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Correspondence to Author: Steven Morales, 

1Department of Radiology, University of Iowa Hospitals and Clinics, USA 2Lankenau Medical Center, USA

Abstract:

Recently three newer oral anticoagulants (rivaroxaban, apixaban, and dabigatran) have been introduced into clinical practice; while they are becoming more commonly seen in the primary care setting; they remain a gray area in the interventional community due to limited exposure. These drugs have been studied as a good alternative to warfarin, however there is a need amongst for radiologists performing percutaneous procedures to become more familiar with their clinical use, potential dangers during invasive procedures, and how to deal with complications as they arise.

Introduction: Recently 3 newer oral anticoagulants (rivaroxaban, apixaban, and dabigatran) are introduced into clinical practice; whereas they’re changing into a lot of normally seen within the medical care setting; they continue to be a area within the interventional community thanks to restricted exposure. These medicine are studied as a decent various to anticoagulant medication, but there’s a desire amongst for radiologists performing arts connective tissue procedures to become a lot of at home with their clinical use, potential dangers throughout invasive procedures, and the way to manage complications as they arise. For over [*fr1] a century anticoagulant medication has been the foremost wide used oral medication in clinical follow. Warfarin’s common use, aspect effects profile and reversal techniques are well established, creating it a well-known drug seen in interventional practices with the overwhelming majority of practitioners snug with its use. Recently 3 newer oral anticoagulants are introduced; whereas they’re changing into a lot of common to the clinical practices they continue to be a area within the interventional community thanks to restricted exposure. In this article these new agents area unit bestowed with stress on their clinical use, potential dangers throughout connective tissue procedure, and methods for a way to manage complications as they arise. Current NOADS Dabigatran (Pradaxa), Rivaroxaban (Xarelto), Apixaban (Eliquis) Mechanism of action Currently there area unit 2 mechanisms of action for NOADS: 1) Direct coagulase inhibitors (dabigatran) work by binding to the situation of coagulase and therefore the inactive kind of fibrin- sure coagulase. a remarkable characteristic of dabigatran is its part intrinsic action reversibility; by quickly dissociatingfrom its web site of action, dabigatran leaves atiny low quantity of enzymatically active coagulase within the liquid body substance, that is probably out there for action reversal [1-4]. 2) Factor Xa inhibitors (rivaroxaban and apixaban) work by obstruction the interaction of issue Xa with issue Va (figure 1) on the surface of activated platelets, thereby obstruction the formation of the clotting factor complicated, that converts factor II to coagulase. By obstruction this pathway the generation of protein is stifled [5]. These mechanisms area unit in distinction thereto of anticoagulant medication, that inhibits the activity of the fatsoluble vitamin dependent action factors (II, VII, IX, X); this impact is achieved by warfarin’s interference with the conversion of fat-soluble vitamin to its epoxide, that is required to treat salt residues on the fat-soluble vitamin dependent natural action factors. By inhibiting carboxylation, the liver then produces action factors with reduced procoagulant activity. conjointly proteins C and S, that area unit natural anticoagulants, area unit stifled by anticoagulant medication, that explains the requirement to bridge with anticoagulant medication or Low mass anticoagulant medication (LMWH) once beginning anticoagulant medication [6].

Advantages of NOAD use:It is acknowledge that tight management of the International Normalized quantitative relation (INR) is vital to the success of anticoagulant medication therapy; but dominant patients agency will be a challenge. it’s been calculable that agency levels area unit therapeutic solely five hundredth of the time [7-9]. one amongst the foremost enticing options of those new agents is that they need been shown to be equal, if not superior, to anticoagulant medication within the management of conditions like blood vessel occlusion (VTE) and cardiac arrhythmia connected stroke. there’s conjointly a lower incidence of intracranial injury with NOAD use as compared to warfarin; this is often comes while not the requirement for normal laboratory watching [10-16]. additionally medical care will be started forthwith while not the requirement for anticoagulant medication or LMWH bridging.

Limitations:Dabigatran and apixaban, though shown to possess lower rates of intracranial injury than that related to anticoagulant medication medical care, have double the chance of inflicting major channel injury. Rivaroxaban is at the start treated double daily, and whereas this can be not an immediate inducer of major morbidity, it are often indirectly problematic in patients with poor compliance. The major limitation of the NOADS is lack of a proverbial reversal agent, that is especially problematic within the actively injury patient. This limitation is presently the most important concern for radiologists activity body covering procedures. many proposals are created for a reversal agent, but there’s no presently on the market reversal agent. some of the planned reversal strategies are going to be mentioned in short later.

