Rivaroxaban in patients with a recent acute coronary syndrome event: integration of trial findings into clinical practice

Figures & data

Figure 1 Schematic overview of the coagulation cascade.

Notes: The coagulation cascade includes three overlapping phases: initiation; amplification and propagation; and clot formation. In the initiation phase, the tissue factor/FVIIa complex activates coagulation factors IX to IXa and X to Xa; FXa cleaves prothrombin, activating conversion to thrombin and generating small amounts of thrombin. In the amplification and propagation phase, thrombin signals for further platelet activation and aggregation; on the surface of the platelets, thrombin activates FV, FVIII, and FXI, and FVIIIa forms a complex with FIXa, which increases thrombin generation. During the clot formation phase, thrombin catalyses the conversion of fibrinogen to fibrin, leading to thrombus formation. Data source: De Caterina et al.¹⁴
Abbreviations: ADP, adenosine diphosphate; vWF, von Willebrand factor.

Figure 2 Pathophysiology of atherothrombosis and therapeutic targets.

Abbreviations: ADP, adenosine diphosphate; COX, cyclooxygenase; GP, glycoprotein; PAR, proteinase-activated receptor; TXA₂, thromboxane A₂; vWF, von Willebrand factor.

Table 1 Summary of clinical trials of oral anticoagulants in ACS

Drug	Trial	Study design	Number of patients	Mechanism of action	Study duration	Primary efficacy outcome	Primary safety outcome
Warfarin	Meta-analysis^Citation10	Meta-analysis of randomized, controlled trials	25,307	Vitamin K antagonist	3 months to 5 years	All-cause death, non-fatal Ml, and non-fatal thromboembolic stroke (Irrespective of INR) ASA + warfarin compared with ASA alone: OR: 0.96 (95% CI: 0.90–1.03); P=0.30 (INR of 2–3) ASA + warfarin compared with ASA alone: OR: 0.73 (95% CI: 0.63–0.84); P<0.0001	Major bleeding* (Irrespective of INR) ASA + warfarin: OR: 1.77 (95% CI: 1.47–2.13); P<0.00001 (INR of 2–3) ASA + warfarin compared with ASA alone: OR: 2.32 (95% CI: 1.63–3.29); P<0.00001
Ximelagatran	ESTEEM^Citation16 (Phase II)	Placebo-controlled, randomized, double-blind, dose-finding	1,883	Oral, direct thrombin inhibitor†	6 months	All cause-death, non-fatal MI, and severe recurrent ischemia rate at 6 months Ximelagatran (24 mg bid, 36 mg bid, 48 mg bid, 60 mg bid combined) 12.7%, placebo 16.3%: HR: 0.76 (95% CI: 0.59–0.98); P=0.036	Major bleeding‡ Ximelagatran (24 mg bid, 36 mg bid, 48 mg bid, 60 mg bid combined) 1.8%, placebo 0.9%: HR: 1.97 (95% CI: 0.80–4.84); ARI 0.9%§
Dabigatran	RE-DEEM^Citation23 (Phase II)	Placebo-controlled, randomized, double-blind, dose-finding	1,861	Oral, direct thrombin inhibitor║	6 months	CV death, non-fatal MI, or non-hemorrhagic stroke rate at 6 months Dabigatran 4.6%, 4.9%, 3.0%, and 3.5% for 50 mg bid, 75 mg bid, 110 mg bid, and 150 mg bid, respectively; placebo 3.8%	ISTH major¶ or clinically relevant minor bleeding Dabigatran 3.5%, 4.3%, 7.9%, and 7.8% for 50 mg bid, 75 mg bid, 110 mg bid, and 150 mg bid, respectively; placebo 2.2%: P<0.001 for linear trend
