FACTOR Xa INHIBITORS















ROCKET-AF - Rivaroxaban vs Warfarin in A Fib, NEJM (2011) [PubMed abstract]
  • The ROCKET-AF study enrolled 14,264 patients with atrial fibrillation and other risk factors for stroke
Main inclusion criteria
  • Nonvalvular A fib and previous stroke, TIA, or systemic embolism OR nonvalvular A fib and at least 2 of the following: heart failure or EF ≤ 35%, age ≥ 75 years, hypertension, diabetes
Main exclusion criteria
  • Significant mitral valve stenosis
  • Prosthetic heart valve
  • Significant GI bleed within 6 months
  • History of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding
  • Platelet count < 90,000/mm³
  • SBP ≥ 180, DBP ≥ 100
  • CrCl < 30 ml/min
  • Concomitant CYP3A4 strong inhibitors/inducers
Baseline characteristics
  • Median age 73 years
  • Average BP - 130/80
  • A fib type: Persistent - 81% | Paroxysmal - 17.5%
  • Average CHADS₂ score - 3.47
  • Previous stroke, systemic embolism, or TIA - 55%
  • Median CrCl - 67 ml/min
Randomized treatment groups
  • Group 1 (7131 patients) - Rivaroxaban 20 mg daily or 15 mg daily if CrCl 30 - 49 ml/min
  • Group 2 (7133 patients) - Warfarin (target INR 2.0 - 3.0)
  • Study treatment was blinded with sham INR values in Group 1
Primary outcome: Composite of stroke or systemic embolism
Results

Duration: Median of 1.9 years
Outcome Rivaroxaban Warfarin Comparisons
Primary outcome (events/100 patient-years) 2.1 2.4 HR 0.88, 95%CI [0.75 - 1.03], p=0.12
Overall mortality (annual rate) 4.5% 4.9% HR 0.92, 95%CI [0.82 - 1.03], p=0.15
All stroke 2.61% 3.12% HR 0.85, 95%CI [0.70 - 1.03], p=0.092
Hemorrhagic stroke 0.41% 0.71% HR 0.59, 95%CI [0.37 - 0.93], p=0.024
Major and nonmajor clinically relevant bleeding 20.7% 20.3% HR 1.03, 95%CI [0.96 - 1.11], p=0.44
Drug discontinuation 23.7% 22.2% N/A
  • During the study, about 35% of the patients in each group took aspirin at some point
  • Patients in the warfarin group were in the therapeutic INR range an average of 55% of the time [2]

Findings: In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.
ARISTOTLE - Apixaban vs Warfarin in A Fib, NEJM (2011) [PubMed abstract]
  • The ARISTOTLE study enrolled 18,201 patients with atrial fibrillation or flutter and at least one other risk factor for stroke
Main inclusion criteria
  • Nonvalvular A fib or flutter and one of the following: previous stroke, TIA, systemic embolism, age ≥ 75 years, symptomatic heart failure (within 3 months) or EF ≤ 40%, diabetes, hypertension requiring treatment
Main exclusion criteria
  • Moderate or severe mitral stenosis
  • Prosthetic heart valve
  • CrCl < 25 ml/min
Baseline characteristics
  • Median age 70 years
  • Prior clinically relevant or spontaneous bleeding - 16.7%
  • A fib type: Persistent or permanent - 85% | Paroxysmal - 15%
  • Average CHADS₂ score - 2.1
  • Previous stroke, systemic embolism, or TIA - 19%
Randomized treatment groups
  • Group 1 (9120 patients) - Apixaban 5 mg twice a day (2.5 mg dose was used if patient met ≥ 2 of these criteria: ≥ 80 years old; weight ≤ 60 kg; creatinine ≥ 1.5 mg/dl)
  • Group 2 (9081 patients) - Warfarin (target INR 2.0 - 3.0)
  • Study treatment was blinded
Primary outcome: Composite of stroke or systemic embolism
Results

Duration: Median of 1.8 years
Outcome Apixaban Warfarin Comparisons
Primary outcome (annual rate) 1.27% 1.60% HR 0.79, 95%CI [0.66 - 0.95], p=0.01
Overall mortality (annual rate) 3.52% 3.94% HR 0.89, 95%CI [0.80 - 0.998], p=0.047
All stroke (annual rate) 1.19% 1.51% HR 0.79, 95%CI [0.65 - 0.95], p=0.01
Hemorrhagic stroke (annual rate) 0.24% 0.47% HR 0.51, 95%CI [0.35 - 0.75], p<0.001
Clinically relevant bleeding (annual rate) 4.07% 6.01% HR 0.68, 95%CI [0.61 - 0.75], p<0.001
Drug discontinuation 25.3% 27.5% p=0.001
  • Patients in the warfarin group were in the therapeutic INR range an average of 62% of the time

Findings: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.
ENGAGE AF-TIMI 48 - Edoxaban vs Warfarin in A Fib, NEJM (2013) [PubMed abstract]
  • The ENGAGE AF-TIMI 48 study enrolled 21,105 patients with atrial fibrillation
Main inclusion criteria
  • Nonvalvular A fib
  • CHADS₂ score ≥ 2
Main exclusion criteria
  • CrCl < 30 ml/min
  • High risk of bleeding
  • Moderate-to-severe mitral stenosis
  • Dual antiplatelet therapy
  • Acute coronary syndrome, stroke, or revascularization within 30 days
Baseline characteristics
  • Median age 72 years
  • Paroxysmal A fib - 25%
  • Average CHADS₂ score - 2.8
  • Previous stroke or TIA - 28%
Randomized treatment groups
  • Group 1 (7034 patients) - Low-dose edoxaban (30 mg once daily)
  • Group 2 (7035 patients) - High-dose edoxaban (60 mg once daily)
  • Group 3 (7036 patients) - Warfarin (target INR 2.0 - 3.0)
  • Study treatment was blinded with sham INR values in Groups 1 and 2
Primary outcome: Composite of stroke or systemic embolism
Results

Duration: Median of 2.8 years
Outcome (%/year) Edox 30 mg Edox 60 mg Warfarin Comparisons
Primary outcome 1.61% 1.18% 1.50% 1 vs 3, p=0.44 | 2 vs 3, p=0.02
Overall mortality 3.8% 3.99% 4.35% 1 vs 3, p=0.006 | 2 vs 3, p=0.08
All stroke 1.91% 1.49% 1.69% 1 vs 3 p=0.12 | 2 vs 3 p=0.11
Hemorrhagic stroke 0.16% 0.26% 0.47% 1 vs 3 p<0.001; | 2 vs 3 p<0.001
Clinically relevant bleeding 7.97% 11.10% 13.02% 1 vs 3 p<0.001 | 2 vs 3 p<0.001
Drug discontinuation (overall) 33% 34% 34% N/A
  • Patients in the warfarin group were in the therapeutic INR range an average of 65% of the time

Findings: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes.





