Hello friends good morning so the outset I wish to thank Dr Anand for having me to deliberate on this topic uh Noak use and the current evidence so as you see this is a quite a big topic uh there are quite a few trials possibly you could um deliberate upon this topic the whole day so I'm sure the the topic that I be covering and the evidence that I'll be talking there would be significant overlap between the previous speakers uh so nevertheless they're all important trials so it's good for all the listeners here to have Clarity on how these trials are done and what is the current understanding of use of nox so nox is newer oral anti coagulant and the newer nomenclature that is the more increasingly used is direct oral anticoagulant so we use the word NOA in this particular talk so the topics that I would cover is just a physiological because when we talk about newer oral anti-coagulant it is important to just have a little overview on the coagulation pathway on which it works and we'll just look into what are the FDA approved prophylactic indication so this is very important at the outset to a certain as to what are the conditions where FTA has approved its usage as axis so we'll look into the key difference because if you look at all the data and all the studies most of them would be comparing NOA with another agent and it has to be another anti-coagulant so I try to mainly focus on Noak as compared with Warfarin which is another vitamin K antagonist so I wouldn't take studies which Compares nox versus placebo the only one study that I would cover is the most recent RT trial which compar noax versus has but otherwise most of the evidence that I would cover would be noax versus it it other competitor or it's another anti coagulant which is vitamin cagon war and when you look at the evidence there's a whole lot of evidence so one possible article which tries to Encompass all the evidence that is prevailing is one metaanalysis which came in landet it's the largest metaanalysis encompassing 72 th000 patients covering around 48 randomized control so this possibly will give a very comprehensive thought of a overview on the evidence of NOA then we'll talk about four Landmark articles which I'm sure many of you would have heard in various formats uh which is imperative that we talk about these Landmark articles which has compared Noak versus werin so this is an interesting article that has looked into nox versus Del can cancer patients who had VTE to prevent further occurrence of VTE and then this is the fourth one I picked up is important as well because we do get lot of CKD patients on dialysis whether NOA are safer and is it found to be Superior or beneficial and and obviously we need to cover the latest trial that has coming in 2024 January in any game which is noax versus aspirin subclinical a so I'll very briefly cover this the sort of important evidence that is prevailing on the use of Mo and after talking all the evidence it is good for all the listeners to have some key take-home recommendations with the use of noas and we'll talk about take home message so when you look at this coagulation pathway which has extrinsic sort of a pathway and then there is the intrinsic pathway and the common pathway and as you would see this you would be reading from your mbbs days so the only thing you need to focus on is this 10A and 5A and you are anti-1 Inhibitors which are the Neal anti-coagulants which are most commonly used at at this 10 and this get converted to thrombin alongs with 13 a converts fibrino into fibrine and fibrine clot is form so the 10 that are currently available in the market and in India Rivero saan apixaban and OK Saban is not available yet and baban so these are the currently available worldwide and sa and river of saan are the ones which are available in India and the direct thrombin inhibitor which acts on the thrin which is needed for conversion of fibo to fibrine or dabigatran which is available and the other ones are argatroban and Balin so this is so the only thing you have to remember is there is this extrinsic pathway there is this intrinsic pathway then both of them together lead to Common pathway which starts from 10 interacting with P leading to thrombin which converts fibrino to fibrine and we need to know where your NOA at so one group acts are the 10 and one group acts are the direct throbin inhibitor so we'll directly jump into what are the approved FDA approved sort of conditions for prophylaxis so one important area we talk about evidence of NE oral anticoagulant is prophylaxis in orthopedic surgery which may be knee joint surgeries or hip joint surgeries to prevent BTE as you see I just listed all the newer oriented violence so the prophylaxis in orthopedic surgery is approved for River oxan in 2011 by FDA approved for aican in 2014 approved for adedo suban in 2015 and the second conditions where it FDA has approved its prophylactic usage is in the stroke prevention so if you look at all the trials the major body of evidence lies in this sort of a dimension to prevent stroke in patients with AF and most of the NOA are approved in non vular AF not in val AF the non Val AF to prevent stroke which we call as stroke prevention in SF stroke prevention in fibrillation it's approved for all these nean tatron rxan aaban andox suban and these are the years in which it is approved not it approved in for berric and now we look into the FDA approved treatment indications for Venus thromboembolism so all these NOA including betrix ban is the is the recent kidon block which is approved in 2017 all these are approved for the treatment of Fus thromboembolism and how about ACS acute coronary syndrome the approval process is completed for River oan and aavan but it has not come as a formal sort of an approval or as a formal guideline but but this is at any point of time these These are sort of figuring out in some of the guidelines so this is completed so but FDA has not still come