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Dabigatran Etexilate

2011; Lippincott Williams & Wilkins; Volume: 123; Issue: 13 Linguagem: Tagalog

10.1161/circulationaha.110.004424

1524-4539

Graeme J. Hankey, John W. Eikelboom,

Venous Thromboembolism Diagnosis and Management

HomeCirculationVol. 123, No. 13Dabigatran Etexilate Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBDabigatran EtexilateA New Oral Thrombin Inhibitor Graeme J. Hankey, MD, FRACP, FRCP and John W. Eikelboom, MBBS, FRACP, FRCPA Graeme J. HankeyGraeme J. Hankey From the Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia (G.J.H.), and Department of Medicine, McMaster University, Hamilton, Ontario, Canada (J.W.E.). and John W. EikelboomJohn W. Eikelboom From the Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia (G.J.H.), and Department of Medicine, McMaster University, Hamilton, Ontario, Canada (J.W.E.). Originally published5 Apr 2011https://doi.org/10.1161/CIRCULATIONAHA.110.004424Circulation. 2011;123:1436–1450Long-term oral anticoagulation is indicated for several cardiovascular diseases, including the prevention of cardiac thromboembolism in patients with atrial fibrillation (AF),1 mechanical heart valves,2 and acute myocardial infarction (MI),3 as well as the secondary prevention of venous thromboembolism (VTE).4For the past 60 years, oral vitamin K antagonists (eg, warfarin, acenocoumarol, phenprocoumon, fluindione) have been widely prescribed.5 However, their impact in preventing thromboembolism has been hampered by several limitations that compromise their effectiveness and safety and make them difficult to use (Table 1). Vitamin K antagonists have a delayed onset and offset of action that often prolong hospitalization, and thus increase healthcare costs. Their large interindividual variability in dose response and narrow therapeutic window demand regular monitoring of the international normalized ratio (INR) and result in complex individualized dosing. Despite careful dose adjustment, the INR is frequently outside the target therapeutic range, which increases the risk of thromboembolism and bleeding.6 Patients treated with a vitamin K antagonist require counseling about drug and food interactions, the need for routine monitoring, and the inherent risk of bleeding. To reduce some of the dose variability, an algorithm based on clinical and genetic data has been developed and validated for estimating the appropriate dose of warfarin,7 but evidence of the cost-effectiveness of pharmacogenetic testing to optimize warfarin dosing in routine clinical practice is lacking.8Table 1. Limitations of Warfarin and Other Oral Vitamin K AntagonistsLimitationClinical ImplicationsSlow onset and offset of actionNeed for bridging with a rapidly acting anticoagulantInterindividual variability in anticoagulant effectVariability in dosing requirementsNarrow therapeutic indexNeed for routine coagulation monitoringFood and drug interactionsDietary precautions; need for routine coagulation monitoringReduced synthesis of all vitamin K–dependent proteinsRisk of skin necrosis in patients with protein C or S deficiency; potential for osteoporosis**Vitamin K antagonists appears to inhibit production of vitamin K–dependent proteins found in bone (osteocalcin synthesized by osteoblasts, matrix Gla protein found in bone cartilage and soft tissue, and protein S synthesized by osteoblasts).As a consequence of the limitations of vitamin K antagonists, the quality of anticoagulant control is frequently suboptimal among those who receive the treatment, and many patients at risk of thromboembolism do not receive treatment; only 50% to 70% of patients with AF at risk of stroke who are eligible for anticoagulant therapy are treated with a vitamin K antagonist.9–11 This very large unmet need has prompted the development and evaluation of new oral anticoagulants that target the inhibition of specific coagulation factors, most commonly activated factor X (Xa) and thrombin (Figure 1).12–15Download figureDownload PowerPointFigure 1. Illustration showing the sites of action of new anticoagulants