178
Pros and Cons of Vitamin K Antagonists and Non–Vitamin K Antagonist Oral Anticoagulants Walter Ageno, MD1
1 Department of Clinical and Experimental Medicine, University of
Insubria, Varese, Italy Semin Thromb Hemost 2015;41:178–187.
Abstract
Keywords
► vitamin K antagonist ► direct thrombin inhibitor ► direct factor Xa inhibitor
Anticoagulant treatment can be currently instituted with two different classes of drugs: the vitamin K antagonists (VKAs) and the newer, “novel” or non–vitamin K antagonist oral anticoagulant drugs (NOACs). The NOACs have several practical advantages over VKAs, such as the rapid onset/offset of action, the lower potential for food and drug interactions, and the predictable anticoagulant response. However, the VKAs currently have a broader spectrum of indications, a standardized monitoring test, and established reversal strategies. The NOACs emerged as alternative options for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Nevertheless, there remain some populations for whom the VKAs remain the most appropriate anticoagulant drug. This article discusses the advantages and disadvantages of VKAs and NOACs.
Vitamin K antagonists (VKAs) have been the only available oral anticoagulant drugs for the prevention and treatment of arterial and venous thromboembolic diseases for more than 60 years. In the last two decades, several newer or novel oral anticoagulants (NOACs), also called non–vitamin K antagonist oral anticoagulants (NOACs) or direct oral anticoagulants (DOACs) or target-specific oral anticoagulants,1 have been developed. These two classes of oral anticoagulants have different pharmacological properties that drive their clinical use. Indeed, the availability of different therapeutic options increases the possibility to individualize anticoagulant treatment choices. The aim of this article is to discuss the advantages and disadvantages of VKAs and NOACs.
Pharmacological Properties There are several differences in the pharmacological profiles of VKAs and NOACs. From a pharmacodynamic point of view, the VKAs inhibit the carboxylation of vitamin K–dependent coagulation factors II (prothrombin), VII, IX, and X and of the natural anticoagulant proteins C and S.2 A potential transient procoagulant effect is reported during the acute phase of
published online February 19, 2015
Address for correspondence Walter Ageno, MD, Department of Clinical and Experimental Medicine, University of Insubria, Via Guicciardini 9, 21100 Varese, Italy (e-mail: [email protected]; [email protected]).
Issue Theme Anticoagulant Therapy: Present and Future; Guest Editor: Job Harenberg, MD.
thrombotic events, when baseline levels of proteins C and S are reduced.3 The peak action is reached after 4 to 5 days; afterward the anticoagulant effect of VKAs is prevalent.3 The NOACs include the direct thrombin inhibitors (e.g., dabigatran etexilate) and the direct factor Xa inhibitors (e.g., apixaban, edoxaban, and rivaroxaban).4 Dabigatran interacts directly and exclusively with the active site of the thrombin molecule and can inactivate both free and fibrin-bound thrombin, which is protected from the action of the indirect thrombin inhibitors and is an important trigger of thrombus expansion.5 Apixaban, edoxaban, and rivaroxaban are direct inhibitors of the activated factor X (FXa). They inhibit not only free FXa but also FXa within the prothrombinase complex, without the need of the cofactor antithrombin.6–8 From a pharmacokinetic point of view, the VKAs have an essentially hepatic metabolism. Warfarin is rapidly absorbed from the gastrointestinal tract, has high bioavailability, and reaches the maximal plasma concentration in 90 minutes.9 Furthermore, warfarin has a plasma half-life of 36 to 42 hours, circulates bound to plasma proteins, and accumulates in the liver where it is transformed by several enzymes of the cytochrome P450 system (mainly CYP2C9, CYP3A4, and
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1544231. ISSN 0094-6176.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Nicoletta Riva, MD1
CYP1A2).3,10 Different half-lives are reported for the less commonly used acenocoumarol (8–9 hours), fluindione (31 hours), and phenprocoumon (5.5 days).3,11 The NOACs have different pharmacokinetic properties,5,6,12,13 which are detailed in ►Table 1. In general, they have a rapid onset of action and reach peak plasma levels within 2 hours from ingestion. The half-lives are shorter than those of VKAs and trough concentrations are reached approximately 12 to 24 hours after intake. Finally, the NOACs have a predominantly renal clearance. The rapid onset of action and the short half-life represent a clear advantage for the NOACs over VKAs, although strict patient adherence is required to guarantee a stable anticoagulant effect. The different pharmacokinetic properties among the NOACs may also guide the choice of the oral anticoagulant. Dabigatran has the highest rate of renal clearance and should be avoided in frail elderly patients at high risk for renal failure.14 On the contrary, rivaroxaban has been reported to accumulate in patients with moderate hepatic insufficiency (Child– Pugh score B).15 Of note, patients with severe renal or liver failure have been excluded from the majority of NOACs trials. The main drawback of VKAs is the high inter- and intraindividual variability in dose–response. Variability depends on endogenous factors (such as age, gender, body weight, comorbidities, and genetics) and environmental factors (such as concomitant medications and diet), which may influence the clearance of the drugs as well as the synthesis or clearance of vitamin-K–dependent coagulation factors.3 For instance, the hepatic metabolism is inhibited by amiodarone and induced by barbiturates and carbamazepine; cholestyramine may reduce the absorption of warfarin, while thyroxine may enhance the metabolism of coagulation factors.3 The chronic use of alcohol and the levels of dietary vitamin K may also play a role. The unpredictable effect of these interactions on the VKAs results in the need for routine monitoring of the international normalized ratio (INR). Experts suggest a regular intake of food containing vitamin K and more frequent INR tests when concomitant interfering drugs are needed.3 The main practical advantage of the NOACs is represented by the predictable anticoagulant response, which allows fixed
Riva, Ageno
dosages without the need for routine monitoring. The NOACs have a low potential for food interaction, but are not completely free from drug interactions: they are all substrate for the efflux transporter P-glycoprotein (P-gp), and factor Xa inhibitors are also metabolized by the cytochrome CYP3A4.16 For instance, some antiepileptic drugs (carbamazepine, phenytoin, phenobarbital) and some antibiotics (rifampicin) are potent P-gp inducers, thus may reduce the NOACs plasma concentration; on the other side, azole-antimycotics (ketoconazole, itraconazole, posaconazole, voriconazole) and HIV protease inhibitors (ritonavir) are strong P-gp and CYP3A4 inhibitors, thus may increase the NOACs plasma concentration.16 Furthermore, dabigatran and edoxaban require dose reduction when associated with verapamil.