out as an approval for usage of these in ACS so this is a sort of an FDA approved indications so we'll just jump into what are the key characteristic difference between the noax and the warin so there are certain pros and cons of noax so the newal antic some of the strength of it is is increasingly effective and use it as a fixed dose there's no need for INR monitoring and most studies very interestingly have shown reduction in s of a bleeding manifestations with noax and the one of the con or the limitations is and obviously it is more pricely than Waring so the pro of warer is it is bound to the alamine and predominant excreted by the liver so it could be used safely in the patients but the limitations of it is one needs to do irr monitoring when using warer and it has a narrow therapeutic sort of a window in which it acts and it has huge interactions with lot of nutritional intake or Diet dietary interactions or something that is common which either pronounces the effect of Warfarin and limits the effect of Warfarin and the response is little unpredictable so there is a unpredictability with regards to the response to warfaring so these are some of the key characteristic strengths and limitations of nox and Waring so we'll jump into because the topic for today for me is the evidence so we'll directly jump into the all the evidence that is available so this is one article I want all the listeners to pay attention to this is the possibly the largest metaanalysis as you see Mammoth number of patients 71683 patients 48 random m control trial it's come in lanet in 2014 so comparison of of the efficacy and safety of Noak with war patients with atrial fibrillation so here they had patients 42411 in noax and 29272 in barar and it did Encompass all the key Landmark articles like Rel rocket Aristotle andf and these are some words which you would have listened I'll go into the little detailing of these trials so most of the trials that I'll be talking have looked into usage of these noxs to prevent the stroke and systemic embolization I just put pictorially as arterial or Venus trism mainly systemic embolization so if you see this is a hugely positive metaanalysis Noak significantly reduced the risk of stroke or systemic thrombosis as compared to the warin and they were all statistically significant most interestingly this meta analysis shows that all cause mortality also there was significant reduction with the use of noax and compared to warin in PTI ptients within a subgroup analysis they made in patients with non Val f with appla in patients with antios antibod when they compared vitamin K antagonist and River oxyon vitamin K antagonist was found to be superior and again detailing into this particular study they looked at the IC bed see the main sort of a concern that we would have with the use of these noax is the IC bleed and interestingly they found in this metaanalysis the risk of bleed was significantly Less in the Noak group as compared to the W which means it is very good especially when when we P the risk of patients developing IC bleed and major the GI bleeds was higher with the use of noat as you see the relative risk was 1.25 and that was statistically significant so there was an mortality benefit there was a stroke reduction there was systemic thrombosis reduction IC bleed reduction but the GI bleed was high with the Noak group and here they did a subgroup analysis about low dose Noak because we have differential dosage of noax we look into the dosage in recommendation with the low dose noax they found that the stroke prevention and the systemic embolization prevention did not happen as you see did not attain statistical significance in fact with the use of low dose noax they found there was increase in the risk of the stroke or systemic thrombosis and that attain Strat so which means when you're using nox it's no good using low dose because that may increase the risk for stroke and definitely did not prevent stroke rather high dose no we'll show you the dose in the recommendation but the risk of bleeding definitely was less when low dose nox was used and that attain statistical sign so these are these are some of the subgroup analysis they did so the conclusions of this meta analysis was nox worth favorable when you look at the risk benefits out of balance the benefit outweighed the risk although there was a with GI bleed but that could be addressed with whatever medical or little interventions but it did not endanger the lives because all cause mortality was significantly less with nox so the nox was favorable in reducing the stroke reducing the mortality and reducing the IC bed so this is a very strong compelling sort of an Evidence largest metaanalysis that possibly you can keep in mind so this is a another interesting sort of a study Noak was D Tarin in patients with cancer in it was a systematic review and metaanalysis so in patients with cancer who develop Venus prom embolism whether the use of direct oral anticoagulant or NOA as compared to diar in low molecular weight did it show benefit in preventing recurrent Venus fism so in this particular metanalysis showed that the nox significantly reduce the risk of recurrent Venus trism as compared to D parin this is in patients with cancer increasingly guing cancer patients who develop who are at a very high risk of develop BTE use of NOA was found to be superior in Del to Del to prevent recurrent VTE and when they looked at Major bleeding it was similar between doax and dearin but non major clinically significant bleed was more with Neal anticoagulant at 11.1% as compared to dalteparin and that also so all the studies if you see they say the risk of bleeding tends to be little higher but I bleeds most of the studies are shown to be less with neural anticoagulant this is non major clinically significant bleed was higher in this is in cancer patients so we'll just very slowly dwell into the key Landmark articles which we need to be