Savaysa Drug Information
Generic name: EDOXABAN TOSYLATE
Uses of Savaysa
Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation SAVAYSA is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). Limitation of Use for NVAF SAVAYSA should not be used in patients with CrCL > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin.
Treatment of Deep Vein Thrombosis and Pulmonary Embolism SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.
Dosage & Administration of Savaysa
Administration Information If a dose of SAVAYSA is missed, the dose should be taken as soon as possible on the same day. Dosing should resume the next day according to the normal dosing schedule. The dose should not be doubled to make up for a missed dose.
SAVAYSA can be taken without regard to food.
Transition to or from
Discontinuation for Surgery and Other Interventions Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures because of the risk of bleeding. If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.
SAVAYSA can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established noting that the time to onset of pharmacodynamic effect is 1-2 hours. Administer a parenteral anticoagulant and then switch to oral SAVAYSA, if oral medication cannot be taken during or after surgical intervention.
Administration Options
For patients who are unable to swallow whole tablets, SAVAYSA tablets may be crushed and mixed with 2 to 3 ounces of water and immediately administered by mouth or through a gastric tube. The crushed tablets may also be mixed into applesauce and immediately administered orally.
| From | To | Recommendation |
|---|---|---|
| Warfarin or other Vitamin K Antagonists | SAVAYSA | Discontinue warfarin and start SAVAYSA when the INR is ≤ 2.5 |
| Oral anticoagulants other than warfarin or other Vitamin K Antagonists | SAVAYSA | Discontinue current oral anticoagulant and start SAVAYSA at the time of the next scheduled dose of the other oral anticoagulant |
| Low Molecular Weight Heparin (LMWH) | SAVAYSA | Discontinue LMWH and start SAVAYSA at the time of the next scheduled administration of LMWH |
| Unfractionated heparin | SAVAYSA | Discontinue the infusion and start SAVAYSA 4 hours later |
| From | To | Recommendation |
|---|---|---|
| Abbreviations: INR=International Normalized Ratio | ||
| SAVAYSA | Warfarin | Oral option: For patients taking 60 mg of SAVAYSA, reduce the dose to 30 mg and begin warfarin concomitantly. For patients receiving 30 mg of SAVAYSA, 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 SAVAYSA to minimize the influence of SAVAYSA on INR measurements. Once a stable INR ≥ 2.0 is achieved, SAVAYSA should be discontinued and the warfarin continued |
| SAVAYSA | Warfarin | Parenteral option: Discontinue SAVAYSA and administer a parenteral anticoagulant and warfarin at the time of the next scheduled SAVAYSA dose. Once a stable INR ≥ 2.0 is achieved the parenteral anticoagulant should be discontinued and the warfarin continued |
| SAVAYSA | Non-Vitamin-K-Dependent Oral anticoagulants | Discontinue SAVAYSA and start the other oral anticoagulant at the time of the next dose of SAVAYSA |
| SAVAYSA | Parenteral anticoagulants | Discontinue SAVAYSA and start the parenteral anticoagulant at the time of the next dose of SAVAYSA |
Side Effects of Savaysa
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The ENGAGE AF-TIMI 48 Study In the ENGAGE AF-TIMI 48 study, the median study drug exposure for the SAVAYSA and warfarin treatment groups was 2.5 years. Bleeding was the most common reason for treatment discontinuation.
Bleeding led to treatment discontinuation in 3.9% and 4.1% of patients in the SAVAYSA 60 mg and warfarin treatment groups, respectively. In the overall population, major bleeding was lower in the SAVAYSA group compared to the warfarin group. Table 6.1 shows major bleeding events (percentage of patients with at least one bleeding event, per year) for the indicated population (CrCL ≤ 95 mL/min).
