- ACRONYMS AND DEFINITIONS
- ACC - American College of Cardiology
- ACCP - American College of Chest Physicians
- AHA - American Heart Association
- ASH - American Society of Hematology
- A fib - Atrial fibrillation
- CABG - Coronary artery bypass grafting
- CAD - Coronary artery disease
- CVD - Cardiovascular disease
- DVT - Deep vein thrombosis
- EF - Ejection Fraction
- HR - Hazard Ratio
- LMWH - Low molecular weight heparins
- MI - Myocardial Infarction
- NNT - Number needed to treat
- NSTEMI - Non-ST elevation myocardial infarction
- NYHA - New York Heart Association heart failure classifications
- PAD - Peripheral artery disease
- PCI - Percutaneous coronary intervention
- PE - Pulmonary embolism
- P-gp - P-glycoprotein
- PI - Manufacturer's package insert
- PVD - Peripheral vascular disease
- RCT - Randomized controlled trial
- Riv - Rivaroxaban
- SQ - Subcutaneously
- TIA - Transient ischemic attack
- ULN - Upper limits of normal
- STEMI - ST-elevation myocardial infarction
- VKA - Vitamin K antagonist (e.g. warfarin)
- VTE - Venous Thromboembolism (DVT and PE)
- DRUGS IN CLASS
- Factor Xa Inhibitors
- Apixaban (Eliquis®)
- Edoxaban (Savaysa®)
- Rivaroxaban (Xarelto®)
- MECHANISM OF ACTION
- Factor Xa and coagulation
- Factor Xa converts Prothrombin to Thrombin (see coagulation cascade illustration)
- Thrombin is a major component in coagulation and platelet activation (see platelet activation)
- Factor Xa inhibitors directly block Factor Xa and prevent it from facilitating thrombin formation
- FDA-APPROVED INDICATIONS
- Apixaban (Eliquis®)
- Nonvalvular atrial fibrillation - see ARISTOTLE study
- Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery - see ADVANCE-1 study and ADVANCE-3 study
- Treatment of Deep Vein Thrombosis (DVT) - see AMPLIFY study
- Treatment of Pulmonary embolism (PE) - see AMPLIFY study
- Reduction in the risk of recurrence of DVT and PE - see AMPLIFY-EXT study
- Edoxaban (Savaysa®)
- Nonvalvular atrial fibrillation - see ENGAGE AF-TIMI 48 study
- Treatment of Deep Vein Thrombosis (DVT) following 5 - 10 days of parenteral anticoagulation - see Hokusai-VTE study
- Treatment of Pulmonary embolism (PE) following 5 - 10 days of parenteral anticoagulation - see Hokusai-VTE study
- Rivaroxaban (Xarelto®)
- Adults
- Nonvalvular atrial fibrillation - see ROCKET-AF study
- Treatment of deep vein thrombosis (DVT) - see EINSTEIN-DVT study
- Treatment of pulmonary embolism (PE) - see EINSTEIN-PE study
- Reduction in the risk of recurrence of DVT and PE - see EINSTEIN CHOICE study
- Prophylaxis of deep vein thrombosis following hip or knee replacement surgery - see RECORD1 study and RECORD3 study
- Prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding - see MAGELLAN study
- High risk for bleeding defined as any of the following: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e. undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy
- Reduction of risk of major cardiovascular events in patients with coronary artery disease - see COMPASS trial
- Reduction of risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after lower extremity revascularization due to symptomatic PAD - see COMPASS trial and VOYAGER PAD
- Pediatric
- Treatment of VTE and reduction in risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment
- Thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease after the Fontan procedure
- ATRIAL FIBRILLATION
- Atrial fibrillation
- Atrial fibrillation (A fib) is a common heart arrhythmia that increases a person's risk of stroke. A fib is sometimes associated with heart valve disorders, particularly mitral disease and prosthetic heart valves. Most patients with A fib do not have valve disorders, and their condition is referred to as "nonvalvular A fib." Rivaroxaban, edoxaban, and apixaban are FDA-approved to prevent stroke in nonvalvular A fib. VKAs should be used in A fib associated with mitral disease and mechanical heart valves, as studies have shown that they are superior to Factor Xa inhibitors in these conditions (see prosthetic heart valves and mitral valve stenosis)
- Studies comparing Factor Xa inhibitors to warfarin in A fib are detailed below
- 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 |
|
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.
