Drugs (2014) 74:451–464 DOI 10.1007/s40265-014-0188-6

ADIS DRUG EVALUATION

Rivaroxaban: A Review of Its Use in Acute Coronary Syndromes Greg L. Plosker

Published online: 18 February 2014 Ó Springer International Publishing Switzerland 2014

Abstract Rivaroxaban (XareltoÒ) is an orally administered highly selective direct inhibitor of factor Xa that has been approved in many countries to reduce the risk of stroke in patients with atrial fibrillation and for the treatment and prevention of venous thromboembolism. More recently, rivaroxaban at a low dosage of 2.5 mg twice daily, co-administered with aspirin alone or aspirin plus either clopidogrel or ticlopidine, was approved for use in the EU for patients with a recent acute coronary syndrome (ACS). The approval of rivaroxaban in ACS was primarily based on findings of the phase III ATLAS ACS 2-TIMI 51 trial, which showed that after a median of 13.1 months of treatment with rivaroxaban 2.5 mg twice daily (combined with aspirin or aspirin plus either clopidogrel or ticlopidine) there was a statistically significant reduction in the rate of the primary composite endpoint, which was death from cardiovascular causes, myocardial infarction or stroke, compared with placebo. Rivaroxaban 2.5 mg twice daily was also associated with a reduction in all-cause and cardiovascular mortality. There was an increase in the risk of major bleeding and intracranial haemorrhage with rivaroxaban 2.5 mg twice daily compared with placebo; however, there was no increase in the risk of fatal bleeding. Aspirin plus either ticagrelor or prasugrel was not evaluated as background dual antiplatelet therapy in ATLAS ACS 2-TIMI 51 and the safety implications of rivaroxaban used in combination with such therapy are unknown. In conclusion, results of the ATLAS ACS 2-TIMI 51 trial suggest a potentially important role for rivaroxaban 2.5 mg The manuscript was reviewed by: N. Meneveau, Department of Cardiology, University Hospital Jean Minjoz, Besanc¸on, France; J.C. Nicolau, Acute Coronary Disease Unit, Heart Institute, University of Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil. G. L. Plosker (&) Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand e-mail: [email protected]

twice daily co-administered with aspirin alone or aspirin plus either clopidogrel or ticlopidine in patients with a recent ACS. Rivaroxaban in patients with a recent acute coronary syndrome (ACS): a summary Rivaroxaban is an orally administered anticoagulant that acts by directly inhibiting factor Xa In many countries, rivaroxaban is approved for reducing the risk of stroke in patients with atrial fibrillation and for the treatment and prevention of venous thromboembolism, for example after hip or knee replacement surgery In the EU, a low dosage of rivaroxaban (2.5 mg twice daily), co-administered with aspirin or aspirin plus either clopidogrel or ticlopidine, is now approved to prevent atherothrombotic events after a recent ACS in patients with elevated biomarkers In patients with a recent ACS, rivaroxaban (coadministered with aspirin alone or aspirin plus clopidogrel or ticlopidine) reduces the risk of death from cardiovascular causes, myocardial infarction or stroke (the primary composite endpoint in the ATLAS ACS 2-TIMI 51 trial) Rivaroxaban 2.5 mg twice daily is also associated with a reduction in all-cause and cardiovascular mortality in patients with ACS and has a more optimal risk-benefit profile than 5 mg twice daily, as shown in the ATLAS ACS 2-TIMI 51 trial Although rivaroxaban 2.5 mg twice daily increases the risk of major bleeding and intracranial haemorrhage in patients with an ACS, it does not increase the risk of fatal bleeding

452

1 Introduction Patients who experience an acute coronary syndrome (ACS), which includes ST-segment elevation myocardial infarction (STEMI), non-STEMI and unstable angina [1– 3], are at risk of having recurrent cardiovascular events even when receiving dual antiplatelet therapy with aspirin and a thienopyridine [4]. With the recent introduction of newer antiplatelet agents, current treatment guidelines for ACS (e.g. in Europe) now recommend aspirin plus either ticagrelor or prasugrel as standard dual antiplatelet maintenance therapy [5], although the extent to which these newer antiplatelet agents have replaced older thienopyridines such as clopidogrel for ACS in clinical practice is unclear. The addition of warfarin to aspirin has been shown to improve cardiovascular outcomes in patients with ACS [6, 7], but the risk of bleeding, the need for frequent monitoring (e.g. international normalized ratio; INR) and the potential for multiple drug interactions with long-term warfarin therapy have limited its use in this population. Similarly, the addition of the direct thrombin inhibitor ximelagatran to aspirin also demonstrated benefits as secondary prophylaxis after myocardial infarction (MI) [8], although development of ximelagatran was discontinued because of liver toxicity [9]. Therefore, it has been suggested that there could be an important role for triple therapy using a newer anticoagulant in addition to background dual antiplatelet therapy in ACS patients [4, 10]. A central aspect of the rationale for including a newer anticoagulant in the treatment of ACS is that thrombin levels are elevated in patients admitted to hospital for ACS, and increased thrombin generation persists for C6 months after the initial event [11, 12]. Thus, the addition of an agent that directly inhibits either thrombin or factor Xa may have the potential to lower the risk of recurrent ischaemic cardiovascular events in ACS [13]. The oral anticoagulant rivaroxaban (XareltoÒ) is a direct inhibitor of factor Xa, a serine protease that initiates the final common pathway of the coagulation cascade to form thrombin [14–16]. As with other newer oral anticoagulants (e.g. dabigatran and apixaban), an important advantage of rivaroxaban over warfarin is that there is no need for routine monitoring of INR, in part because of its predictable pharmacodynamic and pharmacokinetic profile [2, 17]. However, phase II or III trials with dabigatran [18] and apixaban [19] have shown poor risk-benefit ratios in patients with ACS (see Sect. 7). In contrast, findings of the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial [20] (see Sect. 4) demonstrated a more

G. L. Plosker

favourable risk-benefit ratio with a low dosage of rivaroxaban (2.5 mg twice daily) and led to its approval for use in ACS in the EU [15], although rivaroxaban is not approved for ACS in the USA. Rivaroxaban (at higher dosages) is also approved in many countries (e.g. the EU [21, 22] and USA [23]) to reduce the risk of stroke in patients with nonvalvular atrial fibrillation, to prevent venous thromboembolism after total hip or knee replacement surgery, for the treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) and for the prevention of recurrent DVT or PE; however, these indications are outside of the scope of the current review. This article provides an overview of the pharmacology of rivaroxaban and focuses on its use in ACS as per EU labelling [15]. 2 Pharmacodynamic Properties Rivaroxaban inhibits thrombin formation and the development of thrombi by directly inhibiting factor Xa, thereby preventing the conversion of prothrombin to thrombin and interrupting the terminal common pathway of the blood coagulation cascade [14–16]. In vitro enzyme assay studies showed that rivaroxaban competitively inhibited human factor Xa (inhibitory constant [Ki] 0.4 nmol/L) with[10,000-fold greater selectivity than for related serine proteases such as thrombin and factors VIIa, IXa and XIa [14]. Orally administered rivaroxaban demonstrated dosedependent effects on factor Xa inhibition, thrombin formation and prolongation of prothrombin time (PT), but had no significant effect on bleeding times, in rat and rabbit models of venous and arterial thrombosis [14]. In humans, rivaroxaban also dose-dependently inhibited factor Xa and prolonged PT and activated partial thromboplastin time (aPTT) in healthy adult volunteers [24–26] and in patients after total hip or knee replacement surgery [27, 28]. The studies in patients undergoing major orthopaedic surgery also showed that PT values correlated with plasma rivaroxaban concentrations, suggesting a close relationship between the pharmacodynamic and pharmacokinetic properties of the drug [27, 28]. In a porcine model of stent thrombosis, intravenous rivaroxaban 0.11, 0.33 and 1.0 lg/kg/min dose-dependently reduced stent thrombus weight by up to 66 % compared with vehicle (p \ 0.05 for all doses) [29]. When rivaroxaban was used together with dual antiplatelet therapy (aspirin and clopidogrel), stent thrombus formation was almost completely abolished, with a 98 % decrease in stent thrombus weight at the highest dose of rivaroxaban. These findings are consistent with those reported in the ATLAS ACS 2-TIMI 51 study following stent deployment in patients with ACS (see Sect. 4).