Apixaban	APPRAISE-1^Citation24 (Phase II)	Placebo-controlled, randomized, double-blind, dose-finding	1,715	Oral, direct Factor Xa inhibitor║	6 months	CV death, MI, severe recurrent ischemia, or ischemic stroke rate at 6 months (Compared with placebo) Apixaban 2.5 mg bid: HR: 0.73 (95% CI: 0.44–1.19); P=0.21 Apixaban 10 mg od: HR: 0.61 (95% CI: 0.35–1.04); P=0.07	ISTH major or CRNM bleeding¶ (Compared with placebo) Apixaban 2.5 mg bid: HR: 1.78 (95% CI: 0.91–3.48); P=0.09 Apixaban 10 mg od: HR: 2.45 (95% CI: 1.31–4.61); P=0.005
Apixaban	APPRAISE-2^Citation25 (Phase III)	Placebo-controlled, randomized, double-blind	7,392	Oral, direct Factor Xa inhibitor║	241 days (early termination)	CV death, MI, ischemic stroke rate at 1 year Apixaban 5 mg bid 13.2%, placebo 14.0%: HR: 0.95 (95% CI: 0.80–0.11); P=0.51	TIMI major# bleeding Apixaban 5 mg bid 2.4%, placebo 0.9%; ARI 1.5%: P=0.001
Darexaban	RUBY-1^Citation26 (Phase II)	Placebo-controlled, randomized, double-blind	1,279	Oral, direct Factor Xa inhibitor║	26 weeks	Death, stroke, MI, systemic thromboembolism, and severe recurrent ischemia Darexaban 5 mg bid, 10 mg od, 15 mg bid, 30 mg od, 30 mg bid, and 60 mg od event rates 3.8%, 3.8%, 6.3%, 6.4%, 5.9%, 7.8%, and 5.6%, respectively; placebo 4.4%§	ISTH major¶ or clinically relevant non-major bleeding Bleeding rates numerically higher in darexaban arms (5 mg bid, 10 mg od, 15 mg bid, 30 mg od, 30 mg bid, and 60 mg od combined) versus placebo: HR: 2.275 (95% CI: 1.13–4.60); P=0.022 for linear trend
Letaxaban	AXIOM-ACS^Citation27 (Phase II)	Placebo-controlled, randomized, double-blind, dose-finding	2,753	Oral, direct Factor Xa inhibitor║	Premature termination	CV death, non-fatal MI, non-fatal stroke, and myocardial ischemia requiring hospitalization Letaxaban 10 mg bid, 20 mg bid, 40 mg od, 40 mg bid, 80 mg od, 80 mg bid, 160 mg od, and 120 mg bid event rates 5.2%, 2.8%, 4.0%, 6.7%, 5.2%, 5.9%, 5.2%, and 3.6%, respectively; placebo 4.4%	TIMI major bleeding# Letaxaban 10 mg bid, 20 mg bid, 40 mg od, 40 mg bid, 80 mg od, 80 mg bid, 160 mg od, and 120 mg bid event rates 0.0%, 1.2%, 0.4%, 1.6%, 1.2%, 0.8%, 0.4%, and 1.2%, respectively; placebo 0.5%
Rivaroxaban	ATLAS ACS TIMI 46^Citation28 (Phase II)	Placebo-controlled, randomized, double-blind, dose-finding	3,491	Oral, direct Factor Xa inhibitor║	6 months	Death, MI, stroke, or severe recurrent ischemia requiring revascularization during 6 months Rivaroxaban (5 mg, 10 mg, 15 mg, and 20 mg od or same total daily dose bid, combined) 3.9%, placebo 5.5%: HR: 0.69 (95% CI: 0.50–0.96); P=0.0270	Clinically significant bleeding: TIMI major,# TIMI minor,** or requiring medical attention†† Rivaroxaban (5 mg, 10 mg, 15 mg, and 20 mg od, or same total daily dose bid, doses combined) 5.6%, placebo 7.0%: HR: 0.79 (95% CI: 0.60–1.05); P=0.10 (Compared with placebo) Rivaroxaban (5 mg, 10 mg, 15 mg, and 20 mg individual doses): dose-dependent increase, HRs:2.21 (95% CI: 1.25–3.91); 3.35 (95% CI: 2.31–4.87); 3.60 (95% CI: 2.32–5.58); and 5.06 (95% CI: 3.45–7.42); P<0.0001
Rivaroxaban	ATLAS ACS 2 TIMI 51^Citation29 (Phase III)	Placebo-controlled, randomized, double-blind	15,526	Oral, direct Factor Xa inhibitor║	13 months	CV death, MI, stroke rate at 2 years Rivaroxaban (2.5 mg and 5 mg bid doses combined) 8.9%, placebo 10.7%: HR: 0.84 (95% CI: 0.74–0.96); P=0.008	Non-CABG-related TIMI major bleeding# Rivaroxaban (2.5 mg and 5 mg bid doses combined) 2.1 %, placebo 0.6%: ARI 1.5%; P<0.001