Pharmacokinetics:As a generalization NOADS begin peaking among two hours of administration with a mean half-life of around twelve hours. Dabigatran is merely thirty fifth supermolecule certain within the plasma as compared to apixaban and rivaroxaban, that ar eighty fifth supermolecule certain. In aged patients the halflife of rivaroxiban is prolonged from 5-9 hours to 11-13 hours. Dabigatran and rivaroxaban ar excreted primarly through the excretion, whereas apixaban is preponderantly eliminated through the unclean route [5].

Drug interactions:Strong P-glycoprotein inhibitors (amiodarone, verapamil, quinidine, clarithromycin) ought to be used with caution in patients on dabigatran, as these medicine have potential to extend humor levels of dabigatran. On the flipside a bonus of dabigatran is that there’s no result on CYP pathway, that may be a classic concern with anticoagulant medication. P-glycoprotein and CYP 3A4 matter interactions occur with rivaroxaban; so caution ought to be taken once patients ar receiving medicine like ketoconazole, voriconazole and protease inhibitor as they’ll increase medical care result. Finally, there has been low potential for drug interactions with apixaban, but it’s instructed that caution be soft on CYP inhibitors. There are not any proverbial food interactions for any of those drugs[5, 17-19].

CHALLENGES OF victimization NOADS:In distinction to anticoagulant medication, there’s no specific reversal agent which will be used for managing injury that result from NOAD use. These medicine don’t seem to be habitually monitored, that results in associate degree accrued risk of unwanted elevation of humor levels and associated risk of hemorrhage. though there ar laboratory evaluations on the market that obliquely monitor NOAD activity, there’s no manner of directly observance humor levels presently on the market. The indirect strategies ar mentioned in additional detail below.

Lab analysis:There is presently no gold normal for laboratory analysis of those medication but the subsequent tests area unit presently available:Thrombin Time and activated partial clotting factor Time (aPTT): These tests area unit sensitive to the general presence of dabigatran however cannot quantify the levels; if truth be told the aPTT plateaus with higher levels of dabigatran. though not fool proof these tests supply speedy results that will assist in decisive if hemorrhage is secondary to dabigatran or another entity [19,20]. Ecarin curdling time: uses venom to live direct coagulase inhibitors like Dabigatran however not the issue Xa inhibitors. This take a look at but includes a restricted handiness [18,21,22]. Assays of issue Xa activity: a spread of assays are projected and therefore the basics is that the same as those used for observation polysaccharide levels. Laboratories that area unit presently victimisation these assays to watch polysaccharide levels may be custom-made to use these techniques for observation rivaroxaban and apixaban, as they’re higher indicators of plasma concentrations of those explicit medication [18,22]. Rivaroxaban prolongs coagulation factor Time (PT), dilute PT, aPTT, Heptest and coagulation factor induced time period (PiCT) to varied degrees and so these tests haven’t been used clinically for observation. Apixaban has lowest effects of platinum, so anti-Xa levels area unit required to assess humor concentrations [18,22].