EINSTEIN-DVT - Rivaroxaban vs Vitamin K Antagonist for DVT Treatment, NEJM (2010) [PubMed abstract]
  • The EINSTEIN-DVT study enrolled 3449 patients with an acute DVT
Main inclusion criteria
  • Symptomatic, objectively-confirmed, proximal DVT
Main exclusion criteria
  • Symptomatic pulmonary embolism
  • Received LMWH, heparin, or fondaparinux for > 48 hours
  • Treated with vena cava filter, fibrinolysis, or thrombectomy
  • CrCl < 30 ml/min
  • Clinically significant liver disease
  • Taking CYP3A4 strong inhibitors/inducers
  • High risk of bleeding
Baseline characteristics
  • Average age 56 years
  • Median time from onset of symptoms to randomization - 5 days
  • DVT type: Unprovoked - 62% | Recent surgery/immobilization - 34.7% | Estrogen therapy - 7% | Cancer - 6%
  • Known thrombophilia - 6.5%
  • Previous DVT - 19.3%
Randomized treatment groups
  • Group 1 (1731 patients) - Rivaroxaban 15 mg twice a day for 3 weeks, then 20 mg a day for 3 - 12 months
  • Group 2 (1718 patients) - Enoxaparin followed by Vitamin K antagonist (target INR 2-3) for 3 - 12 months
  • In Group 1, 69% of patients received 1 days of treatment with LMWH, heparin, or fondaparinux
Primary outcome: Recurrent symptomatic venous thromboembolism (DVT or PE)
Results

Duration: 3 - 12 months
Outcome Rivaroxaban VKA Comparisons
Primary outcome 2.1% 3.0% HR 0.68, 95%CI [0.44 - 1.04]
Overall mortality 2.2% 2.9% HR 0.67, 95%CI [0.44 - 1.02]
Major or clinically relevant nonmajor bleeding 8.1% 8.1% HR 0.97, 95%CI [0.76 - 1.22]
Net clinical benefit (VTE plus major bleeding) 2.9% 4.2% HR 0.67, 95%CI [0.47 - 0.95]
  • Length of treatment in both groups: 3 months - 12%, 6 months - 63%, 12 months - 25%
  • Premature drug discontinuation: Rivaroxaban - 11.3%, VKA - 14.2%
  • In the VKA group, the INR was in the therapeutic range 58% of the time

Findings: Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation.
AMPLIFY - Apixaban vs Warfarin for VTE Treatment, NEJM (2013) [PubMed abstract]
  • The AMPLIFY study enrolled 5395 patients with acute DVT or PE
Main inclusion criteria
  • Symptomatic, objectively-confirmed, proximal DVT or PE
Main exclusion criteria
  • High bleeding risk
  • Provoked VTE in the absence of a persistent risk factor for recurrence
  • Planned treatment < 6 months
  • Taking CYP3A4 strong inhibitor
  • Dual antiplatelet therapy
  • Received > 2 days of heparin therapy
  • Platelet count < 100,000/mm³
  • CrCl < 25 ml/min
Baseline characteristics
  • Average age 57 years
  • Qualifying event: DVT - 65% | PE - 25% | PE with DVT - 9%
  • VTE type: Unprovoked - 90% | Provoked - 10%
  • Median time from onset of symptoms to randomization - 5 days
  • Known thrombophilia - 2.6%
  • Active cancer - 2.6%
Randomized treatment groups
  • Group 1 (2691 patients) - Apixaban 10 mg twice a day for 7 days, then 5 mg twice a day for 6 months
  • Group 2 (2704 patients) - Enoxaparin followed by warfarin (target INR 2 - 3) for 6 months
Primary outcome: Composite of recurrent symptomatic thromboembolism (DVT or PE) or death related to thromboembolism
Results

Duration: 6 months
Outcome Apixaban Warfarin Comparisons
Primary outcome (overall) 2.3% 2.7% HR 0.84, 95%CI [0.60 - 1.18]
Primary outcome (subgroup with index DVT) 2.2% 2.7% HR 0.83, 95%CI [0.54 - 1.26]
Primary outcome (subgroup with index PE) 2.3% 2.6% HR 0.90, 95%CI [0.50 - 1.61]
Overall mortality 1.5% 1.9% HR 0.79, 95%CI [0.53 - 1.19]
Major or clinically relevant nonmajor bleeding 4.3% 9.7% HR 0.44, 95%CI [0.36 - 0.55], p<0.001
VTE, VTE-related death, or major bleeding 2.8% 4.5% HR 0.62, 95%CI [0.47 - 0.83], p=0.001
Premature drug discontinuation 14% 15.4% N/A
  • In the warfarin group, the INR was in the therapeutic range 61% of the time

