FACTOR Xa INHIBITORS

















Atrial fibrillation (nonvalvular)
  • Atrial fibrillation is a common heart arrhythmia that increases a person's risk of stroke
  • Rivaroxaban, edoxaban, and apixaban are FDA-approved to treat "nonvalvular" atrial fibrillation
  • "Nonvalvular" means atrial fibrillation that occurs in the absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair [1]
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
Major or nonmajor 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 Edoxaban 30 mg Edoxaban 60 mg Warfarin Comparisons
Primary outcome (annual rate) 1.61% 1.18% 1.50% 1 vs 3, p=0.44 | 2 vs 3, p=0.02
Overall mortality (annual rate) 3.8% 3.99% 4.35% 1 vs 3, p=0.006 | 2 vs 3, p=0.08
All stroke (annual rate) 1.91% 1.49% 1.69% 1 vs 3 p=0.12 | 2 vs 3 p=0.11
Hemorrhagic stroke (annual rate) 0.16% 0.26% 0.47% 1 vs 3 p<0.001; | 2 vs 3 p<0.001
Major or nonmajor clinically relevant bleeding (annual rate) 7.97% 11.10% 13.02% 1 vs 3 p<0.001 | 2 vs 3 p<0.001
Drug discontinuation 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.
AHA recommendations:
StraightHealthcare analysis
  • Rivaroxaban, edoxaban, and apixaban are effective alternatives to warfarin for preventing strokes in atrial fibrillation. Factor Xa inhibitors are much more expensive than warfarin, but they do not require continuous monitoring and therapy adjustments that are common with warfarin.
  • Apixaban and edoxaban were slightly superior to warfarin in their respective trials while rivaroxaban was not. The patients in the apixaban and edoxaban trials were lower risk (average CHADS₂ score 2.1 and 2.8, respectively) when compared to the rivaroxaban trial (average CHADS₂ score 3.47).
  • Interestingly, all three Factor Xa inhibitors had a significantly lower incidence of hemorrhagic stroke when compared to warfarin



Deep vein thrombosis (DVT)
  • Deep vein thrombosis is a blood clot that forms in the deep veins of the legs. The clot may break off and travel to the lungs where it becomes a pulmonary embolism. Pulmonary embolisms can be fatal.
  • Rivaroxaban, edoxaban, and apixaban are approved for the treatment of DVT. Rivaroxaban and apixaban are approved for treatment without initial parenteral anticoagulation. Edoxaban is approved for treatment after 5 - 10 days of initial therapy with a parenteral anticoagulant.
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: Group 1 - 11.3%, Group 2 - 14.2%
  • In Group 2, 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 Group 2, 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 Group 2, 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.
Professional recommendations:
StraightHealthcare analysis
  • Rivaroxaban, edoxaban, and apixaban are as effective as warfarin for treating DVT
  • Apixaban and rivaroxaban are approved for treatment without initial parenteral therapy. Edoxaban is approved for treatment following 5 - 10 days of parenteral therapy.



Pulmonary embolism (PE)
  • Pulmonary embolism is a blood clot that travels to the lungs and lodges in the lung tissue. The affected tissue cannot oxygenate properly. Pulmonary embolisms can be fatal.
  • All three Factor Xa inhibitors are approved for the treatment of PE. Rivaroxaban and apixaban are approved for treatment without initial parenteral anticoagulation. Edoxaban is approved for treatment after 5 - 10 days of initial therapy with a parenteral anticoagulant.
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 Group 2, 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 Group 2, 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 Group 2, 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.
Professional guidelines:
StraightHealthcare analysis
  • Rivaroxaban, edoxaban, and apixaban are as effective as warfarin for treating PE
  • Apixaban and rivaroxaban are approved for treatment without initial parenteral therapy. Edoxaban is approved for treatment following 5 - 10 days of parenteral therapy.