- 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 |
|
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.
- 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 |
|
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:
- Summary
- Rivaroxaban, edoxaban, and apixaban are effective alternatives to warfarin for preventing strokes in nonvalvular atrial fibrillation. Factor Xa inhibitors are much more expensive than warfarin, but they do not require lab monitoring and dose adjustments that are common with warfarin.
- Apixaban and edoxaban were slightly superior to warfarin in their respective trials, while rivaroxaban was equivalent. Patients in the apixaban and edoxaban trials had lower average CHADS2 scores (2.1 and 2.8, respectively) than those in the rivaroxaban study (3.47), which may have affected the results. All three Factor Xa inhibitors had a lower risk of hemorrhagic stroke than warfarin.
- DEEP VEIN THROMBOSIS (DVT)
- Deep vein thrombosis (DVT)
- Deep vein thromboses are treated with anticoagulants to hasten reabsorption, stop extension, and prevent pulmonary embolism. For decades, the only available oral therapies were vitamin K antagonists like warfarin. The 3 studies below compared the effects of rivaroxaban, apixaban, and edoxaban to vitamin K antagonists in patients with acute DVT.
- 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] |
|
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.
- 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 |
|
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
- 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 |
|
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
- Summary
- In the studies above, rivaroxaban, edoxaban, and apixaban were noninferior to warfarin for DVT treatment, and apixaban and edoxaban were associated with fewer bleeding events
- Initial parenteral therapy is not required with apixaban or rivaroxaban, while 5 - 10 days are recommended with edoxaban
- PULMONARY EMBOLISM
- Pulmonary embolism (PE)
- Pulmonary embolisms are treated with anticoagulants to hasten reabsorption and prevent extension. For decades, the only available oral therapies were vitamin K antagonists like warfarin. The 3 studies below compared the effects of rivaroxaban, apixaban, and edoxaban to vitamin K antagonists in patients with acute PE.
- 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 |
|
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.
- 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 |
|
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
- 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 |
|
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
- Summary
- In the studies above, rivaroxaban, edoxaban, and apixaban were noninferior to warfarin for PE treatment, and apixaban and edoxaban were associated with fewer bleeding events
- Initial parenteral therapy is not required with apixaban or rivaroxaban, while 5 - 10 days are recommended with edoxaban
- VTE - SECONDARY PREVENTION
- Overview
- After a VTE has been treated for 3 - 6 months, extended anticoagulation is recommended in some patients to prevent recurrence. In the first study below, rivaroxaban was compared to aspirin for extended VTE prevention, and in the second study, apixaban was compared to placebo.
- 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.
- 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
- CANCER-ASSOCIATED VTE
- Cancer-associated VTE treatment
- Low molecular weight heparins like dalteparin have traditionally been the preferred treatment for cancer-associated VTE. The two studies detailed below compared edoxaban and apixaban to dalteparin in cancer patients with acute VTE.
- 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
- STUDY
- Design: Randomized controlled trial (N=1170 | length = 6 months) in patients with cancer who had symptomatic or incidental VTE
- Treatment: Apixaban 10 mg twice daily for 7 days then 5 mg twice daily vs Dalteparin 200 IU/kg once daily for one month then 150 IU/kg once daily
- Primary outcome: Objectively confirmed recurrent venous thromboembolism during the trial period
- Results:
- Primary outcome: Apixaban - 5.6%, Dalteparin - 7.9% (HR 0.63 95%CI [0.37 to 1.07])
- Major bleeding: Apixaban - 3.8%, Dalteparin - 4% (p=0.60)
- Findings: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding
- Professional recommendations
- Summary
- In the two studies above, edoxaban and apixaban were noninferior to dalteparin for treating cancer-associated VTE. However, edoxaban was associated with a higher risk of major bleeding events, which the authors note were mainly upper GI bleeds in patients with gastrointestinal cancer.
- Rivaroxaban has also been found to be noninferior to dalteparin in several small studies. [PMID 34627853, PMID 29746227]
- Cancer-associated VTE prevention in high-risk patients
- Malignancy is a major risk factor for VTE, and there has been interest in giving cancer patients routine thromboprophylaxis. Studies evaluating prophylactic heparins have had mixed results, and current guidelines do not recommend their use.
