Usefulness of Rivaroxaban for Secondary Prevention of Acute Coronary Syndrome in Patients With History of Congestive Heart Failure (from the ATLAS-ACS-2 TIMI-51 Trial)

Patients with both acute coronary syndromes (ACS) and congestive heart failure are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fibrinolysis. We hypothesized that patients with the overlap of ACS and CHF would thus derive particular benefit from antithrombotic therapy with rivaroxaban. ATLAS-ACS-2 Thrombolysis in Myocardial Infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526). In this post hoc subgroup analysis, subjects with a history of CHF at randomization (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite end point of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confidence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no significant increase in noncoronary artery bypass graft-related Thrombolysis in Myocardial Infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial hemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding. These findings require further prospective evaluation in an adequately powered phase 3 study. Patients with both acute coronary syndromes (ACS) and congestive heart failure are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fibrinolysis. We hypothesized that patients with the overlap of ACS and CHF would thus derive particular benefit from antithrombotic therapy with rivaroxaban. ATLAS-ACS-2 Thrombolysis in Myocardial Infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526). In this post hoc subgroup analysis, subjects with a history of CHF at randomization (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite end point of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confidence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no significant increase in noncoronary artery bypass graft-related Thrombolysis in Myocardial Infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial hemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding. These findings require further prospective evaluation in an adequately powered phase 3 study. There is an elevated risk of recurrent ischemic events after an acute coronary syndrome (ACS) despite currently available medical therapy. Dual antiplatelet therapy is often used to minimize this residual risk, but these antiplatelet therapies may be ineffective due to excess thrombin generation that persists well after the ACS event.1Angiolillo DJ Capodanno D Goto S Platelet thrombin receptor antagonism and atherothrombosis.Eur Heart J. 2010; 31: 17-28Crossref PubMed Scopus (208) Google Scholar, 2Merlini PA Bauer KA Oltrona L Ardissino D Cattaneo M Belli C Mannucci PM Rosenberg RD Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.Circulation. 1994; 90: 61-68Crossref PubMed Scopus (569) Google Scholar Congestive heart failure (CHF) patients are also at an increased risk for thrombotic events which is thought to be related to persistent activation of the renin-angiotensin-aldosterone neurohormonal system and the sympathetic nervous system leading to increases in both platelet aggregation and reduced fibrinolysis.3Lip GY Gibbs CR Does heart failure confer a hypercoagulable state? Virchow's triad revisited.J Am Coll Cardiol. 1999; 33: 1424-1426Crossref PubMed Scopus (319) Google Scholar, 4Jug B Vene N Salobir BG Sebestjen M Sabovic M Keber I Procoagulant state in heart failure with preserved left ventricular ejection fraction.Int Heart J. 2009; 50: 591-600Crossref PubMed Scopus (47) Google Scholar Given this increase in thrombotic risk, several trials have evaluated the safety and efficacy of anticoagulation in patients with CHF. The Warfarin/Aspirin Study in Heart failure trial and the HELAS trial (Antithrombotic therapy in heart failure: a randomized comparison of warfarin vs aspirin) demonstrated that neither warfarin nor aspirin reduced the risk of myocardial infarction, nonfatal stroke, or death as compared with placebo.5Cokkinos DV Toutouzas PK Antithrombotic therapy in heart failure: a randomized comparison of warfarin vs. aspirin (HELAS).Eur J Heart Fail. 1999; 1: 419-423Crossref PubMed Scopus (15) Google Scholar, 6Cleland JG Findlay I Jafri S Sutton G Falk R Bulpitt C Prentice C Ford I Trainer A Poole-Wilson PA The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure.Am