Table 6.1: Adjudicated Bleeding Events for NVAF Patients with CrCL ≤ 95 mL/min The on-treatment period is during treatment or within 2 days of stopping study treatment. The difference in hemorrhagic stroke rate from Table 14.1 is because Table 14.1 includes events occurring during treatment or within 3 days of stopping study treatment and this table only includes patients with CrCL ≤ 95 mL/min. The most common site of a major bleeding event was the gastrointestinal (GI) tract.
Table 6.2 shows the number of and the rate at which patients experienced GI bleeding in the SAVAYSA 60 mg and warfarin treatment groups. The comparative rates of major bleeding on SAVAYSA and warfarin were generally consistent among subgroups ( see Figure 6.1 ). Bleeding rates appeared higher in both treatment arms (SAVAYSA and warfarin) in the following subgroups of patients: those receiving aspirin, those in the United States, those more than 75 years old and those with reduced renal function.
Figure 6.1: Adjudicated Major Bleeding in the ENGAGE AF-TIMI 48 During or within 2 days of stopping study treatment Study Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. Interstitial Lung Disease (ILD) was reported as a serious adverse event on treatment for SAVAYSA 60 mg and warfarin in patients, respectively. Many of the cases in both treatment groups were confounded by the use of amiodarone, which has been associated with ILD, or by infectious pneumonia.
In the overall study period, there were 5 and 0 fatal ILD cases in the SAVAYSA 60 mg and warfarin groups, respectively. The Hokusai VTE Study The safety of SAVAYSA in the treatment of VTE was assessed in the Hokusai VTE study. Bleeding in Patients with DVT and/or PE in the Hokusai VTE Study The major safety outcome was Clinically Relevant Bleeding, defined as the composite of Major and Clinically Relevant Non-Major (CRNM) Bleeding that occurred during or within three days of stopping study treatment.
The incidence of Clinically Relevant Bleeding was lower in SAVAYSA than warfarin. Table 6.3 shows the number of patients experiencing bleeding events in the Hokusai VTE Study. In the Hokusai VTE study, among all patients the most common bleeding adverse reactions (≥ 1%) are shown in Table 6.4.
Table 6.4: Adverse Reactions Occurring in ≥ 1% of Patients Treated in Hokusai VTE 72 55 Bleeding in Patients with VTE in the Hokusai VTE Cancer Study The safety of SAVAYSA in patients with cancer and VTE was evaluated in the Hokusai VTE Cancer study. The median duration of SAVAYSA exposure was 211 days (range, 2 to 423). The incidence of major bleeding was higher in the SAVAYSA arm than in the dalteparin arm.
Table 6.5 presents the bleeding results from the Hokusai VTE Cancer study. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytopenia Gastrointestinal disorders: abdominal pain Immune system disorders: angioedema, hypersensitivity Nervous system disorders: dizziness, headache Renal and urinary disorders: anticoagulant-related nephropathy Skin and subcutaneous tissue disorders: urticaria
| Event A subject can be included in multiple sub-categories if he/she had an event for those categories. | SAVAYSA 60 mg Includes all patients with CrCL ≤ 95 mL/min randomized to receive 60 mg once daily, including those who were dose-reduced to 30 mg once daily because of prespecified baseline conditions. N = 5417 n (%/year) | Warfarin N = 5485 n (%/year) | SAVAYSA 60 mg vs. Warfarin HR (95% CI) |
|---|---|---|---|
| Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, n = number of patients with events, N = number of patients in Safety population, | |||