- A risk prediction tool called the Khorana score (scale 0 - 6 with higher scores indicating greater risk) has been developed to help identify cancer patients at high VTE risk. (Khorana score calculator) A score of 3 or higher is considered high risk, and a score of 1 to 2 is considered intermediate risk. Studies have suggested that prophylaxis may be beneficial in patients with a score of 3 or greater.
- The two studies detailed below compared apixaban and rivaroxaban to placebo for VTE prevention in cancer patients with a Khorana score of 2 or more.
- 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.
- 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.
- Summary
- In the AVERT trial, apixaban was superior to placebo in preventing VTE, but it had no effect on overall mortality and caused more major bleeding. In the CASSINI trial, rivaroxaban was not superior to placebo for preventing VTE or improving mortality. One weakness of both studies is that only a third of participants had a Khorana score of 3 or greater, which means higher-risk patients were underrepresented. These two studies do not support routine thromboprophylaxis in cancer patients.
- VTE PREVENTION DURING HOSPITALIZATION
- Overview
- The MAGELLAN study detailed below compared rivaroxaban to enoxaparin for VTE prevention in acutely ill hospitalized patients
- 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.
- Summary
- In the MAGELLAN study, an extended course of rivaroxaban was superior to enoxaparin in preventing VTE in hospitalized patients, but the risk of clinically relevant bleeding was higher with rivaroxaban. Analyses that combined VTE and bleeding events found that rivaroxaban caused significantly more negative outcomes (VTE + bleeding) than enoxaparin. This study does not support the use of rivaroxaban for VTE prevention in medically ill hospitalized patients.
- HIP AND KNEE REPLACEMENT
- 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
- 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 |
|
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.
- 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 |
|
Findings: Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar rates of bleeding.
- 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 |
|
Findings: Among patients undergoing hip replacement, thromboprophylaxis with apixaban, as compared with enoxaparin, was associated with lower rates of venous
thromboembolism, without increased bleeding.
- 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 |
|
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]
- Summary
- 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 that rivaroxaban for 5 days followed by aspirin was as effective as continuous rivaroxaban. See aspirin for VTE prevention after joint replacement for more.
- A study published in 2020 found that rivaroxaban was superior to enoxaparin for preventing VTE in patients undergoing nonmajor lower extremity orthopedic surgery [PMID 32223113]
- STABLE CAD AND PVD
- Overview
- Daily aspirin is universally recommended in patients with CAD and PVD
- Two studies have now been published that looked at the effect of adding low-dose rivaroxaban (2.5 mg twice daily) to aspirin in these conditions. The COMPASS trial published in 2017 looked at stable CAD and PVD, and another trial published in 2020 looked at low-dose rivaroxaban in patients with PVD who had undergone revascularization. Both studies are detailed below.
- 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 |
|
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.
- STUDY
- Design: Randomized placebo-controlled trial (N=6564 | length = 28 months) in patients with PVD who had undergone successful revascularization
- Treatment: Rivaroxaban 2.5 mg twice daily vs Placebo. All patients received aspirin 100 mg once daily.
- Primary outcome: Composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes
- Results:
- Primary outcome (3-year estimate): Rivaroxaban - 17.3%, Placebo - 19.9% (p=0.009). For the components of the composite outcome, rivaroxaban was only superior to placebo for acute limb ischemia.
- Overall mortality: Rivaroxaban - 9.8%, Placebo - 9.1% (p=0.34)
- TIMI major bleeding: Rivaroxaban - 2.65%, Placebo - 1.87% (p=0.07)
- ISTH major bleeding: Rivaroxaban - 5.94%, Placebo - 4.06% (p=0.007)
- Findings: In patients with peripheral artery disease who had undergone lower-extremity revascularization, rivaroxaban at a dose of 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes than aspirin alone. The incidence of TIMI major bleeding did not differ significantly between the groups. The incidence of ISTH major bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone
- Summary
- 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 and PVD. The combination group had more major bleeding events but a significantly lower overall mortality and superior net clinical benefit. Based on the net clinical benefit, the number needed to treat (NNT) for the addition of rivaroxaban 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. Contrarily, the COMMANDER HF trial did not find a benefit of low-dose rivaroxaban in patients with heart failure and CAD.
- The second trial that looked at low-dose rivaroxaban in PVD after revascularization found that rivaroxaban was superior to placebo for acute limb ischemia; however, rivaroxaban was associated with more bleeding events and had no effect on mortality
- EXPLORATORY STUDIES | Acute coronary syndrome
- Overview
- 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
- 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.