Role of NOADS in clinical apply:This topic remains heatedly debated, but once coping with these medication, it’s vital to stay the entire clinical state of affairs in mind. The schema given by Shulman et al [23] as made public below, may be a terribly helpful and straightforward guide to adapt to clinical apply. the selection of anticoagulants may be divided into many broad teams supported the patient’s clinical state of affairs Group 1: Patient population wherever Coumadin may be a superior alternative compared to NOADS: A. For patients already on Coumadin with consistent authority results, there’s very little indication to modify to the newer medication. For these patients, merely reducing the frequency of authority testing might improve the convenience and therefore satisfactoriness of Coumadin treatment. B. Patients with poor compliance can face a better risk of stroke with NOADs as compared to Coumadin, significantly given the short 0.5 lives of dabigatran and rivaroxaban, as failure to require the medication quickly ends up in loss of medical aid impact. Lack of an acceptable lab-monitoring take a look at any compounds this drawback. C. Patients with failure with creatinine clearance of but 30mL/ min. D. Mechanical heart valve replacement. Valve occlusion has been reportable with dabigatran [4]. E. Patients older than seventy five years. F. History of epithelial duct (g.i.) disease, particularly lower g.i. bleeds. Dabigatran contains hydroxy acid, necessary for its absorption and includes a high concentration of the active drug within the colon. G. Drug price; though in several things NOADS could also be price neutral or maybe cost effective. Group 2: NOADS area unit superior to Coumadin. A. Patients with sensible compliance however variable authority results. but it’s imperative that potential insubordination is totally evaluated and excluded. B. Drug interactions: If the patient is already taking medications that have the potential to interfere with Coumadin metabolism (e.g. antibiotic medical care, therapy, amiodarone, Tylenol etc.) or there’s a future decide to introduce these medication, NOADS could also be superior to Coumadin. C. fresh diagnosed arrhythmia with no contraindications as mentioned above; the advantage being a comparatively speedy onset of medical aid while not polysaccharide bridging. Frequent volumetric analysis of dose with research lab tests isn’t needed with NOADS. Group 3: Patients needing conversion from established Coumadin to NOADS. A. because of the potential for hyperbolic effectuality and reduced risk of intracranial bleed, some patients could also be sensible candidates for conversion to NOAD medical care. One instructed protocol is to start out NOADS only authority has reduced below a pair of.3. purpose of care authority monitors are not used throughout transition as dabigatran might result in elevated baseline authority [15,23-25]. Group 4: Conversion from NOADS to Coumadin. For patients World Health Organization are not any longer candidates for NOADS, Coumadin may be started as presently as these medications area unit stopped, with analysis of the authority three or four days later. but in patients with creatinine clearance of but 15-30 mL/min, authority ought to be checked earlier to rule out excessive medical aid necessitating Coumadin dose adjustment [23]. Pre-procedural management of patients on NOADS As always, shut communication with patient’s primary team managing the medical aid is important. Elective procedures and low risk interventions: generally stopping NOADS forty eighthours before procedure is adequate. This short amount of interruption sometimes doesn’t need bridging medical care with polysaccharide or LMWH. Urgent, however not emerging surgery: If doable the procedure ought to be delayed by twelve hours, as this can be adequate time for metabolism. Since the half-life isn’t dose dependent, this strategy is additionally applicable to NOAD drug. Emergency procedure: this may be mentioned later within the management of hemorrhage secondary to NOADS [23].

Postoperative management:In general for low hemorrhage risk procedures, NOADS may be resumed in twenty four hours, in higher risk cases {they ought to|they ought to|they must} be command for 48-72 hours once surgery; during which case a polysaccharide infusion should ab initio be used for medical aid. In cases wherever viscus palsy is a problem, like with post surgery placement, bridging with polysaccharide could also be required, as patients cannot take oral medications [23]. Strategies to manage NOADS evoked trauma complications General thought and preventive measures: As dabigatran particularly depends on excretory organ perform for its elimination, it’s imperative that excretory organ perform be reviewed before its initiation and before any interventional procedure; precautions should even be taken in patients with acute renal disorder. the problem of acute renal disorder is very vital within the post procedure amount, because the development of distinction evoked renal disorder or hypovolaemic prerenal insufficiency will occur in patients with major trauma. Initial workout ought to incorporates mistreatment normally accessible workplace tests to work out the etiology of trauma. though specific laboratory observance of NOADS has not been outlined there square measure comparatively straightforward initial steps that may be taken in patients with acute hemorrhage. for example, a traditional coagulase Time and aPTT implies that the trauma sensitivity isn’t thanks to dabigatran. equally a traditional platinum or undetectable anti-factor X activity excludes astringent pathology secondary to rivaroxaban and apixaban.

Severe or critical hemorrhage:Monitoring of the patient’s important signs and prompt revitalisation is predominate within the management of any acute life threatening bleed. If the supply of hemorrhage may be determined and is endovascularly or surgically accessible, imperative intervention ought to be performed if applicable. All anticoagulants ought to be out of print till the supply of hemorrhage is known and trauma has resolved. If the trauma is confirmed to be secondary to dabigatran, haemodialysis may be done. qualitative analysis wouldn’t be effective for rivaroxaban or apixaban, as these medication show up to eighty fifth protein binding [26]. we’ve projected associate degree formula for management of hemorrhage for patients on NOADS (figure 2).