| Major Bleeding A major bleeding event (the study primary safety endpoint) was defined as clinically overt bleeding that met one of the following criteria: fatal bleeding; symptomatic bleeding in a critical site such as retroperitoneal, intracranial, intraocular, intraspinal, intra-articular, pericardial, or intramuscular with compartment syndrome; a clinically overt bleeding event that caused a fall in hemoglobin of at least 2.0 g/dL (or a fall in hematocrit of at least 6.0% in the absence of hemoglobin data), when adjusted for transfusions (1 unit of transfusion = 1.0 g/dL drop in hemoglobin). | 357 (3.1) | 431 (3.7) | 0.84 (0.73, 0.97) |
| Intracranial Hemorrhage (ICH) ICH includes primary hemorrhagic stroke, subarachnoid hemorrhage, epidural/subdural hemorrhage, and ischemic stroke with major hemorrhagic conversion. | 53 (0.5) | 122 (1.0) | 0.44 (0.32, 0.61) |
| Hemorrhagic Stroke | 33 (0.3) | 69 (0.6) | 0.49 (0.32, 0.74) |
| Other ICH | 20 (0.2) | 55 (0.5) | 0.37 (0.22, 0.62) |
| Gastrointestinal Gastrointestinal (GI) bleeds include bleeding from upper and lower GI tract. Lower GI tract bleeding includes rectal bleeds. | 205 (1.8) | 150 (1.3) | 1.40 (1.13, 1.73) |
| Fatal Bleeding Fatal bleed is a bleeding event during the on-treatment period and adjudicated as leading directly to death within 7 days. | 21 (0.2) | 42 (0.4) | 0.51 (0.30, 0.86) |
| ICH | 19 (0.2) | 36 (0.3) | 0.54 (0.31, 0.94) |
| Non-intracranial | 2 (< 0.1) | 6 (< 0.1) | ---- |
| SAVAYSA N = 5417 n (%/year) | Warfarin N = 5485 n (%/year) | |
|---|---|---|
| Major Gastrointestinal (GI) Bleeding GI bleeding was defined by location as upper or lower GI | 205 (1.78) | 150 (1.27) |
| Upper GI | 123 (1.06) | 88 (0.74) |
| Lower GI Lower GI bleeding included anorectal bleeding | 85 (0.73) | 64 (0.54) |
| GUSTO GUSTO – Severe or life-threatening bleeding that caused hemodynamic compromise and requires intervention Severe GI bleeding | 16 (0.14) | 17 (0.14) |
| Fatal GI bleeding | 1 (< 0.1) | 2 (< 0.1) |
| SAVAYSA (N = 4118) | Warfarin (N = 4122) | |
|---|---|---|
| Abbreviations: N = number of patients in the modified intent-to-treat population; n = number of events; CRNM = clinically relevant non-major | ||
| Clinically Relevant Bleeding Primary Safety Endpoint: Clinically Relevant Bleeding (composite of Major and CRNM). (Major/CRNM), n (%) | 349 (8.5) | 423 (10.3) |
| Major Bleeding A major bleeding event was defined as clinically overt bleeding that met one of the following criteria: associated with a fall in hemoglobin level of 2.0 g/dL or more, or leading to transfusion of two or more units of packed red cells or whole blood; occurring in a critical site or organ: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; contributing to death., n (%) | 56 (1.4) | 66 (1.6) |
| Fatal bleeding | 2 (<0.1) | 10 (0.2) |
| Intracranial fatal | 0 (0.0) | 6 (0.1) |
| Non-fatal critical organ bleeding | 13 (0.3) | 25 (0.6) |
| Intracranial bleeding | 5 (0.1) | 12 (0.3) |
| Non-fatal non-critical organ bleeding | 41 (1.0) | 33 (0.8) |
| Decrease in Hb ≥ 2 g/dL | 40 (1.0) | 33 (0.8) |
| Transfusion of ≥ 2 units of RBC | 28 (0.7) | 22 (0.5) |
| CRNM Bleeding CRNM bleeding was defined as overt bleeding not meeting the criteria for a major bleeding event but that was associated with a medical intervention, an unscheduled contact (visit or telephone call) with a physician, temporary cessation of study treatment, or associated with discomfort for the subject such as pain, or impairment of activities of daily life. | 298 (7.2) | 368 (8.9) |
| Any Bleed | 895 (21.7) | 1056 (25.6) |
| SAVAYSA 60 mg (N = 4118) n (%) | Warfarin (N = 4122) n (%) | |
|---|---|---|