- 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.
- Summary
- 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
- EXPLORATORY STUDIES | Heart failure with CAD
- Overview
- 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
- 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.
- Summary
- 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.
- SIDE EFFECTS
- Bleeding
- The therapeutic effect of Factor Xa inhibitors is to inhibit clot formation, therefore they will inherently increase the risk of unwanted bleeding
- In atrial fibrillation and VTE trials, apixaban and edoxaban conferred a lower risk of bleeding when compared to warfarin while the risk with rivaroxaban was similar to warfarin
- See reversing Factor Xa inhibitors below for a review of stopping bleeding in emergency situations
- CONTRAINDICATIONS
- All Factor Xa inhibitors
- Active pathological bleeding
- Known hypersensitivity reaction
- PRECAUTIONS
- Kidney disease
- Liver disease
- Apixaban (Eliquis®)
- Child-Pugh A: no adjustment necessary
- Child-Pugh B: has not been studied. No dosage recommendation given.
- Child-Pugh C: DO NOT USE
- Edoxaban (Savaysa®)
- Child-Pugh A: no adjustment necessary
- Child-Pugh B/C: DO NOT USE
- Rivaroxaban (Xarelto®)
- Child-Pugh A: no adjustment necessary
- Child-Pugh B/C: DO NOT USE
- Elderly
- Apixaban (Eliquis®)
- The recommended dose of apixaban in atrial fibrillation 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 [12]
- Edoxaban and rivaroxaban
- No age-specific dosage recommendations are made
- Body weight
- Apixaban (Eliquis®)
- The pharmacokinetics of apixaban are affected by body weight. This has raised the question as to whether body weight affects its efficacy. A post hoc analysis of the ARISTOTLE trial found no significant difference in efficacy across a range of body weights. [PMID 30773022]
- For atrial fibrillation, the apixaban dosing guidelines recommend a lower dose in some patients who weigh < 132 pounds (see below)
- The recommended dose of apixaban in atrial fibrillation 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 [12]
- Edoxaban (Savaysa®)
- In the treatment of VTE, the recommended dose is 30 mg once daily in patients who weigh < 132 pounds (60 kg) [21]
- Rivaroxaban (Xarelto®)
- No weight-based dosage recommendations are made
- Prosthetic heart valves
- Factor Xa inhibitors are not recommended in patients who require anticoagulation for mechanical heart valves. The direct thrombin inhibitor dabigatran was compared to warfarin in patients with mechanical heart valves, and the trial was terminated early because dabigatran was clearly inferior. [PMID 23991661]. After these negative results, Factor Xa inhibitors were never studied.
- Warfarin is the preferred anticoagulant in all patients with mechanical heart valves. See bioprosthetic heart valves and transcatheter aortic valve replacement for antithrombotic recommendations in other types of heart valves.
- Antiphospholipid antibody (APA) syndrome
- Antiphospholipid antibody syndrome is an autoimmune syndrome that increases a person's risk for thrombosis. Patients with APA syndrome who are triple positive (positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies) are at greatest risk for thrombosis.
- A small study that compared rivaroxaban to warfarin in patients with triple-positive APA syndrome was stopped early when rivaroxaban was found to be clearly inferior to warfarin for preventing thromboembolic events. [PMID 30002145] Another study that compared rivaroxaban to warfarin for preventing recurrent thrombosis in patients with APA syndrome did not prove that rivaroxaban was noninferior to warfarin. [PMID 31610549] If this study had more power, it's likely rivaroxaban would have been inferior.
- After these studies were published, the prescribing information for Factor Xa inhibitors was updated to state that the drugs are not recommended in APA syndrome, especially in patients who are triple positive
- Mitral valve stenosis
- Factor Xa inhibitors are not recommended in patients with moderate to severe mitral valve stenosis. A study (N=4531) published in 2022 found that VKAs were superior to rivaroxaban in preventing cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation. [PMID 36036525]
- LAB (PT, INR, aPTT) EFFECTS
- Factor Xa inhibitors prolong the partial thromboplastin time (aPTT), prothrombin time (PT), and INR. The effect is small and highly variable making these studies of no practical value in monitoring the therapeutic effect of Factor Xa inhibitors. [10, 12]
- In situations where measuring the effect of Factor Xa inhibitors may be necessary (e.g. emergency surgery), anti-Xa levels may be useful. Anti-Xa levels measure the concentration of Factor Xa inhibitors in the blood.