Indications and Contraindications VKAs are currently used for the prevention and treatment of venous thromboembolism (VTE), including both usual and unusual site VTE: for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), valvular heart diseases, or prosthetic heart valves and for other less common indications. The NOACs have been initially assessed for the prevention of VTE in patients undergoing major orthopedic surgery (total hip and knee replacement surgery). For this indication, they were at least noninferior in efficacy and safety to the current standard of care, low-molecular-weight heparin (LMWH), with the advantage of the oral administration.17,18 However, when evaluated for the extended thromboprophylaxis in acutely ill medical patients, the NOACs resulted in a more than twofold higher incidence of major bleeding than shortterm enoxaparin followed by placebo, and the increased bleeding risk was evident during both concomitant active treatment and prolonged treatment.19 The NOACs have been extensively investigated in the treatment of deep vein thrombosis and pulmonary embolism. In the acute phase of VTE, dabigatran and edoxaban have been started after the initial parenteral anticoagulation, while rivaroxaban and apixaban were directly administered as a
Table 1 Pharmacological properties of the novel oral anticoagulants Apixaban
Dabigatran
Edoxaban
Rivaroxaban
Bioavailability
50%
6.5%
62%
66% (without food) >80% (with food)
Time to peak concentration
1–4 h
0.5–2 h
1–2 h
2–4 h
Half-life
8–13 h
12–14 h
10–14 h
5–9 h (young) 11–13 h (elderly)
Hepatic clearance
73%
20%
65%
65%
Renal clearance
27%
80%
35%
35%
Plasma protein binding
90%
35%
55%
90%
Cytochrome P450 metabolism
Yes
No
Minimal
Yes
P-glycoprotein transport
Yes
Yes
Yes
Yes
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Pros and Cons of VKA/NOAC
Pros and Cons of VKA/NOAC
Riva, Ageno
single drug, although higher dosages were chosen for the first few weeks.20 Compared with the standard regimen LMWH/ VKA, the NOACs were noninferior in terms of efficacy and showed lower rates of major and fatal bleeding,20 emerging as an alternative to the standard treatment.21 Similar results arose in the extended secondary prevention of VTE, where the NOACs resulted effective in preventing recurrent VTE with an acceptable incidence of major bleeding.22–24 So far, there is no evidence regarding the use of the NOACs in patients with severe thrombophilia (e.g., the antiphospholipid antibody syndrome) or in patients with VTE occurring in unusual sites including the cerebral or the splanchnic veins. Four large randomized controlled trials investigated the NOACs in patients with nonvalvular AF and reported a favorable risk–benefit profile. The NOACs resulted in an approximately 20% reduction in the risk of stroke and 10% reduction in all-cause mortality compared with VKAs.25 The rate of major bleeding was similar, with fewer intracranial hemorrhages (ICHs) and more gastrointestinal bleeds.25 The European Society of Cardiology recommends the use of NOACs, as long as their use complies with the criteria used in the clinical trials.26 Recent evidence suggests that the NOACs are effective also in patients undergoing cardioversion and AF ablation.27,28 Nonetheless, patients with valvular AF (defined as the presence of rheumatic valve diseases, mainly mitral stenosis, or prosthetic heart valves) were excluded from the trials and remain candidates for treatment with VKAs.26 Moreover, in patients with mechanical heart valves, dabigatran showed increased rates of both bleeding and thromboembolic complications compared with warfarin,29 and its use in this setting has been forbidden by the regulatory agencies. The NOACs have also been investigated in patients with acute coronary syndromes.30 Compared with placebo, treatment with NOACs resulted in 30% reduction of major cardiovascular events, when added to single antiplatelet therapy (aspirin), and in 13% reduction of the same end point, when added to dual antiplatelet therapy (aspirin and clopidogrel). In both groups, there was a significant increase in the risk of clinically relevant bleeding.30 Neither VKAs nor NOACs have been evaluated in addition to the novel antiplatelet agents (prasugrel, ticagrelor) and their concomitant use should be avoided.