Findings: A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding
Hokusai-VTE - Edoxaban vs Warfarin for VTE Treatment, NEJM (2013) [PubMed abstract]
  • The Hokusai-VTE study enrolled 8240 patients with acute VTE
Main inclusion criteria
  • Acute, symptomatic proximal DVT or PE confirmed by imaging
Main exclusion criteria
  • Received heparin, LMWH, or fondaparinux for > 48 hours
  • Received thrombectomy, fibrinolysis, or vena cava filter
  • CrCl < 30 ml/min
  • Dual antiplatelet therapy
  • High risk for bleeding
  • Significant liver disease
Baseline characteristics
  • Average age 56 years
  • Qualifying event: DVT - 60% | PE - 40%
  • Type of VTE: Unprovoked - 66% | Temporary risk factor - 28% | Cancer - 9%
  • Previous VTE - 18%
Randomized treatment groups
  • Group 1 (4118 patients) - Edoxaban 60 mg once daily (30 mg once daily if CrCl 30 - 50 ml/min or if body weight ≤ 132 pounds) for 3 - 12 months
  • Group 2 (4122 patients) - Warfarin with target INR 2 - 3 for 3 - 12 months
  • All patients received initial therapy with open-label enoxaparin or unfractionated heparin for at least 5 days
  • Edoxaban was started after discontinuation of initial heparin. Warfarin was started with initial heparin.
  • Treatment was to be continued for at least 3 months and up to 12 months
Primary outcome: Recurrent symptomatic VTE or VTE-related death
Results

Duration: 12 months
Outcome Edoxaban Warfarin Comparisons
Primary outcome (overall) 3.2% 3.5% HR 0.89, 95%CI [0.70 - 1.13]
Primary outcome (subgroup with index DVT) 3.4% 3.3% HR 1.02, 95%CI [0.75 - 1.38]
Primary outcome (subgroup with index PE) 2.8% 3.9% HR 0.73, 95%CI [0.50 - 1.06]
Major or clinically relevant nonmajor bleeding 8.5% 10.3% HR 0.81, 95%CI [0.71 - 0.94], p=0.004
  • In both groups, 40% of patients were treated for 12 months
  • In the warfarin group, the INR was in the therapeutic range 63.5% of the time

Findings: Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism.





EINSTEIN-PE - Rivaroxaban vs Vitamin K Antagonist for PE Treatment, NEJM (2012) [PubMed abstract]
  • The EINSTEIN-PE study enrolled 4832 patients with acute PE
Main inclusion criteria
  • Acute, symptomatic, objectively-confirmed PE with or without DVT
Main exclusion criteria
  • Received LMWH, heparin, or fondaparinux for > 48 hours
  • Treated with vena cava filter, fibrinolysis, or thrombectomy
  • CrCl < 30 ml/min
  • Clinically significant liver disease
  • Taking CYP3A4 strong inhibitors/inducers
  • High risk of bleeding
Baseline characteristics
  • Average age 58 years
  • PE extent: Limited - 12.6% | Intermediate - 58% | Extensive - 24%
  • Concurrent symptomatic DVT - 25%
  • PE type: Unprovoked - 64% | Recent surgery/immobilization - 33% | Estrogen therapy - 8.8% | Active cancer - 4.6%
  • Known thrombophilia - 5.4%
  • Previous VTE - 19%
  • Median time from symptoms to randomization - 4 days
Randomized treatment groups
  • Group 1 (2420 patients) - Rivaroxaban 15 mg twice a day for 3 weeks, then 20 mg once daily for 3 - 12 months
  • Group 2 (2413 patients) - Enoxaparin followed by Vitamin K antagonist (target INR 2-3) for 3 - 12 months
  • Duration of treatment was determined by treating physician
Primary outcome: Recurrent symptomatic venous thromboembolism during treatment
Results

Duration: Average of 265 days
Outcome Rivaroxaban VKA Comparisons
Primary outcome 2.1% 1.8% HR 1.12, 95%CI [0.75 - 1.68], p=0.57
Overall mortality 2.4% 2.1% HR 1.13, 95%CI [0.77 - 1.65], p=0.53
Major or clinically relevant nonmajor bleeding 10.3% 11.4% HR 0.90, 95%CI [0.76 - 1.07], p=0.23
Net clinical benefit (VTE plus major bleeding) 3.4% 4.0% HR 0.85, 95%CI [0.63 - 1.14], p=0.28
  • In the VKA group, the INR was in the therapeutic range 62.7% of the time

Findings: A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile.
AMPLIFY - Apixaban vs Warfarin for VTE Treatment, NEJM (2013) [PubMed abstract]
  • The AMPLIFY study enrolled 5395 patients with acute DVT or PE
Main inclusion criteria
  • Symptomatic, objectively-confirmed, proximal DVT or PE
Main exclusion criteria
  • High bleeding risk
  • Provoked VTE in the absence of a persistent risk factor for recurrence
  • Planned treatment < 6 months
  • Taking CYP3A4 strong inhibitor
  • Dual antiplatelet therapy
  • Received > 2 days of heparin therapy
  • Platelet count < 100,000/mm³
  • CrCl < 25 ml/min
Baseline characteristics
  • Average age 57 years
  • Qualifying event: DVT - 65% | PE - 25% | PE with DVT - 9%
  • VTE type: Unprovoked - 90% | Provoked - 10%
  • Median time from onset of symptoms to randomization - 5 days
  • Known thrombophilia - 2.6%
  • Active cancer - 2.6%
Randomized treatment groups
  • Group 1 (2691 patients) - Apixaban 10 mg twice a day for 7 days, then 5 mg twice a day for 6 months
  • Group 2 (2704 patients) - Enoxaparin followed by warfarin (target INR 2 - 3) for 6 months
Primary outcome: Composite of recurrent symptomatic thromboembolism (DVT or PE) or death related to thromboembolism
Results

Duration: 6 months
Outcome Apixaban Warfarin Comparisons
Primary outcome (overall) 2.3% 2.7% HR 0.84, 95%CI [0.60 - 1.18]
Primary outcome (subgroup with index DVT) 2.2% 2.7% HR 0.83, 95%CI [0.54 - 1.26]
Primary outcome (subgroup with index PE) 2.3% 2.6% HR 0.90, 95%CI [0.50 - 1.61]
Overall mortality 1.5% 1.9% HR 0.79, 95%CI [0.53 - 1.19]
Major or clinically relevant nonmajor bleeding 4.3% 9.7% HR 0.44, 95%CI [0.36 - 0.55], p<0.001
VTE, VTE-related death, or major bleeding 2.8% 4.5% HR 0.62, 95%CI [0.47 - 0.83], p=0.001
Premature drug discontinuation 14% 15.4% N/A
  • In the warfarin group, the INR was in the therapeutic range 61% of the time