Rivaroxaban in ACS: A Review

Also supporting clinical findings in patients with ACS are results of a randomised crossover (rivaroxaban 5, 10 or 20 mg with or without aspirin) and parallel-group (compared with aspirin plus clopidogrel) study in 51 healthy volunteers, which showed that rivaroxaban dose-dependently inhibited ex vivo thrombus formation under low and high shear rates, representing conditions in the venous system and stenosed arteries, respectively [30]. Concurrent administration of aspirin with low-dose rivaroxaban had an additive antithrombotic effect in this study. Due to its predictable pharmacokinetics and pharmacodynamics, routine coagulation monitoring with rivaroxaban is not required [15]. If measurement of rivaroxaban exposure is required in special situations, such as suspected overdose or other emergencies, both prothrombin time (using a sensitive agent such as Neoplastin Plus) and antifactor Xa chromogenic assays have been identified as potential assays for assessing plasma rivaroxaban concentrations using validated rivaroxaban calibrators and controls [15, 31]. At this time, the quantitative anti-factor Xa assay may be the most reliable, although it is not widely available in clinical practice. Results of various pharmacodynamic drug interaction studies in healthy volunteers found no clinically relevant effect on bleeding times when naproxen [32] or aspirin [33] were coadministered with rivaroxaban compared with rivaroxaban alone, although concomitant administration of clopidogrel and rivaroxaban increased bleeding time by 3.8-fold from baseline compared with an increase of 1.1-fold from baseline with rivaroxaban alone (p-value not reported) [34].

3 Pharmacokinetic Properties This section provides a brief overview of the pharmacokinetic properties of rivaroxaban, including data in patients with ACS. Recent reviews that include more detailed information on the pharmacokinetics of rivaroxaban are also available [35–37]. 3.1 General Pharmacokinetic Profile Following oral single-dose administration of rivaroxaban 10 mg, peak plasma drug concentration (Cmax) is achieved in 2–4 h and oral bioavailability is 80–100 % [15, 24]; neither Cmax nor area under the plasma concentration-time curve (AUC) is affected by food intake at dosages of B10 mg, and rivaroxaban may be taken without regard to meals when used at the recommended oral dosage of 2.5 mg twice daily in ACS [15, 38]. Rivaroxaban has a volume of distribution at steady state of &50 L [15, 26] and is &92–95 % bound to plasma protein, primarily albumin [15].

453

Approximately one-third of an orally administered dose of rivaroxaban is eliminated unchanged in the urine (primarily via active tubular secretion [35]) and two-thirds is metabolized in the liver, half of which is then eliminated as metabolites in the urine and the other half being eliminated as metabolites in the faeces [15, 39]. Metabolic degradation of rivaroxaban is mediated by cytochrome P450 (CYP) 3A4 and 2J2 isoenzymes, as well as CYP-independent mechanisms, and there are no active metabolites [15, 39]. Rivaroxaban is not an inhibitor or inducer of CYP isoenzymes [36]. Rivaroxaban is also a substrate for, but not an inhibitor or inducer of, the transporter protein P-glycoprotein [15, 36, 40]. The systemic clearance of rivaroxaban is &10 L/h [15] and its terminal elimination half-life (t‘) is 5–9 h in younger adults (20–45 years of age) [25], but is prolonged to 11–13 h in older individuals (60–76 years of age) [41]. There were no clinically relevant effects of gender, age, race or bodyweight on the pharmacokinetics of rivaroxaban in phase I trials and no dosage adjustments of rivaroxaban are required in patients with ACS on the basis of these parameters [15]. 3.2 In Patients with Acute Coronary Syndromes The pharmacokinetics and pharmacodynamics of rivaroxaban in patients with ACS were evaluated in a population pharmacokinetic model [42] developed using data from 2,290 patients who participated in the phase II ATLAS ACS-TIMI 46 trial (see Sect. 4.1) and received total daily dosages of rivaroxaban 5–20 mg. A near-linear relationship was demonstrated between plasma rivaroxaban concentrations and PT (the primary pharmacodynamic endpoint of the study), with low interindividual variability. The effect of age, renal function and bodyweight on exposure to rivaroxaban in patients with ACS was similar to that observed in earlier phase I studies (Sect. 3.1). Moreover, the estimated pharmacokinetic and pharmacodynamic parameters in patients with ACS were similar to those in patients treated with rivaroxaban for other approved indications, suggesting a predictable and consistent anticoagulant effect across patient populations [42]. Specific findings from the analysis related to drug exposure and the influence of covariates (e.g. renal function) are presented in Table 1. Additional data from the analysis included an estimated oral absorption rate of 1.24 h-1 (coefficient of variation [CV] 139 %), an apparent clearance of 6.48 L/h (CV 31 %) and a volume of distribution of 57.9 L (CV 10 %) [42]. Median predicted pharmacokinetic parameters have also been estimated for rivaroxaban 2.5 mg twice daily (the approved regimen in ACS) on the basis of population pharmacokinetic data for rivaroxaban in the prevention of

454

G. L. Plosker

Table 1 Influence of covariates on simulated steady-state exposure for rivaroxaban 2.5 mg twice daily in patients with acute coronary syndromes (median values and 5th to 95th percentiles are reported) Covariate

AUC (ng
h/mL)

Cmax (ng/mL)

Cmin (ng/mL)

Renal function CLCR \50 mL/min

542 (295–865)

63.3 (38.9–90.3)

27.9 (8.5–53.3)

CLCR 50 to \80 mL/min

426 (221–653)

51.0 (31.1–72.1)

19.7 (6.2–38.2)

CLCR C80 mL/min

361 (209–589)

44.0 (27.6–66.2)

16.4 (6.0–33.5)

\50 years

328 (183–527)

39.9 (23.9–56.9)

14.0 (5.2–30.1)

50–75 years [75 years

397 (226–654) 469 (277–901)

48.0 (30.3–72.0) 51.3 (38.9–92.9)

18.3 (6.5–38.0) 22.6 (7.7–49.9)

\53 kg

394 (215–671)

50.4 (31.2–77.4)

16.8 (5.3–36.4)

53 to \66 kg

373 (210–630)

45.1 (27.7–68.0)

17.0 (6.2–37.4)

C66 kg

365 (216–588)

43.4 (28.1–63.4)

17.5 (6.7–34.9)

Age

Lean body mass

Data from a population pharmacokinetic model developed using pharmacokinetic samples from 2,290 patients in the phase II ATLAS ACS-TIMI 46 trial (see Sect. 4.1 for study details) [43] AUC area under the plasma drug concentration-time curve, CLCR creatinine clearance, Cmax peak plasma drug concentration, Cmin trough plasma drug concentration

venous thromboembolism in patients undergoing total hip replacement [35]. When compared with once-daily administration, the twice-daily regimen was associated with lower Cmax and higher trough plasma drug concentrations (Cmin) [35], a finding also noted in the phase II ATLAS ACS-TIMI 46 trial [43]. 3.3 In Special Patient Populations As noted in Sect. 3.1, about one-third of a rivaroxaban dose is eliminated unchanged in the urine. Therefore, a marked reduction in renal function may affect the pharmacokinetics and pharmacodynamic effects of rivaroxaban, as was shown in a phase I study with rivaroxaban 10 mg once daily [44]. Compared with healthy volunteers with normal renal function, subjects with mild (creatinine clearance [CLCR] 50–79 mL/min), moderate (CLCR 30–49 mL/min) or severe (CLCR 15–29 mL/min) renal impairment had increased rivaroxaban AUC values by 44, 52 and 64 %, respectively [44]. The impact of renal impairment on the pharmacodynamic effects of rivaroxaban, in terms of the overall inhibition of factor Xa activity and prolongation of PT, was even more pronounced [15, 44]. In patients with ACS who had mild or moderate renal impairment and received rivaroxaban 2.5 mg twice daily in the ATLAS ACS-TIMI 46 study, AUC values were increased by 18 and 50 %, respectively, compared with those who had normal renal function [42]. The EU summary of product characteristics (SPC) states that rivaroxaban is not recommended for patients with CLCR \15 mL/min and the drug should be used with caution in patients with CLCR values between 15 and

29 mL/min; dosage adjustments for rivaroxaban 2.5 mg twice daily are not necessary in patients with mild or moderate renal impairment [15]. The majority of a rivaroxaban dose is metabolized by the liver (Sect. 3.1). A pharmacokinetic study in subjects with mild or moderate (Child Pugh A or B) hepatic impairment showed a 2.3-fold increase in AUC values for individuals with moderate disease compared with healthy subjects, and there was a trend toward greater factor Xa inhibition and prolonged PT [45]. Therefore, rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with moderate or severe (Child Pugh B or C) hepatic impairment [15]. 3.4 Drug Interactions Pharmacokinetic drug interactions between rivaroxaban and aspirin [33], clopidogrel [34], naproxen [32], enoxaparin sodium [15, 46] or warfarin [15] were not observed in randomized studies in healthy volunteers, although co-administration of rivaroxaban with agents that interfere with platelet function and homeostasis may result in more pronounced pharmacodynamic effects [15, 30]. The EU SPC advises caution when rivaroxaban is used together with aspirin, clopidogrel or nonsteroidal anti-inflammatory drugs, although rivaroxaban is usually used together with aspirin and clopidogrel in the setting of ACS [15]. The EU SPC also states that the concurrent use of rivaroxaban and other anticoagulants, such as enoxaparin sodium or warfarin, should be avoided (except when transitioning from one anticoagulant to another) [15].