| Bleeding ADRs Adjudicated Any Bleeding by location for all bleeding event categories (including Major and CRNM) | ||
| Vaginal Gender specific vaginal bleeding percentage is based on number of female subjects in each treatment group | 158 (9) | 126 (7.1) |
| Cutaneous soft tissue | 245 (5.9) | 414 (10) |
| Epistaxis | 195 (4.7) | 237 (5.7) |
| Gastrointestinal bleeding | 171 (4.2) | 150 (3.6) |
| Lower gastrointestinal | 141 (3.4) | 126 (3.1) |
| Oral/pharyngeal | 138 (3.4) | 162 (3.9) |
| Macroscopic hematuria/urethral | 91 (2.2) | 117 (2.8) |
| Puncture site | 56 (1.4) | 99 (2.4) |
| Non-Bleeding ADRs | ||
| Rash | 147 (3.6) | 151 (3.7) |
| Abnormal liver function tests | 322 (7.8) | 322 (7.8) |
| Anemia | 72 (1.7) | 55 (1.3) |
| SAVAYSA (N = 522) | Dalteparin (N = 524) | |
|---|---|---|
| Abbreviations: N = number of patients in the modified intent-to-treat population; n = number of events; CRNM = clinically relevant non-major | ||
| Major Bleeding A major bleeding event was defined as clinically overt bleeding that met one of the following criteria: associated with a fall in hemoglobin level of 2.0 g/dL or more, or leading to transfusion of two or more units of packed red cells or whole blood; occurring in a critical site or organ: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; contributing to death., n (%) | 32 (6.1%) | 16 (3.1%) |
| Fatal bleeding | 1 (0.2%) All events in this table, except for the fatal bleeding event on SAVAYSA, are based on adjudicated events. The fatal bleeding event on SAVAYSA was adjudicated as a major bleed; however, the adjudicated cause of death was cancer-related death. | 2 (0.4%) |
| Intracranial | 0 | 1 (0.2%) |
| Lower gastrointestinal | 1 (0.2%) | 1 (0.2%) |
| Non-fatal critical organ bleeding | 5 (1%) | 6 (1.1%) |
| Intracranial bleeding | 2 (0.4%) | 2 (0.4%) |
| Non-fatal non-critical organ bleeding | 27 (5.2%) | 8 (1.5%) |
| Gastrointestinal | 22 (4.2%) | 4 (0.8%) |
| Upper gastrointestinal | 18 (3.4%) | 3 (0.6%) |
| Lower gastrointestinal | 3 (0.6%) | 1 (0.2%) |
| Decrease in Hb ≥ 2 g/dL | 28 (5.4%) | 11 (2.1%) |
| CRNM Bleeding CRNM bleeding was defined as overt bleeding not meeting the criteria for a major bleeding event but that was associated with a medical intervention, an unscheduled contact (visit or telephone call) with a physician, temporary cessation of study treatment, or associated with discomfort for the subject such as pain or impairment of activities of daily life., n (%) | 70 (13.4%) | 48 (9.2%) |
| Any Bleeding, n (%) | 137 (26.2%) | 104 (19.8%) |
Warnings & Cautions for Savaysa
Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with CrCL > 95 mL/min SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the randomized ENGAGE AF-TIMI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with SAVAYSA 60 mg daily compared to patients treated with warfarin. In these patients another anticoagulant should be used.
Increased Risk of Stroke with Discontinuation of SAVAYSA in Patients with Nonvalvular Atrial Fibrillation Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If SAVAYSA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described in the transition guidance.
Risk of Bleeding
SAVAYSA increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue SAVAYSA in patients with active pathological bleeding.
Concomitant use of drugs affecting hemostasis may increase the risk of bleeding. These include aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Reversal of Anticoagulant Effect There is no established way to reverse the anticoagulant effects of SAVAYSA, which can be expected to persist for approximately 24 hours after the last dose.