aware so the all the landmark articles that I show have come in anym but a word of caution most of these are Pharma funded and there are hugely Pharma funded trials and none of them are institution driven trials so the reli trial came in NM in 20 09 comparing dabigatran versus warin patient with atrial fibrillation mainly come with Canadian and Dutch authors so here all the studies had good number of patients 18,3 here they compared two doses of dabigatran so in one group they had 110 mgram dabigatran compared to warfarin so they showed stroke reduction and systemic thrombosis was similar between the two groups and the bleeding was lower with dbig so they did not show superiority of dbig R but the higher dose of diatron 150 mg per BD showed significantly reduced risk of stroke and systemic thrombosis and even the bleeding was similar so goes on to show that 150 mgbd of deetron had a better benefit than 110 mgbd of Daval so the rocket AF trial so this is River oxan versus warar in non Val R fibrillation again a PHA F trial coming NM in 2011 so again good number of patients 14,264 randomized between Riv oyan and warin they looked at the stroke and systemic thrombosis it was a non- inferiority study so there was no difference between rivox and it was non- inferior which means rivox performed as good as warin and bleeding also there was no difference and when they looked at IC bleed intal bleed was less in Riv oxyon as compared to so wherever I show thumbs up there was some benefits with the use of Noak and the Fatal bleed also was significantly Less in rivox Burn as compared to Warf goes on to so it was non inferior it was as good as Warfarin but the key benefit is it showed reduction in the IC bleed and the Fatal bleed which is also very important when you're using anti- coagulations then came this Aristotle trial where apixaban versus warin in patients with atal fibrillation good number of patients 18,21 so randomized between apixaban 5 mgbd and and Warfarin here they looked at stroke and systemic thrombosis was significantly less with the use of apixaban as compared to warin and major bleed also significantly less with the piix band and IC bleed also sign so this is a hugely positive study Aristotle which leans towards more compelling benefit of newal anticoagulant and there is more benefit with reduction in I bleed reduction in stroke and reduction in major bleeding so that is about Aristotle then this is engage AF T trial this is comparing edoxaban versus warer in patients with atrial fibrillation big group of patients 21,5 so they compared high dose edoxaban low dose edoxaban and Warfarin 60 mg of edoxaban 30 mg of edox suburn and 7,35 in each of these patients so the stroke prevention and systemic thromboses it was non inferior to warer in all the doses but edoxaban higher dose showed a trend towards favorable benefit in reducing the risk of stroke and systemic thrombosis lower dose so we saw the similar Trend with dabigatran where higher dose was more beneficial but lower dose was non it was very similar lower dose in fact showed unfavorable Trend but the higher dose showed more towards favorable Trend with Ed oxa burn and again like dbig gatron like apixaban the major bleed was less with nox as compared to war in statistically significant and death due to se cardiovascular events also was significantly Less in adoor group as compared to warin and that was the statistical significance so which goes on to show if you see most of the studies are showing benefit with noax in reducing the risk of IC bleed or major fatal bleed and some of them showing benefit with regards to prevention of stroke and systemic thrombosis so this is the interesting thought of an observational study it's a retrospective study of benefit of AIX aan in end stage kidney disease who are on dialyses with atal fibrillation so large group of retrospective data 25523 patients small group on epixon 2351 compared to 23171 these are end stage renal disease or dialysis who received NOA so they looked at stroke reduction and stroke prevention and systemic trombosis there's no difference between apixaban and warin but here when they compared higher dose versus lower dose in the retrospective data 5 mgbd and 2.5 again goes on like dabigatran like adox higher dose had a benefit significant benefit in reducing stroke prevention and reducing systemic thrombosis attain statistical significance at high dose this was a subgroup analysis they did and highay also showed reduction in the risk of patients dying in with patient in patients with n stage renal disease so again goes on to show dabigatran high do more effective in sort of reducing the stroke or mitigating the stroke and systemic thrombosis and even edox higher dose was shown to reduce the stroke and reduce the risk of systemic thrombosis in a kidney failure also dose reduction is something one possibility to think of avoiding with the Pix although recommendation say some dose adjustment is needed and major bleed also significantly less with aican when compared to warin in end stage renal disease goes on to show that these are the agents which are safeer even in the end stage Ral disease so just coming to the last sort of a trial that I'll be discussing which just came in January 2024 a pick a burn for stroke prevention in subclinical af these are all clinical AF subclinical AF and it is shown that patients with sub clinical AF are 2.5 fold times higher risk of developing stroke and more than onethird of elderly patients with hypertension do have subclinical AF and these patients are at risk of developing stroke in 1% per year so this study was done to address whether the use of aixa bur reduces the risk of the stroke here the the mean sort of a Chad W score was 3.9 plus orus 1.1 the Chad score is usually in the range of 0 to 9 nine pending highest risk for developing stroke so they had 4,12 patients 2015 in axagon group and9 again shows the stroke prevention and systemic thrombosis