Notes:

* Major bleeding rate defined as intracranial hemorrhages, bleeding events requiring transfusions, or a ≥2 g/dL drop in hemoglobin;

† patients also received ASA;

‡ major bleeding was defined as fulfilling one or more of the following criteria: fatal bleeding; clinically overt bleeding associated with a fall in hemoglobin of at least 20 g/L or leading to transfusion of two or more units of whole blood or erythrocytes; bleeding in areas of special concern, such as intracranial, intraspinal, intraocular, retroperitoneal, pericardial, or atraumatic intraarticular bleeding;

§ P-value not available;

║ patients also received standard of care of ASA or ASA plus thienopyridine according to guidelines;

¶ ISTH major or clinically relevant bleeding are defined as fatal bleeding or symptomatic bleeding in a critical area or organ (for example, intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular), bleeding causing a hemoglobin decrease of 2 g/dL or requiring a ≥2 U transfusion;

# TIMI major bleeding event is defined as any intracranial bleeding or clinically overt bleeding event that is associated with a decrease in hemoglobin of ≥5 g/dL or an absolute drop in hematocrit of ≥ 15%;

** TIMI minor bleeding defined as clinically overt (including imaging), resulting in a hemoglobin drop of 3 to <5 g/dL;

†† bleeding requiring medical attention was defined as a bleeding event that required medical treatment, surgical treatment, or laboratory assessment and did not meet criteria for TIMI major or minor bleeding.

Abbreviations: ACS, acute coronary syndrome; ARI, absolute risk increase; ASA, acetylsalicylic acid; bid, twice daily; CABG, coronary artery bypass graft; CI, confidence interval; CRNM, clinically relevant non-major; CV, cardiovascular; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; INR, international normalized ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction; N/A, not applicable; od, once daily; TIMI, Thrombolysis in Myocardial Infarction.

Table 2 Efficacy and safety outcomes in the Phase III ATLAS ACS 2 TIMI 51 study*

Endpoint	Rivaroxaban			Placebo (N=5,113)
Efficacy	2.5 mg bid (N=5,114)	5 mg bid (N=5,115)	Combined (N=10,229)
Death from cardiovascular causes, MI, or stroke – primary endpoint	313 (9.1)	313 (8.8)	626 (8.9)	376 (10.7)
Death from cardiovascular causes	94 (2.7)	132 (4.0)	226 (3.3)	143 (4.1)
MI	205 (6.1)	179 (4.9)	384 (5.5)	229 (6.6)
Stroke
Any	46 (1.4)	54 (1.7)	100 (1.6)	41 (1.2)
Ischemic	30 (1.0)	35 (0.9)	65 (0.9)	34 (1.0)
Death from any cause, MI, or stroke – secondary endpoint	320 (9.3)	321 (9.1)	641 (9.2)	386 (11.0)
Death from any cause	103 (2.9)	142 (4.4)	245 (3.7)	153 (4.5)
Stent thrombosis	47 (2.2)	51 (2.3)	98 (2.3)	72 (2.9)
Safety	(N=5,115)	(N=5,110)	(N=10,225)	(N=5,125)
TIMI major bleeding not associated with CABG	65 (1.8)	82 (2.4)	147 (2.1)	19 (0.6)
TIMI minor bleeding	32 (0.9)	49 (1.6)	81 (1.3)	20 (0.5)
TIMI bleeding requiring medical attention	492 (12.9)	637 (16.2)	1,129 (14.5)	282 (7.5)
Intracranial hemorrhage	14 (0.4)	18 (0.7)	32 (0.6)	5 (0.2)
Fatal bleeding	6 (0.1)	15 (0.4)	21 (0.3)	9 (0.2)