Bleeding Complications and Other Side Effects Bleeding is the most common complication of VKAs, with an incidence of major bleeding of approximately 2% per year in randomized clinical trials, and ranging from 1.0 to 7.4% per year in observational cohort studies.31 VKAs also carry high case-fatality rates from major bleeding and in particular intracranial bleeding (13 and 45%, respectively).32 Other side effects, such as skin necrosis and purple toe syndrome, are rarely reported.33 The incidence of major bleeding complications with the NOACs has been reported to range from 1.6 to 3.6% per year in AF patients34,35 and to occur in approximately 1% of VTE Seminars in Thrombosis & Hemostasis
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patients treated for 3 to 12 months.20 The most important clinical advantage, which is common to all the NOACs, is represented by the reduction in the risk of ICH by more than 50% when compared with VKAs.20,36 The exact mechanism beyond these lower rates of ICH is unknown and possible explanations include the inhibition of a single coagulation factor or the lack of a direct effect on factor VIIa, as opposed to the VKAs.37 Conversely, all the NOACs, but apixaban, were associated with approximately 25% increased risk of gastrointestinal bleeding.25,38,39 The most common side effect of dabigatran is dyspepsia, which is reported in 11% of patients in the RE-LY trial40 and in 3% of patients in the RE-COVER trial.41 The formulation of dabigatran contains a tartaric acid core, which is necessary to create an acid environment that enhances the drug absorption.5 Furthermore, the use of dabigatran in the primary and secondary prevention of cardiovascular diseases has been associated with an approximately 30% increased risk of acute coronary syndromes.42,43 This adverse outcome was particularly evident in comparison with warfarin,43 hence some authors suggested a protective effect of the comparator drug warfarin.44 However, a recently published meta-analysis showed that the greater risk of coronary events was a common class effect of the oral direct thrombin inhibitors (dabigatran, ximelagatran, and AZD0837)45 and the European Heart Rhythm Association recommended factor Xa inhibitors in AF patients with a recent episode of acute coronary syndrome.16
The Role of Laboratory Tests VKAs require routine laboratory monitoring to assess their anticoagulant effect and to adjust the daily dosage.46 The specific laboratory test is the INR, which standardizes the results of the prothrombin time (PT) using different International Sensitivity Indexes (ISI) for each thromboplastin.46 Because VKAs have long half-lives and their inhibition on the synthesis of coagulation factors lasts for days, the relationship between the last dose of the drugs and the timing of INR test is irrelevant.46 Monitoring the anticoagulant effect of VKAs is mandatory for two main reasons: the VKAs have a highly variable anticoagulant response and a narrow therapeutic window. The target INR range is 2.0 to 3.0 for most indications and it is well known that subtherapeutic INR levels correlate with an increased thrombotic risk, while supratherapeutic levels correlate with an increased bleeding risk.47,48 The time within the therapeutic range (TTR) has been used as predictor of clinical outcomes, as it was inversely correlated with major hemorrhages and thrombotic events.49 VTE patients with TTR 65%.50 Unfortunately, in real-life clinical practice, stable anticoagulation control is difficult to achieve. In a meta-analysis assessing warfarin-treated AF patients in the United States, the overall mean TTR was 55%, with some differences between the community usual care setting and the anticoagulation clinics (mean TTR 51 and 63%, respectively).51
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Pros and Cons of VKA/NOAC
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Reversal of the Anticoagulant Effect Rapid reversal of anticoagulation is recommended in case of major or life-threatening bleeding events during oral anticoagulant treatment. Therapeutic options include the administration of phytonadione in patients receiving VKAs and blood derivatives such as fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), vitamin K, and recombinant factor VIIa (rVIIa). Phytonadione (vitamin K1) has been used in clinical trials for the treatment of VKAs-associated coagulopathy.3 When administered for the management of the bleeding patient, intravenously administered phytonadione was shown to reduce the INR more rapidly than with oral or subcutaneous administrations.3 Caution should be used when using intravenous phytonadione because of the risk of anaphylactoid reactions.3 FFP has a relatively long preparation time, because of the need for thawing and blood-group matching before infusion. Other disadvantages are the risk of allergic reaction or infection transmission, and volume overload. As 1 mL of FFP contains around 1 unit of clotting factors, more than 1 L might be needed to normalize the coagulation levels.59 PCCs contain significant quantities of the vitamin K–dependent coagulation factors II, IX, and X (three-factor PCCs) and also factor VII (four-factor PCC). The clotting factor concentration is approximately 25-fold higher than FFP, and 40 mL of PCCs is enough to provide 1,000 units of clotting factors.59,60 Furthermore, PCCs are prepared using viral inactivation methods.60 Thromboembolic complications after PCCs infusion were reported in 1.4% (95% confidence interval [CI], 0.8–2.1) and viral transmission in 1.9% (95% CI, 0.3–4.9) of patients.61 Several retrospective studies evaluated the use of FFP and PCCs in patients with VKA-related major bleeding and found that PCCs resulted in faster INR reversal than FFP.62–64 However, whether this result correlates with better outcomes is still debated. For instance, Majeed et al compared 100 patients with intracerebral hemorrhage who received four-factor PCCs with 35 patients who received FFP and found that 30-day all-cause mortality was not significantly different, after adjustment for age, hematoma volume, and localization.65 The only published randomized controlled trial, evaluating 202 patients with acute major bleeding during VKA treatment showed that four-factor PCCs were superior to FFP in obtaining rapid INR reduction and noninferior in achieving effective hemostasis.66 Despite inconclusive results, current guidelines suggest four-factor PCC rather than FFP for VKA-associated major bleeding.67 So far, no study directly compared three-factor and four-factor PCCs, although the latter were reported to achieve INR correction more frequently.68 In case of unavailability of four-factor PCCs, a small amount of FFP together with three-factor PCCs is suggested, as a source of factor VII.59 Additional intravenous vitamin K is advised, to sustain the endogenous synthesis of coagulation factors, given the short half-lives of PCCs and FFP compared with VKAs.67 The use of rVIIa for warfarin reversal is not sustained by evidence69 and is currently off label. Seminars in Thrombosis & Hemostasis