Rivaroxaban in ACS: A Review

Rivaroxaban is a substrate for CYP3A4 isoenzymes and P-glycoprotein (see Sect. 3.1), and the potential for pharmacokinetic drug interactions between rivaroxaban and concomitantly administered inhibitors or inducers of CYP3A4 and/or P-glycoprotein was assessed during the clinical development of rivaroxaban [15, 36]. Clinically relevant increases in plasma rivaroxaban concentrations were observed only when rivaroxaban was administered concurrently with strong inhibitors of both CYP3A4 and P-glycoprotein, such as azole antimycotics (e.g. ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors (e.g. ritonavir); concomitant use of such agents with rivaroxaban is not recommended [15, 36]. When rivaroxaban was co-administered with clarithromycin (a strong CYP3A4 inhibitor and moderate P-glycoprotein inhibitor), erythromycin (a moderate inhibitor of CYP3A4 and P-glycoprotein) or fluconazole (a moderate CYP3A4 inhibitor) there was a less pronounced increase in rivaroxaban exposure that was deemed to be not clinically relevant [15]. Concomitant administration of rivaroxaban and the strong CYP3A4 inducer rifampicin (rifampin) reduced the mean rivaroxaban AUC by &50 % (with parallel reduction in pharmacodynamic effects). Caution is advised if using rivaroxaban with rifampicin or other potent inducers of CYP3A4 (e.g. phenytoin, carbamazepine, phenobarbital, St John’s Wort) [15]. The pharmacokinetic properties of rivaroxaban were not affected by concomitant administration of antacid (aluminium-magnesium hydroxide) [38], ranitidine [38] or omeprazole [47] in healthy volunteers.

4 Therapeutic Efficacy The therapeutic efficacy of rivaroxaban in the prevention of atherothrombotic events in adult patients after an ACS was demonstrated in the phase III ATLAS ACS 2-TIMI 51 trial (Sect. 4.2), which is the focus of this section. Various subgroup and other analyses from the study have also been reported and are discussed in Sect. 4.3. Findings from an earlier phase II trial with rivaroxaban in ACS (ATLAS ACS-TIMI 46), which led to the phase III trial, are also briefly discussed in Sect. 4.1. 4.1 Phase II ATLAS ACS-TIMI 46 Trial The ATLAS ACS-TIMI 46 trial was a randomized, doubleblind, dose-escalation study conducted at 297 sites in 27 countries and included 3491 patients with a recent ACS [43]. To be eligible for inclusion in the trial, patients had to have symptoms suggestive of an ACS that lasted C10 min at rest and either a diagnosis of STEMI or a diagnosis of non-STEMI or unstable angina with one of the following:

455

(i) elevated cardiac enzyme markers, (ii) C1 mm ST-segment deviation or (iii) TIMI risk score of C3. Major exclusion criteria included a history of intracranial haemorrhage, haemoglobin \10 g/dL or platelet count \90,000 per lL of blood. Randomization of patients was stratified according to the antiplatelet therapy (low-dose aspirin alone [stratum 1; n = 761] or low-dose aspirin plus either clopidogrel or ticlopidine [stratum 2; n = 2,730]) intended by the clinical investigator. An important strength of ATLAS ACS-TIMI 46 trial is that it evaluated a wide range of rivaroxaban dosage regimens [43]. In each stratum, patients were randomized 1–7 days after the index event and stabilization in a 1:1:1 ratio to receive rivaroxaban 5–20 mg/day administered once daily, the same total daily dosage of rivaroxaban administered twice daily or placebo for a planned duration of 6 months. In stratum 1, three dose tiers of rivaroxaban were tested (5, 10 and 20 mg), whereas four dose tiers (5, 10, 15 and 20 mg) were evaluated in stratum 2. The primary efficacy outcome was the time to first episode of death, MI, stroke or severe recurrent ischaemia requiring revascularization up to 6 months from enrolment [43]. The main secondary efficacy outcome was the same as the primary composite outcome, but excluded severe recurrent ischaemia requiring revascularization. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor or requiring medical attention). The primary analysis for efficacy was in the intent-to-treat (ITT) population (i.e. randomized patients regardless of whether they received study treatment), whereas the primary safety analysis included randomized patients who received at least one dose of study drug. Baseline characteristics were well matched between treatment groups, although heterogeneity was noted between strata 1 and 2. Overall, results of the phase II trial showed that, compared with placebo, rivaroxaban was associated with a trend towards a reduction in the risk of the primary composite efficacy endpoint, and there was a dose-dependent increase in bleeding events with rivaroxaban [43]. Across the entire ITT population (both strata combined), the incidence of the primary efficacy endpoint was 5.6 % for rivaroxaban (all regimens combined) compared with 7.0 % for placebo (hazard ratio [HR] 0.79; 95 % CI 0.60–1.05; p = 0.10). However, rivaroxaban significantly reduced the main secondary efficacy outcome compared with placebo in the overall cohort (3.9 vs. 5.5 %; HR 0.69; 95 % CI 0.50–0.96; p = 0.027). When considering the individual components of the primary composite efficacy outcome, the point estimates for death, MI and stroke, but not severe recurrent ischaemia requiring revascularization, favoured rivaroxaban [43]. In terms of the primary efficacy outcome for both strata combined, HR values were generally most favourable with the two lowest doses of rivaroxaban

456

administered in twice daily regimens. For example, at a total daily dosage of 5 mg/day, HRs for rivaroxaban compared with placebo for the primary efficacy endpoint were 1.01 (95 % CI 0.56–1.83) when administered once daily and 0.60 (95 % CI 0.29–1.25) when given twice daily; corresponding values for 10 mg/day were 0.77 (95 % CI 0.50–1.20) and 0.63 (95 % CI 0.39–1.01), and corresponding values for 20 mg/day were 0.69 (95 % CI 0.40–1.20) and 0.87 (95 % CI 0.53–1.44). Compared with placebo, HRs for clinically significant bleeding were 2.21 (95 % CI 1.25–3.91) for a total daily dose of 5 mg, 3.35 (95 % CI 2.31–4.87) for 10 mg, 3.60 (95 % CI 2.32–5.58) for 15 mg and 5.06 (95 % CI 3.45–7.42) for 20 mg [43]. When clinical efficacy was considered together with the dose-dependent increase in clinically significant bleeding (p \ 0.001), this led to the selection of rivaroxaban 2.5 and 5 mg twice daily for evaluation in the phase III trial [2, 43]. 4.2 Phase III ATLAS ACS 2-TIMI 51 Trial The ATLAS ACS 2-TIMI 51 trial was a randomized, double-blind, phase III study conducted at 766 sites in 44 countries and included 15,526 patients with a recent ACS [20]. Patients were eligible for inclusion in the study if they were C18 years of age, presented with symptoms suggestive of an ACS and were diagnosed with STEMI, nonSTEMI or unstable angina. In addition to the index event, patients \55 years of age were required to have either diabetes mellitus or a previous MI. Enrolment occurred within 7 days of hospital admission for an ACS and all patients had to be stabilized prior to enrolment, including the completion of initial management strategies, such as revascularization procedures. Key exclusion criteria were a history of intracranial haemorrhage, haemoglobin \10 g/ dL, platelet count\90,000 per lL of blood, CLCR \30 mL/ min, clinically significant gastrointestinal bleeding within the previous year, and previous ischaemic stroke or transient ischaemic attack (TIA) in patients who were taking both aspirin and a thienopyridine. Patients were randomized in a 1:1:1 ratio to receive rivaroxaban 2.5 mg twice daily (n = 5,174), rivaroxaban 5 mg twice daily (n = 5,176) or placebo (n = 5,176) in addition to standard therapy, which included low-dose aspirin (75–100 mg/day [2]), for a maximum follow-up period of 31 months [20]. Randomization was stratified on the basis of the clinical investigators’ intended use of a thienopyridine (clopidogrel or ticlopidine) according to national or local guidelines. The primary efficacy endpoint was a composite of death from cardiovascular causes, MI or stroke; the secondary efficacy endpoint was death from any cause, MI or stroke. TIMI major bleeding not related to coronary artery bypass grafting (CABG) was the primary safety endpoint (see Sect. 5). Efficacy analyses were