in the coagulation cascade. Vessel injury exposes tissue factor (TF), which interacts with activated factor (F) VII to initiate coagulation. Cleavage of prothrombin (factor II) by the prothrombinase complex (factor Xa and its cofactor, factor Va) leads to the generation of thrombin (factor IIa). Thrombin converts fibrinogen to fibrin and provides positive feedback through activation of factors V, VIII, and XI in the coagulation cascade. Factors Va, VIIIa, and XIa promote the production of additional thrombin, which leads to cross-linkage of fibrin strands and the formation of a hemostatic plug. Thrombin also activates platelets through cleavage of the platelet membrane–bound protease-activated receptors 1, 3, and 4. Factor Xa inhibitors block the conversion of prothrombin (factor II) to thrombin (factor IIa) by factor Xa incorporated within the prothrombinase complex (the complex of factor Xa and factor Va bound to the activated platelet surface). Thrombin inhibitors block thrombin-mediated conversion of fibrin. These drugs also block thrombin-mediated feedback activation of factors V and VIII. Modified from Eriksson et al.13The first evidence supporting thrombin as a suitable target for new oral anticoagulants came from studies with the oral direct thrombin inhibitor ximelagatran.16 Ximelagatran underwent extensive evaluation in phase III randomized, controlled trials for the prevention and treatment of VTE, stroke prevention in patients with AF, and treatment of MI. For all of these indications, fixed-dose, unmonitored ximelagatran was noninferior to conventional anticoagulant therapy or superior to placebo in the prevention of thromboembolic events, but its further development was precluded by unacceptable liver toxicity.16Pharmacology of DabigatranMechanism of ActionDabigatran etexilate is a low-molecular-weight prodrug that exhibits no pharmacological activity. After oral administration, dabigatran etexilate is converted to its active form, dabigatran, a potent, competitive, and reversible direct inhibitor of the active site of thrombin, the final effector in blood coagulation (Figure 1).15,17–19Thrombin has an active site and 2 secondary binding exosites.14 Exosite 1 acts as a dock for substrates such as fibrin to promote orientation for active site binding. Exosite 2 is the heparin-binding domain. Dabigatran is a univalent direct thrombin inhibitor that binds to the active site, thereby inactivating both fibrin-bound and unbound (ie, free) thrombin.14,20 Indirect thrombin inhibitors such as unfractionated heparin and low-molecular-weight heparin cannot inhibit fibrin-bound thrombin. The ability to inhibit fibrin-bound thrombin is an important theoretical advantage of dabigatran over the heparins because bound thrombin can continue to trigger thrombus expansion.21,22 By inhibiting thrombin, dabigatran prevents the conversion of fibrinogen into fibrin, positive feedback amplification of coagulation activation, cross-linking of fibrin monomers, platelet activation, and inhibition of fibrinolysis (Figure 1).FormulationDabigatran etexilate is available in capsule form. It is formulated together with tartaric acid to reduce the variability of dabigatran etexilate absorption, which is dependent on an acid environment.19 A dabigatran etexilate coating is applied onto a tartaric acid core to form tiny pellets (≈1-mm diameter). A single capsule contains hundreds of these pellets, the exact number depending on the dose strength of the capsule. In this way, dabigatran etexilate absorption is independent of gastrointestinal tract acidity and is not materially affected by coadministration of a proton pump inhibitor.23AbsorptionAfter oral administration, dabigatran etexilate is rapidly absorbed and quickly and completely hydrolyzed to its active moiety, dabigatran, by nonspecific ubiquitous esterases in the gut, plasma, and liver.24,25 Because bioconversion of dabigatran etexilate begins in the gut, the drug enters the portal vein as a combination of prodrug and active compound. The absolute bioavailability after oral administration of dabigatran etexilate