Overview
  • After a patient with a VTE has been treated for 3 - 6 months, it is recommended that some patients continue anticoagulant therapy indefinitely
  • In the studies detailed below, rivaroxaban was compared to aspirin and apixaban was compared to placebo for the secondary prevention of VTE
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.
Professional recommendations:
StraightHealthcare analysis
  • Not surprisingly, rivaroxaban and apixaban were superior to aspirin and placebo, respectively, in preventing recurrent VTE



Overview
  • Patients undergoing hip or knee replacement surgery are at a high risk of VTE for an extended period of time following surgery
  • Rivaroxaban and apixaban are FDA-approved for the prevention of DVT after hip and knee surgery
  • Rivaroxaban and apixaban were compared to enoxaparin in the studies detailed below
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 sub-q 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 sub-q 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 sub-q 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
Major bleeding or clinically relevant nonmajor 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.
ACCP recommendations
  • The ACCP guidelines from 2012 state that low molecular weight heparins (e.g. enoxaparin) are the preferred agents for thromboembolism prophylaxis after major orthopedic surgeries
  • Apixaban, rivaroxaban, and dabigatran are acceptable alternatives for patients unwilling to inject themselves daily with low molecular weight heparins, but they lack long-term safety data [6]
StraightHealthcare analysis
  • Both rivaroxaban and apixaban are effective for prophylaxis against blood clots after major orthopedic surgery
  • In three of the trials above, Factor Xa inhibitors were superior to enoxaparin
  • In the ADVANCE-1 study, apixaban was comparable to enoxaparin with fewer bleeding events
  • A study published in 2018 found rivaroxaban for 5 days followed by aspirin to be as effective as continuous rivaroxaban. See aspirin for VTE prevention after joint replacement for more.



Overview
  • When patients are hospitalized and immobile, they are at greater risk for a VTE
  • Anticoagulants and/or mechanical devices (e.g. leg compression devices) are often used to help prevent VTE in hospitalized patients
  • In the APEX study detailed below, betrixaban was compared to enoxaparin for VTE prevention in hospitalized patients. Based on the results of APEX, betrixaban received an FDA-approved indication for prophylaxis of VTE in adult patients hospitalized for an acute medical illness.
APEX Study - Betrixaban vs Enoxaparin for VTE Prevention in Hospitalized Patients, NEJM (2016) [PubMed abstract]
  • The APEX study enrolled 7513 patients who were hospitalized with an acute medical illness
Main inclusion criteria
  • Age ≥ 40 years
  • Hospitalized for less than 96 hours for a specified acute medical illness (heart failure, respiratory failure, infectious disease, rheumatic disease, or ischemic stroke)
  • One of the following risk factors for VTE: ≥ 75 years old, 60 - 74 years old with D-dimer ≥ 2 X ULN, 40 - 59 years old with D-dimer ≥ 2 X ULN and a history of VTE or cancer
Main exclusion criteria:
  • History of significant bleeding
  • Likely to require major surgery
  • CrCl < 15 ml/min
  • Platelet count < 100,000 mm³
  • Dual antiplatelet therapy
  • Need for prolonged anticoagulation
Baseline characteristics
  • Average age 76 years
  • Admitting diagnosis: Heart failure 45% | Infection 29% | Respiratory failure 12% | Stroke 11% | Rheumatic disorder 3%
  • D-dimer ≥ 2 X ULN - 62%
  • Age ≥ 75 years - 68%
  • History of cancer - 12%
  • History of VTE - 8%
Randomized treatment groups
  • Group 1 (3759 patients) - Betrixaban loading dose of 160 mg followed by 80 mg once daily for 35 to 42 days
  • Group 2 (3754 patients) - Enoxaparin 40 mg SQ once daily for 10 ± 4 days
  • Each group was given a placebo version of the opposing therapy
  • The median number of days of hospitalization was 10 in both groups
  • All asymptomatic patients had a lower extremity ultrasound between days 35 - 42
Primary outcome: Composite of asymptomatic proximal DVT between day 32 and day 47, symptomatic proximal or distal DVT, symptomatic nonfatal PE, or death from VTE between day 1 and day 42
Results

Duration: 47 days
Outcome Betrixaban Enoxaparin Comparisons
Primary outcome 5.3% 7.0% RR 0.76, 95%CI [0.63 - 0.92], p=0.006
Major or clinically relevant nonmajor bleeding 3.1% 1.6% RR 1.97, 95%CI [1.44 - 2.68], p<0.001
Overall mortality 5.7% 5.8% N/A
Median number of days of active treatment 36 days 9 days N/A

Findings: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts.
StraightHealthcare analysis
  • In the APEX study, betrixaban reduced the likelihood of VTE when compared to enoxaparin at the expense of more clinically relevant bleeding events
  • Enoxaparin was given for a median of 9 days and betrixaban was given for a median of 36 days. This makes it difficult to draw any conclusions about the comparative efficacy of the two treatments.