G. L. Plosker

conducted using a modified ITT (mITT) approach, which included randomized patients and the endpoint events that occurred after randomization and no later than the completion of the treatment phase of the study, 30 days after early permanent discontinuation of the study drug, or 30 days after randomization for patients who did not receive a study drug. The statistical analysis was prespecified to occur between the combined-dose group for rivaroxaban and placebo, stratified according to the investigator’s intention to use a thienopyridine [20]. If the difference significantly favoured rivaroxaban then each of the two dosage regimens of rivaroxaban was simultaneously compared with placebo using a similar stratified approach. A description of and results from the safety analysis of the study are presented in Sect. 5. Baseline characteristics of patients were generally well matched between study groups, including mean age (61.5–61.9 years) and the proportion of patients with a history of hypertension (67.1–67.6 %), hypercholesterolaemia (48.2–49.1 %), diabetes (31.8–32.3 %) or previous MI (26.3–27.3 %) [20]. Across the treatment groups, the proportion of patients with STEMI, non-STEMI and unstable angina as the index event was 50.3, 25.6 and 24.0 %, respectively, and a thienopyridine was intended for use in 93 % of patients (stratum 2) [20]; clopidogrel was selected as the thienopyridine in the overwhelming majority ([99 %) of cases [48]. The mean duration of treatment with a study drug was 13.1 months and the proportion of patients who discontinued study treatment prematurely was 26.9 % with rivaroxaban 2.5 mg twice daily, 29.4 % with rivaroxaban 5 mg twice daily and 26.4 % in the placebo group [20]. Results showed that rivaroxaban significantly reduced the rate of the primary composite efficacy endpoint compared with placebo, and this beneficial effect was observed with each of the rivaroxaban regimens and when data for rivaroxaban were combined (Table 2) [20]. For the combined-dose analysis, 8.9 % of patients who were randomized to rivaroxaban experienced a primary endpoint event compared with 10.7 % of those randomized to placebo (HR 0.84; 95 % CI 0.74–0.96; p = 0.008). A primary endpoint event occurred in 9.1 % of patients randomized to rivaroxaban 2.5 mg twice daily compared with 10.7 % of placebo recipients (HR 0.84; 95 % CI 0.72–0.97; p = 0.02). Corresponding values for the comparison between rivaroxaban 5 mg twice daily and placebo were 8.8 vs. 10.7 % (HR 0.85; 95 % CI 0.73–0.98; p = 0.03). For the individual components of the primary efficacy endpoint, HR values were 0.80 (p = 0.04) for death from cardiovascular causes, 0.85 (p = 0.047) for MI and 1.24 (not significant) for stroke when rivaroxaban was compared with placebo in the combined-dose analysis.

Rivaroxaban in ACS: A Review

457

Table 2 Key efficacy endpoints from the phase III ATLAS ACS 2-TIMI 51 trial in patients with a recent acute coronary syndrome [20] Study group (no. of pts)

Efficacy endpoint (% of pts with endpoint event) [hazard ratio; 95 % CI; p-value vs. placebo] Primary endpointa

Secondary endpointb

Death from CV causes

Death from any cause

RIV 2.5 mg bid (n = 5,114)

9.1 [0.84; 0.72–0.97; p = 0.02]

9.3 [0.83; 0.72–0.97; p = 0.02]

2.7 [0.66; 0.51–0.86; p = 0.002]

2.9 [0.68; 0.53–0.87; p = 0.002]

RIV 5 mg bid (n = 5,115)

8.8 [0.85; 0.73–0.98; p = 0.03]

9.1 [0.84; 0.73–0.98; p = 0.02]

4.0 [0.94; 0.75–1.20; p = 0.63]

4.4 [0.95; 0.76–1.19; p = 0.66]

RIV combined (n = 10,229)

8.9 [0.84; 0.74–0.96; p = 0.008]

9.2 [0.84; 0.74–0.95; p = 0.006]

3.3 [0.80; 0.65–0.99; p = 0.04]

3.7 [0.81; 0.66–1.00; p = 0.04]

Placebo (n = 5,113)

10.7

11.0

4.1

4.5

bid twice daily, CV cardiovascular, MI myocardial infarction, pts patients, RIV rivaroxaban a b

Composite of death from CV causes, MI or stroke Composite of death from any cause, MI or stroke

There were also statistically significant reductions in the rate of the secondary composite efficacy endpoint with rivaroxaban compared with placebo (Table 2) [20]. For the combined analysis of both regimens, a secondary endpoint event occurred in 9.2 % of patients randomized to rivaroxaban compared with 11.0 % of those in the placebo group (HR 0.84; 95 % CI 0.74–0.95; p = 0.006). A secondary endpoint event occurred in 9.3 % of patients randomized to rivaroxaban 2.5 mg twice daily compared with 11.0 % of placebo recipients (HR 0.83; 95 % CI 0.72–0.97; p = 0.02). Corresponding values for the comparison between rivaroxaban 5 mg twice daily and placebo were 9.1 vs. 11.0 % (HR 0.84; 95 % CI 0.73–0.98; p = 0.02). Rivaroxaban 2.5 mg twice daily significantly reduced the risk of death from cardiovascular (2.7 vs. 4.1 %; HR 0.66; 95 % CI 0.51–0.86; p = 0.002) or any (2.9 vs. 4.5 %; HR 0.68; 95 % CI 0.53–0.87; p = 0.002) cause compared with placebo (Table 2) [20]. Rivaroxaban 5 mg twice daily was not significantly different from placebo for these mortality endpoints and differed significantly from rivaroxaban 2.5 mg twice daily (p = 0.009 for both comparisons). Interestingly, there was a statistically significant reduction in MI with rivaroxaban 5 mg twice daily (4.9 vs. 6.6 %; HR 0.79; 95 % CI 0.65–0.97; p = 0.02), but not with rivaroxaban 2.5 mg twice daily (6.1 vs. 6.6 %; HR 0.90; 95 % CI 0.75–1.09) when compared with placebo. Rivaroxaban 2.5 mg twice daily significantly reduced the rate of stent thrombosis compared with placebo (2.2 vs. 2.9 %; HR 0.65; 95 % CI 0.45–0.94; p = 0.02) and similar findings were reported for the combined-dose analysis (2.3 vs. 2.9 %; HR 0.69; 95 % CI 0.51–0.93; p = 0.02). However, the difference between rivaroxaban 5 mg twice daily and placebo only approached statistical significance (p = 0.08) for this endpoint in the mITT analysis (but significantly [p = 0.04] favoured rivaroxaban 5 mg twice daily over placebo in the ITT analysis).

Efficacy results from the ITT analyses were generally consistent with those reported in the prespecified mITT analyses [20]. In addition, the reduction in the rate of the primary composite efficacy endpoint with rivaroxaban compared with placebo was consistent across subgroups, other than for patients with a history of stroke or TIA [20] (see also Sect. 4.3). Subgroups included in the analysis for risks of the primary efficacy endpoint included antiplatelet therapy (aspirin plus thienopyridine or aspirin alone), age (\65 or C65 years), sex (male or female), weight (\60, C60 to \90 or C90 kg), renal function (CLCR \50 or C50 mL/min), previous MI (yes or no), previous stroke or TIA (yes or no), diabetes mellitus (yes or no), index event (STEMI, non-STEMI or unstable angina) and region (various) [20]. Most, but not all, of these subgroups were prespecified in an earlier report of the study design details [2]. 4.3 Subgroup and Other Analyses of ATLAS ACS 2-TIMI 51 Trial Since each of the rivaroxaban dosage regimens evaluated in the phase III trial significantly reduced the rate of primary endpoint events compared with placebo (Sect. 4.2), a further evaluation of the two regimens was deemed important [49]. The detailed analysis of the two active treatment arms of ATLAS ACS 2-TIMI 51 showed a more favourable balance of efficacy (most notably all-cause death) and safety (most notably fatal bleeding) with rivaroxaban 2.5 mg twice daily than with the 5 mg twice daily regimen [49]. Although there were no statistically significant differences between the active treatment groups for the primary composite endpoint (9.1 vs. 8.8 %; p = 0.89), MI (6.1 vs. 4.9 %; p = 0.23), stroke (1.4 vs. 1.7 %; p = 0.38) or stent thrombosis (2.2 vs. 2.3 %; p = 0.59), the lower dosage regimen had more favourable results for