Findings: A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding
Hokusai-VTE - Edoxaban vs Warfarin for VTE Treatment, NEJM (2013) [PubMed abstract]
  • The Hokusai-VTE study enrolled 8240 patients with acute VTE
Main inclusion criteria
  • Acute, symptomatic proximal DVT or PE confirmed by imaging
Main exclusion criteria
  • Received heparin, LMWH, or fondaparinux for > 48 hours
  • Received thrombectomy, fibrinolysis, or vena cava filter
  • CrCl < 30 ml/min
  • Dual antiplatelet therapy
  • High risk for bleeding
  • Significant liver disease
Baseline characteristics
  • Average age 56 years
  • Qualifying event: DVT - 60% | PE - 40%
  • Type of VTE: Unprovoked - 66% | Temporary risk factor - 28% | Cancer - 9%
  • Previous VTE - 18%
Randomized treatment groups
  • Group 1 (4118 patients) - Edoxaban 60 mg once daily (30 mg once daily if CrCl 30 - 50 ml/min or if body weight ≤ 132 pounds) for 3 - 12 months
  • Group 2 (4122 patients) - Warfarin with target INR 2 - 3 for 3 - 12 months
  • All patients received initial therapy with open-label enoxaparin or unfractionated heparin for at least 5 days
  • Edoxaban was started after discontinuation of initial heparin. Warfarin was started with initial heparin.
  • Treatment was to be continued for at least 3 months and up to 12 months
Primary outcome: Recurrent symptomatic VTE or VTE-related death
Results

Duration: 12 months
Outcome Edoxaban Warfarin Comparisons
Primary outcome (overall) 3.2% 3.5% HR 0.89, 95%CI [0.70 - 1.13]
Primary outcome (subgroup with index DVT) 3.4% 3.3% HR 1.02, 95%CI [0.75 - 1.38]
Primary outcome (subgroup with index PE) 2.8% 3.9% HR 0.73, 95%CI [0.50 - 1.06]
Major or clinically relevant nonmajor bleeding 8.5% 10.3% HR 0.81, 95%CI [0.71 - 0.94], p=0.004
  • In both groups, 40% of patients were treated for 12 months
  • In the warfarin group, the INR was in the therapeutic range 63.5% of the time

Findings: Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism.





EINSTEIN CHOICE trial - Rivaroxaban vs Aspirin for Secondary Prevention of VTE, NEJM (2017) [PubMed abstract]
  • The EINSTEIN CHOICE trial enrolled 3396 patients with VTE who had completed 6 - 12 months of treatment with anticoagulation
Main inclusion criteria
  • Confirmed symptomatic PE and/or DVT treated for 6 to 12 months with anticoagulation without interruption for > 1 week
Main exclusion criteria
  • Liver disease with coagulopathy
  • CrCl < 30 ml/min
  • Indication for anticoagulant or antiplatelet therapy
  • High risk of bleeding
Baseline characteristics
  • Average age 58 years
  • Index event: DVT - 51% | PE - 33% | Both - 15%
  • Provoked VTE - 58% | Unprovoked VTE - 42%
  • Known thrombophilia - 7%
  • Previous VTE - 18%
Randomized treatment groups
  • Group 1 (1107 patients) - Rivaroxaban 20 mg once daily
  • Group 2 (1127 patients) - Rivaroxaban 10 mg once daily
  • Group 3 (1131 patients) - Aspirin 100 mg once daily
  • Study drugs were administered for up to 12 months
Primary outcome: Composite of symptomatic, recurrent fatal or nonfatal venous thromboembolism and unexplained death for which pulmonary embolism could not be ruled out
Results

Duration: Median of 351 days
Outcome Riv 20 mg Riv 10 mg Aspirin Comparisons
Primary outcome 1.5% 1.2% 4.4% 1 or 2 vs 3 p<0.001
Major bleeding 0.5% 0.4% 0.3% p>0.05 for all comparisons
Overall mortality 0.7% 0.2% 0.6% N/A
DVT 0.8% 0.6% 2.6% N/A
PE 0.5% 0.4% 1.7% N/A
Provoked index event (primary outcome) 1.4% 0.9% 3.6% N/A
Unprovoked index event (primary outcome) 1.8% 1.5% 5.6% N/A

Findings: Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates.
AMPLIFY-EXT Study - Apixaban vs Placebo for Secondary Prevention of VTE, NEJM (2013) [PubMed abstract]
  • The AMPLIFY-EXT study enrolled 2486 patients with VTE who had completed 6 - 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy
Main inclusion criteria
  • Objectively confirmed, symptomatic DVT and/or PE
  • Treated for 6 to 12 months with standard anticoagulant therapy
  • Clinical equipoise about the continuation or cessation of anticoagulant therapy
Main exclusion criteria
  • Required ongoing anticoagulant therapy
  • Required DAPT or aspirin ≥ 165 mg daily
  • CrCl < 25 ml/min
  • Significant liver disease
Baseline characteristics
  • Average age - 56 years
  • DVT - 65%
  • PE - 35%
  • Unprovoked VTE - 92%
  • Previous VTE - 13%
Randomized treatment groups
  • Group 1 (840 patients): Apixaban 2.5 mg twice a day
  • Group 2 (813 patients): Apixaban 5 mg twice a day
  • Group 3 (829 patients): Placebo twice a day
Primary outcome:
  • Efficacy: composite of symptomatic recurrent VTE or death from any cause
  • Safety: major bleeding
Results

Duration: 12 months
Outcome Apixaban 2.5 mg Apixaban 5 mg Placebo Comparisons
Primary outcome 3.8% 4.2% 11.6% 1 vs 3 p<0.001 | 2 vs 3 p<0.001
Major bleeding 0.2% 0.1% 0.5% 1 vs 3 p>0.05 | 2 vs 3 p>0.05
Overall mortality 0.8% 0.5% 1.7% N/A

Findings: Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding.




