aspirin is continued but the P2 i12 inhibitor is interrupted at least 3 to five days if it's tagore and then 7 to 10 days if it's procil or CIT gr now this is an area once again that communication it's really important not just with the surgeon but also with the cardiologist why well not all STS are the same maybe that patient has multiple stent maybe they have a stent in a critical area and these factors weigh in as to whether you may actually consider not interrupting the anti therapy or although we don't recommend it routinely we do offer an option to bridge them with a glycoprotein 2b3a inhibitor not done very often but once again there has to be an individualized aspect to management but certainly managing patients who have had a coronary stent and need an elective surgery is a challenging area for sure and then in terms of aspirin is there anything that you want to highlight in particular about the guideline yes and this is a third area that generated some controversy and like the other areas among the guidelin panel there was a lot of discussion and there was some dis agreement among the panelists but eventually the consensus for a patient that is on aspirin and needs non-cardiac surgery was to continue the aspirin as the default management and this once again like some other areas May raise some eyebrows and how did we come to that decision well it was based on as I said direct evidence but we also combin indirect data and interpretation in the data so for example there's a lot of discussion and debate about the Poise 2 study a very important Landmark trial looking at peroperative ASA use and some panelists felt that the results of that trial might have been lessened in terms of their applicability because about a third of patients were taking an nsid and an nsid might have affected the anti-platelet effect of the aspirin some panelists also pointed out that in that trial the increase and bleeding observed with peroperative use of aspirin was limited to those patients who initiated aspirin peroperatively and did not appear to occur in patients who continued aspirin so if they were prior users they didn't appear to be as increased risk for bleeding if they continued peroperatively but at the same time we offer an important caveat and that is in those patients that we the clinician deems to be at increased risk for bleeding yes you should interrupt aspirin once again this is a conditional or weak recommendation but that's the direction we're taking and if you do interrupt it as I said before at least 7 to 10 days over versus a longer period of interruption to mitigate against the risk for bleeding so the default was to continue aspirin but of course we allow interruption in many circumstances where bleeding risk is considered to be high so I'd really like to congratulate you again on this really thoughtful guideline it's a great summary of peroperative management and I'd encourage our listeners to read the guideline and the executive summary for more details that wraps up this episode of curbside consults I'd like to thank Dr James duettes for joining us today to discuss this clinical practice guideline we are always looking for ways to improve our podcast and educational material so if you have any comments or suggestions please leave a review on iTunes or email us at resident 360 at nj.org our production team at njm resident 360 includes Karen Buckley Lyn Winston Perry K Simmons Mike tomases Tim Vining Scott Williams and Kathy Stern also a special thanks to our njm education editor Dr Opie hanik curb site consults is brought to you by njm Resident 360 a product of njm group