Notes:

* Event rates are reported as Kaplan–Meier estimates through 24 months, and are thus not presented as numerical percentages. Data for the efficacy endpoints correspond to the mITT analysis, with P-values presented for both mITT and ITT analyses. Before the unblinding of the study results, 184 patients were excluded from the efficacy analysis because of violations in the Good Clinical Practice guidelines at three sites. MI and stroke categories include fatal and non-fatal events. Stroke includes ischemic, hemorrhagic, and stroke of uncertain cause. Stent thrombosis (definite, probable, or possible) analyses were conducted among patients who had received a stent prior to randomization. Data for the safety endpoints correspond to the safety analysis. From The New England Journal of Medicine, Mega JL, Braunwald E, Wiviott SD, et al, ATLAS ACS 2–TIMI 51 Investigators, Rivaroxaban in patients with a recent acute coronary syndrome, Volume 366, Pages 9–19.²⁹ Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Abbreviations: bid, twice daily; CABG, coronary artery bypass graft; ITT, intention-to-treat; MI, myocardial infarction; mITT, modified intention-to-treat; TIMI, Thrombolysis in Myocardial Infarction.

De CaterinaRHustedSWallentinLEuropean Society of Cardiology Working Group on Thrombosis Task Force on Anticoagulants in Heart DiseaseGeneral mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis – Task Force on Anticoagulants in Heart DiseaseThromb Haemost2013109456957923447024

 PubMed Web of Science ®Google Scholar

AndreottiFTestaLBiondi-ZoccaiGGCreaFAspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patientsEur Heart J200627551952616143706

 PubMed Web of Science ®Google Scholar

WallentinLWilcoxRGWeaverWDESTEEM InvestigatorsOral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trialLancet2003362938678979713678873

 PubMed Web of Science ®Google Scholar

OldgrenJBudajAGrangerCBRE-DEEM InvestigatorsDabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trialEur Heart J201132222781278921551462

 PubMed Web of Science ®Google Scholar

AlexanderJHBeckerRCBhattDLAPPRAISE Steering Committee and InvestigatorsApixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trialCirculation2009119222877288519470889

 PubMed Web of Science ®Google Scholar

AlexanderJHLopesRDJamesSAPPRAISE-2 InvestigatorsApixaban with antiplatelet therapy after acute coronary syndromeN Engl J Med2011365869970821780946

 PubMed Web of Science ®Google Scholar

StegPGMehtaSRJukemaJWRUBY-1 InvestigatorsRUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndromeEur Heart J201132202541255421878434

 PubMed Web of Science ®Google Scholar

GoldsteinSBatesEBhattDSafety evaluation of the factor Xa inhibitor TAK-442 in subjects with acute coronary syndromes: phase 2 AXIOM-ACS trial resultsEur Heart J201132Abstract Supplement Abstract P2430

 PubMedGoogle Scholar

MegaJLBraunwaldEMohanaveluSATLAS ACS-TIMI 46 study groupRivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trialLancet20093749683293819539361

 PubMed Web of Science ®Google Scholar

MegaJLBraunwaldEWiviottSDATLAS ACS 2–TIMI 51 InvestigatorsRivaroxaban in patients with a recent acute coronary syndromeN Engl J Med2012366191922077192

 PubMed Web of Science ®Google Scholar