Overview
  • Daily aspirin is universally recommended in patients with stable cardiovascular disease
  • In 2017, the COMPASS trial was performed to see if rivaroxaban could improve outcomes in these patients
  • In 2018, rivaroxaban was FDA-approved for the "Reduction of Risk of Major CV Events in Patients with Chronic CAD or PAD" based on results of the COMPASS trial
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
Net clinical benefit (primary outcome minus fatal bleeding or symptomatic bleeding into critical organ) 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.
StraightHealthcare analysis
  • The COMPASS trial found that the combination of rivaroxaban 2.5 mg twice daily + aspirin was superior to aspirin alone in preventing cardiovascular events in patients with stable CAD. The combination group had more major bleeding events but a significantly lower overall mortality and superior net clinical benefit. Contrarily, the COMMANDER HF trial did not find a benefit of low-dose rivaroxaban in patients with heart failure and CAD.
  • Based on the net clinical benefit, the number needed to treat (NNT) for the addition of rivaroxaban (2.5 mg twice daily) to aspirin to benefit one person is 83. It should also be noted that the trial was stopped early which has the potential to exaggerate results.



Acute coronary syndrome
  • Acute coronary syndrome (ACS) is defined as myocardial infarction or unstable angina
  • Standard treatment for ACS includes aspirin +/- P2Y12 inhibitor
  • Past studies have shown that the addition of a vitamin K antagonist to standard therapy improves ischemic outcomes but worsens bleeding events
  • To see if Factor Xa inhibitors perform better, two studies (one with apixaban and one with rivaroxaban) were performed that added Factor Xa inhibitors to antiplatelet therapy in patients with ACS
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.
StraightHealthcare analysis
  • Apixaban did not improve outcomes in patients with ACS. Rivaroxaban improved outcomes but increased the risk of significant bleeding. The lowest dose of rivaroxaban showed a benefit for overall mortality when compared to placebo.
  • The apixaban study used a full dose of apixaban where the rivaroxaban study used a smaller dose not seen in other studies. This likely contributed to the difference in outcomes. The rivaroxaban study also excluded patients with a history of stroke or TIA while taking aspirin and a P2Y12 inhibitor.
  • In select patients, low-dose anticoagulants may improve outcomes in patients with acute coronary syndrome, although the risk of increased bleeding events is significant

Cryptogenic stroke
  • Cryptogenic strokes are strokes that occur without an identifiable source of thrombosis or embolism
  • Two hypothesized etiologies for cryptogenic strokes are undiagnosed atrial fibrillation and a heart defect called a patent foramen ovale (PFO). A PFO allows blood to pass between the left and right atrium, and therefore, it could allow a venous embolism to become an arterial embolism (paradoxical embolism).
  • Theoretically, anticoagulation could help prevent recurrent cryptogenic strokes if atrial fibrillation or paradoxical embolism are significant sources of these types of strokes
  • A study published in 2018 compared rivaroxaban to aspirin for the prevention of recurrent cryptogenic stroke
NAVIGATE ESUS Study - Rivaroxaban vs Aspirin for Secondary Prevention of Cryptogenic Stroke, NEJM (2018) [PubMed abstract]
  • The NAVIGATE ESUS study enrolled 7213 patients diagnosed with a cryptogenic stroke
Main inclusion criteria
  • Ischemic stroke on imaging within 7 days - 6 months
  • Age > 49 years (if 50 - 59 years required to have 1 additional vascular risk factor)
  • At least 20 hours of cardiac rhythm monitoring to rule out A fib lasting ≥ 6 minutes
Main exclusion criteria
  • Lacunar infarct
  • ≥ 50% stenosis in arteries supplying the area of ischemia
  • Mechanical heart valve
  • A fib
  • Severe mitral stenosis
Baseline characteristics
  • Average age - 67 years
  • PFO - 7%
  • Aspirin use before qualifying stroke - 17%
  • Previous stroke or TIA - 17%
Randomized treatment groups
  • Group 1 (3609 patients): Rivaroxaban 15 mg once daily
  • Group 2 (3604 patients): Aspirin 100 mg once daily
Primary outcome:
  • Efficacy: first recurrent stroke (including ischemic, hemorrhagic, or undefined stroke) or systemic embolism in a time-to-event analysis
  • Safety: major bleeding at any site in the body
Results