DISCUSSION AND CONCLUSION:NOADS offer a decent various to Coumadin for patients World Health Organization have undergone careful choice supported the standards represented higher than. the dearth of reversal agent may be a important concern for the specialist activity a transdermal procedure, but additional analysis might reveal a additional full proof strategy for managing NOAD associated hemorrhage. within the in the meantime shut pre and postprocedural observance can facilitate to cut back associated morbidity and mortality

REFERENCES:1. Direct Thrombin Inhibitor Trialists’ Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet. 2002; 359: 294-302. 2. Hauptmann J, Stürzebecher J. Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. Thromb Res. 1999; 93: 203-241. 3. Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review. Thromb Res. 2003; 109 Suppl 1: S9-15. 4. Van de Werf F, Brueckmann M, Connolly SJ, Friedman J, Granger CB, Härtter S, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: THE Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J. 2012; 163: 931-937. 5. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet. 2009; 48: 1-22. 6. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001; 119: 8S-21S. 7. Holford NH. Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the doseeffect relationship. Clin Pharmacokinet. 1986; 11: 483- 504. 8. Tan G, Cohen H, Taylor F, Gabbay J. Audit of start of anticoagulation treatment in inpatients. J Clin Pathol. 1993; 46: 67-71. 9. Vadher B, Patterson DL, Leaning M. Prediction of the international normalized ratio and maintenance dose during the initiation of warfarin therapy. Br J Clin Pharmacol. 1999; 48: 63-70. 10. Garcia DA, Wallentin L, Lopes RD, Thomas L, Alexander JH, Hylek EM, et al. Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Am Heart J. 2013; 166: 549-558. 11. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365: 981-992. 12. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010; 363: 2499-2510. 13. Granger CB, Armaganijan LV. Newer oral anticoagulants should be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism. Circulation. 2012; 125: 159-164. 14. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365: 883-891. 15. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361: 1139-1151. 16. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009; 361: 2342-2352. 17. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008; 47: 285-295. 18. Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban-an oral, direct factor Xa inhibitor--in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008; 47: 203-216. 19. Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007; 64: 292-303. 20. Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm. 2012; 69: 1473-1484. 21. Lange U, Nowak G, Bucha E. Ecarin chromogenic assay- -a new method for quantitative determination of directthrombin inhibitors like hirudin. Pathophysiol Haemost Thromb. 2003; 33: 184-191. 22. Wong PC, Crain EJ, Xin B, Wexler RR, Lam PY, Pinto DJ, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost. 2008; 6: 820-829. 23. Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood. 2012; 119: 3016-3023. 24. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013; 368: 709-718. 25. Schulman S. RE-MEDY RE-SONATE Trial Investigators. Extended anticoagulation in venous thromboembolism. N Engl J Med. 2013; 368: 2329. 26. Fawole A, Daw HA, Crowther MA. Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. Cleve Clin J Med. 2013; 80: 443-451. 27. Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost. 2009; 7 Suppl 1: 107-110. 28. Levi M, Bijsterveld NR, Keller TT. Recombinant factor VIIa as an antidote for anticoagulant treatment. Semin Hematol. 2004; 41: 65- 69. 29. Levi M, Peters M, Büller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit Care Med. 2005; 33: 883-890. 30. Ng HJ, Crowther MA. New anti-thrombotic agents: emphasis on hemorrhagic complications and their management. Semin Hematol. 2006; 43: S77-83. 31. Wittkowsky AK. New oral anticoagulants: a practical guide for clinicians. J Thromb Thrombolysis. 2010; 29: 182-191. 32. Friederich PW, Levi M, Bauer KA, Vlasuk GP, Rote WE, Breederveld D, et al. Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation. 2001; 103: 2555-2559. 33. Bernstein RA, Alberts MJ, Garcia DA. Letter by Bernstein et al regarding article, “reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2012; 125: e614. 34. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011; 124: 1573-1579. 35. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a threefactor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009; 49: 1171-1177. 36. Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012; 87 Suppl 1: S141-145. 37. Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012; 108: 217-224. 38. Siegal DM, Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis. 2013; 35: 391-398.

Citation:

Steven Morales. Beyond Warfarin: A Primer for Interventional Radiologists on Newer Oral Anticoagulant Drugs (NOADS). Journal of Obesity Research 2024.