is only ≈6.5%, so relatively high doses must be given to ensure that adequate plasma concentrations are achieved.24,26Dabigatran plasma concentrations and anticoagulant effects are dose dependent and predictable, and peak within 0.5 to 2 hours (average, 1.5 hours) of oral administration.23–25 Steady-state dabigatran concentrations are achieved ≈3 days after multiple-dose administration in healthy volunteers.24 At steady state, plasma concentrations in patients with AF taking 150 mg twice daily (BID) are ≈180 ng/mL at peak and 90 ng/mL at trough (11.5 hours after ingestion).19 There is no unexpected accumulation of dabigatran after multiple dosing.MetabolismBioconversion of dabigatran etexilate to dabigatran is completed in the liver, and ≈20% is conjugated with glucuronic acid (to acyl glucuronides) and excreted via the biliary system.27 Dabigatran etexilate is not metabolized by the cytochrome P450 enzymes or other oxidoreductases, but is a substrate for p-glycoprotein (see below).In patients with mild hepatic impairment, the area under the curve after a single oral dose of dabigatran etexilate was comparable to that in healthy control subjects, and the bioconversion of the prodrug was only slightly reduced.24,28Half-LifeThe mean terminal half-life of dabigatran after oral administration is ≈8 hours after a single dose, and ranges from 12 to 14 hours after multiple doses (Table 2).23–25,29–31 In older healthy volunteers, more typical of the patient population for which dabigatran may be indicated, the half-life is about 13 hours.23,32 The half-life is increased to >24 hours in patients with a creatinine clearance of 200 ng/mL).34,35 A dilute thrombin time assay (Hemoclot test, Hyphen Biomed, France) has been certified in Europe since late 2010 for the quantitative determination of dabigatran plasma levels. It can be calibrated with dabigatran standards.Prolongation of blood coagulation times is maximal at peak plasma concentrations of dabigatran (≈2 hours). The effect declines to ≈50% of the peak inhibition at 12 hours after administration, reflecting the half-life of the drug.35–37Reversing the Anticoagulant Effect of DabigatranPatients Undergoing Invasive ProceduresDabigatran etexilate should ideally be discontinued at least 24 hours before invasive procedures and at least 48 hours before procedures associated with a high risk of bleeding. The duration of discontinuation of dabigatran before procedures also depends on renal function. Table 3 provides guidance for discontinuation of dabigatran etexilate before elective invasive procedures according to renal function and risk of bleeding.34Table 3. Guide to the Discontinuation of Dabigatran Etexilate Before Invasive Procedures Such as Elective Surgery in Patients Receiving Once- or Twice-Daily Dosing With a Standard or High Risk of BleedingRenal Function (Creatinine Clearance), mL/minHalf-Life, h*Timing of Discontinuation After Last Dose of Dabigatran Before SurgeryStandard Risk of BleedingHigh Risk of Bleeding†>8013 (11–22)24 h2–4 d>50–≤8015 (12–34)24 h2–4 d>30–≤5018 (13–23)≥2 d (48 h)4 d≤3027 (22–35)2–5 d>5 d*Data are from renal impairment study in healthy volunteers,32 geometric mean (range).†Types of surgery associated with a high risk of bleeding (or major surgery in which complete hemostasis may be required) include but are not limited to cardiac surgery, neurosurgery, abdominal surgery, or surgery involving a major organ. Other procedures such as spinal anesthesia may also require complete hemostatic function. Other important determinants of bleeding risk include advancing age, comorbidities (eg, major cardiac, respiratory, or liver disease), and concomitant use of antiplatelet therapy.Adapted from Van Ryn et al34 with permission of the publisher. Copyright © 2010, Schattauer GmbH.Renal function should assessed by measurement of the serum creatinine (so that creatinine clearance can be calculated) at least 5 days before the procedure. In patients with normal renal function, discontinuation of dabigatran 24 hours before surgery will decrease plasma levels to ≈25% of steady-state trough