- REVERSING FACTOR Xa INHIBITORS
- Overview
- One of the main concerns with Factor Xa Inhibitors is the lack of a proven agent to rapidly reverse their effect in the case of an emergency
- In patients with normal kidney and liver function, the anticoagulant effect of Factor Xa inhibitors is mostly gone by 24 hours after the last dose
- The manufacturers of rivaroxaban, apixaban, and edoxaban mention prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) as possible agents to quickly reverse the anticoagulant effects of Factor Xa inhibitors. The effect of these agents on clinical outcomes has not been validated in clinical trials [11, 12, 21]
- Prothrombin complex concentrate (PCC)
- Several small studies have shown that PCC is effective in reversing the effects of Factor Xa inhibitors
- In one study, PCC reversed the effects of rivaroxaban [PMID 21900088]. In another study, PCC reversed the effects of edoxaban [PMID 25403645].
- A cohort study found that PCC was effective in stopping major bleeding in patients taking rivaroxaban and apixaban [PMID 25403645]
- Andexanet alfa
- An agent called andexanet alfa has also been developed to counteract the effects of Factor Xa inhibitors. Andexanet alfa is a human Factor Xa "decoy" that binds Factor Xa inhibitors and stops them from inactivating endogenous Factor Xa.
- A study published in the NEJM in 2019 found that andexanet alfa was effective in achieving excellent or good hemostasis in 82% (204/249) of patients who had acute major bleeding within 18 hours of taking a Factor Xa inhibitor. [PMID 30730782]
- In 2018, the FDA approved andexanet alfa (Andexxa®) for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding
- Professional guidelines
- Two professional organizations have issued guidelines on reversing Factor Xa inhibitors. Links to both guidelines are available below.
- STOPPING BEFORE PROCEDURES
- Professional recommendations
- Manufacturer recommendations
- Apixaban (Eliquis®)
- Manufacturer recommends stopping for 48 hours prior to procedure with moderate-to-high risk of significant bleeding
- Manufacturer recommends stopping for 24 hours prior to procedure with low risk of significant bleeding [12]
- Edoxaban (Savaysa®)
- Manufacturer recommends discontinuing edoxaban at least 24 hours before invasive or surgical procedures [21]
- Rivaroxaban (Xarelto®)
- Manufacturer recommends stopping for 24 hours prior to procedure if needed [11]
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- All Factor Xa inhibitors
- Drugs that increase the risk of bleeding - drugs that inhibit coagulation may increase the risk of bleeding when taken with Factor Xa inhibitors
- Drugs that may increase the risk of bleeding include:
- Anagrelide (Agrylin®)
- Aspirin
- Direct thrombin inhibitors (dabigatran)
- Factor Xa inhibitors (e.g. rivaroxaban, apixaban)
- Fish oil (e.g. Vascepa®)
- P2Y12 inhibitors (e.g. clopidogrel, ticagrelor, prasugrel)
- NSAIDs (e.g. ibuprofen, naproxen)
- SSRIs and SNRIs (e.g. fluoxetine, venlafaxine)
- Vorapaxar (Zontivity®)
- Warfarin (Coumadin®)
- 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
- 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
- P-glycoprotein inducers - edoxaban is a p-glycoprotein substrate, and p-glycoprotein inducers may decrease its exposure. Do not combine edoxaban with rifampin. Other p-glycoprotein inducers may also lower exposure.