Duration: Trial terminated after a median of 11 months due to lack of benefit
Outcome Rivaroxaban Aspirin Comparisons
Recurrent stroke or systemic embolism 5.1% 4.8% HR 1.07, 95%CI[0.87 - 1.33]
Major bleeding 1.8% 0.7%, HR 2.72, 95%CI[1.68 - 4.39], p<0.001

Findings: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding.
StraightHealthcare analysis
  • The results of this study are surprising given the fact that undiagnosed atrial fibrillation and paradoxical embolism are thought to be significant sources of cryptogenic strokes
  • Patients with cryptogenic stroke should only be treated with antiplatelet therapy

Cancer-associated VTE treatment
  • Patients with cancer are at high risk for VTE
  • Current VTE guidelines recommend low molecular weight heparins (LMWH) for the treatment of VTE in patients with cancer
  • A study published in 2018 compared edoxaban to dalteparin for the treatment of VTE in cancer patients
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
StraightHealthcare analysis
  • Edoxaban was equally effective as dalteparin in treating cancer-associated VTE. Edoxaban had significantly more major bleeding events.
  • The authors note in their discussion that the difference in bleeding events was mainly due to upper gastrointestinal bleeds in patients with gastrointestinal cancers
  • The edoxaban group was treated for a longer period than the dalteparin group. The authors state that this was primarily due to patient acceptance (oral vs injection).
  • Edoxaban appears to be a good alternative to LMWH for VTE treatment in cancer patients. Patients with gastrointestinal cancers may carry a slightly higher risk of bleeding on edoxaban when compared to LMWHs.
  • A previous study that compared warfarin to LMWH in cancer patients is reviewed here - PMID 26284719

Cancer-associated VTE prevention
  • All patients with cancer are at higher risk for VTE. A risk predictor called the Khorana score has been developed to help quantify a patient's risk of VTE based on five factors. A score ≥ 3 is considered relatively high risk, and a score of 1 - 2 is considered intermediate risk.
  • The study below compared apixaban to placebo for VTE prevention in patients with a Khorana score ≥ 2.
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.
StraightHealthcare analysis
  • In this trial, apixaban reduced the absolute risk of VTE by 6% while increasing the risk of major bleeding 1.7%
  • Of note, there was a trend towards significantly greater overall mortality in the apixaban group (HR 1.29, 95%CI [0.98 - 1.71]). A study that has enough power to evaluate mortality should be performed before apixaban is recommended in these patients.
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.
StraightHealthcare analysis
  • In the CASSINI trial, rivaroxaban was not superior to placebo for preventing a composite of VTE and VTE-associated death in high-risk cancer patients
  • The authors of the trial were quick to highlight the fact that their "intervention-period analysis" which only included the time patients were on active treatment found rivaroxaban to be superior. Unfortunately, these types of analyses are biased because they select for positive responders and healthier patients.

Heart failure with CAD
  • It has been hypothesized that worsening heart failure can activate thrombin-related pathways that lead to inflammation, VTE, and poorer outcomes
  • The COMMANDER HF study looked at the effects of rivaroxaban in patients with CHF and CAD
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.
StraightHealthcare analysis
  • Low-dose rivaroxaban did not improve outcomes among patients with CHF and CAD. The results are somewhat surprising given that rivaroxaban did improve outcomes in patients with stable CVD (see COMPASS trial). The COMPASS trial excluded patients with NYHA class III and IV disease.










