New oral anticoagulants—what the cardiothoracic surgeon needs to know
2014; Elsevier BV; Volume: 148; Issue: 5 Linguagem: Inglês
10.1016/j.jtcvs.2014.05.060
ISSN1097-685X
AutoresTsuyoshi Kaneko, Maroun Yammine, Sary F. Aranki,
Tópico(s)Cardiac Imaging and Diagnostics
ResumoSee related commentary on pages 1802-3. See related commentary on pages 1802-3. Oral anticoagulation for cardiothoracic patients has traditionally been synonymous with the use of warfarin. The recent introduction of new oral anticoagulants (NOACs) targeting factor Xa or thrombin represents a new approach for anticoagulation. Cardiothoracic surgeons need to familiarize themselves with these agents, because more preoperative patients will be taking NOACs. Thus, strategies for discontinuation before surgery with or without bridging have become paramount. The rapid onset of action, wide therapeutic index, and a steady therapeutic state without the need for monitoring has made these new agents more attractive than warfarin for these indications. The currently available NOACs are dabigatran etexilate (Pradaxa; Boehringer Ingelheim, Ridgefield, Conn), rivaroxaban (Xarelto; Bayer HealthCare AG, Leverkusen, Germany), apixaban (Eliquis; Bristol-Myers Squibb, New York, NY), and edoxaban (Savaysa; Daiichi Sankyo, Tokyo, Japan; not approved in the United States). We have reviewed the pharmacologic profile, clinical evidence for safety and efficacy, currently approved indications, and strategies to guide in the perioperative treatment of patients taking NOACs. Warfarin was approved for human use in 1954 and has been the mainstay oral anticoagulant in clinical practice ever since, until recently. Warfarin inhibits vitamin K-dependant synthesis of calcium-dependant clotting factors and the regulatory proteins C and S. Multiple food–drug and drug–drug interactions with food and other medications has complicated the use of warfarin (Table 1 and Appendix 1). The narrow therapeutic index with frequent monitoring has been a burden of therapy because of the frequent dose adjustment needed, and the long half-life of warfarin (approximately 60 hours) requires several days to restore the therapeutic anticoagulation level after interruption.Table 1Characteristics of new anticoagulants compared with warfarinVariableWarfarinDabigatranRivaroxabanApixabanEdoxabanMechanism of actionVitamin K antagonistThrombin inhibitorFactor Xa inhibitorFactor Xa inhibitorFactor Xa inhibitorT1/2 (h)≤40137-1112.710-14ExcretionRenal (metabolized in liver)Renal (80%)Renal (66%)/hepatobiliaryRenal (25%)/fecalRenal (50%)/fecalBioavailability (%)≤957.2≤80≤6662Drug interactionsMultiple (see Appendix 1)Inhibitors of p-gpInhibitors of p-gp and CYP3A4Inhibitors of p-gp and CYP3A4Inhibitors of p-gpFood interactionsLeafy green vegetables (high in vitamin K), alcohol, cranberry juiceNoNoNoNoMonitoringYesNoNoNoNoApproved doseVariable150 mg bid (AF); 110 mg bid (AF-Europe)10 mg daily (VTE)20 mg daily (AF)15 mg bid for first 21 d, then 20 mg daily (treatment of DVT)5 mg bid (AF)30 mg daily (VTE, Japan) 60 mg daily for VTE, 30 or 60 mg daily for AF (FDA and Europe pending approval)Dose reductionDepending on INR75 mg bid for CrCl 30-50 mL/min Consider stopping for acute renal failure (AF)Avoid use with p-gp inhibitor, rifampin15 mg daily for CrCl 15-50 mL/min (AF)Avoid use in strong dual inhibitor of p-gp and CYP3A42.5 mg bid (AF) for ≥2 of the following: age >80 y, body weight 1.5 mg/dL2.5 mg bid or stop when used with strong dual inhibitor of p-gp and CYP3A4Reduce to half dose for CrCl 30-50 mL/min, weight ≤60 kg, or were taking a potent p-gp inhibitorApproved indications (FDA)Prevention and treatment of VTE, AF, mechanical valvesNonvalvular AF, treatment of DVT, prevention of VTE recurrenceVTE prevention after hip or knee replacement, nonvalvular AF, treatment of DVT, prevention of VTE recurrenceNonvalvular AF, VTE prevention after hip or knee replacementNot approvedT1/2, Half-life; p-gp, permeability glycoprotein; bid, twice daily; AF, atrial fibrillation; VTE, venous thromboembolism; DVT, deep venous thromboembolism; FDA, US Food and Drug Administration; INR, international normalized ratio; CrCl, creatinine clearance; Cr, creatinine. Open table in a new tab T1/2, Half-life; p-gp, permeability glycoprotein; bid, twice