458

cardiovascular death (2.7 vs. 4.0 %; p = 0.009) and allcause death (2.9 vs. 4.4 %; p = 0.009). With respect to safety, rivaroxaban 2.5 mg twice daily had significantly lower rates of TIMI non-CABG major or minor bleeding (2.7 vs. 4.0 %; p = 0.021), fatal bleeding (0.1 vs. 0.4 %; p = 0.044), TIMI bleeding requiring medical attention (12.9 vs. 16.2 %; p \ 0.001) and TIMI minor bleeding (0.9 vs. 1.6 %; p = 0.046) than rivaroxaban 5 mg twice daily. Although the between-group differences for intracranial haemorrhage and for TIMI non-CABG major bleeding did not reach statistical significance, there was a general trend towards more favourable results (i.e. less bleeding) with the lower dosage regimen [49]. These overall findings are supported by a Bayesian analysis of data from ATLAS ACS 2-TIMI 51, which also showed a greater net clinical benefit with the lower dosage regimen of rivaroxaban (reported as an abstract) [50]. The main findings of ATLAS ACS 2-TIMI 51 were echoed in an analysis that included events only in patients who received dual antiplatelet therapy throughout the study period (reported as an abstract) [51]. The analysis included 14,473 patients and 84 % of the events included in the original data set. In this analysis, rivaroxaban significantly reduced the rate of the primary composite efficacy endpoint compared with placebo (8.6 vs. 11.9 %; HR 0.83; 95 % CI 0.72–0.95; p = 0.007), and this beneficial effect was observed with both the 2.5 (9.3 vs. 11.9 %; p = 0.031) and 5 mg (7.9 vs. 11.9 %; p = 0.014) twice daily regimens. Rivaroxaban 2.5 mg twice daily, but not the higher dosage regimen, also significantly reduced cardiovascular death (2.1 vs. 3.6 %; p = 0.005) and all-cause death (2.4 vs. 4.0 %; p = 0.004) compared with placebo. Another subgroup analysis focused on patients with STEMI as the index event in ATLAS ACS 2-TIMI 51 (n = 7,817) and showed that rivaroxaban reduced cardiovascular events in this population, an effect that emerged within the first month of treatment [52]. Using a similar mITT approach as was used in the original analysis, rivaroxaban reduced the rate of the primary composite efficacy endpoint compared with placebo, although the betweengroup difference did not achieve statistical significance (8.3 vs. 9.7 %; HR 0.85; 95 % CI 0.70–1.03; p = 0.09); however, in the ITT analysis the difference was statistically significant (8.4 vs. 10.6 %; p = 0.019). Rivaroxaban 2.5 mg twice daily significantly reduced cardiovascular death compared with placebo in the mITT (2.2 vs. 3.9 %; p = 0.006) and ITT (2.5 vs. 4.2 %; p = 0.006) analyses; a similar effect was not observed with rivaroxaban 5 mg twice daily. In the combined-dose analysis, rivaroxaban increased the risk of non-CABG TIMI major bleeding (2.2 vs. 0.6 %; p \ 0.001) and intracranial haemorrhage (0.6 vs. 0.1 %; p = 0.015), but not fatal bleeding (0.2 vs. 0.1 %; p = 0.51), compared with placebo. For rivaroxaban

G. L. Plosker

2.5 mg twice daily compared with placebo, the event rates were 1.7 vs. 0.6 % (p \ 0.001) for non-CABG TIMI major bleeding, 0.4 vs. 0.1 % (p = 0.031) for intracranial haemorrhage and 0.04 vs. 0.1 % (p = 0.33) for fatal bleeding; corresponding results for rivaroxaban 5 mg twice daily compared with placebo were 2.7 vs. 0.6 % (p \ 0.001), 0.8 vs. 0.1 % (p = 0.008) and 0.4 vs. 0.1 % (p = 0.12). Although limited data are available regarding other subgroups according to the index event in ATLAS ACS 2-TIMI 51, the benefit of rivaroxaban was consistently demonstrated whether subjects had STEMI, non-STEMI or unstable angina as their index event [48]. Nevertheless, the approval of rivaroxaban for patients with ACS (in the EU) is restricted to those with elevated cardiac biomarkers (Sect. 6), which may limit the use of rivaroxaban in patients with unstable angina. It is also noteworthy that patients with non-STEMI were required to have elevated cardiac biomarkers for inclusion in the phase III trial [2, 48]. Moreover, 84 % of patients in stratum 2 (intended use of a thienopyridine) had elevated cardiac biomarkers [48]. A further analysis of data from ATLAS ACS 2-TIMI 51 focused on patients who had a stent placed before or at the time of the index event (n = 9,631) and showed statistically significant reductions in stent thrombosis with rivaroxaban 2.5 or 5 mg twice daily (pooled data for both regimens) [1.5 vs. 1.9 %; HR 0.65; p = 0.017] and rivaroxaban 2.5 mg twice daily (1.5 vs. 1.9 %; HR 0.61; p = 0.023), but not rivaroxaban 5 mg twice daily (1.5 vs. 1.9 %; HR 0.70; p = 0.089) compared with placebo [53]. Among stented patients who received dual antiplatelet therapy and rivaroxaban 2.5 mg twice daily, there was a statistically significant reduction in cardiovascular mortality compared with dual antiplatelet therapy plus placebo (HR 0.56; 95 % CI 0.35–0.89; p = 0.014). While outcomes consistently favoured rivaroxaban across most major subgroups of ATLAS ACS 2-TIMI 51, the exception was the relatively small proportion of patients who had a prior ischaemic stroke (1.8 % of subjects) or TIA (0.9 % of subjects); for this subgroup, outcomes tended to be better with placebo [48]. A prior ischaemic stroke or TIA was an exclusion criterion for stratum 2 (patients whose clinical investigator intended to use a thienopyridine in addition to aspirin), and patients with a prior haemorrhagic stroke were excluded completely from the trial. Thus, most of the subjects with a history of stroke or TIA were from stratum 1 (aspirin only). For both strata combined, the HR for the primary efficacy outcome comparing rivaroxaban 2.5 mg twice daily with placebo was 1.84 (95 % CI 0.82–4.01) among patients with a history of ischaemic stroke or TIA; for those without a prior ischaemic stroke or TIA the HR was 0.91 (95 % CI 0.69–0.94) [48].

Rivaroxaban in ACS: A Review

Rivaroxaban (pooled data for both dosage regimens) significantly reduced the incidence of spontaneous MI (4.4 vs. 5.7 %; HR 0.80; 95 % CI 0.67–0.95; p = 0.01), STEMI events (1.6 vs. 2.3 %; HR 0.73; 95 % CI 0.54–0.97; p = 0.03) and large MIs with peak biomarker elevations [10 times the upper limit of normal (1.7 vs. 2.4 %; HR 0.73; 95 % CI 0.55–0.96; p = 0.02) compared with placebo (reported as an abstract) [54]. Rivaroxaban also reduced the risk of cardiovascular events regardless of concurrent use of omeprazole or esomeprazole in the ATLAS ACS 2-TIMI 51 stratum receiving background dual antiplatelet treatment including a thienopyridine (reported as an abstract plus poster) [55]. The study authors noted that previous pharmacodynamic drug interaction studies suggested that proton pump inhibitors (PPIs) may reduce the effects of concomitantly administered clopidogrel. However, in this subgroup analysis, which included &15 % of patients (n = 2,203) included in the ATLAS ACS 2-TIMI 51 trial, rivaroxaban (pooled data for both regimens) with background dual antiplatelet therapy reduced the risk of the primary composite endpoint compared with placebo regardless of concomitant PPI use. For patients who received a PPI, the HR was 0.68 (95 % CI 0.50–0.93), and corresponding values for those who did not receive a PPI were HR 0.86 (95 % CI 0.75–0.99).