levels. Plasma levels fall to ≈12% to 15% of trough levels after 36 hours and ≈5% to 10% after 48 hours.34 In patients with severe renal impairment (creatinine clearance <30 mL/min), dabigatran should be permanently discontinued (unless renal function improves) and surgery delayed for at least 5 days, if at all possible. After the procedure and recovery of renal function, dabigatran can be reinitiated as soon as clinically indicated. If oral medication is not feasible, parenteral heparinization should be considered if an immediate anticoagulant effect is required.In patients at high risk of bleeding or undergoing major surgery in which normal hemostasis is required, dabigatran etexilate should be stopped 2 to 5 days before surgery (Table 3).34 A TT should be performed 6 to 12 hours before surgery and a normal result obtained; if the TT test is not available, the aPTT, although less precise, can be used. If the TT is elevated, consideration should be given to delaying surgery because, in the absence of heparin, other direct thrombin inhibitors (eg, lepirudin and bivalirudin), fibrin/fibrinogen degradation products, or high concentrations of serum proteins (eg, myeloma), prolongation of the TT indicates the presence of dabigatran in the blood. The serum creatinine should also be checked in patients who have unexpectedly prolonged TT values because the clearance of dabigatran is delayed in patients with renal impairment.Patients With Bleeding While Taking DabigatranUnlike warfarin and heparin, no specific antidote is available to reverse the anticoagulant effects of dabigatran.17,19 The management of bleeding complications in patients receiving dabigatran etexilate should be individualized according to the location and severity of the hemorrhage (Figure 2).34 First, dabigatran etexilate should be discontinued. Discontinuation of the drug may suffice in patients with normal renal function who have mild bleeding. Second, the source of bleeding should be investigated, if possible, mechanically compressed, and, if necessary, controlled surgically. Third, an adequate diuresis must be maintained because dabigatran predominantly undergoes renal excretion. Fourth, transfusion of blood products (packed red cells or fresh-frozen plasma) may be required, depending on associated anemia or coagulopathy. Fresh-frozen plasma does not reverse the anticoagulant effect of dabigatran. If the above measures fail to control bleeding, the use of hemodialysis or administration of nonspecific prohemostatic agents may be considered.Download figureDownload PowerPointFigure 2. Guide to the management of bleeding in patients taking dabigatran. PCC indicates prothrombin complex concentrates (nonactivated or activated); rFVIIa, recombinant activated factor VII. Adapted from Van Ryn et al34 with permission of the publisher. Copyright © 2010, Schattauer GmbH. *Recommendation is based only on limited nonclinical data; there is no experience in volunteers or patients.Dabigatran is dialyzable because of its relatively low (≈35%) plasma protein binding.34,37 In cases of severe bleeding or overdose (see below), when rapid reversal of the anticoagulant effects of dabigatran is required, hemodialysis could be effective in accelerating plasma clearance of dabigatran, especially in patients with renal impairment. The supporting data come from an open-label study in which a single 50-mg dose of dabigatran etexilate was administered to 6 patients with end-stage renal failure on maintenance hemodialysis.34 On the basis of the mean concentration differences at the inlet and outlet lines, the mean fraction of the drug removed by dialysis was 62% at 2 hours and 68% at 4 hours.34Recombinant activated factor VII (rFVIIa; NovoSeven, NovoNordisk, Bagsvaerd, Denmark) is an approved potent procoagulant and general hemostatic agent that can initiate hemostasis at sites of bleeding by directly activating thrombin on the surface of platelets in the absence of tissue factor.34 Healthy volunteer and ex vivo data suggest that rFVIIa antagonizes the anticoagulant effect of a variety of anticoagulants.15 In a rat