The anticoagulant effect of SAVAYSA cannot be reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not available. Hemodialysis does not significantly contribute to edoxaban clearance.
Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of SAVAYSA. The use of prothrombin complex concentrates (PCC), or other procoagulant reversal agents such as activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical outcome studies. When PCCs are used, monitoring for anticoagulation effect of edoxaban using clotting test (PT, INR, or aPTT) or anti-FXa activity is not useful and is not recommended.
Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 12 hours after the last administration of SAVAYSA.
The next dose of SAVAYSA should not be administered earlier than 2 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction).
If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
Patients with Mechanical Heart Valves or Moderate to Severe Mitral Stenosis The safety and efficacy of SAVAYSA has not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis. The use of SAVAYSA is not recommended in these patients.
Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including SAVAYSA, are not recommended for use in patients with triple positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive ), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
Drug Interactions with Savaysa
Anticoagulants, Antiplatelets, Thrombolytics, and SSRIs/SNRIs Co-administration of anticoagulants, antiplatelet drugs, thrombolytics and SSRIs or SNRIs may increase the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with anticoagulants, aspirin, other platelet aggregation inhibitors, and/or NSAIDs. Long-term concomitant treatment with SAVAYSA and other anticoagulants is not recommended because of increased risk of bleeding.
Short term co-administration may be needed for patients transitioning to or from SAVAYSA. In clinical studies with SAVAYSA concomitant use of aspirin (low dose ≤ 100 mg/day) or thienopyridines, and NSAIDs was permitted and resulted in increased rates of Clinically Relevant Bleeding. Carefully monitor for bleeding in patients who require chronic treatment with low dose aspirin and/or NSAIDs.
As with other anticoagulants the possibility may exist that patients are at an increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets.
P-gp Inducers Avoid the concomitant use of SAVAYSA with rifampin.
P-gp Inhibitors Treatment of NVAF Based on clinical experience from the ENGAGE AF-TIMI 48 study, dose reduction in patients concomitantly receiving P-gp inhibitors resulted in edoxaban blood levels that were lower than in patients who were given the full dose. Consequently, no dose reduction is recommended for concomitant P-gp inhibitor use. Treatment of Deep Vein Thrombosis and Pulmonary Embolism
Pregnancy Safety for Savaysa
Pregnancy Risk Summary Available data about SAVAYSA use in pregnant women are insufficient to determine whether there are drug-associated risks for adverse developmental outcomes. In animal developmental studies, no adverse developmental effects were seen when edoxaban was administered orally to pregnant rats and rabbits during organogenesis at up to 16-times and 8-times, respectively, the human exposure, when based on body surface area and AUC, respectively (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions.
Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. Fetal/Neonatal adverse reactions Use of anticoagulants, including edoxaban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.
Labor or delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. SAVAYSA use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches.
Data Animal Data Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no malformation was seen when edoxaban was administered orally at doses up to 300 mg/kg/day, or 49 times the human dose of 60 mg/day normalized to body surface area. Increased post-implantation loss occurred at 300 mg/kg/day, but this effect may be secondary to the maternal vaginal hemorrhage seen at this dose.
In rabbits, no malformation was seen at doses up to 600 mg/kg/day (49 times the human exposure at a dose of 60 mg/day when based on AUC). Embryo-fetal toxicities occurred at maternally toxic doses, and included absent or small fetal gallbladder at 600 mg/kg/day, and increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day, which is equal to or greater than 20 times the human exposure. In a rat pre- and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day, which is up to 3 times the human exposure when based on AUC.
Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day.
Pediatric Use of Savaysa
Pediatric Use The safety and effectiveness of SAVAYSA have not been established in pediatric patients with confirmed VTE (PE and/or DVT). Effectiveness was not demonstrated in an adequate and well-controlled study conducted in 145 SAVAYSA-treated pediatric patients, from birth to less than 18 years of age with confirmed VTE (PE and/or DVT), treated for 3 months up to a maximum of 12 months.