5 Tolerability This section focuses on the safety (bleeding) endpoints from the ATLAS ACS 2-TIMI 51 trial [20]. In addition, Table 3 presents an overview of the general tolerability profile of rivaroxaban, including adverse events reported in C1 % of patients in any treatment group (rivaroxaban 2.5 mg twice daily, rivaroxaban 5 mg twice daily or placebo) in the ATLAS ACS 2-TIMI 51 trial [20]. The EU SPC also provides information on adverse events reported in other phase III trials with rivaroxaban (including various other indications and dosage regimens) [15]. The safety analysis included all randomized patients who received at least one dose of study medication; the primary safety endpoint was the incidence of non-CABG TIMI major bleeding, although a number of secondary bleeding outcomes were also evaluated [2, 20]. Results of the safety analysis from the ATLAS ACS 2-TIMI 51 trial showed that rivaroxaban significantly increased the risk of TIMI major bleeding not related to CABG compared with placebo (primary safety endpoint), but was not associated with an increased risk of fatal bleeding, which occurred in 0.1–0.4 % across all treatment groups [20]. Although this was the case in the combineddose analysis as well as for each of the rivaroxaban dosage

459 Table 3 General tolerability profile of rivaroxaban in the phase III ATLAS ACS 2-TIMI 51 trial [20] Adverse eventa

Alanine aminotransferase increased

Incidence (% of patients) Rivaroxaban 2.5 mg twice daily (n = 5,114)

Rivaroxaban 5 mg twice daily (n = 5,115)

Placebo (n = 5,113)

0.9

0.8

1.0

Atrial fibrillation

1.2

1.1

1.3

Cardiac failure

2.2

1.8

1.8

Cough

1.2

1.1

1.4

Chest pain

2.2

1.9

1.8

Dizziness

1.2

1.0

1.0

Dyspnoea

1.1

1.3

1.5

Hypertension

1.7

1.2

1.5

Nasopharyngitis

0.9

0.6

1.0

Non-cardiac chest pain

1.7

1.9

1.9

a

Reported in C1 % of patients in any treatment group

regimens [20], it is noteworthy that a detailed analysis of the two active treatment arms of ATLAS ACS 2-TIMI 51 (Sect. 4.3) showed a significantly higher rate of fatal bleeding among patients who received rivaroxaban 5 mg twice daily than among those who received rivaroxaban 2.5 mg twice daily [49]. Findings from the safety analysis of the main trial are summarized in Table 4, including definitions for TIMI major bleeding, TIMI minor bleeding and bleeding requiring medical attention. In the combined-dose analysis for the primary safety endpoint, 2.1 % of patients randomized to rivaroxaban experienced TIMI major bleeding not associated with CABG compared with 0.6 % of those randomized to placebo (HR 3.96; 95 % CI 2.46–6.38; p \ 0.001) [20]. The percentage of patients with this primary safety endpoint event was also significantly higher for each rivaroxaban regimen than with placebo (Table 4). For TIMI minor bleeding, TIMI bleeding requiring medical attention and intracranial haemorrhage, all comparisons showed significantly higher rates with rivaroxaban than with placebo, aside from the comparison between rivaroxaban 2.5 mg twice daily and placebo for TIMI minor bleeding (0.9 vs. 0.5 %; HR 1.62; 95 % CI 0.92–2.82; p = 0.09) [Table 4] [20]. Data for intracranial haemorrhage are noteworthy in that the incidence was 0.4 % with rivaroxaban 2.5 mg twice daily (p \ 0.05 vs. placebo), 0.7 % with rivaroxaban 5 mg twice daily (p \ 0.01 vs. placebo) and 0.2 % with placebo. Overall, the regimen of rivaroxaban 2.5 mg twice daily was associated with less bleeding than the higher dosage regimen [20]. Comparisons between these two groups

460

G. L. Plosker

Table 4 Safety endpoints from the phase III ATLAS ACS 2-TIMI 51 trial in patients with a recent acute coronary syndrome [20] Study group (no. of pts)

Safety endpoint (% of pts with endpoint event) [hazard ratio; 95 % CI] TIMI major bleeding not associated with CABGa

TIMI minor bleedingb

TIMI bleeding requiring medical attentionc

Intracranial haemorrhage

Fatal bleeding

RIV 2.5 mg bid (n = 5,114)

1.8 [3.46; 2.08–5.77]***

0.9 [1.62; 0.92–2.82]

12.9 [1.79; 1.55–2.07]***

0.4 [2.83; 1.02–7.86]*

0.1 [0.67; 0.24–1.89]

RIV 5 mg bid (n = 5,115) RIV combined (n = 10,229)

2.4 [4.47; 2.71–7.36]*** 2.1 [3.96; 2.46–6.38]***

1.6 [2.52; 1.50–4.24]***,  1.3 [2.07; 1.27–3.37]**

16.2 [2.39; 2.08–2.75]***,   14.5 [2.09; 1.83–2.38]***

0.7 [3.74; 1.39–10.07]** 0.6 [3.28; 1.28–8.42]**

0.4 [1.72; 0.75–3.92]  0.3 [1.19; 0.54–2.59]

Placebo (n = 5,113)

0.6

0.5

7.5

0.2

0.2

bid twice daily, CABG coronary artery bypass grafting, pts patients, RIV rivaroxaban, TIMI Thrombolysis in Myocardial Infarction * p \ 0.05, ** p \ 0.01, *** p \ 0.001 vs. placebo;

 

p \ 0.05,

  

p \ 0.001 vs. RIV 2.5 mg bid (favouring the lower dosage)

a

Primary safety endpoint; defined as any intracranial bleeding or clinically overt bleeding event that is associated with a decrease in haemoglobin of C5 g/dL or an absolute drop in haematocrit of C15 % [2]

b

Defined as any clinically overt bleeding event, including bleeding that is evident on imaging studies, that is associated with a decrease in haemoglobin that is C3 g/dL but is \5 g/dL from baseline haemoglobin value [2]

c

Defined as any bleeding event that requires medical treatment, surgical treatment or laboratory evaluation and does not meet criteria for TIMI major or TIMI minor bleeding event [2]

showed statistically significant differences favouring the lower dosage regimen for rates of TIMI minor bleeding (0.9 vs. 1.6 %; p = 0.046), TIMI bleeding requiring medical attention (12.9 vs. 16.2 %; p \ 0.001) and fatal bleeding (0.1 vs. 0.4 %; p = 0.04) [Table 4].

6 Dosage and Administration Rivaroxaban is approved in the EU for the prevention of atherothrombotic events in adult patients after an ACS with elevated cardiac biomarkers [15]. It is administered orally and, at the dosage used in ACS, may be taken without regard to food (see Sect. 3.1). The recommended dosage of rivaroxaban for this indication is 2.5 mg twice daily and it should be co-administered with either low-dose aspirin (75–100 mg once daily) alone or a combination of lowdose aspirin plus either clopidogrel 75 mg once daily or a standard daily dose of ticlopidine. Initiation of treatment should occur as soon as possible after stabilization of the ACS event (including revascularization procedures), but C24 h after hospitalization and at the time parenteral anticoagulation would normally be discontinued. Extending treatment duration beyond 1 year should be done on an individual basis. For patients with mild or moderate renal impairment, no dosage adjustment of rivaroxaban is necessary [15]. Rivaroxaban should be used with caution in patients with severe renal impairment (CLCR 15–29 mL/min), as plasma rivaroxaban concentrations are significantly increased (see Sect. 3.3). Rivaroxaban is not recommended in patients

with CLCR \15 mL/min. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhosis with Child Pugh B and C, are contraindications to rivaroxaban. Local prescribing information should be consulted for additional information on precautions, contraindications, use in special patient populations, drug interactions and converting patients from warfarin (or other vitamin K antagonists) or parenteral anticoagulants to rivaroxaban, or vice versa.

7 Place of Rivaroxaban in the Management of Acute Coronary Syndromes In patients with a recent ACS, rivaroxaban 2.5 mg twice daily co-administered with background antiplatelet therapy reduced the risk of death from cardiovascular causes, MI or stroke (the primary composite endpoint), as well as cardiovascular and all-cause mortality, in the ATLAS ACS 2-TIMI 51 trial (Sect. 4.2). Although there was an increased risk of major bleeding and intracranial haemorrhage in patients receiving rivaroxaban, there was not an increase in the risk of fatal bleeding (Sect. 5). These overall favourable findings with low-dose rivaroxaban are in contrast to unfavourable risk-benefit profiles of other novel oral anticoagulants, including the direct factor Xa inhibitor apixaban and the direct thrombin inhibitor dabigatran, as well as the protease-activatedreceptor 1 antagonist vorapaxar (an antiplatelet agent that inhibits thrombin-induced platelet aggregation), each co-

Rivaroxaban in ACS: A Review

461

Table 5 Randomized double-blind phase II [18] or III [19, 20, 56] studies in patients with a recent acute coronary syndrome in which newer oral anticoagulants rivaroxaban, apixaban or dabigatran, or the antiplatelet vorapaxar, was compared with placebo when added to standard therapy Reference (study acronym)

Regimen (no. of patients)a

Percentage of patients [hazard ratio; 95 % CI; p-value vs. placebo] Primary/main efficacy endpointb

Major safety endpointc

Alexander et al. [19] (APPRAISE-2)

API 5 mg bid (n = 3,705)

7.5 [0.95; 0.80–1.11; p = 0.51]

1.3 [2.59; 1.50–4.46; p = 0.001]

Placebo (n = 3,687)

7.9

0.5

Mega et al. [20] (ATLAS ACS 2-TIMI 51)

RIV 2.5 mg bid (n = 5,114) RIV 5 mg bid (n = 5,115)

9.1 [0.84; 0.72–0.97; p = 0.02] 8.8 [0.85; 0.73–0.98; p = 0.03]

1.8 [3.46; 2.08–5.77; p \ 0.001] 2.4 [4.47; 2.71–7.36; p \ 0.001]