daily; AF, atrial fibrillation; VTE, venous thromboembolism; DVT, deep venous thromboembolism; FDA, US Food and Drug Administration; INR, international normalized ratio; CrCl, creatinine clearance; Cr, creatinine. One major advantage compared with NOACs is its reversibility. In an emergency setting, warfarin can be reversed with fresh frozen plasma, and patients can undergo a procedure safely. Vitamin K provides excess cofactor for ongoing coagulation factor carboxylation in the setting of irreversible inhibition by warfarin and, therefore, requires synthesis of new coagulation factors to have an effect. For additional information on warfarin, see Appendix 1. These limitations have led to development of NOACs targeting factor Xa or thrombin (factor IIa). We reviewed the use of warfarin after cardiac surgery at Brigham and Women's Hospital. In 2011, of 1257 cardiac cases performed, 586 patients (46.6%) were discharged with warfarin. Similarly, in 2012, of 1234 cardiac cases performed, 557 patients (45.1%) were discharged with warfarin. These data included all patients who were taking warfarin; hence, both patients who were taking it preoperatively and had started taking it postoperatively were counted. The characteristics of dabigatran, rivaroxaban, apixaban, and edoxaban are compared with warfarin in Table 1. Dabigatran etexilate is a direct thrombin inhibitor and comes in the form of a prodrug with a bioavailability of 7.2%.1Troconiz I.F. Tillmann C. Liesenfeld K.H. Schafer H.G. Stangier J. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 148) in patients undergoing primary elective total hip replacement surgery.J Clin Pharmacol. 2007; 47: 371-382Crossref PubMed Scopus (95) Google Scholar It is converted to the active form dabigatran in the liver. It directly blocks the active site and prevents conversion of fibrinogen into fibrin. The half-life of dabigatran is about 13 hours in healthy individuals and is cleared by the kidneys (renal excretion, 80%). Renal function should be monitored in patients with renal insufficiency, because poor renal function can impair renal excretion and prolong the effect of anticoagulation. Accordingly, the dose adjustment should be determined by the creatinine clearance (Table 1). Interaction with permeability glycoprotein (p-gp) inhibitors such as quinidine, ketoconazole, and verapamil can increase the plasma concentration by reducing the clearance of dabigatran etexilate.2Paikin J.S. Eikelboom J.W. Cairns J.A. Hirsh J. New antithrombotic agents—insights from clinical trials.Nat Rev Cardiol. 2010; 7: 498-509Crossref PubMed Scopus (43) Google Scholar This is more significant in patients with renal failure, and patients with severe renal impairment (creatinine clearance < 30 mL/min) should not be taking a p-gp inhibitor and dabigatran. Because the plasma concentration and anticoagulant effect are dose dependent and predictable, it does not require repeated monitoring, unlike warfarin. The peak effect occurs within 0.5 to 2 hours, with a steady state achieved within 3 days.3Hankey G.J. Eikelboom J.W. Dabigatran etexilate: a new oral thrombin inhibitor.Circulation. 2011; 123: 1436-1450Crossref PubMed Scopus (299) Google Scholar It is known that a plasma trough dabigatran level of <50 ng/mL is associated with an increased risk of thromboembolism4Van de Werf F. Brueckmann M. Connolly S.J. Friedman J. Granger C.B. 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: 931-937Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar; however, the trough level is not commonly measured clinically at this point. Rivaroxaban, which is derived from 2-oxazolidone, is an oral inhibitor of factor Xa, binding reversibly to its active site. Rivaroxaban has an oral bioavailability of 80%, and a half-life of 7 to 11 hours; 67% is cleared renally but approximately one half of that is excreted unchanged in the urine.5Kubitza D. Becka M. Voith B. Zuehlsdorf M. Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor.Clin Pharmacol Ther. 2005; 78: 412-421Crossref PubMed Scopus (591) Google Scholar In addition to interaction with p-gp inhibitors, rivaroxaban is metabolized by way of CYP3A4; thus, strong inhibitors of CYP3A4, such as human immunodeficiency virus protease inhibitors, macrolide antibiotics (erythromycin), and azole antifungal agents (eg, ketoconazole), should be avoided because these agents will increase the risk of bleeding. No monitoring is required for rivaroxaban. It is the only NOAC approved by the Food and Drug Administration (FDA) approved for once daily dose. Apixaban is an oral direct inhibitor of factor Xa, and its bioavailability is ≤66%. Its half-life is approximately 12.7 hours, and 25% of the drug is cleared renally.6Eraso P.L.H. Merli G.J. Implications of new anticoagulants in primary practice.Int J Clin Pract. 2013; 67: 139-156Crossref PubMed Scopus (18) Google Scholar Administration of a strong dual inhibitor of CYP3A4 plus a p-gp (ie, ketoconazole, itraconazole, ritonavir, or clarithromycin) will increase the risk of bleeding and should be avoided. Edoxaban is also an oral direct inhibitor of factor Xa. Its bioavailability is 62%, and the half-life is 10 to 14 hours, which allows daily dosing. Approximately 50% of drug is renally excreted. Because Edoxaban is p-gp transporter, it has interactions with strong p-gp inhibitors but minimal interaction with CYP3A4 inhibitors.7Mendell J. Noveck R.J. Shi M. Pharmacokinetics of the direct factor Xa inhibitor edoxaban and digoxin administered alone and in combination.J Cardiovasc Pharmacol. 2012; 60: 335-341Crossref PubMed Scopus (34) Google Scholar It is worth emphasizing that because amiodarone is a moderate p-gp inhibitor and dronedarone a strong p-gp inhibitor, using dabigatran, rivaroxaban, and apixaban for patients with either amiodarone or dronedarone can increase the effect of anticoagulation about 50% and, therefore, should be avoided.2Paikin J.S. Eikelboom J.W. Cairns J.A. Hirsh J. New antithrombotic agents—insights from clinical trials.Nat Rev Cardiol. 2010; 7: 498-509Crossref PubMed Scopus (43) Google Scholar This effect is smaller with edoxaban, and amiodarone and edoxaban can be administered if one of the doses is decreased. In contrast, dronedarone is a strong p-gp inhibitor, and the dose of edoxaban should be reduced by 50% if dronedarone is co-administered.7Mendell J. Noveck R.J. Shi M. Pharmacokinetics of the direct factor Xa inhibitor edoxaban and digoxin administered alone and in combination.J Cardiovasc Pharmacol. 2012; 60: 335-341Crossref PubMed Scopus (34) Google Scholar Safe concomitant use of amiodarone and apixaban have been reported.8Flaker G.C. Hohnloser S. Wojdyla D. Hylek E. Garcia D. Sullivan R. et al.Apicaban is efficacious and safe in patients with atrial fibrillation using concomitant amiodarone: an analysis from the ARISTOTLE trial.J Am Coll Cardiol. 2013; 61Google Scholar The currently approved indications and dosage for NOACs are listed in Table 1 and Appendix 1. Advantages and disadvantages of NOACs compared with warfarin are listed in Table 2.Table 2Advantages and disadvantages of NOACs compared with warfarinAdvantages Freedom from frequent blood monitoring and dose adjustments Fewer interaction with food and other medications Fast onset and offset Rapidly cleared after discontinuation and easier to manage preoperatively Reducing thrombosis and fatal bleedingDisadvantages Lack of reversal agent Higher cost per pill Underdosing when patient forgets to take medication Dose adjustments required for patients with renal failure Contraindicated for valve prosthesis, pregnancy, children, and patients requiring dialysis Contraindicated for those with neuraxial anesthesia or spinal puncture Open table in a new tab Dabigatran, rivaroxaban, and apixaban have been approved by the FDA for prevention of stroke in patients with nonvalvular atrial fibrillation (AF) on the basis of the following results. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared 2 doses of dabigatran (110 mg twice daily or 150 mg twice daily) with warfarin (international normalized ratio [INR], 2-3) for stroke prevention in patients with nonvalvular AF and ≥1 risk factor for stroke.9Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8845) Google Scholar For the prevention of the composite outcome of stroke or systemic embolism, dabigatran 110 mg twice daily was not inferior to warfarin, and dabigatran 150 mg twice daily was superior to warfarin. The incidence of intracranial, life-threatening, or any type of bleeding was reduced in both dabigatran dosage groups, and low-dose dabigatran also reduced the incidence of major bleeding. The high-dose dabigatran group had a greater incidence of gastrointestinal bleeding. The original report had a significantly greater incidence statistically of myocardial infarction in the 150-mg dabigatran group compared with the warfarin group; however, after readjudication of myocardial infarction, the difference was nonsignificant.10Connolly S.J. Ezekowitz M.D. Yusuf S. Reilly P.A. Wallentin L. Randomized Evaluation of Long-Term Anticoagulation Therapy InvestigatorsNewly identified events in the RE-LY trial.N Engl J Med. 2010; 363: 1875-1876Crossref PubMed Scopus (552) Google Scholar The FDA did not approve the 110-mg twice daily dose, however, citing that they could not identify a subgroup of patients for whom the lower dose would be preferred over the higher dose.11Beasley B.N. Unger E.F. Temple R. Anticoagulant options—why the FDA approved a higher but not a lower dose of dabigatran.N Engl J Med. 2011; 364: 1788-1790Crossref PubMed Scopus (216) Google Scholar The Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) compared rivaroxaban 20 mg daily with warfarin (INR, 2-3).12Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. et al.ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7155) Google Scholar For the primary endpoint of stroke and systemic embolism, rivaroxaban was not inferior to warfarin. The rates of major and nonmajor clinically relevant bleeding events were similar, and significant reductions in the rate of intracranial hemorrhage and fatal bleeding occurred in the rivaroxaban group. However, an increase in major gastrointestinal bleeding was observed in the rivaroxaban group. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial compared apixaban 5 mg twice daily with warfarin (INR, 2-3).13Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. et al.Apixaban in patients with atrial fibrillation.N Engl J Med. 2011; 364: 806-817Crossref PubMed Scopus (2027) Google Scholar Apixaban was superior to warfarin for the primary endpoint of the composite outcome of stroke and systemic embolism. The rate of major bleeding events, intracranial hemorrhage, and all-cause mortality were all significantly lower in the apixaban group. No difference was seen in the incidence of gastrointestinal bleeding between the 2 groups. The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial was recently published. That trial compared 30 mg and 60 mg once daily edoxaban to warfarin.14Giugliano R.P. Ruff C.T. Braunwald E. Murphy S.A. Wiviott S.D. Halperin J.L. et al.ENGAGE AF-TIMI 48 InvestigatorsEdoxaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3543) Google Scholar Edoxaban in both dosages was not inferior to warfarin when compared using the primary endpoint of stroke or systemic embolism. The annualized rates of major bleeding and causes of cardiovascular death were significantly lower in both edoxaban groups compared with warfarin. Major gastrointestinal bleeding was less frequent with low-dose edoxaban than with warfarin but was more frequent with high-dose edoxaban than with warfarin. A recent meta-analysis of all 4 randomized warfarin-controlled studies showed that NOACs significantly reduced stroke or systemic embolic events by 19% compared with warfarin, mainly by reducing hemorrhagic stroke.15Ruff C.T. Giugliano R.P. Braunwald E. Hoffman E.B. Deenadayalu N. Ezekowitz M.D. et al.Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.Lancet. 2014; 383: 955-962Abstract Full Text Full Text PDF PubMed Scopus (3316) Google Scholar NOACs also reduced all-cause mortality and intracranial hemorrhage but resulted in an increased incidence of gastrointestinal bleeding. See Appendix 1 for the incidence of gastrointestinal bleeding with the use of NOACs. Adverse events of NOACs in major atrial fibrillation trial are summarized in Table 3.Table 3Adverse events of NOACs in major atrial fibrillation trial (all hazard ratios of stroke and systemic embolism obtained from noninferiority analysis)VariableRE-LY trialARISTOTLE trialENGAGE trialROCKET AF trialWarfarinDabigatran9Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8845) Google Scholar (mg bid)WarfarinApixaban12Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. et al.ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7155) Google Scholar (5 mg bid)WarfarinEdoxaban13Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. et al.Apixaban in patients with atrial fibrillation.N Engl J Med. 2011; 364: 806-817Crossref PubMed Scopus (2027) Google Scholar (mg bid)WarfarinRivaroxaban14Giugliano R.P. Ruff C.T. Braunwald E. Murphy S.A. Wiviott S.D. Halperin J.L. et al.ENGAGE AF-TIMI 48 InvestigatorsEdoxaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3543) Google Scholar (20 mg daily)1101503060Total patients6022601560769081912070367034703571337131Stroke and systemic embolism (%/y)1.691.531.111.61.271.51.611.182.42.1 HR for stroke and systemic embolism vs warfarin0.91∗HR calculation not significantly different.0.660.791.07†Analysis according to 97.5% confidence interval.0.79†Analysis according to 97.5% confidence interval.0.88∗HR calculation not significantly different.Ischemic stroke (%/y)1.21.320.921.050.971.251.771.251.421.34 HR for ischemic stroke vs warfarin1.11∗HR calculation not significantly different.0.760.92∗HR calculation not significantly different.1.411.00∗HR calculation not significantly different.0.94∗HR calculation not significantly different.Hemorrhagic stroke (%/y)0.380.120.100.470.240.470.160.260.440.26 HR for hemorrhagic stroke vs warfarin0.310.260.510.330.540.59Major bleeding (%/y)3.362.713.111.690.963.431.612.755.425.55 HR for major bleeding vs warfarin0.800.93∗HR calculation not significantly different.0.570.470.801.04∗HR calculation not significantly different.Intracranial bleeding (%/y)0.740.230.300.800.330.850.260.391.180.77 HR for intracranial bleeding vs warfarin0.310.400.420.300.470.67Major GI bleeding (%/y)1.021.121.510.860.761.230.821.512.163.15 HR for major GI bleeding vs warfarin1.10∗HR calculation not significantly different.1.500.89∗HR calculation not significantly different.0.671.23P < .001‡HR was not reported in the study's report or assigned appendix.RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; ARISTOLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ENGAGE, ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48); ROCKET AF, Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; bid, twice daily; HR, hazard ratio; GI, gastrointestinal.∗ HR calculation not significantly different.† Analysis according to 97.5% confidence interval.‡ HR was not reported in the study's report or assigned appendix. Open table in a new tab RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; ARISTOLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ENGAGE, ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48); ROCKET AF, Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; bid, twice daily; HR, hazard ratio; GI, gastrointestinal. An interest has developed to use NOACs for anticoagulation in those with prosthetic heart valves. Dabigatran is the only drug that has been studied in this patient population to date. A large phase II randomized controlled study, namely the randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN) trial, was initiated in 2012.16Eikelboom J.W. Connolly S.J. Brueckmann M. Granger C.B. Kappetein A.P. Mack M.J. et al.the RE-ALIGN InvestigatorsDabigatran versus warfarin in patients with mechanical heart valves.N Engl J Med. 2013; 369: 1206-1214Crossref PubMed Scopus (1002) Google Scholar That trial included patients who had undergone implantation of a mechanical valve (aortic or mitral) or implantation of a mitral bileaflet valve 50 mL/min), the last dose should be given 3 days before surgery, because 48 to 60 hours of interruption will lead to a minimal anticoagulant effect of <3% to 6% at surgery. The dose adjustments stratified by renal function are highlighted in Figure 1. For minor surgery, such as bronchoscopy or pacemaker insertion, a mild to moderate anticoagulation effect of <12% to 25% has been accepted at surgery and can be achieved by stopping the NOAC 2 days before the procedure in patients with normal renal function. Although these approaches are reasonable according to the pharmacokinetic profiles, the only supportive empirical evidence has comes from the RE-LY trial, a randomized controlled study between dabigatran and warfarin for stroke prevention in patients with nonvalvular AF, in which a protocol similar to that