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The most important clinical advantage of the NOACs is represented by their greater ease of use. Thanks to their wide therapeutic window and predictable pharmacological responses,3 the NOACs are administered at fixed doses without routine laboratory monitoring of their anticoagulant effect. However, the plasmatic concentration of the NOACs can be substantially increased or reduced in patients with severe renal impairment or taking concomitant interfering medications, and their therapeutic effect in patients with extreme body weights is not known. In these situations, as well as in other emergency situations such as the presence of bleeding or thrombotic events, the need for emergency surgery, or if overdose is suspected, the measurement of their anticoagulant effect may be required.52,53 Laboratory tests that provide a global assessment of the coagulation (such as activated partial thromboplastin time [aPTT], PT, and INR) can be affected by the NOACs, but their levels do not accurately reflect their plasma concentrations.52 The aPTT showed a curvilinear correlation with dabigatran: a steep increase at low concentrations and an almost linear correlation at concentrations >200 ng/mL.54 During chronic therapy with dabigatran 150 mg twice daily, the median aPTT has been reported to be 2 times higher than control subjects at peak and 1.5 times higher at trough.54 aPTT has been therefore proposed as qualitative test for dabigatran because it may identify excessive anticoagulant effect (especially when aPTT ratio is >2.5).55 The prolongation of PT was linearly dependent on rivaroxaban concentrations, although only small changes were reported at therapeutic dosages.52 Furthermore, there was some variation depending on the different commercial thromboplastins (e.g., Neoplastin Plus and RecombinPlasTin were the most responsive).56 PT has been proposed as qualitative test to identify the presence or absence of rivaroxaban, while it is generally less sensitive for apixaban.57 The INR is not suitable for measurement of the anticoagulant effect of the NOACs.55 More specific laboratory tests have been proposed to provide a quantitative determination of the NOACs. The thrombin time (TT) is significantly prolonged even with low concentrations of dabigatran.46 TT is easily available in clinical laboratories, but it has excessive responsiveness to the drug. Therefore, samples are usually diluted with normal plasma to obtain the dilute thrombin time (dTT). The dTT showed linear correlation with dabigatran concentrations, while it is insensitive to factor Xa inhibitors.52 Chromogenic assays for anti–factor Xa activity have shown a linear correlation with therapeutic plasma concentrations of rivaroxaban and apixaban.56 However, these tests require specific calibrators for each drug, and standardization is required to reduce interlaboratory variability.57 In addition, the NOACs also have short half-lives and rapid onset/offset of the anticoagulant effect, which makes critically important to correlate the laboratory results with the last drug intake.46 Because of the high percentage of renal excretion, point-ofcare qualitative assays have been recently proposed to determine the concentration of NOACs from urine samples.58 These methods showed very high sensitivity and specificity; however, further validation is needed before they can be used in everyday clinical practice.
Riva, Ageno
Pros and Cons of VKA/NOAC
Riva, Ageno
The experience regarding the emergency reversal of the NOACs is still limited. So far, PCCs are the most extensively studied reversal strategy, but there are only few studies conducted in humans. Eerenberg et al, in a randomized, double-blind, placebo-controlled, crossover trial, evaluated the effect of a single bolus of PCCs (50 U/kg) administered to 12 healthy volunteers receiving dabigatran 150 mg twice daily or rivaroxaban 20 mg twice daily for 2.5 days.70 PCCs reversed the anticoagulant effect of rivaroxaban (expressed as normalization of the PT), but had no influence on dabigatran (lack of normalization of partial thromboplastin time, ecarin clotting time, and TT).70 Levi et al, in an open-label, parallelgroup study, compared the effect of three-factor and fourfactor PCCs (50 U/kg) in 35 healthy volunteers receiving rivaroxaban 20 mg twice daily for 4 days.71 Four-factor PCCs showed a greater reduction of PT, while three-factor PCCs showed a greater normalization of thrombin generation parameters, suggesting that both preparations have the potential to obtain partial reversal of rivaroxaban.71 PCCs currently represent the best choice for the management of patients presenting NOACs-associated bleeding, although their use in patients treated with dabigatran is less supported by preclinical evidence. Activated PCCs (aPCCs), in an ex vivo study, corrected thrombin generation parameters in plasma from healthy volunteers receiving one single dose of dabigatran.72 Although these results need to be confirmed in bleeding patients, aPCCs (80 U/kg) might also be considered for dabigatran reversal.73 The lack of specific antidotes remains the main concern associated with the use of the NOACs. However, several molecules are currently undergoing clinical assessment. A humanized monoclonal antibody targeting dabigatran (aDabi-Fab) demonstrated to neutralize the anticoagulant activity of dabigatran rapidly and completely in animal models and in human plasma in vitro.74 Preliminary results, from an ongoing phase 2 randomized, placebo-controlled trial, showed that a recombinant factor Xa with structural modifications (andexanet alfa) reversed factor Xa inhibition in healthy volunteers taking apixaban75 or rivaroxaban.76 In principle, given the short half-lives of the NOACs, discontinuation of the drug, adequate supportive measures, and an accurate management of the bleeding source should be sufficient to control most bleeding events.73 Additional strategies, if needed, include the use of oral activated charcoal, which has been suggested to absorb the NOACs after a recent ingestion or overdose,77 and hemodialysis. This latter, however, represents an option for dabigatran removal only, due to the low plasma protein binding of this drug.78
Periprocedural Management The different pharmacological properties of VKAs and NOACs have also an impact on their periprocedural management. In patients undergoing elective major procedures, current guidelines recommend discontinuing warfarin 5 days before the procedure (a slightly shorter period is enough for acenocoumarol, while a longer period is required for phenprocoumon) to obtain a preoperative INR
Pros and Cons of Vitamin K Antagonists and Non–Vitamin K Antagonist Oral Anticoagulants Walter Ageno, MD1
1 Department of Clinical and Experimental Medicine, University of
Insubria, Varese, Italy Semin Thromb Hemost 2015;41:178–187.