Contraindications for Savaysa
SAVAYSA is contraindicated in patients with: Active pathological bleeding. Active pathological bleeding
Overdosage Information for Savaysa
A specific reversal agent for edoxaban is not available. Overdose of SAVAYSA increases the risk of bleeding. The following are not expected to reverse the anticoagulant effects of edoxaban: protamine sulfate, vitamin K, and tranexamic acid.
Hemodialysis does not significantly contribute to edoxaban clearance.
Clinical Studies of Savaysa
Transition to Other Anticoagulants in the ENGAGE AF-TIMI 48 Study In the ENGAGE AF-TIMI 48 study, the schemes for transitioning from study medication to open-label warfarin at the end of study were associated with similar rates of stroke and systemic embolism in the SAVAYSA 60 mg and warfarin groups. In the SAVAYSA 60 mg group 7 (0.2%) of 4529 patients had a stroke or SEE compared to 7 (0.2%) of 4506 patients in the warfarin arm. 14.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism The Hokusai VTE Study SAVAYSA for the treatment of patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) was studied in a multi-national, double-blind study (Hokusai VTE) (NCT00986154) which compared the efficacy and safety of SAVAYSA 60 mg orally once daily to warfarin (titrated to INR 2.0 to 3.0) in patients with acute symptomatic venous thromboembolism (VTE) (DVT or PE with or without DVT). All patients had VTE confirmed by appropriate diagnostic imaging at baseline and received initial heparin therapy with low molecular weight heparin (LMWH) or unfractionated heparin for at least 5 days and until INR (sham or real) was ≥ 2.0 on two measurements.
Blinded drug treatment in the warfarin arm was started concurrently with initial heparin therapy and in the SAVAYSA arm after discontinuation of initial heparin. Patients randomized to SAVAYSA received 30 mg once daily if they met one or more of the following criteria: CrCL 30 to 50 mL/min, body weight ≤ 60 kg, or concomitant use of specific P-gp inhibitors (verapamil and quinidine or the short-term concomitant administration of azithromycin, clarithromycin, erythromycin, oral itraconazole or oral ketoconazole). The edoxaban dosage regimen was to be returned to the regular dosage of 60 mg once daily at any time the subject is not taking the concomitant medication provided no other criteria for dose reduction are met.
Other P-gp inhibitors were not permitted in the study. Patients on antiretroviral therapy (ritonavir, nelfinavir, indinavir, saquinavir) as well as cyclosporine were excluded from the Hokusai VTE study. The concomitant use of these drugs with SAVAYSA has not been studied in patients.
The treatment duration was from 3 months up to 12 months, determined by investigator based on patient clinical features. Patients were excluded if they required thrombectomy, insertion of a caval filter, use of a fibrinolytic agent, or use of other P-gp inhibitors, had a creatinine clearance < 30 mL/min, significant liver disease, or active bleeding. The primary efficacy outcome was symptomatic VTE, defined as the composite of recurrent DVT, new non-fatal symptomatic PE, and fatal PE during the 12-month study period.
A total of 8292 patients were randomized to receive SAVAYSA or warfarin and were followed for a mean treatment duration of 252 days for SAVAYSA and 250 days for warfarin. The mean age was approximately 56 years. The presenting diagnosis was PE (with or without DVT) in 40.7% and DVT only in 59.3% of patients.
At baseline, 27.6% of patients had temporary risk factors only (e.g., trauma, surgery, immobilization, estrogen therapy). Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 9% of patients in both groups. In the warfarin group, the median TTR (time in therapeutic range, INR 2.0 to 3.0) was 65.6%.
A total of 8240 patients (n = 4118 for SAVAYSA and n = 4122 for warfarin) received study drug and were included in the modified intent-to-treat (mITT) population. SAVAYSA was demonstrated to be non-inferior to warfarin for the primary endpoint of recurrent VTE (Table 14.3, Figure 14.3). The treatment duration was for a minimum of 6 months and up to 12 months.