RIV combined (n = 10,229)

8.9 [0.84; 0.74–0.96; p = 0.008]

2.1[3.96; 2.46–6.38; p \ 0.001]

Placebo (n = 5,113)

10.7

0.6

DAB 50 mg bid (n = 369)

4.6

3.5d

DAB 75 mg bid (n = 368)

4.9

4.3d

DAB 110 mg bid (n = 406)

3.0

7.9d

DAB 150 mg bid (n = 347)

3.5

7.8d

Placebo (n = 371)

3.8

2.2

Oldgren et al. [18]

Tricoci et al. [56] (TRACER)

e

VOR 2.5 mg/day (n = 6,473)

18.5 [0.92; 0.85–1.01; p = 0.07]

7.2 [1.35; 1.16–1.58; p \ 0.001]

Placebo (n = 6,471)

19.9

5.2

API apixaban, bid twice daily, CABG coronary artery bypass grafting, CV cardiovascular, DAB dabigatran, GUSTO Global Use of Strategies to Open Occluded Coronary Arteries; ISTH International Society of Thrombosis and Haemostasis; MI myocardial infarction, RIV rivaroxaban, TIMI Thrombolysis in Myocardial Infarction, VOR vorapaxar a

Number of patients evaluated for efficacy (in phase III trials) or safety (in phase II trial)

b

Primary/main composite endpoints for efficacy were as follows: Alexander et al. CV death, MI, ischaemic stroke (median follow-up 241 days; study terminated early after safety review); Mega et al. CV death, MI, stroke (median follow-up 13.1 months); Oldgren et al. CV death, MI, nonhaemorrhagic stroke (mean exposure 159–165 days); Tricoci et al. CV death, MI, stroke, recurrence of ischaemic event with hospitalization, urgent coronary revascularization (Kaplan–Meier 2-year rate; study terminated early [median follow-up 502 days] after safety review)

c

Major safety endpoints were as follows: Alexander et al. major bleeding (TIMI definition); Mega et al. major bleeding (TIMI definition) not associated with CABG; Oldgren et al. major or clinically relevant minor bleeding (ISTH definition); Tricoci et al. moderate or severe bleeding (GUSTO definition) [clinically significant TIMI bleeding was also a major safety endpoint in this study, but data are not shown in the table] d

p \ 0.001 for dose-related linear trend

e

Following a loading dose of 40 mg

administered with standard background antiplatelet therapy in patients with a recent ACS (Table 5). The phase III APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events 2) trial [19], in which patients were randomised to receive apixaban 5 mg twice daily or placebo, was terminated prematurely because of an increase in major bleeding events with apixaban in the absence of a significant reduction in recurrent ischaemic events. This unsuccessful outcome may have been attributed, at least in part, to using the same dosage regimen of apixaban as is approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (in contrast to ALTAS ACS 2-TIMI 51, which used a comparatively low dosage of rivaroxaban) and the relatively high proportion of patients (&10 %) with a history of cerebrovascular disease [19]. Similar findings were reported in the phase III TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial [56], which was also stopped early after a safety review because vorapaxar significantly increased major bleeding events,

but had no effect on the primary composite efficacy outcome, compared with placebo. Another major trial (TRA 2°P [Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events]-TIMI 50) in patients with a history of MI, ischaemic stroke or peripheral arterial disease showed a reduction in the risk of cardiovascular death or ischaemic events among patients who received vorapaxar, but there was also an increased risk of moderate or severe bleeding, including intracranial haemorrhage [57]. The RE-DEEM (Randomized Dabigatran Etexilate Dose-Finding Study in Patients With Acute Coronary Syndromes) study [18], a large placebo-controlled, phase II dose-escalation trial with twice-daily regimens of dabigatran 50–150 mg in patients with a recent ACS, showed a dose-related increase in major or clinically relevant minor bleeding events (primary composite outcome) with dabigatran compared with placebo. There were relatively few ischaemic cardiovascular events in the trial and only minor numerical differences were observed between treatment groups [18].

462

Also of interest are results of a recent meta-analysis showing that the addition of a direct thrombin or factor Xa inhibitor to dual antiplatelet therapy in patients with a recent ACS modestly reduced major adverse cardiac events (HR 0.87; 95 % CI 0.80–0.95), but more than doubled the risk of major bleeding (HR 2.34; 95 % CI 2.06–2.66) [58]. Limitations of this study include those inherent to metaanalyses, which combine and analyse data from multiple trials. An editorial accompanying the ATLAS ACS 2-TIMI 51 study suggests an important role of low-dose rivaroxaban in relatively young and healthy patients with an ACS (in general, the study population of the phase III trial), but notes that it is unclear whether findings of the study are applicable to higher-risk patients with an ACS who are commonly treated in routine clinical practice [9]. While results of the ATLAS ACS 2-TIMI 51 trial led to the approval of rivaroxaban 2.5 mg twice daily in patients with a recent ACS in the EU, rivaroxaban is not approved for ACS in the USA. As noted in a commentary by members of the US FDA committee that voted against recommending the expanded indication for rivaroxaban at a meeting in 2012, an important factor in their decision was missing follow-up (e.g. vital status) data for a relatively high proportion of patients in ATLAS ACS 2-TIMI 51 compared with other contemporary ACS trials [13]. Following the submission of additional vital status information by the study sponsor, the FDA again declined approval of rivaroxaban for ACS in 2013; more recently in January 2014 the agency’s Cardiovascular and Renal Drugs Advisory Committee voted against recommending approval of rivaroxaban for use in the 90-day period after an ACS [59]. The focus on the first 90 days of treatment in the manufacturer’s third attempt to gain approval of rivaroxaban for ACS in the USA was in response to a suggestion by the FDA (after the 2013 decision) that they may consider approval for use during a limited time period following an ACS. The manufacturer’s third submission included extensive post hoc analysis of data from ATLAS ACS 2-TIMI 51 [59]. Despite advances in the treatment of patients with ACS, mortality rates remain high (&12–13 % at 6 months after STEMI or non-STEMI), highlighting the need for more optimal treatment regimens and adherence to treatment guidelines [5, 60]. For example, with the introduction of newer antiplatelet agents and their inclusion in current treatment guidelines for ACS (e.g. in Europe) [5], dual antiplatelet therapy in ACS may gradually evolve to aspirin plus either ticagrelor or prasugrel for most patients, rather than more traditional antiplatelet therapy including older thienopyridines such as clopidogrel; however, the extent to which these guidelines have been implemented in clinical practice to date is unclear. Also of potential interest are

G. L. Plosker

recent findings from an open-label trial in patients receiving oral anticoagulants and undergoing percutaneous coronary intervention, showing that patients randomized to receive clopidogrel without aspirin had a significant reduction in bleeding complications and no increase in the rate of thrombotic events compared with those randomized to receive clopidogrel with aspirin [61]. Further studies of interest in patients with a recent ACS could evaluate the relative benefits and risks of contemporary dual antiplatelet therapy (including ticagrelor or prasugrel) with or without rivaroxaban [62]; the phase II and III ATLAS ACS trials were initiated before prasugrel and ticagrelor were available. In conclusion, results of the well-designed phase III ATLAS ACS 2-TIMI 51 trial, which included more than 15,000 patients, suggest a potentially important role for low-dose rivaroxaban co-administered with aspirin alone or aspirin plus either clopidogrel or ticlopidine in patients with a recent ACS. Data selection sources: Relevant medical literature (including published and unpublished data) on rivaroxaban was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 3 Feb 2014], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Rivaroxaban, acute coronary syndrome Study selection: Studies in patients with a recent acute coronary syndrome who received rivaroxaban. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes based on any comments received were made by the author on the basis of scientific and editorial merit.

References 1. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007;50(22):2173–95. 2. Gibson CM, Mega JL, Burton P, et al. Rationale and design of the Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute Coronary SyndromeThrombolysis in Myocardial Infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am Heart J. 2011;161(5):815–821.e6. 3. Jneid H, Alam M, Virani SS, et al. Redefining myocardial infarction: what is new in the ESC/ACCF/AHA/WHF third universal definition of myocardial infarction? Methodist Debakey Cardiovasc J. 2013;9(3):169–72. 4. Patrick WL, Patel C, Guddeti R, et al. Is there a need for ‘‘triple therapy’’? Role of anticoagulation with dual antiplatelet therapy

Rivaroxaban in ACS: A Review

5.

6.

7.

8.

9. 10. 11.

12.

13.

14.

15.

16. 17.

18.

19.

20.

21.

22.