Abstract
Keywords
► vitamin K antagonist ► direct thrombin inhibitor ► direct factor Xa inhibitor
Anticoagulant treatment can be currently instituted with two different classes of drugs: the vitamin K antagonists (VKAs) and the newer, “novel” or non–vitamin K antagonist oral anticoagulant drugs (NOACs). The NOACs have several practical advantages over VKAs, such as the rapid onset/offset of action, the lower potential for food and drug interactions, and the predictable anticoagulant response. However, the VKAs currently have a broader spectrum of indications, a standardized monitoring test, and established reversal strategies. The NOACs emerged as alternative options for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Nevertheless, there remain some populations for whom the VKAs remain the most appropriate anticoagulant drug. This article discusses the advantages and disadvantages of VKAs and NOACs.
Vitamin K antagonists (VKAs) have been the only available oral anticoagulant drugs for the prevention and treatment of arterial and venous thromboembolic diseases for more than 60 years. In the last two decades, several newer or novel oral anticoagulants (NOACs), also called non–vitamin K antagonist oral anticoagulants (NOACs) or direct oral anticoagulants (DOACs) or target-specific oral anticoagulants,1 have been developed. These two classes of oral anticoagulants have different pharmacological properties that drive their clinical use. Indeed, the availability of different therapeutic options increases the possibility to individualize anticoagulant treatment choices. The aim of this article is to discuss the advantages and disadvantages of VKAs and NOACs.
Pharmacological Properties There are several differences in the pharmacological profiles of VKAs and NOACs. From a pharmacodynamic point of view, the VKAs inhibit the carboxylation of vitamin K–dependent coagulation factors II (prothrombin), VII, IX, and X and of the natural anticoagulant proteins C and S.2 A potential transient procoagulant effect is reported during the acute phase of
published online February 19, 2015
Address for correspondence Walter Ageno, MD, Department of Clinical and Experimental Medicine, University of Insubria, Via Guicciardini 9, 21100 Varese, Italy (e-mail: [email protected]; [email protected]).
Issue Theme Anticoagulant Therapy: Present and Future; Guest Editor: Job Harenberg, MD.
thrombotic events, when baseline levels of proteins C and S are reduced.3 The peak action is reached after 4 to 5 days; afterward the anticoagulant effect of VKAs is prevalent.3 The NOACs include the direct thrombin inhibitors (e.g., dabigatran etexilate) and the direct factor Xa inhibitors (e.g., apixaban, edoxaban, and rivaroxaban).4 Dabigatran interacts directly and exclusively with the active site of the thrombin molecule and can inactivate both free and fibrin-bound thrombin, which is protected from the action of the indirect thrombin inhibitors and is an important trigger of thrombus expansion.5 Apixaban, edoxaban, and rivaroxaban are direct inhibitors of the activated factor X (FXa). They inhibit not only free FXa but also FXa within the prothrombinase complex, without the need of the cofactor antithrombin.6–8 From a pharmacokinetic point of view, the VKAs have an essentially hepatic metabolism. Warfarin is rapidly absorbed from the gastrointestinal tract, has high bioavailability, and reaches the maximal plasma concentration in 90 minutes.9 Furthermore, warfarin has a plasma half-life of 36 to 42 hours, circulates bound to plasma proteins, and accumulates in the liver where it is transformed by several enzymes of the cytochrome P450 system (mainly CYP2C9, CYP3A4, and
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1544231. ISSN 0094-6176.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Nicoletta Riva, MD1
CYP1A2).3,10 Different half-lives are reported for the less commonly used acenocoumarol (8–9 hours), fluindione (31 hours), and phenprocoumon (5.5 days).3,11 The NOACs have different pharmacokinetic properties,5,6,12,13 which are detailed in ►Table 1. In general, they have a rapid onset of action and reach peak plasma levels within 2 hours from ingestion. The half-lives are shorter than those of VKAs and trough concentrations are reached approximately 12 to 24 hours after intake. Finally, the NOACs have a predominantly renal clearance. The rapid onset of action and the short half-life represent a clear advantage for the NOACs over VKAs, although strict patient adherence is required to guarantee a stable anticoagulant effect. The different pharmacokinetic properties among the NOACs may also guide the choice of the oral anticoagulant. Dabigatran has the highest rate of renal clearance and should be avoided in frail elderly patients at high risk for renal failure.14 On the contrary, rivaroxaban has been reported to accumulate in patients with moderate hepatic insufficiency (Child– Pugh score B).15 Of note, patients with severe renal or liver failure have been excluded from the majority of NOACs trials. The main drawback of VKAs is the high inter- and intraindividual variability in dose–response. Variability depends on endogenous factors (such as age, gender, body weight, comorbidities, and genetics) and environmental factors (such as concomitant medications and diet), which may influence the clearance of the drugs as well as the synthesis or clearance of vitamin-K–dependent coagulation factors.3 For instance, the hepatic metabolism is inhibited by amiodarone and induced by barbiturates and carbamazepine; cholestyramine may reduce the absorption of warfarin, while thyroxine may enhance the metabolism of coagulation factors.3 The chronic use of alcohol and the levels of dietary vitamin K may also play a role. The unpredictable effect of these interactions on the VKAs results in the need for routine monitoring of the international normalized ratio (INR). Experts suggest a regular intake of food containing vitamin K and more frequent INR tests when concomitant interfering drugs are needed.3 The main practical advantage of the NOACs is represented by the predictable anticoagulant response, which allows fixed
Riva, Ageno
dosages without the need for routine monitoring. The NOACs have a low potential for food interaction, but are not completely free from drug interactions: they are all substrate for the efflux transporter P-glycoprotein (P-gp), and factor Xa inhibitors are also metabolized by the cytochrome CYP3A4.16 For instance, some antiepileptic drugs (carbamazepine, phenytoin, phenobarbital) and some antibiotics (rifampicin) are potent P-gp inducers, thus may reduce the NOACs plasma concentration; on the other side, azole-antimycotics (ketoconazole, itraconazole, posaconazole, voriconazole) and HIV protease inhibitors (ritonavir) are strong P-gp and CYP3A4 inhibitors, thus may increase the NOACs plasma concentration.16 Furthermore, dabigatran and edoxaban require dose reduction when associated with verapamil.