The efficacy of SAVAYSA was based upon the rate of recurrent VTE (mITT) during the overall study period. SAVAYSA was non-inferior to dalteparin for the rate of recurrent VTE. Recurrent VTE occurred in of patients in the SAVAYSA and dalteparin groups, respectively.
| Events | SAVAYSA 30 mg Includes patients dose-reduced to 15 mg for the 30 mg treatment group and 30 mg for the 60 mg treatment group (N = 7002) n (%/yr) The event rate (%/yr) is calculated as number of events/subject-year exposure. | SAVAYSA 60 mg (N = 7012) n (%/yr) | Warfarin (N = 7012) n (%/yr) | SAVAYSA 30 mg vs. warfarin HR (CI) 97.5% CI for primary endpoint of First Stroke or SEE. 95% CI for Ischemic Stroke, Hemorrhagic Stroke or Systemic Embolism p-value | SAVAYSA 60 mg vs. warfarin HR (CI) p-value |
|---|---|---|---|---|---|
| Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, n = number of events, mITT = Modified Intent-to-Treat, N = number of patients in mITT population, SEE = Systemic Embolic Event, yr = year. | |||||
| First Stroke or SEE | 253 (1.6) | 182 (1.2) | 232 (1.5) | 1.07 (0.87, 1.31) p = 0.44 | 0.79 (0.63, 0.99) p = 0.017 |
| Ischemic Stroke | 225 (1.4) | 135 (0.9) | 144 (0.9) | 1.54 (1.25, 1.90) | 0.94 (0.75, 1.19) |
| Hemorrhagic Stroke | 18 (0.1) | 39 (0.3) | 75 (0.5) | 0.24 (0.14, 0.39) | 0.52 (0.36, 0.77) |
| Systemic Embolism | 10 (< 0.1) | 8 (< 0.1) | 13 (< 0.1) | 0.75 (0.33, 1.72) | 0.62 (0.26, 1.50) |
| STROKE TYPE Renal Function Subgroups Renal function subgroups are based on estimated creatinine clearance in mL/min calculated using the Cockcroft-Gault formula. | Treatment Arm | n (N) | Event Rate (%/yr) | SAVAYSA 60 mg vs. Warfarin HR (95% CI) |
|---|---|---|---|---|
| Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, n = number of events, mITT = Modified Intent-to-Treat, N = number of patients in mITT population, yr = year. | ||||
| PRIMARY ENDPOINT (STROKE/SEE) | ||||
| ≤ 95 (Indicated Population) | Warfarin | 211 (5485) | 1.8 | 0.68 (0.55, 0.84) |
| SAVAYSA 60 mg | 142 (5417) | 1.2 | ||
| ≤ 50 83% of patients with pre-randomization CrCL ≤ 50 mL/min in the SAVAYSA 60 mg group were dose-reduced and consequently received SAVAYSA 30 mg daily. All patients in the warfarin group with CrCL ≤ 50 mL/min were treated in the same way as those with higher levels of CrCL. | Warfarin | 50 (1356) | 2.0 | 0.90 (0.60, 1.34) |
| SAVAYSA 60 mg | 45 (1372) | 1.8 | ||
| > 50 to ≤ 80 | Warfarin | 135 (3053) | 2.0 | 0.53 (0.40, 0.70) |
| SAVAYSA 60 mg | 71 (3020) | 1.1 | ||
| > 80 to ≤ 95 | Warfarin | 26 (1076) | 1.0 | 1.05 (0.61, 1.82) |
| SAVAYSA 60 mg | 26 (1025) | 1.1 | ||