- 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
- Examples of these medications include:
- Carbamazepine (Tegretol®)
- Phenytoin (Dilantin®)
- Rifampin
- St. John's Wort
- 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])
- Metabolism and clearance
- Apixaban (Eliquis®)
- CYP3A4 - major substrate
- P-glycoprotein - substrate
- BCRP - substrate
- CYP2J2 - minor substrate
- CYP1A2 - minor substrate
- CYP2C8 - minor substrate
- CYP2C9 - minor substrate
- CYP2C19 - minor substrate
- Edoxaban (Savaysa®)
- CYP3A4 - minor substrate
- P-glycoprotein - substrate
- Rivaroxaban (Xarelto®)
- CYP3A4 - substrate
- CYP2J2 - substrate
- P-glycoprotein - substrate
- BCRP - substrate
- SWITCHING BETWEEN OTHER ANTICOAGULANTS
- Apixaban (Eliquis®)
- Warfarin to apixaban - warfarin should be discontinued and apixaban started when the INR is below 2.0
- Switching between apixaban and anticoagulants other than warfarin - discontinue one being taken and begin the other at the next scheduled dose
- Switching from apixaban to warfarin - apixaban raises INR, so initial INR measurements are not useful. Use parenteral anticoagulant if necessary while starting warfarin. Start warfarin and parenteral anticoagulant at the time of next scheduled apixaban dose. [12]
- Edoxaban (Savaysa®)
- Warfarin to edoxaban - discontinue warfarin and start edoxaban when the INR is ≤ 2.5
- Switching between edoxaban and anticoagulants other than warfarin - discontinue one being taken and begin the other at the next scheduled dose
- Low Molecular Weight Heparin (LMWH) to edoxaban - discontinue LMWH and start edoxaban at the time of the next scheduled administration of LMWH
- Unfractionated heparin to edoxaban - discontinue the infusion and start edoxaban 4 hours later
- Edoxaban to warfarin
- Oral option - For patients taking 60 mg of edoxaban, reduce the dose to 30 mg and begin warfarin concomitantly. For patients receiving 30 mg of edoxaban, reduce the dose to 15 mg and begin warfarin concomitantly. INR must be measured at least weekly and just prior to the daily dose of edoxaban to minimize the influence of edoxaban on INR measurements. Once a stable INR ≥ 2.0 is achieved, edoxaban should be discontinued and the warfarin continued
- Parenteral option - Discontinue edoxaban and administer a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose. Once a stable INR ≥ 2.0 is achieved the parenteral anticoagulant should be discontinued and the warfarin continued [21]
- Rivaroxaban (Xarelto®)
- Warfarin to rivaroxaban - discontinue warfarin and start rivaroxaban as soon as the INR is below 3.0 to avoid periods of inadequate anticoagulation.
- Rivaroxaban to warfarin - rivaroxaban raises INR, so initial INR measurements are not useful. Use parenteral anticoagulant if necessary while starting warfarin. Start warfarin and parenteral anticoagulant at the time of next scheduled rivaroxaban dose
- Switching from rivaroxaban to anticoagulants other than warfarin - discontinue rivaroxaban and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next rivaroxaban dose would have been taken
- Switching from anticoagulants other than warfarin to rivaroxaban - For patients currently receiving an anticoagulant other than warfarin, start rivaroxaban 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start rivaroxaban at the same time. [11]
- LONG TERM SAFETY
- Apixaban was approved for use in the U.S. in December 2012
- Edoxaban was approved for use in the U.S. in January 2015
- Rivaroxaban was approved for use in the U.S. in July 2011
- The overall long term safety of these drugs is not well-defined, but they have been studied in a number of large trials that have shown them to be safe and effective
- DOSING
- BIBLIOGRAPHY
- 1 - PMID 16908781
- 2 - PMID 21830957 - ROCKET-AF study
- 3 - PMID 21870978 - ARISTOTLE
- 4 - PMID 22858728 - AHA 2012 A fib GL
- 5 - PMID 21128814 - EINSTEIN-DVT
- 6 - PMID 22315278 - ACCP GL 2012
- 7 - PMID 22449293 - EINSTEIN-PE
- 8 - PMID 18579811 - RECORD1
- 9 - PMID 18579812 - RECORD3
- 10 - PMID 21175312 ADVANCE-3
- 11 - Rivaroxaban PI
- 12 - Apixaban PI
- 13 - PMID 21900088
- 14 - PMID 21780946 - APPRAISE-2
- 15 - PMID 22077192 - ATLAS study
- 16 - PMID 23808982 - AMPLIFY study
- 17 - PMID 19657123 - ADVANCE-1 study
- 18 - PMID 24682348 - AHA 2014 A fib GL
- 19 - PMID 24251359 - ENGAGE study
- 20 - PMID 23991658 - Hokusai study
- 21 - Edoxaban PI
- 22 - PMID 26867832 - ACCP 2016 VTE update
- 23 - Betrixaban PI
- 24 - PMID 23216615 - Apixaban for Extended Treatment of Venous Thromboembolism, NEJM (2013)