Indications and Contraindications VKAs are currently used for the prevention and treatment of venous thromboembolism (VTE), including both usual and unusual site VTE: for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), valvular heart diseases, or prosthetic heart valves and for other less common indications. The NOACs have been initially assessed for the prevention of VTE in patients undergoing major orthopedic surgery (total hip and knee replacement surgery). For this indication, they were at least noninferior in efficacy and safety to the current standard of care, low-molecular-weight heparin (LMWH), with the advantage of the oral administration.17,18 However, when evaluated for the extended thromboprophylaxis in acutely ill medical patients, the NOACs resulted in a more than twofold higher incidence of major bleeding than shortterm enoxaparin followed by placebo, and the increased bleeding risk was evident during both concomitant active treatment and prolonged treatment.19 The NOACs have been extensively investigated in the treatment of deep vein thrombosis and pulmonary embolism. In the acute phase of VTE, dabigatran and edoxaban have been started after the initial parenteral anticoagulation, while rivaroxaban and apixaban were directly administered as a
Table 1 Pharmacological properties of the novel oral anticoagulants Apixaban
Dabigatran
Edoxaban
Rivaroxaban
Bioavailability
50%
6.5%
62%
66% (without food) >80% (with food)
Time to peak concentration
1–4 h
0.5–2 h
1–2 h
2–4 h
Half-life
8–13 h
12–14 h
10–14 h
5–9 h (young) 11–13 h (elderly)
Hepatic clearance
73%
20%
65%
65%
Renal clearance
27%
80%
35%
35%
Plasma protein binding
90%
35%
55%
90%
Cytochrome P450 metabolism
Yes
No
Minimal
Yes
P-glycoprotein transport
Yes
Yes
Yes
Yes
Seminars in Thrombosis & Hemostasis
Vol. 41
No. 2/2015
179
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Pros and Cons of VKA/NOAC
Pros and Cons of VKA/NOAC
Riva, Ageno
single drug, although higher dosages were chosen for the first few weeks.20 Compared with the standard regimen LMWH/ VKA, the NOACs were noninferior in terms of efficacy and showed lower rates of major and fatal bleeding,20 emerging as an alternative to the standard treatment.21 Similar results arose in the extended secondary prevention of VTE, where the NOACs resulted effective in preventing recurrent VTE with an acceptable incidence of major bleeding.22–24 So far, there is no evidence regarding the use of the NOACs in patients with severe thrombophilia (e.g., the antiphospholipid antibody syndrome) or in patients with VTE occurring in unusual sites including the cerebral or the splanchnic veins. Four large randomized controlled trials investigated the NOACs in patients with nonvalvular AF and reported a favorable risk–benefit profile. The NOACs resulted in an approximately 20% reduction in the risk of stroke and 10% reduction in all-cause mortality compared with VKAs.25 The rate of major bleeding was similar, with fewer intracranial hemorrhages (ICHs) and more gastrointestinal bleeds.25 The European Society of Cardiology recommends the use of NOACs, as long as their use complies with the criteria used in the clinical trials.26 Recent evidence suggests that the NOACs are effective also in patients undergoing cardioversion and AF ablation.27,28 Nonetheless, patients with valvular AF (defined as the presence of rheumatic valve diseases, mainly mitral stenosis, or prosthetic heart valves) were excluded from the trials and remain candidates for treatment with VKAs.26 Moreover, in patients with mechanical heart valves, dabigatran showed increased rates of both bleeding and thromboembolic complications compared with warfarin,29 and its use in this setting has been forbidden by the regulatory agencies. The NOACs have also been investigated in patients with acute coronary syndromes.30 Compared with placebo, treatment with NOACs resulted in 30% reduction of major cardiovascular events, when added to single antiplatelet therapy (aspirin), and in 13% reduction of the same end point, when added to dual antiplatelet therapy (aspirin and clopidogrel). In both groups, there was a significant increase in the risk of clinically relevant bleeding.30 Neither VKAs nor NOACs have been evaluated in addition to the novel antiplatelet agents (prasugrel, ticagrelor) and their concomitant use should be avoided.