  • Reference: Manufacturer's PI
Apixaban (Eliquis®) dosing
Indication Dosing recommendations
Atrial fibrillation
  • 5 mg twice a day
  • The recommended dose of apixaban is 2.5 mg twice daily in patients with any 2 of the following characteristics:
    • Age ≥ 80 years
    • Body weight ≤ 132 pounds (60 kg)
    • Serum creatinine ≥ 1.5 mg/dl
VTE treatment
  • 10 mg twice a day for 7 days, then 5 mg twice a day
  • No dose adjustment recommended in kidney disease
VTE secondary prevention
  • 2.5 mg twice a day after at least 6 months of treatment
  • No dose adjustment recommended in kidney disease
DVT prophylaxis following hip or knee surgery
  • 2.5 mg twice a day starting 12 - 24 hours after surgery
  • Hip replacement: 35 days of therapy
  • Knee replacement: 12 days of therapy
  • No dose adjustment recommended in kidney disease

  • Reference: Manufacturer's PI
Betrixaban (Bevyxxa®) dosing
Indication Dosing recommendations
Prophylaxis of VTE in adult patients hospitalized for an acute medical illness
  • CrCl > 30 ml/min: Initial single dose of 160 mg, followed by 80 mg once daily
  • CrCl 15 - 30 ml/min: Initial single dose of 80 mg followed by 40 mg once daily
  • Recommended duration of therapy is 35 - 42 days
  • If a dose is missed, the dose should be taken as soon as possible on the same day. The dose should not be doubled to make up for a missed dose.

  • Reference: Manufacturer's PI
Edoxaban (Savaysa®) dosing
Indication Dosing recommendations
Atrial fibrillation
  • CrCl > 95 ml/min: Not recommended
  • CrCl 51 - 95 ml/min: 60 mg once daily
  • CrCl 15 - 50 ml/min: 30 mg once daily
  • CrCl < 15 ml/min: DO NOT USE
  • May take without regard to food
  • In the ENGAGE study, edoxaban 60 mg once daily was not as effective in patients with CrCl > 95 ml/min
VTE treatment
(after 5 - 10 days of parenteral anticoagulant)
  • CrCl > 50 ml/min: 60 mg once daily
  • CrCl 15 - 50 ml/min: 30 mg once daily
  • CrCl < 15 ml/min: - DO NOT USE
  • Weight ≤ 132 lbs (60 kg): 30 mg once daily
  • With certain P-gp inhibitors (see drug interactions below): 30 mg once daily
  • May take without regard to food
  • Before starting Edoxaban, patients should be treated for 5 - 10 days with a parenteral anticoagulant

  • Reference: Manufacturer's PI
Rivaroxaban (Xarelto®) dosing
Indication Dosing recommendations
Atrial fibrillation
  • CrCl > 50 ml/min: 20 mg once daily with evening meal
  • CrCl ≤ 50 ml/min: 15 mg once daily with evening meal
VTE treatment
  • CrCl ≥ 30 ml/min: 15 mg twice a day with food for 21 days, then 20 mg once daily with food
  • CrCl < 30 ml/min: DO NOT USE
  • Take at the same time each day
VTE secondary prevention
  • CrCl ≥ 30 ml/min: 10 mg once daily, after at least 6 months of standard anticoagulant treatment
  • CrCl < 30 ml/min: DO NOT USE
  • May take without regard to food
DVT prophylaxis following hip or knee surgery
  • CrCl ≥ 30 ml/min: 10 mg once daily starting 6 - 10 hours after surgery
  • CrCl < 30 ml/min: DO NOT USE
  • Hip replacement: 35 days of therapy
  • Knee replacement: 12 days of therapy
  • May take without regard to food
Reduction in risk of major CV events in patients with CAD or PAD
  • 2.5 mg twice a day
  • Should be given with aspirin 75 - 100 mg once daily
  • No dose adjustment necessary in kidney disease
  • May take without regard to food

Liver disease dosing recommendations
Child-Pugh class
Drug A B C
Apixaban No adjustment necessary Use with caution. No dosage recommendation given. Do not use
Betrixaban No adjustment necessary Do not use Do not use
Edoxaban No adjustment necessary Do not use Do not use
Rivaroxaban No adjustment necessary Do not use Do not use

Elderly
Apixaban (Eliquis®) Other

Body weight
Apixaban (Eliquis®) Edoxaban (Savaysa®) Other

Prosthetic heart valve

Antiphospholipid antibody syndrome (APA)