Heart J. 2004; 148: 157-164Crossref PubMed Scopus (360) Google Scholar No completed randomized controlled trials, although, have prospectively evaluated the efficacy of the novel oral anticoagulants in the ACS—CHF overlap population. ATLAS ACS-2-Thrombolysis in Myocardial Infarction (TIMI)-51 was a randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of rivaroxaban for the secondary prevention of atherothrombotic events after ACS.7Mega JL Braunwald E Wiviott SD Bassand JP Bhatt DL Bode C Burton P Cohen M Cook-Bruns N Fox KA Goto S Murphy SA Plotnikov AN Schneider D Sun X Verheugt FW Gibson CM Investigators AATRivaroxaban in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 366: 9-19Crossref PubMed Scopus (1592) Google Scholar The purpose of this analysis was to evaluate the efficacy and safety of rivaroxaban among patients with a history of CHF to determine if this high-risk population derived particular benefit. ATLAS ACS-2-TIMI-51 was a randomized, double-blind, placebo-controlled phase 3 trial that enrolled 15,526 subjects at least 18 years of age who presented with symptoms of ACS and were diagnosed with STEMI, non–ST-elevation myocardial infarction (MI), or unstable angina. Subjects were recruited within 1 to 7 days after hospital admission for the index event. After stabilization and initial management strategies, subjects were administered aspirin, and were stratified by administration of thienopyridine (either clopidogrel or ticlopidine) at the discretion of the prescribing physician. Subjects were then randomly assigned to receive either rivaroxaban 2.5 mg BID, rivaroxaban 5 mg BID, or placebo and were followed up for 24 months (median of 13 months and up to 31 months).7Mega JL Braunwald E Wiviott SD Bassand JP Bhatt DL Bode C Burton P Cohen M Cook-Bruns N Fox KA Goto S Murphy SA Plotnikov AN Schneider D Sun X Verheugt FW Gibson CM Investigators AATRivaroxaban in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 366: 9-19Crossref PubMed Scopus (1592) Google Scholar Major exclusion criteria included history of intracranial hemorrhage or history of either ischemic stroke or TIA in subjects receiving both aspirin and thienopyridine. Full inclusion and exclusion criteria have been previously published.8Gibson CM Mega JL Burton P Goto S Verheugt F Bode C Plotnikov A Sun X Cook-Bruns N Braunwald E Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis 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 (e816): 815-821Crossref PubMed Scopus (82) Google Scholar This subgroup analysis focuses on subjects who reported a previous history of CHF at enrollment. This was determined by history and review of medical records, given that echocardiogram data before the index event was not collected. Furthermore, the investigators did not use postevent echocardiograms to classify patients, as a significant amount left ventricular dysfunction seen in the acute setting may subsequently resolve. The primary efficacy end point of this analysis was the composite of cardiovascular (CV) death, MI, or stroke. In addition, CHF-related deaths, defined as all deaths that have been adjudicated to be caused by CHF or cardiogenic shock, were also investigated. The primary safety end point was noncoronary artery bypass graft (CABG)-related TIMI major bleeding. Additional details of the end points, design, and results of ATLAS ACS-2-TIMI-51 have been previously described.7Mega JL Braunwald E Wiviott SD Bassand JP Bhatt DL Bode C Burton P Cohen M Cook-Bruns N Fox KA Goto S Murphy SA Plotnikov AN Schneider D Sun X Verheugt FW Gibson CM Investigators AATRivaroxaban in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 366: 9-19Crossref PubMed Scopus (1592) Google Scholar, 8Gibson CM Mega JL Burton P Goto S Verheugt F Bode C Plotnikov A Sun X Cook-Bruns N Braunwald E Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis 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 (e816): 815-821Crossref PubMed Scopus (82) Google Scholar All analyses were performed using Stata version 13 (StataCorp, LP, Texas). Categorical variables were reported as frequencies and percentages. The mean ± standard deviation was reported for parametric continuous variables, and the median (IQR) was reported for nonparametric continuous variables. Baseline characteristics were calculated for