shown in Figure 1 was adopted for patients undergoing a major procedure.9Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8845) Google Scholar In that study, 4500 patients had had their anticoagulation interrupted. No statistically significant difference was found in perioperative major bleeding among the dabigatran-treated patients (3.8% with the 110-mg dose, 5.1% with the 150-mg dose) and warfarin-treated patients (4.6%). NOACs do not require routine monitoring; however, in the case of emergency surgery or acute bleeding, blood monitoring tests can be used. For dabigatran, the diluted thrombin time can be determined using the Hemoclot assay (Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany). That assay provides direct assessment of thrombin activity and can be performed before surgery. A diluted thrombin time of <65 is ideal before surgery to decrease the risk of bleeding.21Lai A. Davidson N. Galloway S.W. Thachil J. Perioperative management of patients on new oral anticoagulants.Br J Surg. 2014; 101: 742-749Crossref PubMed Scopus (2) Google Scholar If the diluted thrombin time is not available, the activated partial thromboplastin time or prothrombin time can be used to monitor dabigatran to achieve a goal target similar to that of other anticoagulants (heparin) but has a lower slope, with an increase in concentration, is less reliable than the thromboplastin time, and must be used with caution.22Dager W.E. Gosselin R.C. Kitchen S. Dwyre D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study.Ann Pharmacother. 2012; 46: 1627-1636Crossref PubMed Scopus (87) Google Scholar For factor Xa inhibitors, antifactor Xa assay can be performed for rivaroxaban and apixaban. The prothrombin time can also be used, although it is less reliable.23Samama M.M. Martinoli J.L. LeFlem L. Guinet C. Plu-Bureau G. Depasse F. et al.Assessment of laboratory assays to measure rivaroxaban—an oral, direct factor Xa inhibitor.Thromb Haemost. 2010; 103: 815-825Crossref PubMed Scopus (411) Google Scholar The factor Xa assay can estimate the level of factor Xa inhibitors; however, no data have shown a safe level for bleeding. The activated partial thromboplastin time has been unpredictable in factor Xa inhibitors.23Samama M.M. Martinoli J.L. LeFlem L. Guinet C. Plu-Bureau G. Depasse F. et al.Assessment of laboratory assays to measure rivaroxaban—an oral, direct factor Xa inhibitor.Thromb Haemost. 2010; 103: 815-825Crossref PubMed Scopus (411) Google Scholar Currently, no reversal agent is available for a NOAC, although a phase II trial is underway for a dabigatran reversal agent.24Marlu R. Hodaj E. Paris A. Albaladejo P. Crackowski J.L. Pernod G. Effect of nonspecific reversal agents on anticoagulant activity of dabigatran, rivaroxaban: a randomised crossover ex vivo study in healthy volunteers.Thromb Haemost. 2012; 108: 217-224Crossref PubMed Scopus (488) Google Scholar In the case of major bleeding, the NOACs must first be stopped. The source of bleeding must be controlled, surgically if needed, and the urine output must be maintained to continue renal excretion. It is important to remember that the use of fresh frozen plasma does not reverse the effect of an NOAC. If these measures fail, hemodialysis or other renal replacement therapy can be considered in hemodynamically stable patients taking dabigatran owing to its relatively low plasma protein binding (−35%) and high rate of renal excretion (80%).6Eraso P.L.H. Merli G.J. Implications of new anticoagulants in primary practice.Int J Clin Pract. 2013; 67: 139-156Crossref PubMed Scopus (18) Google Scholar How effective dialysis would be in the case of factor Xa inhibitors, each of which has a considerably greater rate of protein binding, is not known. Activated coagulation factors and prothrombin complex are currently recommended in the reversal of the NOAC effect. Small reports have been published of factor VIIa recombinant reversing the activity of dabigatran and rivaroxaban,25Hughes S. Available at: http://www.medscape.com/viewarticle/818169. Accessed December 20, 2013.Google Scholar and in vivo studies are ongoing to confirm the effect of prothrombin complex concentrate. A reversal agent for factor Xa (Andexanet alfa, PRT4445; Portola Pharmaceutical, South San Francisco, Calif) and