tail model of template bleeding, addition of rFVIIa (0.1 or 0.5 mg/kg) significantly reduced bleeding time and prolongation of aPTT associated with high-dose dabigatran in a dose-dependent manner.34,38 rFVIIa at 0.5 mg/kg reduced bleeding time from 11.6-fold (ratio to control) to 1.1-fold and aPTT prolongation by dabigatran from 8.3-fold to 3.8-fold.38 However, the clinical utility of rFVIIa in patients taking dabigatran who are actively bleeding has not been established.Prothrombin complex concentrates (PCCs) comprise activated PCCs (APCC) and nonactivated PCCs. Nonactivated PCCs are "4-factor concentrates" containing adequate amounts of vitamin K–dependent factors II, VII, IX, and X (eg, Beriplex, Octaplex, and ProplexT) or "3-factor concentrates" containing significantly lower amounts of factor VII (less than one third of factor IX) (eg, Prothrombinex-HT, Profilnine, and Bebulin). Activated PCCs such as Factor Eight Inhibitor Bypassing Activity, Vapor Heated (Feiba VH; Baxter, Vienna, Austria) contain vitamin K–dependent coagulation factors II, IX, and X and protein C, mainly in nonactivated forms, and factor VII, mainly in the activated form.34 In a rat tail model of template bleeding, addition of APCC (Feiba VH) at a dose of 50 or 100 U/kg significantly reduced prolongation of bleeding time effects associated with high-dose dabigatran.38 Activated PCCs at 100 U/kg reduced bleeding time prolongation by dabigatran from 11.6-fold (ratio to control) to 1.4-fold.38 The aPTT was not shortened in the presence of APCC.35 However, APCC preparations have also been reported to have thrombogenic potential, so the potential benefits need to be evaluated in the context of the potential risks. Findings similar to those reported with Feiba VH have been shown with nonactivated PCC BeriplexP/N (CSL Behring, Marburg, Germany); in a renal injury bleeding model in rabbits, bleeding with high-dose dabigatran was reduced after administration of Beriplex (data on file),34 although no effects on anticoagulation parameters of aPTT or TT were seen. Further in vitro studies using human plasma show complete reversal of the dabigatran-inhibited endogenous thrombin potential with APCC (Feiba VH) but not with rFVIIa (NovoSeven).34 Thus, the predictive value of ex vivo monitoring of neutralization of dabigatran anticoagulant activity for reversing bleeding is not yet well understood.Other prohemostatic agents that might be considered if bleeding cannot be controlled include desmopressin, aprotinin, tranexamic acid, and aminocaproic acid. However, there is no evidence that any of these agents will reverse the anticoagulant effect of dabigatran.Patients With an Overdose of DabigatranDabigatran etexilate is a lipophilic molecule (log P=3.8) that has been shown in vitro to be successfully adsorbed by classic activated charcoal therapy.34 Although this has not been tested in vivo or in patients, it seems reasonable to administer charcoal within 1 to 2 hours of overdose before dabigatran etexilate is absorbed from the gastrointestinal tract. It is possible that dabigatran could be removed from plasma via hemoperfusion over a charcoal filter, but this has not been evaluated in humans.Long-Term Hepatic SafetyNo liver toxicity or significant excess elevation in liver enzymes has been recorded to date during extensive liver function monitoring in ≈40 000 patients enrolled in clinical trials of dabigatran.39–50 A possible reason why the direct thrombin inhibitor ximelagatran may be hepatotoxic is that the oxidoreductases that cleave the hydroxyl-amidine group of the prodrug and convert it to melagatran, the active drug, are present mostly in the liver, which results in short-lived but measurable plasma concentrations of ximelagatran (≈0.3-μmol/L peaks).51 One study has demonstrated that ximelagatran in concentrations of 10 μmol/L increases membrane fluidity by changing membrane lipid composition in human hepatocytes in vitro, whereas melagatran does not.52 In contrast, esterases that convert dabigatran etexilate to its active form are located throughout the body, including plasma and