all eligible subjects who were randomized in the trial. Differences in means across treatment groups were compared using the analysis of variance test for continuous variables and chi-square test for categorical variables. Event rates were calculated as numerical percentages, not as Kaplan-Meier estimates. Hazard ratios (HR) with 2-sided 95% confidence intervals were calculated using Cox proportional hazard models and log-rank p values were reported. In all efficacy analyses, the stratification variable (i.e., intent to administer thienopyridine) was included as a covariate in the Cox regression models. In the safety analyses, however, the unstratified Cox proportional hazards models were used due to the small number of events per each stratification group. Efficacy analyses were performed in the modified intention-to-treat population, defined as all randomized subjects and the end point events that occurred after randomization and no later than either the completion of the treatment phase of the study (i.e., the global treatment end date), 30 days after early permanent discontinuation of the study drug, or 30 days after randomization for subjects who did not receive a study drug. Safety analyses were performed in the safety population, which included all subjects who received at least 1 dose of study drug and who were censored at 2 days after discontinuation of study drug.7Mega JL Braunwald E Wiviott SD Bassand JP Bhatt DL Bode C Burton P Cohen M Cook-Bruns N Fox KA Goto S Murphy SA Plotnikov AN Schneider D Sun X Verheugt FW Gibson CM Investigators AATRivaroxaban in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 366: 9-19Crossref PubMed Scopus (1592) Google Scholar, 8Gibson CM Mega JL Burton P Goto S Verheugt F Bode C Plotnikov A Sun X Cook-Bruns N Braunwald E Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis 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 (e816): 815-821Crossref PubMed Scopus (82) Google Scholar Testing between the combined-dose group for rivaroxaban and placebo was prespecified per the study protocol to preserve the alpha at a level of 0.05 based on the log-rank test. All tests were 2-sided, and p value of <0.05 was considered statistically significant. Before data unblinding, a total of 3 sites were excluded from the efficacy analyses due to violations of Good Clinical Practice guidelines. All safety and efficacy end points were adjudicated by an independent, blinded clinical events committee. All analyses were performed by the PERFUSE Study using an of the clinical trial The investigators all of the and for The the to review and on this but no The to all the data in the study and for the to for of the 15,526 subjects enrolled in the 51 a total of subjects with history of CHF were included in this Subjects were in treatment There were no significant in characteristics between treatment characteristics of all randomized subjects with history of = mg BID (n = mg = (2.5 mg 5 mg (n = mean ± ± ± ± ± mean ± ± ± ± ± was calculated using the mean ± ± ± ± ± antiplatelet therapy medical myocardial ischemic ischemic from index acute coronary syndrome to randomization median coronary for index artery bypass graft for index or receptor p value for all was was calculated using the in a p value for all was In ACS subjects with history of CHF, was a significant in the primary end point of CV death, MI, or stroke with the rivaroxaban as well as each of rivaroxaban 2.5 mg BID and 5 mg BID compared with placebo (rivaroxaban 2.5 mg BID vs placebo: vs HR 0.59, 95% CI p = 0.001; rivaroxaban 5 mg BID vs placebo: vs HR 0.61, 95% CI p = 0.002; The of CHF the treatment of rivaroxaban efficacy was compared in patients with CHF were compared without patients without CHF interaction = the of the primary composite end point were evaluated both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = Both the 2.5 mg BID and 5 mg BID doses of rivaroxaban also reduced all-cause mortality by and Myocardial infarction was reduced among subjects who received rivaroxaban 5 mg BID, and a was also in who received 2.5 mg BID = There was no significant in in either rivaroxaban compared with efficacy end point in subjects with history of CHF subjects without previous history of CHF in ACS in subjects with history of end vs 2.5 mg BID vs 5 mg = = = = = = efficacy