prevention was significantly less with the use of apixaban so the number of Strokes was 55 compared to 86 it amounted to 78% per patient year compared to 1.24% per patient year attaining statistical significance and they looked at the bleed major bleeding was significantly higher only this is one study rtcr study we show all the previous studies you saw tole engage Mi and R all of them tended to show lower risk of bleed but this is one study made he showed major bleeding was high in the pixon group and that rain statistical 1.71% versus 94% in aspin but as you see this trial was comparing not Apples to Apples but aan was compared with Aspirin because all the previous trials you saw NOA being compared with warin so that's why the major risk of bleed was higher with apixaban as compared to Aspirin because aspirin is anti platet epican is noax and the Fatal bleed surprisingly was higher in aspirin and lesser in apixaban so this was the most recent trial which again goes on to show that these agents are successful in preventing the stroke and systemic thrombosis but as you see this is a subclinical a compared with Aspirin so just coming so those was all about the evidence so we'll very briefly to summarize all the evidence into what has come as a accepted recommendation is most recommendations come in stroke prevention in patients with non vular AF so this is something you can keep as a take home message so apixaban for stroke prevention in af standard dose is 5 mg dose reduction to 2.5 mg twice a day may be needed if patient's age is more than 80 years or if patient's weight is less than 60 KES or creatinine more than 1.5 so again here you may have to exercise little discretion because we saw that study where the benefit was more in even end stage kidney disease with PMG video of apixaban so that is something you can keep in back of your mind and dabigatran 150 mg BD and dose reduction is not needed and Edo suban 60 mg once a day standard dose dose reduction to 30 mg may be needed in patients who weigh less than 60 k for ctin clearance which is between 15 to 49 River oxyon standard dose is 20 mg OD do reduction of 15 mg in patients with catin clearance less than 15 to 49 and what about liver failure child C sosis none of these NOA can be used child B has to be used with caution River oxy cannot be used in child B in child day all of them can be used abatron apixaban oxan and River oxan so what about recommendations in patients in af with acute coronary syndrome it is very similar to uh stroke prevention so 5 mg BD 2.5 mg in patients with more than 80 years less than 60 K get more than D is the same as previous 115 110 mg so adox 60 mg standard reduced to 30 mg in patients weighing less than 60 kgs catin clearance to 49 River oxy bomb 20 mg reduced to 10 mg clearance is less than 30 to 49 so these are the recommendations for AF so how about recommendations for treatment so for the treatment this is little different because obviously the earlier one was prevention initially is 10 mgbd for 7 days only apixaban gets treatment at the outset otherwise all the all the other NOA you have to use low moleular weight Hein initially 10 mg twice a day for 7 Days followed by 5mg BD for diatron you had to overlap it the initial therapy is low molecular weight Orin and then you can change out to 150 mgbd of D gatron Riv you can give at the outside 15 mgbd to 21 days followed by 20 mg once a dayoan hearin or low moleular is the initial Choice after which it can be change out to 60 mg OD so I wouldn't expect most of you to remember all this you can refer all this you create a protocol and keep it in your ICU and refer to this when you have the patients to treat with it and long-term prevention of recurrent Venus thomism especially in patients with cancer so Epix 2.5 mgbd and aigan 150 mgbd River Ox 10 mg o and edox 60 mg o so those are sort of accepted recommendations that is endorsed by many of the guidelines and what about the recommendations for VTE prevention in Orthopedic patients apixaban 2.5 mg y a Deaton 150 mg rivox 10 mg andox bom 30 mg and how about in post acute coronary syndrome without AF to prevent AO thrombosis only river oan is sort of suggested at 2.5 mg twice a day the small dose along with aspirin and P2 y12 inhibitor so these are some of the recommendations that has been endorsed by Vi of the guidelines so the take home message is NOA newal anticoagulants have good physiological plausibility that they work on the physiological pathway of intrinsic and extrinsic on Inhibitors and direct thrombin Inhibitors but noax has good evidence both in prophylaxis and treatment in prophylaxis mainly in the stroke prevention all the major trials are done in stroke prevention in acute in atrial fibrillation or atrial fibrillation following acute coronary syndrome or preventing Venus thrombembolism in Orthopedic surgeries so these are there's a good amount of good sort of an Evidence in these conditions treatment there is good evidence for treating Venus thromboembolism uh and many of the drugs need you one needs to start with low moleular weight Heine and then change over to Noak but only for um so River oxan and apixaban you could start off up front without the need for low molecular weight hearin and treatment is also to prevent recurrent Venus someone who's had a BT mainly in cancer patients there is a good evidence but the caution one needs to exercise is all the studies all these major trials rocket trial Aral trial reli trial all these have come in the top Journal that we look up any game but all all these trials are Pharma funded so one has to keep that in back of mind so but there is good evidence so so just look into from that perspective and exercise your deliberation so thank you one and all I request each of you to submit your valuable work to journal of acute care which comes out every 3 to four months and can visit my website ww. pra.com to re to this lecture so thank you thank you one and all