Hokusai VTE Cancer Study - Edoxaban vs Dalteparin for Treatment of Cancer-associated VTE, NEJM (2018) [PubMed abstract]
  • The Hokusai VTE cancer study enrolled 1046 patients with cancer-associated VTE
Main inclusion criteria
  • Active cancer defined as cancer diagnosed within the previous 6 months; recurrent, regionally advanced, or metastatic cancer; cancer for which treatment had been administered within 6 months before randomization; or hematologic cancer that was not in complete remission
  • Symptomatic or incidentally detected DVT involving the popliteal, femoral, or iliac vein, or inferior vena cava
  • Symptomatic or incidentally detected PE involving segmental or more proximal pulmonary arteries
Main exclusion criteria
  • Basal-cell or squamous-cell skin cancer
  • CrCl < 30 ml/min
  • Platelet count < 50,000/mm³
  • Received fibrinolysis
Baseline characteristics
  • Average age - 64 years
  • PE +/- DVT - 63%
  • DVT only - 37%
  • Metastatic cancer - 53%
  • Previous VTE - 11%
Randomized treatment groups
  • Group 1 (522 patients): LMWH for 5 days followed by Edoxaban 60 mg once daily for 6 - 12 months
  • Group 2 (524 patients): Dalteparin 200 IU/kg SQ once daily for 1 month followed by 150 IU/kg once daily for 6 - 12 months
  • Treatment was open label
Primary outcome: Composite of recurrent VTE or major bleeding during the 12 months after randomization, regardless of treatment duration
Results

Duration: 12 months
Outcome Edoxaban Dalteparin Comparisons
Median length of treatment 211 days 184 days p=0.01
Primary outcome 12.8% 13.5% HR 0.97, 95%CI [0.70 - 1.36], p=0.87
Recurrent VTE 7.9% 11.3% HR 0.71, 95%CI [0.48 - 1.06], p=0.09
Major bleeding 6.9% 4.0%, HR 1.77, 95%CI [1.03 - 3.04], p=0.04

Findings: Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin





AVERT trial - Apixaban vs Placebo for Prevention of VTE in High-risk Cancer Patients, NEJM (2018) [PubMed abstract]
  • The AVERT trial enrolled 574 patients with cancer who were at high-risk for VTE (Khorana score ≥ 2)
Main inclusion criteria
  • Newly diagnosed cancer or progression of known cancer
  • Initiating new course of chemotherapy for ≥ 3 months
  • Khorana score ≥ 2
Main exclusion criteria
  • High risk for bleeding
  • Acute leukemia
  • Myeloproliferative neoplasm
  • CrCl < 30 ml/min
  • Platelet count < 50,000/mm³
Baseline characteristics
  • Average age - 61 years
  • Tumor type: Lymphoma - 25% | Gynecologic - 25% | Pancreatic - 13% | Lung - 10% | Stomach - 7%
  • Khorana score: Two - 65% | Three - 25% | Four - 9%
  • Previous VTE - 3%
Randomized treatment groups
  • Group 1 (291 patients): Apixaban 2.5 mg twice daily
  • Group 2 (283 patients): Placebo twice daily
Primary outcome:
  • Efficacy: Objectively documented venous thromboembolism over a follow-up period of 180 days
  • Safety: Major bleeding episode
Results

Duration: 180 days
Outcome Apixaban Placebo Comparisons
Primary outcome (VTE) 4.2% 10.2% HR 0.41, 95%CI [0.26 - 0.65], p<0.001
Primary outcome (major bleeding) 3.5% 1.8% HR 2.0, 95%CI [1.01 - 3.95], p=0.046
Overall mortality 12.2% 9.8% HR 1.29, 95%CI [0.98 - 1.71]

Findings: Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo.
CASSINI trial - Rivaroxaban vs Placebo for Prevention of VTE in High-risk Ambulatory Cancer Patients, NEJM (2019) [PubMed abstract]
  • The CASSINI trial randomized 841 patients with cancer who were at high-risk for VTE (Khorana score ≥ 2)
Main inclusion criteria
  • Ambulatory outpatient
  • Solid tumor or lymphoma
  • Khorana score ≥ 2
  • Plan to start a new cancer treatment regimen within 1 week
Main exclusion criteria
  • Brain tumor or brain mets
  • High risk for bleeding
  • CrCl < 30 ml/min
  • Platelet count < 50,000/mm³
Baseline characteristics
  • Median age - 63 years
  • Tumor type: Pancreatic - 33% | Gastric - 21% | Lung - 16% | Other - 11% | Lymphoma - 7%
  • Khorana score: Two - 69% | Three - 24% | Four - 6%
  • Previous VTE - 1.7%
Randomized treatment groups
  • Group 1 (420 patients): Rivaroxaban 10 mg once daily for 180 days
  • Group 2 (421 patients): Placebo once daily for 180 days
  • Patients underwent screening US of both lower extremities at Week 8, Week 16, and 180 days
Primary outcome:
  • Efficacy: Composite of objectively confirmed symptomatic or asymptomatic proximal DVT in a lower limb, symptomatic DVT in an upper limb or distal DVT in a lower limb, symptomatic or incidental PE, and death from venous thromboembolism
  • Safety: Occurrence of major bleeding
Results

Duration: 180 days
Outcome Rivaroxaban Placebo Comparisons
Primary outcome (efficacy) 6.0% 8.8% HR 0.66, 95%CI [0.40 - 1.09], p=0.10
Primary outcome (safety) 2.0% 1.0% HR 1.96, 95%CI [0.59 - 6.49], p=0.26
Overall mortality 20% 23.8% HR 0.83, 95%CI [0.62 - 1.11]
Premature drug discontinuation 43.7% 50.2% N/A

Findings: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding.