end point (n = (0.42, = (0.44, = death (n = = = = infarction (n = (0.44, = (0.44, = = (n = = = = death (n = = = = All hazard ratios and 95% confidence intervals are based on the Cox proportional hazards models stratified by the use of thienopyridine from the from the of randomization the end of the trial. population included the randomized subjects and the end point events that occurred after randomization and no later than the completion of the treatment phase of the study (i.e., the global treatment end date), 30 days after early permanent discontinuation of the study drug, or 30 days after randomization for subjects who did not receive a study Subjects from 3 sites were excluded from the efficacy analyses to due to of clinical All were adjudicated by an independent, blinded clinical events in a All hazard ratios and 95% confidence intervals are based on the Cox proportional hazards models stratified by the use of thienopyridine from the from the of randomization the end of the trial. population included the randomized subjects and the end point events that occurred after randomization and no later than the completion of the treatment phase of the study (i.e., the global treatment end date), 30 days after early permanent discontinuation of the study drug, or 30 days after randomization for subjects who did not receive a study drug. Subjects from 3 sites were excluded from the efficacy analyses to due to of clinical guidelines. All were adjudicated by an independent, blinded clinical events CHF-related deaths occurred in (n = patients receiving rivaroxaban 2.5 mg BID, (n = patients receiving rivaroxaban 5 mg BID, and (n = patients receiving with rivaroxaban 2.5 mg BID was with significant in the of CHF-related deaths = 95% CI to p = rivaroxaban 5 mg BID was not 95% CI p = the of bleeding events was in this subgroup of CHF The primary safety end point of TIMI major bleeding occurred in 0.4% (n = subjects receiving rivaroxaban 2.5 mg BID, 1.1% (n = subjects receiving rivaroxaban 5 mg BID, and (n = subjects receiving placebo (2.5 mg BID vs placebo: HR 95% CI p = 5 mg BID vs placebo: HR 95% CI p = were no significant in the risk of either intracranial hemorrhage or fatal bleeding either dose of rivaroxaban was compared with fatal bleeding occurred in the placebo group (n = and no fatal bleeding events were with rivaroxaban 5 mg BID in subjects with history of end vs 2.5 mg 5 mg = = = = = = TIMI (n = = = = hemorrhage (n = = = = bleeding (n = = = All hazard ratios and 95% confidence intervals are based on the unstratified Cox proportional hazards models from the safety population from the of randomization the end of the trial by thienopyridine use was not due to the small number of events per Safety population subjects at the of administration of the dose of a study drug 2 days after the discontinuation of a study All end points were adjudicated by an independent, blinded clinical events in a All hazard ratios and 95% confidence intervals are based on the unstratified Cox proportional hazards models from the safety population from the of randomization the end of the trial by thienopyridine use was not due to the small number of events per Safety population subjects at the of administration of the dose of a study drug 2 days after the discontinuation of a study drug. All end points were adjudicated by an independent, blinded clinical events In patients with history of CHF and an ACS event rivaroxaban reduced the risk of recurrent MI, stroke, and CV death without an increase in either fatal intracranial or major bleeding. The of CHF was as a significant treatment and the of rivaroxaban in the CHF population were as as in the population vs risk No subgroup in the ATLAS 51 trial demonstrated a interaction of this benefit was by a in either CV or all-cause mortality. The number of patients to to a death from was patients for the 2.5 mg BID dose of rivaroxaban and patients for the 5 mg BID rivaroxaban The mechanism of death in trials is not deaths are to CHF-related deaths, which were demonstrated to be reduced with rivaroxaban 2.5 mg BID as compared with however, may have also been to MI, and also to an end point which was not as an in the trial. is that in patients, may both fatal and events and ischemic as well as events and CM S G P D R RD A Cohen of fatal or