a synthetic small molecule reversal agent (PER977; Perosphere, Inc, Danbury, Conn) are in late stage development. Resuming NOACs after surgery must be done with caution. The rapid onset of action, with a peak level occurring 1 to 3 hours after ingestion, can cause significant bleeding in cases of incomplete hemostasis. Also, postoperative bowel dysmotility and acid suppression therapy can affect the absorption of the medication. Although direct evidence is lacking, resuming NOACs beyond the second or third day after major cardiothoracic surgery, after complete hemostasis and removal of the chest tube and pacing wires, is recommended.13Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. et al.Apixaban in patients with atrial fibrillation.N Engl J Med. 2011; 364: 806-817Crossref PubMed Scopus (2027) Google Scholar This recommendation needs to be balanced with the return of bowel motility in cases of esophageal and abdominal surgery. In such cases, bridging anticoagulation with heparin or enoxaparin should be considered. A summary of the perioperative strategy is shown in Figure 1. For minor procedures with complete hemostasis, NOACs can be resumed 6 to 8 hours postoperatively.19Bergmark B. Giugliano R.P. Perioperative management of target-specific oral anticoagulants.Hosp Pract (1995). 2014; 42: 38-45Crossref PubMed Scopus (2) Google Scholar As expected, the cost of NOACs is more expensive than that of warfarin, which has been on the market for decades. The annual cost of warfarin is $545 (without INR testing), significantly less than the cost of dabigatran at $3650, rivaroxaban at $3650, and apixaban at $3445. However, the cost effectiveness has been extensively studied, especially for stroke prevention in patients with AF. The elimination of INR testing, decrease in adverse events, and decrease in the hospital length of stay will offset the increased drug costs of NOACs. Harrington and associates26Harrington A.R. Armstrong E.P. Nolan Jr., P.E. Malone D.C. Cost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation.Stroke. 2013; 44: 1676-1681Crossref PubMed Scopus (204) Google Scholar created a Markov analysis model using the data from large randomized controlled studies of NOACs. They compared the cost between warfarin and NOACs and calculated a willingness to pay threshold of $50,000 per quality-adjusted life year gained for each medication. Although warfarin had the lowest cost ($77,813) followed by rivaroxaban 20 mg ($78,738), dabigatran 150 mg ($82,719), and apixaban 5 mg ($85,326), the quality-adjusted life year gained was greatest for apixaban (8.47) followed by dabigatran (8.41), and rivaroxaban (8.26) and lowest for warfarin (7.97). Cardiothoracic surgeons will increasingly encounter patients taking NOACs. The indications and use of NOACs are expected to increase as the knowledge and experience continues to build. Although the RE-ALIGN trial was stopped owing to the high complication rate, different regimens for NOACs in the setting of mechanical valves are anticipated. Other conditions that require anticoagulation, such as heparin-induced thrombocytopenia, could be treated in the future using NOACs. Future approval of a fourth NOAC, namely edoxaban, might eventually lead to a decrease in their cost and will be as cost-effective as warfarin. The development of reversal agents for NOACs will make management safer in urgent situations or in cases in which an overdose is suspected. NOACs offer many advantages over warfarin. They are more convenient to use than warfarin with fewer drug–drug and food–drug interactions. Multiple, large, randomized clinical studies have confirmed the safety and efficacy of these NOACs. The clinical indications are increasing, such as venous thromboembolism prevention and treatment and the prevention of stroke in patients with nonvalvular AF. Currently, these drugs are not indicated for anticoagulation for a mechanical prosthesis. Cardiothoracic surgeons will face more patients taking these drugs in the future. Knowledge regarding the pharmacokinetic profile, interruption and restarting in the setting of surgery, and treatment in the case of severe bleeding is important for the treatment of patients taking this medication.
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