Bleeding Complications and Other Side Effects Bleeding is the most common complication of VKAs, with an incidence of major bleeding of approximately 2% per year in randomized clinical trials, and ranging from 1.0 to 7.4% per year in observational cohort studies.31 VKAs also carry high case-fatality rates from major bleeding and in particular intracranial bleeding (13 and 45%, respectively).32 Other side effects, such as skin necrosis and purple toe syndrome, are rarely reported.33 The incidence of major bleeding complications with the NOACs has been reported to range from 1.6 to 3.6% per year in AF patients34,35 and to occur in approximately 1% of VTE Seminars in Thrombosis & Hemostasis
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patients treated for 3 to 12 months.20 The most important clinical advantage, which is common to all the NOACs, is represented by the reduction in the risk of ICH by more than 50% when compared with VKAs.20,36 The exact mechanism beyond these lower rates of ICH is unknown and possible explanations include the inhibition of a single coagulation factor or the lack of a direct effect on factor VIIa, as opposed to the VKAs.37 Conversely, all the NOACs, but apixaban, were associated with approximately 25% increased risk of gastrointestinal bleeding.25,38,39 The most common side effect of dabigatran is dyspepsia, which is reported in 11% of patients in the RE-LY trial40 and in 3% of patients in the RE-COVER trial.41 The formulation of dabigatran contains a tartaric acid core, which is necessary to create an acid environment that enhances the drug absorption.5 Furthermore, the use of dabigatran in the primary and secondary prevention of cardiovascular diseases has been associated with an approximately 30% increased risk of acute coronary syndromes.42,43 This adverse outcome was particularly evident in comparison with warfarin,43 hence some authors suggested a protective effect of the comparator drug warfarin.44 However, a recently published meta-analysis showed that the greater risk of coronary events was a common class effect of the oral direct thrombin inhibitors (dabigatran, ximelagatran, and AZD0837)45 and the European Heart Rhythm Association recommended factor Xa inhibitors in AF patients with a recent episode of acute coronary syndrome.16
The Role of Laboratory Tests VKAs require routine laboratory monitoring to assess their anticoagulant effect and to adjust the daily dosage.46 The specific laboratory test is the INR, which standardizes the results of the prothrombin time (PT) using different International Sensitivity Indexes (ISI) for each thromboplastin.46 Because VKAs have long half-lives and their inhibition on the synthesis of coagulation factors lasts for days, the relationship between the last dose of the drugs and the timing of INR test is irrelevant.46 Monitoring the anticoagulant effect of VKAs is mandatory for two main reasons: the VKAs have a highly variable anticoagulant response and a narrow therapeutic window. The target INR range is 2.0 to 3.0 for most indications and it is well known that subtherapeutic INR levels correlate with an increased thrombotic risk, while supratherapeutic levels correlate with an increased bleeding risk.47,48 The time within the therapeutic range (TTR) has been used as predictor of clinical outcomes, as it was inversely correlated with major hemorrhages and thrombotic events.49 VTE patients with TTR 65%.50 Unfortunately, in real-life clinical practice, stable anticoagulation control is difficult to achieve. In a meta-analysis assessing warfarin-treated AF patients in the United States, the overall mean TTR was 55%, with some differences between the community usual care setting and the anticoagulation clinics (mean TTR 51 and 63%, respectively).51
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Reversal of the Anticoagulant Effect Rapid reversal of anticoagulation is recommended in case of major or life-threatening bleeding events during oral anticoagulant treatment. Therapeutic options include the administration of phytonadione in patients receiving VKAs and blood derivatives such as fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), vitamin K, and recombinant factor VIIa (rVIIa). Phytonadione (vitamin K1) has been used in clinical trials for the treatment of VKAs-associated coagulopathy.3 When administered for the management of the bleeding patient, intravenously administered phytonadione was shown to reduce the INR more rapidly than with oral or subcutaneous administrations.3 Caution should be used when using intravenous phytonadione because of the risk of anaphylactoid reactions.3 FFP has a relatively long preparation time, because of the need for thawing and blood-group matching before infusion. Other disadvantages are the risk of allergic reaction or infection transmission, and volume overload. As 1 mL of FFP contains around 1 unit of clotting factors, more than 1 L might be needed to normalize the coagulation levels.59 PCCs contain significant quantities of the vitamin K–dependent coagulation factors II, IX, and X (three-factor PCCs) and also factor VII (four-factor PCC). The clotting factor concentration is approximately 25-fold higher than FFP, and 40 mL of PCCs is enough to provide 1,000 units of clotting factors.59,60 Furthermore, PCCs are prepared using viral inactivation methods.60 Thromboembolic complications after PCCs infusion were reported in 1.4% (95% confidence interval [CI], 0.8–2.1) and viral transmission in 1.9% (95% CI, 0.3–4.9) of patients.61 Several retrospective studies evaluated the use of FFP and PCCs in patients with VKA-related major bleeding and found that PCCs resulted in faster INR reversal than FFP.62–64 However, whether this result correlates with better outcomes is still debated. For instance, Majeed et al compared 100 patients with intracerebral hemorrhage who received four-factor PCCs with 35 patients who received FFP and found that 30-day all-cause mortality was not significantly different, after adjustment for age, hematoma volume, and localization.65 The only published randomized controlled trial, evaluating 202 patients with acute major bleeding during VKA treatment showed that four-factor PCCs were superior to FFP in obtaining rapid INR reduction and noninferior in achieving effective hemostasis.66 Despite inconclusive results, current guidelines suggest four-factor PCC rather than FFP for VKA-associated major bleeding.67 So far, no study directly compared three-factor and four-factor PCCs, although the latter were reported to achieve INR correction more frequently.68 In case of unavailability of four-factor PCCs, a small amount of FFP together with three-factor PCCs is suggested, as a source of factor VII.59 Additional intravenous vitamin K is advised, to sustain the endogenous synthesis of coagulation factors, given the short half-lives of PCCs and FFP compared with VKAs.67 The use of rVIIa for warfarin reversal is not sustained by evidence69 and is currently off label. Seminars in Thrombosis & Hemostasis