MAGELLAN Study - Rivaroxaban vs Enoxaparin for VTE Prevention in Acutely Ill Medical Patients [PubMed abstract]
  • The MAGELLAN study enrolled 8101 patients who were hospitalized for an acute medical illness
Main inclusion criteria
  • ≥ 40 years old
  • Hospitalized for < 72 hours before randomization
  • Reduced mobility
  • Hospitalized for one of the following: NYHA III or IV heart failure, active cancer, ischemic stroke, acute infectious or inflammatory disease, respiratory insufficiency
Main exclusion criteria
  • History of hemorrhagic stroke
  • Significant bleeding within 30 days
  • Indication for surgery
  • Known coagulopathy
Baseline characteristics
  • Median age 71 years
  • Median duration of hospitalization - 11 days
  • History of VTE - 4.6%
  • Medical illness: Infection - 45% | Heart failure - 32% | Respiratory insufficiency - 28% | Ischemic stroke - 17% | Active cancer - 7%
Randomized treatment groups
  • Group 1 (4050 patients): Rivaroxaban 10 mg once daily for 35±4 days.
  • Group 2 (4051 patients): Enoxaparin 40 mg SQ once daily for 10±4 days
  • Each group received matching placebo of comparator treatment
  • All patients had lower extremity ultrasound performed after the last dose of study medication
Primary outcomes
  • 1. Composite of asymptomatic proximal or symptomatic venous thromboembolism up to day 10
  • 2. Composite of asymptomatic proximal or symptomatic venous thromboembolism up to day 35
Results

Duration: 35 days
Outcome Rivaroxaban Enoxaparin Comparisons
Primary outcome up to day 10 2.7% 2.7% p=0.003 (noninferiority)
Primary outcome up to day 35 4.4% 5.7% p=0.02 (superiority)
Overall mortality (day 35) 5.1% 4.8% N/A
Clinically relevant bleeding (day 10) 2.8% 1.2% p<0.001
Primary outcome + bleeding (day 10) 6.6% 4.6% p<0.001
Primary outcome + bleeding (day 35) 9.4% 7.8% p=0.02

Findings: In acutely ill medical patients, rivaroxaban was noninferior to enoxaparin for standard-duration thromboprophylaxis. Extended-duration rivaroxaban reduced the risk of venous thromboembolism. Rivaroxaban was associated with an increased risk of bleeding.




RECORD1 Study - Rivaroxaban vs Enoxaparin After Hip Replacement, NEJM (2008) [PubMed abstract]
  • The RECORD1 study enrolled 4541 patients undergoing total hip replacement
Main inclusion criteria
  • Scheduled to undergo total hip replacement
Main exclusion criteria
  • High bleeding risk
  • Bilateral hip replacement
  • CrCl < 30 ml/min
  • Clinically significant liver disease
Baseline characteristics
  • Average age 63 years
  • History of VTE - 2.3%
  • Average duration of surgery - 90 minutes
Randomized treatment groups
  • Group 1(2266 patients) - Rivaroxaban 10 mg once daily through day 35 after surgery
  • Group 2 (2275 patients) - Enoxaparin 40 mg SQ once daily through day 35 after surgery
  • Rivaroxaban was started 6 - 8 hours after wound closure
  • Enoxaparin was initiated 12 hours before surgery and restarted 6 to 8 hours after wound closure
Primary outcome: Composite of symptomatic thromboembolism (DVT and PE), thromboembolism detected on venography performed at Day 36, and death from any cause up to 36 days
Results

Duration: 36 days
Outcome Rivaroxaban Enoxaparin Comparisons
Primary outcome 1.1% 3.7% diff -2.6%, 95%CI [-3.7 to -1.5], p<0.001
Symptomatic VTE during treatment 0.3% 0.5% diff -0.2%, 95%CI [-0.6 to 0.1], p=0.22
Any on-treatment bleeding 6% 5.9% p=0.94
Major bleeding 0.3% 0.1% p=0.18
  • About 31% of the randomized patients were not included in the final efficacy analysis, primarily because they did not undergo proper venography at Day 36 [8]

Findings: A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles.
RECORD3 Study - Rivaroxaban vs Enoxaparin After Knee Replacement, NEJM (2008) [PubMed abstract]
  • The RECORD3 study enrolled 2531 patients undergoing total knee replacement
Main inclusion criteria
  • Scheduled to undergo total knee replacement
Main exclusion criteria
  • High risk for bleeding
  • Clinically significant liver disease
Baseline characteristics
  • Average age 68 years
  • History of VTE - 3.6%
  • Average duration of surgery - 97 minutes
Randomized treatment groups
  • Group 1 (1254 patients) - Rivaroxaban 10 mg once daily for 10 - 14 days
  • Group 2 (1277 patients) - Enoxaparin 40 mg SQ daily for 10 - 14 days
  • Rivaroxaban was started 6 - 8 hours after wound closure
  • Enoxaparin was initiated 12 hours before surgery and restarted 6 to 8 hours after wound closure
Primary outcome: Composite of symptomatic thromboembolism, DVT detected on venography performed on Days 11 - 15, and death from any cause at 13 - 17 days after surgery
Results

Duration: 17 days
Outcome Rivaroxaban Enoxaparin Comparisons
Primary outcome 9.6% 18.9% diff -9.2%, 95%CI [-12.4 to -5.9], p<0.001
Symptomatic VTE 0.7% 2% diff -1.3%, 95%CI [-2.2 to -0.4], p=0.005
Any bleeding 4.9% 4.8% p=0.93
Major bleeding 0.6% 0.5% p=0.77
  • About 33% of the randomized patients were not included in the final efficacy analysis, primarily because they did not undergo proper venography between Days 11 - 15

Findings: Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar rates of bleeding.
ADVANCE-3 Study - Apixaban vs Enoxaparin After Hip Replacement, NEJM (2010) [PubMed abstract]
  • The ADVANCE-3 study enrolled 5407 patients undergoing total hip replacement
Main inclusion criteria
  • Scheduled to undergo total hip replacement or revision of previous total hip replacement
Main exclusion criteria
  • Known or suspected coagulation disorder
  • History of HIT syndrome
  • High risk for bleeding
  • CrCl < 30 ml/min
  • Significant liver disease
Baseline characteristics
  • Average age 60 years
  • History of DVT - 1.6%
  • History of PE - 0.5%
  • Average duration of surgery - 1.49 hours
  • Average duration of hospitalization - 9 days
Randomized treatment groups
  • Group 1 (2708 patients) - Apixaban 2.5 mg twice a day for 32 - 38 days
  • Group 2 (2699 patients) - Enoxaparin 40 mg SQ once daily for 32 - 38 days
  • Apixaban was started 12 - 24 hours after wound closure
  • Enoxaparin was started 12 hours before surgery and continued after surgery according to the investigator’s standard of care
Primary outcome: Composite of symptomatic VTE, DVT detected on venography performed at the end of therapy, and death from any cause
Results