the liver. Consequently, dabigatran etexilate is almost immediately converted to the active dabigatran, so levels of the prodrug in the plasma are only just above levels of detection, even at peak, and are not detectable after 2 hours.Potential Advantages of DabigatranThe potential advantages and disadvantages of dabigatran compared with warfarin and other vitamin K antagonists are shown in Tables 4 and 5.Table 4. Advantages of Dabigatran Compared With Warfarin and Other Oral Vitamin K AntagonistsAdvantageClinical ImplicationsRapid onset of actionNo need for bridgingPredictable anticoagulant effectNo need for routine coagulation monitoringSpecific coagulation enzyme targetLow risk of off-target adverse effectsLow potential for food interactionsNo dietary precautionsLow potential for drug interactionsFew drug restrictionsTable 5. Disadvantages of Dabigatran Compared With Warfarin and Other Vitamin K AntagonistsFeaturesWarfarinDabigatranFamiliarityExtensiveMinimalMonitoringWell established (INR)Uncertain (TT, ECT, aPTT)ClearanceNonrenalRenal 80%ReversalVitamin K, FFP, PCCNilINR indicates international normalized ratio; TT, thrombin time; ECT, ecarin clotting time; aPTT, activated partial thromboplastin time; FFP, fresh-frozen plasma; and PCC, prothrombin complex concentrate.Prevention of VTEEvidenceAfter the phase II Boehringer Ingelheim Study in Thrombosis (BISTRO) trials showed that dabigatran etexilate was effective for the prevention of VTE,39,40 2 doses of dabigatran etexilate were evaluated in phase III trials for venous thromboprophylaxis after hip or knee arthroplasty: 150 or 220 mg once daily started postoperatively with a half-dose of 75 or 110 mg on the day of surgery (Table 6.41–45Table 6. Phase III Randomized, Controlled Trials Of Dabigatran41–45,48,49TrialPatientsNo.InterventionDuration of TreatmentPrimary Outcome, % or %/y (n/N)Rate Ratio (95% CI)Absolute Risk Difference (95% CI), %Major Bleed, % or %/y (n/N)Rate Ratio (95% CI)Prevention of VTETotal VTE and death RE-MODEL41TKA2101Enoxaparin SC 40 mg OD6–10 d37.7% (193/512)1.3% (9/694)Dabigatran 220 mg OD36.4% (183/503)0.97 (0.82–1.13)−1.3 (−7.3–4.6)1.5% (10/679)1.14 (0.46–2.78)Dabigatran 150 mg OD40.5% (213/526)2.8 (−3.1–8.7)1.3% (9/703) RE-NOVATE42THA3494Enoxaparin SC 40 mg OD28–35 d6.7% (60/897)1.6% (18/1154)Dabigatran 220 mg OD6.0% (53/880)0.90 (0.63–1.29)−0.7 (−2.9–1.6)2.0% (23/1146)1.29 (0.70–2.37)Dabigatran 150 mg OD8.6% (75/874)1.9 (−0.6–4.4)1.3% (15/1163) RE-MOBILIZE43TKA2615Enoxaparin SC 30 mg BID12–15 d25.3% (163/643)1.4% (12/868)Dabigatran 220 mg OD31.1% (188/604)1.23 (1.03–1.47)5.8 (0.8–10.8)0.6% (5/857)0.42 (0.15–1.19)Dabigatran 150 mg OD33.7% (219/649)8.4 (3.4–13.3)0.6% (5/871) RE-NOVATE II44THA2055Enoxaparin SC 40 mg OD28–35 d8.8% (69/785)0.9% (9/1003)Dabigatran 220 mg OD7.7% (61/792)0.88 (0.63–1.22)−1.1 (−3.8 to 1.6)1.4% (14/1010)1.54 (0.67–3.55)Treatment of VTERecurrent VTE and related death RE-COVER45Acute VTE2564Warfarin (INR 2.0 to 3.0)6 mo2.1% (27/1265)1.9% (24/1265)Dabigatran 150 mg BID2.4% (30/1274)1.10* (0.65–1.84)0.4 (−0.8–1.5)1.6% (20/1274)0.82* (0.45–1.48)Prevention of stroke and systemic embolism in AFStroke or systemic embolism RE-LY48,49AF18 113Warfarin (INR 2.0 to 3.0)2.0 y (median)1.71%/y (202/6022)3.57%/y (421/6022)Dabigatran 150 mg BID1.11%/y (134/6076)0.65 (0.52–0.81)3.32%/y (399/6076)0.93 (0.81–1.07)Dabigatran 110 mg BID1.54%/y (183/6015)0.90 (0.74–1.10)2.87%/y (342/6015)0.80 (0.70–0.93)CI indicates confidence interval; BID, twice daily; VTE, venous thromboembolism; TKA, total knee arthroplasty; THA, total hip arthroplasty; INR, international normalized ratio; AF, atrial fibrillation; RE-MODEL, Dabigatran Etexilate 150 mg or 220 mg Once Daily Versus Enoxaparin 40 mg Once Daily for Prevention of Thrombosis After Knee Surgery; RE-NOVATE, Dabigatran Etexilate Compared With Enoxaparin in Prevention of VTE Following Total Hip Arthroplasty; RE-MOBILIZE, Dabigatran Etexilate Versus Enoxaparin in Prevention of VTE Post Total Knee Replacement; RE-COVER, Dabigatran Etexilate Versus Warfarin in the Treatment of Acute Venous Thromboembolism; and RE-LY, Randomized