Mitral valve stenosis












Drug interactions

All Factor Xa inhibitors
Drugs that increase the risk of bleeding

Apixaban (Eliquis®)
Drugs that are combined P-glycoprotein inhibitors and CYP3A4 strong inhibitors
  • Apixaban is a substrate of P-glycoprotein and CYP3A4
  • Drugs that are combined P-glycoprotein inhibitors and CYP3A4 strong inhibitors may increase apixaban levels
  • For patients receiving apixaban doses of 5 or 10 mg twice a day, reduce the dose by 50% when taken with these drugs
  • In patients who are already taking 2.5 mg twice a day, these medications should not be taken with apixaban
  • Examples of p-glycoprotein inhibitors that are also CYP3A4 strong inhibitors include ketoconazole, itraconazole, and ritonavir
  • One exception to the recommendation is clarithromycin. Pharmacokinetic data suggest that no dose adjustment is necessary when clarithromycin is given with apixaban.
Drugs that are combined P-glycoprotein inducers and CYP3A4 strong inducers
  • Apixaban should not be taken with drugs that act as both P-glycoprotein inducers and CYP3A4 strong inducers because exposure to apixaban is greatly reduced
  • Examples of these medications include rifampin, carbamazepine, phenytoin, and St John's wort

Betrixaban (Bevyxxa®)
P-glycoprotein inhibitors and inducers
  • Betrixaban is a P-glycoprotein substrate. Concomitant P-glycoprotein inhibitors may increase betrixaban exposure and increase bleeding risk. For patients receiving or starting concomitant P-glycoprotein inhibitors, the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily
  • DO NOT USE betrixaban with P-glycoprotein inducers, because the therapeutic effect of betrixaban may be reduced

Edoxaban (Savaysa®)
Certain P-glycoprotein inhibitors
  • Edoxaban dosing for the treatment of DVT and PE should be 30 mg once daily when taken with the following P-glycoprotein inhibitors:
    • Verapamil
    • Quinidine
    • Azithromycin
    • Clarithromycin
    • Erythromycin
    • Itraconazole
    • Ketoconazole
Rifampin
  • DO NOT COMBINE. Rifampin is a P-glycoprotein inducer.

Rivaroxaban (Xarelto®)
Drugs that are combined P-glycoprotein inhibitors and CYP3A4 strong inhibitors
  • Rivaroxaban is a substrate for P-glycoprotein and CYP3A4 and should not be taken with drugs that act as both P-glycoprotein inhibitors and CYP3A4 strong inhibitors. Rivaroxaban blood levels and bleeding risk may increase.
  • The manufacturer states that Erythromycin (E.E.S®, Ery-tab®) and Clarithromycin (Biaxin®) are exceptions and may be administered with rivaroxaban
    • Examples of these medications include:
      • Ketoconazole (Nizoral®)
      • Itraconazole (Sporanox®)
      • Lopinavir and Ritonavir (Kaletra®)
      • Ritonavir (Norvir®)
      • Indinavir (Crixivan®)
      • Conivaptan (Vaprisol®)
Drugs that are combined P-glycoprotein inducers and CYP3A4 strong inducers
  • Rivaroxaban should not be taken with drugs that act as both P-gp inducers and CYP3A4 strong inducers
  • Blood levels of rivaroxaban may decrease
Drugs that are combined P-glycoprotein inhibitors and CYP3A4 moderate inhibitors in patients with decreased kidney function (CrCl ≤ 80 ml/min)
  • In patients with decreased kidney function (CrCl ≤ 80 ml/min), rivaroxaban should not be taken with drugs that are combined P-glycoprotein inhibitors and CYP3A4 moderate inhibitors unless the potential benefit outweighs the risk
  • While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-glycoprotein and weak or moderate CYP3A4 inhibitors did not show an increase in bleeding in patients with CrCl 30 to < 50 mL/min (HR 1.05, 95%CI [0.77 - 1.42])

  • Reference Manufacturer's PI
Metabolism and elimination
Drug P-glycoprotein CYP3A4 CYP2J2 ABCG2 (BCRP) transporter Other
Apixaban Substrate Major substrate Minor substrate Substrate CYP1A2, CYP2C8, CYP2C9, and CYP2C19 minor substrate
Betrixaban Substrate - - - -
Edoxaban Substrate Minor substrate - - -
Rivaroxaban Substrate Substrate Substrate Substrate -