23.

in acute coronary syndromes (ATLAS study & TRAP study). Curr Cardiol Rep. 2013;15:411. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(23): 2999–3054. Rothberg MB, Celestin C, Fiore LD, et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143(4):241–50. Andreotti F, Testa L, Biondi-Zoccai GG, et al. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J. 2006;27(5):519–26. Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003;362(9386): 789–97. Roe MT, Ohman EM. A new era in secondary prevention after acute coronary syndrome. N Engl J Med. 2012;366(1):85–7. Armstrong PW, Harrington RA. Road mapping ATLAS ACS 2: are we there yet? Eur Heart J. 2012;33(20):2510–2. Merlini PA, Bauer KA, Oltrona L, et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation. 1994;90(1):61–8. Skeppholm M, Kallner A, Malmqvist K, et al. Is fibrin formation and thrombin generation increased during and after an acute coronary syndrome? Thromb Res. 2011;128(5):483–9. Krantz MJ, Kaul S. The ATLAS ACS 2-TIMI 51 trial and the burden of missing data: (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51). J Am Coll Cardiol. 2013;62(9):777–81. Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 - an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005;3(3):514–21. Bayer Pharma AG. Xarelto (rivaroxaban) 2.5 mg film-coated tablets: EU summary of product characteristics. Berlin: Bayer Pharma AG; 2013. Rupprecht HJ, Blank R. Clinical pharmacology of direct and indirect factor Xa inhibitors. Drugs. 2010;70:2153–70. Sattari M, Lowenthal DT. Novel oral anticoagulants in development: dabigatran, rivaroxaban, and apixaban. Am J Ther. 2011;18(4):332–8. Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32(22):2781–9. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8):699–708. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9-19 [plus supplementary appendix]. European Medicines Agency. Xarelto 10 mg film-coated tablets: summary of product characteristics; 2013. http://www.medicines. org.uk/emc/medicine/21265. Accessed 31 Oct 2013. European Medicines Agency. Xarelto 20 mg film-coated tablets: summary of product characteristics; 2013. http://www.medicines. org.uk/emc/medicine/25586/SPC. Accessed 31 Oct 2013. Xarelto (rivaroxaban) tablets for oral use: US prescribing information; 2013. http://www.janssenpharmaceuticalsinc.com/assets/ xareltopi.pdf. Accessed 5 Nov 2013.

463 24. Kubitza D, Becka M, Voith B, et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4): 412–21. 25. Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873–80. 26. Mueck W, Becka M, Kubitza D, et al. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct factor Xa inhibitor—in healthy subjects. Int J Clin Pharmacol Ther. 2007;45(6):335–44. 27. Mueck W, Borris LC, Dahl OE, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost. 2008;100(3):453–61. 28. Mueck W, Eriksson BI, Bauer KA, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47(3):203–16. 29. Becker EM, Perzborn E, Klipp A, et al. Effects of rivaroxaban, acetylsalicylic acid and clopidogrel as monotherapy and in combination in a porcine model of stent thrombosis. J Thromb Haemost. 2012;10:2470–80. 30. Wolzt M, Gouya G, Kapiotis S, et al. Open-label randomized study of the effect of rivaroxaban with or without acetylsalicylic acid on thrombus formation in a perfusion chamber. Thromb Res. 2013;132(2):240–7. 31. Tripodi A, Chantarangkul V, Guinet C, et al. The International Normalized Ratio calibrated for rivaroxaban has the potential to normalize prothrombin time results for rivaroxaban-treated patients: results of an in vitro study. J Thromb Haemost. 2011;9(1):226–8. 32. Kubitza D, Becka M, Mueck W, et al. Rivaroxaban (BAY 59-7939)—an oral, direct factor Xa inhibitor—has no clinically relevant interaction with naproxen. Br J Clin Pharmacol. 2007;63(4):469–76. 33. Kubitza D, Becka M, Mueck W, et al. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban—an oral, direct factor Xa inhibitor—are not affected by aspirin. J Clin Pharmacol. 2006;46(9):981–90. 34. Kubitza D, Becka M, Mueck W, et al. Co-administration of rivaroxaban—a novel, oral, direct factor Xa inhibitor—and clopidogrel in healthy subjects [abstract no. 1272]. Eur Heart J. 2007;28(Suppl. 1):189. 35. Gopalakrishnan L, Kumar V, Kohli P, et al. Pharmacokinetic evaluation of rivaroxaban for the treatment of acute coronary syndromes. Expert Opin Drug Metab Toxicol. 2012;8(7):889–900. 36. Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol. 2012;26(1):27–32. 37. Duggan ST. Rivaroxaban: a review of its use for the prophylaxis of venous thromboembolism after total hip or knee replacement surgery. Am J Cardiovasc Drugs. 2012;12(1):57–72. 38. Kubitza D, Becka M, Zuehlsdorf M, et al. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006;46(5):549–58. 39. Weinz C, Schwarz T, Kubitza D, et al. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos. 2009;37(5):1056–64. 40. Gnoth MJ, Buetehorn U, Muenster U, et al. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther. 2011;338(1):372–80. 41. Kubitza D, Becka M, Roth A, et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in

464

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

G. L. Plosker healthy elderly subjects. Curr Med Res Opin. 2008;24(10): 2757–65. Xu XS, Moore K, Burton P, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. Br J Clin Pharmacol. 2012;74(1): 86–97. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374(9683):29–38. Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2010;70(5):703–12. Halabi A, Kubitza D, Zuehlsdorf M, et al. Effect of hepatic impairment on the pharmacokinetics, pharmacodynamics and tolerability of rivaroxaban an oral, direct factor Xa inhibitor [abstract]. J Thromb Haemost. 2007;5(Suppl. 2):P-M-635. Kubitza D, Becka M, Schwers S, et al. Investigation of pharmacodynamic and pharmacokinetic interactions between rivaroxaban and enoxaparin in healthy male subjects. Clin Pharm Drug Dev. 2013;2(3):270–7. Moore KT, Plotnikov AN, Thyssen A. Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban. J Cardiovasc Pharmacol. 2011;58(6):581–8. Janssen Research & Development, LLC Advisory Committee Briefing Document: Rivaroxaban for Reducing the Risk of Cardiovascular Events (Cardiovascular Death, Myocardial Infarction and Stroke) After Acute Coronary Syndrome (ACS); 2012. http:// www.fda.gov/downloads/advisorycommittees/committeesmeeting materials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ ucm304757.pdf. Accessed 5 Dec 2013. Mega JL, Braunwald E, Wiviott S, et al. Comparison of the efficacy and safety of two rivaroxaban doses in acute coronary syndrome (from ATLAS ACS 2-TIMI 51). Am J Cardiol. 2013;112:472–8. Arora R, Lang C, Quddus A. Bayesian net-clinical benefit analysis of rivaroxaban in patients with acute coronary syndromes [abstract]. J Am Coll Cardiol. 2013;61(10):E1534. Mega JL, Braunwald E, Murphy S, et al. Rivaroxaban in the setting of continued dual antiplatelet therapy: findings from the ATLAS ACS 2-TIMI 51 trial [abstract]. J Am Coll Cardiol. 2013;61(10):E4.

52. Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (AntiXa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary SyndromeThrombolysis In Myocardial Infarction-51). J Am Coll Cardiol. 2013;61(18):1853–9. 53. Gibson CM, Chakrabarti AK, Mega J, et al. Reduction of stent thrombosis in patients with acute coronary syndrome treated with rivaroxaban in ATLAS ACS 2-TIMI 51. J Am Coll Cardiol. 2013;62:286–90. 54. Cavender M, Braunwald E, Michael Gibson CC, et al. Rivaroxaban reduces spontaneous and large myocardial infarctions: Findings from the ATLAS ACS 2 - TIMI 51 trial [abstract]. J Am Coll Cardiol. 2013;61(10):E3. 55. O’Donoghue ML, Mega JL, Braunwald E, et al. The efficacy and safety of low-dose rivaroxaban with or without a proton pump inhibitor: insights from the ATLAS ACS 2-TIMI 51 trial [abstract plus poster]. Annual meeting and scientific sessions of the American Heart Association, Dallas; 16–20 Nov 2013. 56. Tricoci P, Huang Z, Held C, et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012;366(1):20–33. 57. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366(15):1404–13. 58. Oldgren J, Wallentin L, Alexander JH, et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J. 2013;34(22):1670–80. 59. Neale T. Third strike for Xarelto for ACS; 2014. http://www. medpagetoday.com/Cardiology/AcuteCoronarySyndrome/43845. Accessed 20 Jan 2014. 60. Steg G, James SK, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J. 2012;33:2569–619. 61. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107–15. 62. Verheugt FWA. Low-dose anticoagulation for secondary prevention in acute coronary syndrome. Am J Cardiol. 2013;111:618–26.