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The most important clinical advantage of the NOACs is represented by their greater ease of use. Thanks to their wide therapeutic window and predictable pharmacological responses,3 the NOACs are administered at fixed doses without routine laboratory monitoring of their anticoagulant effect. However, the plasmatic concentration of the NOACs can be substantially increased or reduced in patients with severe renal impairment or taking concomitant interfering medications, and their therapeutic effect in patients with extreme body weights is not known. In these situations, as well as in other emergency situations such as the presence of bleeding or thrombotic events, the need for emergency surgery, or if overdose is suspected, the measurement of their anticoagulant effect may be required.52,53 Laboratory tests that provide a global assessment of the coagulation (such as activated partial thromboplastin time [aPTT], PT, and INR) can be affected by the NOACs, but their levels do not accurately reflect their plasma concentrations.52 The aPTT showed a curvilinear correlation with dabigatran: a steep increase at low concentrations and an almost linear correlation at concentrations >200 ng/mL.54 During chronic therapy with dabigatran 150 mg twice daily, the median aPTT has been reported to be 2 times higher than control subjects at peak and 1.5 times higher at trough.54 aPTT has been therefore proposed as qualitative test for dabigatran because it may identify excessive anticoagulant effect (especially when aPTT ratio is >2.5).55 The prolongation of PT was linearly dependent on rivaroxaban concentrations, although only small changes were reported at therapeutic dosages.52 Furthermore, there was some variation depending on the different commercial thromboplastins (e.g., Neoplastin Plus and RecombinPlasTin were the most responsive).56 PT has been proposed as qualitative test to identify the presence or absence of rivaroxaban, while it is generally less sensitive for apixaban.57 The INR is not suitable for measurement of the anticoagulant effect of the NOACs.55 More specific laboratory tests have been proposed to provide a quantitative determination of the NOACs. The thrombin time (TT) is significantly prolonged even with low concentrations of dabigatran.46 TT is easily available in clinical laboratories, but it has excessive responsiveness to the drug. Therefore, samples are usually diluted with normal plasma to obtain the dilute thrombin time (dTT). The dTT showed linear correlation with dabigatran concentrations, while it is insensitive to factor Xa inhibitors.52 Chromogenic assays for anti–factor Xa activity have shown a linear correlation with therapeutic plasma concentrations of rivaroxaban and apixaban.56 However, these tests require specific calibrators for each drug, and standardization is required to reduce interlaboratory variability.57 In addition, the NOACs also have short half-lives and rapid onset/offset of the anticoagulant effect, which makes critically important to correlate the laboratory results with the last drug intake.46 Because of the high percentage of renal excretion, point-ofcare qualitative assays have been recently proposed to determine the concentration of NOACs from urine samples.58 These methods showed very high sensitivity and specificity; however, further validation is needed before they can be used in everyday clinical practice.
Riva, Ageno
Pros and Cons of VKA/NOAC
Riva, Ageno
The experience regarding the emergency reversal of the NOACs is still limited. So far, PCCs are the most extensively studied reversal strategy, but there are only few studies conducted in humans. Eerenberg et al, in a randomized, double-blind, placebo-controlled, crossover trial, evaluated the effect of a single bolus of PCCs (50 U/kg) administered to 12 healthy volunteers receiving dabigatran 150 mg twice daily or rivaroxaban 20 mg twice daily for 2.5 days.70 PCCs reversed the anticoagulant effect of rivaroxaban (expressed as normalization of the PT), but had no influence on dabigatran (lack of normalization of partial thromboplastin time, ecarin clotting time, and TT).70 Levi et al, in an open-label, parallelgroup study, compared the effect of three-factor and fourfactor PCCs (50 U/kg) in 35 healthy volunteers receiving rivaroxaban 20 mg twice daily for 4 days.71 Four-factor PCCs showed a greater reduction of PT, while three-factor PCCs showed a greater normalization of thrombin generation parameters, suggesting that both preparations have the potential to obtain partial reversal of rivaroxaban.71 PCCs currently represent the best choice for the management of patients presenting NOACs-associated bleeding, although their use in patients treated with dabigatran is less supported by preclinical evidence. Activated PCCs (aPCCs), in an ex vivo study, corrected thrombin generation parameters in plasma from healthy volunteers receiving one single dose of dabigatran.72 Although these results need to be confirmed in bleeding patients, aPCCs (80 U/kg) might also be considered for dabigatran reversal.73 The lack of specific antidotes remains the main concern associated with the use of the NOACs. However, several molecules are currently undergoing clinical assessment. A humanized monoclonal antibody targeting dabigatran (aDabi-Fab) demonstrated to neutralize the anticoagulant activity of dabigatran rapidly and completely in animal models and in human plasma in vitro.74 Preliminary results, from an ongoing phase 2 randomized, placebo-controlled trial, showed that a recombinant factor Xa with structural modifications (andexanet alfa) reversed factor Xa inhibition in healthy volunteers taking apixaban75 or rivaroxaban.76 In principle, given the short half-lives of the NOACs, discontinuation of the drug, adequate supportive measures, and an accurate management of the bleeding source should be sufficient to control most bleeding events.73 Additional strategies, if needed, include the use of oral activated charcoal, which has been suggested to absorb the NOACs after a recent ingestion or overdose,77 and hemodialysis. This latter, however, represents an option for dabigatran removal only, due to the low plasma protein binding of this drug.78
Periprocedural Management The different pharmacological properties of VKAs and NOACs have also an impact on their periprocedural management. In patients undergoing elective major procedures, current guidelines recommend discontinuing warfarin 5 days before the procedure (a slightly shorter period is enough for acenocoumarol, while a longer period is required for phenprocoumon) to obtain a preoperative INR