Duration: Average of 34 days
Outcome Apixaban Enoxaparin Comparisons
Primary outcome 1.4% 3.9% diff -2.5%, 95%CI [-3.5 to -1.5], p<0.001
Major VTE 0.5% 1.1% diff -0.7%, 95%CI [-1.3 to -0.2], p=0.01
Clinically relevant bleeding 4.8% 5% diff -0.2%, 95%CI [-1.4 to 1.0], p=0.72
  • The average duration of treatment was 34 days in both groups
  • About 28% of the randomized patients were not included in the final efficacy analysis, primarily because they did not undergo proper venography at the end of treatment

Findings: Among patients undergoing hip replacement, thromboprophylaxis with apixaban, as compared with enoxaparin, was associated with lower rates of venous thromboembolism, without increased bleeding.
ADVANCE-1 Study - Apixaban vs Enoxaparin After Knee Replacement, NEJM (2009) [PubMed abstract]
  • The ADVANCE-1 study enrolled 3195 patients undergoing total knee replacement
Main inclusion criteria
  • Scheduled to undergo total knee replacement surgery for one or both knees, including revision of a previously inserted artificial joint
Main exclusion criteria
  • Known or suspected coagulation disorder
  • History of HIT syndrome
  • High risk for bleeding
  • CrCl < 30 ml/min
  • Significant liver disease
Baseline characteristics
  • Average age 66 years
  • History of DVT - 3.3%
  • History of PE - 0.5%
  • Bilateral knee surgery - 2.1%
  • Average duration of surgery - 1.54 hours
  • Average duration of hospitalization - 6.3 days
Randomized treatment groups
  • Group 1 (1599 patients) - Apixaban 2.5 mg twice a day for 10 - 14 days
  • Group 2 (1596 patients) - Enoxaparin 30 mg twice a day for 10 - 14 days
  • Study drug was started 12 - 24 hours after surgery
Primary outcome: Composite of symptomatic VTE, DVT detected on venography at the end of treatment, and death from any cause during the intended treatment period
Results

Duration: Average of 11.6 days
Outcome Apixaban Enoxaparin Comparisons
Primary outcome 9% 8.8% diff 0.11, 95%CI [-2.22 to 2.44]
Major bleeding events 0.7% 1.4% diff -0.81%, 95%CI [-1.49 to 0.14], p=0.05
  • The average duration of treatment was 11.6 days in both groups
  • About 28% of the randomized patients were not included in the final efficacy analysis, primarily because they did not undergo proper venography at the end of treatment

Findings: As compared with enoxaparin for efficacy of thromboprophylaxis after knee replacement, apixaban did not meet the prespecified statistical criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding and it had a similar adverse-event profile.





COMPASS Trial - Rivaroxaban 2.5 mg twice daily + ASA vs Rivaroxaban 5 mg twice daily vs ASA in Stable CVD, NEJM (2017) [PubMed abstract]
  • The COMPASS trial enrolled 27,395 patients with stable CAD
Main inclusion criteria
  • Documented CAD and/or PAD (patients < 65 years required to have additional risk factors or more extensive disease)
Main exclusion criteria
  • High bleeding risk
  • History of hemorrhagic or lacunar stroke
  • NYHA class III or IV heart failure
  • GFR < 15 ml/min
  • Need for dual antiplatelet therapy or anticoagulation
Baseline characteristics
  • Average age 68 years
  • Documented CAD - 91%
  • Documented PAD - 27%
  • Previous myocardial infarction - 62%
  • Previous stroke - 4%
Randomized treatment groups
  • Group 1 (9152 patients) - Rivaroxaban 2.5 mg twice daily + aspirin 100 mg once daily
  • Group 2 (9117 patients) - Rivaroxaban 5 mg twice daily
  • Group 3 (9126 patients) - Aspirin 100 mg once daily
  • Study aspirin was enteric coated
  • Groups 2 and 3 received placebo pills of opposing therapies
  • The trial had another factor where patients were randomized to a pantoprazole or placebo. That part of the trial is still ongoing.
Primary outcome: Composite of cardiovascular death, stroke, or myocardial infarction
Results

Duration: After a mean of 23 months, the trial was stopped early for superiority of the Riv 2.5 mg + ASA
Outcome Riv 2.5 mg + ASA Riv 5 mg ASA Comparisons
Primary outcome 4.1% 4.9% 5.4% 1 vs 3 p<0.001 | 2 vs 3 p=0.12
Overall mortality 3.4% 4.0% 4.1% 1 vs 3 p=0.01 | 2 vs 3 p=0.67
Myocardial infarction 1.9% 2.0% 2.2% 1 vs 3 p=0.14 | 2 vs 3 p=0.24
Stroke 0.9% 1.3% 1.6% 1 vs 3 p<0.001 | 2 vs 3 p=0.12
Major bleeding 3.1% 2.8% 1.9% 1 vs 3 p<0.001 | 2 vs 3 p<0.001
Primary outcome + bleeding 4.7% 5.5% 5.9% 1 vs 3 p<0.001 | 2 vs 3 p=0.36
  • A subgroup analysis that only included patients with CAD (N=24,824) found similar results [PMID 29132879] as did one that only included patients with PAD (N=7470) [PMID 29132880]

Findings: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events.