events with standard dose in medical an trial Am Heart Scholar CHF patients have a risk of A E I of in patients with heart failure.Am J Cardiol. Full Full PubMed Scopus Google Scholar, in congestive heart Heart Fail. 2010; PubMed Scopus Google Scholar, of in congestive heart Engl J Med. PubMed Scopus Google Scholar, CM of risk for and a Med. PubMed Scopus Google Scholar, Congestive heart failure and risk of a Full Full PubMed Scopus Google Scholar and this may have been a of death in the subgroup of CHF patients than in the trial as a In to the 51 analysis, the mortality benefit in CHF subjects in this study was not by an increase in TIMI major and the of fatal bleeding the lower in the rivaroxaban groups as compared with with the 51 was a in the risk of in the rivaroxaban 5 mg BID JL Braunwald E Wiviott SD Bassand JP Bhatt DL Bode C Burton P Cohen M Cook-Bruns N Fox KA Goto S Murphy SA Plotnikov AN Schneider D Sun X Verheugt FW Gibson CM Investigators AATRivaroxaban in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 366: 9-19Crossref PubMed Scopus (1592) Google Scholar In was a of fatal bleeding in the 5 mg BID than the 2.5 mg BID and this may have of the mortality in the 5 mg BID JL Braunwald E Wiviott SD Bassand JP Bhatt DL Bode C Burton P Cohen M Cook-Bruns N Fox KA Goto S Murphy SA Plotnikov AN Schneider D Sun X Verheugt FW Gibson CM Investigators AATRivaroxaban in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 366: 9-19Crossref PubMed Scopus (1592) Google Scholar The benefit in this subgroup of subjects may be due at least in part to the persistent generation of excess thrombin after ACS and the of CHF subjects to have reduced PA Bauer KA Oltrona L Ardissino D Cattaneo M Belli C Mannucci PM Rosenberg RD Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.Circulation. 1994; 90: 61-68Crossref PubMed Scopus (569) Google Scholar, S at the of coagulation and thrombin in and Med. PubMed Scopus Google M D E F M R B L and in heart failure: of oral anticoagulants and heart J 2004; PubMed Scopus Google Scholar CHF, of the of and been with elevated thrombin and of patients to E C S Platelet thrombin and in patients with heart Heart J. PubMed Scopus Google Scholar, I J B A in patients with heart failure and a novel 2010; PubMed Scopus Google Scholar also be that have thrombin on and of thrombin to these may and receptor and cardiovascular Med. 1994; PubMed Scopus Google Scholar, P The thrombin receptor in ventricular Cardiol. Full PubMed Scopus Google Scholar, E events the generation of in PubMed Scopus Google Scholar, P A R R J generation after coronary artery bypass with myocardial PubMed Scopus Google Scholar There are between previous which to a benefit of anticoagulation therapy in the setting of DV Toutouzas PK Antithrombotic therapy in heart failure: a randomized comparison of warfarin vs. aspirin (HELAS).Eur J Heart Fail. 1999; 1: 419-423Crossref PubMed Scopus (15) Google Scholar, 6Cleland JG Findlay I Jafri S Sutton G Falk R Bulpitt C Prentice C Ford I Trainer A Poole-Wilson PA The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure.Am Heart J. 2004; 148: 157-164Crossref PubMed Scopus (360) Google S PM B S DL JP SD DJ P R and aspirin in patients with heart failure and Engl J Med. 2012; 366: PubMed Scopus Google Scholar and the study. These enrolled a of CHF subjects and were not to CHF subjects who also an ACS event. These warfarin and did not the efficacy of This 51 data that CHF patients who ACS may be a population for anticoagulation therapy to recurrent ACS Given these the phase 3 trial was to test the that rivaroxaban 2.5 mg BID the composite of all-cause MI, or stroke in patients with CHF and F B JG M DJ SD M Rationale and design of a randomized, double-blind, study comparing the efficacy and safety of oral rivaroxaban with placebo for the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery an of heart failure: the J Heart Fail. PubMed Scopus Google Scholar from be the trial to prospectively or the that rivaroxaban recurrent ACS events in with CHF as part of a secondary prevention In patients with history of CHF who an ACS secondary prevention with rivaroxaban was with a significant of the composite of CV death, MI, or stroke without an increase in either fatal or major bleeding. These findings are prospectively in the 3 study.