APPRAISE-2 Study - Apixaban vs Placebo in ACS, NEJM (2011) [PubMed abstract]
  • The APPRAISE-2 study enrolled 7392 patients with acute coronary syndrome
Main inclusion criteria
  • Acute coronary syndrome within past 7 days + 2 or more of the following: ≥ 65 years old, diabetes, history of prior MI within 5 years, history of stroke, peripheral vascular disease, heart failure or EF < 40% in association with the index event, CrCl < 60 ml/min
Main exclusion criteria
  • CrCl < 20 ml/min
  • High risk for bleeding
  • NYHA class IV heart failure
  • Any history of intracranial bleeding
  • Platelet count < 100,000/mm³
  • Taking CYP3A4 strong inhibitor
Baseline characteristics
  • Median age 67 years
  • Index event: STEMI - 39.6% | NSTEMI - 41.6% | Unstable angina - 18.1%
  • Management of index event: PCI - 44% | Medical therapy - 55% | CABG - 0.6%
  • Heart failure - 28%
  • Prior coronary revascularization - 28%
Randomized treatment groups
  • Group 1 (3705 patients) - Apixaban 5 mg twice a day
  • Group 2 (3687 patients) - Placebo twice a day
  • At randomization, 97% of patients were taking aspirin and 81% were receiving aspirin + P2Y12 inhibitor, predominantly clopidogrel
Primary outcome: Composite of cardiovascular death, myocardial infarction, or ischemic stroke
Results

Duration: After a median follow-up of 241 days, the study was stopped early due to net harm with apixaban
Outcome Apixaban Placebo Comparisons
Primary outcome 7.5% 7.9% HR 0.95, 95%CI [0.80 - 1.11], p=0.51
Overall mortality 4.2% 3.9% HR 1.08, 95%CI [0.86 - 1.35], p=0.51
Major or clinically relevant nonmajor bleeding 3.2% 1.2% HR 2.64, 95%CI [1.87 - 3.72], p<0.001
Intracranial bleeding 0.3% 0.1% HR 4.06, 95%CI [1.15 - 14.38], p=0.03

Findings: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events.
ATLAS-ACS Study - Rivaroxaban vs Placebo in ACS, NEJM (2012) [PubMed abstract]
  • The ATLAS-ACS study enrolled 15,526 patients with acute coronary syndrome
Main inclusion criteria
  • Acute coronary syndrome (if < 55 years old then diabetes or history of previous heart attack were also required)
Main exclusion criteria
  • Previous intracranial hemorrhage
  • Platelet count < 90,000/mm³
  • Previous stroke or TIA while taking aspirin and P2Y12 inhibitor
  • CrCl < 30 ml/min
  • Significant GI bleed within 12 months
Baseline characteristics
  • Average age 62 years
  • Index event: STEMI - 50% | NSTEMI - 25.6% | Unstable angina - 24.4%
  • PCI or CABG for index event - 60.4%
  • Median CrCl - 85 ml/min
Randomized treatment groups
  • Group 1 (5174 patients) - Rivaroxaban 2.5 mg twice a day
  • Group 2 (5176 patients) - Rivaroxaban 5 mg twice a day
  • Group 3 (5176 patients) - Placebo twice a day
  • In all groups, 98.6% of patients were receiving aspirin and 93% of patients were receiving a P2Y12 inhibitor
Primary outcome: Composite of cardiovascular death, myocardial infarction, or stroke (ischemic or hemorrhagic)
Results

Duration: Average of 13.1 months
Outcome Riv 2.5 mg Riv 5 mg Placebo Comparisons
Primary outcome 9.1% 8.8% 10.7% 1 vs 3 p=0.02 | 2 vs 3 p=0.03
Overall mortality 2.9% 4.4% 4.5% 1 vs 3 p=0.002 | 2 vs 3 p=0.66
TIMI bleeding requiring medical attention 12.9% 16.2% 7.5% 1 vs 3 p<0.001 | 2 vs 3 p<0.001
Intracranial hemorrhage 0.4% 0.7% 0.2% 1 vs 3 p=0.04 | 2 vs 3 p=0.005
Premature drug discontinuation 26.9% 29.4% 26.4% N/A

Findings: In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding.




COMMANDER HF STUDY - Rivaroxaban vs Placebo in Heart Failure with CAD, NEJM (2018) [PubMed abstract]
  • The COMMANDER HF study enrolled 5022 patients with heart failure and CAD
Main inclusion criteria
  • Heart failure with EF ≤ 40%
  • CAD
  • Treated for an episode of worsening heart failure within the previous 21 days
  • BNP ≥ 200 pg/ml or NT-proBNP ≥ 800 pg/ml
Main exclusion criteria
  • A fib
  • High risk of bleeding
  • CrCl < 20 ml/min
  • Heart failure not due to CAD
Baseline characteristics
  • Average age - 66 years
  • Median BNP - 700 pg/ml
  • Median EF - 35%
  • NYHA class: I - 3% | II - 44% | III - 49% | IV - 4%
Randomized treatment groups
  • Group 1 (2507 patients): Rivaroxaban 2.5 mg twice daily
  • Group 2 (2515 patients): Placebo twice daily
  • All patients received standard therapy for heart failure
  • Aspirin, alone or in combination with a thienopyridine, was taken by 93.1% of the patients, with 34.8% taking dual antiplatelet therapy at baseline
Primary outcome: Composite of death from any cause, myocardial infarction, or stroke
Results

Duration: Median of 21.1 months
Outcome Rivaroxaban Placebo Comparisons
Primary outcome 25% 26% HR 0.94, 95%CI [0.84 – 1.05], p=0.27
Overall mortality 22% 22% HR 0.98, 95%CI [0.87 – 1.10]
Myocardial infarction 3.9% 4.7% HR 0.83, 95%CI [0.63 – 1.08]
Stroke 2% 3% HR 0.66, 95%CI [0.47 - 0.95]
Major bleeding 3.3% 2.0%, HR 1.68, 95%CI[1.18 - 2.39], p=0.003

Findings: Rivaroxaban at a dose of 2.5 mg twice daily was not associated with a significantly lower rate of death, myocardial infarction, or stroke than placebo among patients with worsening chronic heart failure, reduced left ventricular ejection fraction, coronary artery disease, and no atrial fibrillation.