| > 95 See Boxed Warning | Warfarin | 21 (1527) | 0.6 | 1.87 (1.10, 3.17) |
| SAVAYSA 60 mg | 40 (1595) | 1.0 | ||
| ISCHEMIC STROKE | ||||
| ≤ 95 (Indicated Population) | Warfarin | 129 (5485) | 1.1 | 0.80 (0.62, 1.04) |
| SAVAYSA 60 mg | 102 (5417) | 0.9 | ||
| ≤ 50 | Warfarin | 28 (1356) | 1.1 | 1.11 (0.66, 1.84) |
| SAVAYSA 60 mg | 31 (1372) | 1.2 | ||
| > 50 to ≤ 80 | Warfarin | 83 (3053) | 1.2 | 0.63 (0.44, 0.89) |
| SAVAYSA 60 mg | 52 (3020) | 0.8 | ||
| > 80 to ≤ 95 | Warfarin | 18 (1076) | 0.7 | 1.11 (0.58, 2.12) |
| SAVAYSA 60 mg | 19 (1025) | 0.8 | ||
| > 95 | Warfarin | 15 (1527) | 0.4 | 2.16 (1.17, 3.97) |
| SAVAYSA 60 mg | 33 (1595) | 0.9 | ||
| HEMORRHAGIC STROKE | ||||
| ≤ 95 (Indicated Population) | Warfarin | 70 (5485) | 0.6 | 0.50 (0.33, 0.75) |
| SAVAYSA 60 mg | 34 (5417) | 0.3 | ||
| ≤ 50 | Warfarin | 18 (1356) | 0.7 | 0.66 (0.32, 1.36) |
| SAVAYSA 60 mg | 12 (1372) | 0.5 | ||
| > 50 to ≤ 80 | Warfarin | 45 (3053) | 0.7 | 0.38 (0.22, 0.67) |
| SAVAYSA 60 mg | 17 (3020) | 0.3 | ||
| > 80 to ≤ 95 | Warfarin | 7 (1076) | 0.3 | 0.76 (0.24, 2.38) |
| SAVAYSA 60 mg | 5 (1025) | 0.2 | ||
| > 95 | Warfarin | 6 (1527) | 0.2 | 0.98 (0.31, 3.05) |
| SAVAYSA 60 mg | 6 (1595) | 0.2 | ||
| Primary Endpoint | SAVAYSA Includes patients dose-reduced to 30 mg. Among the 1452 (17.6%) patients with low body weight (≤ 60 kg), moderate renal impairment (CrCL ≤ 50 mL/min), or concomitant use of P-gp inhibitors in the Hokusai VTE study, 22 (3.0%) of the SAVAYSA patients (30 mg once daily, n = 733) and 30 (4.2%) of warfarin patients (n = 719) had a symptomatic recurrent VTE event n/N (%) | Warfarin n/N (%) | SAVAYSA vs. Warfarin HR (95% CI) |
|---|---|---|---|
| Abbreviations: mITT = modified intent-to-treat; HR =hazard ratio vs. warfarin; CI =confidence interval; N = number of patients in mITT population; n = number of events | |||
| All patients with symptomatic recurrent VTE Primary Efficacy Endpoint: Symptomatic recurrent VTE (i.e., the composite endpoint of DVT, non-fatal PE and fatal PE) | 130/4118 (3.2) | 146/4122 (3.5) | 0.89 (0.70,1.13) |
| PE with or without DVT | 73/4118 (1.8) | 83/4122 (2.0) | - |
| Fatal PE and Death where PE cannot be ruled out | 24/4118 (0.6) | 24/4122 (0.6) | - |
| Non-fatal PE | 49/4118 (1.2) | 59/4122 (1.4) | - |
| DVT only | 57/4118 (1.4) | 63/4122 (1.5) | - |
| Index PE Index PE refers to patients whose presenting diagnosis was PE (with or without concomitant DVT) patients with symptomatic recurrent VTE | 47/1650 (2.8) | 65/1669 (3.9) | - |
| Index DVT Index DVT refers to patients whose presenting diagnosis was DVT only patients with symptomatic recurrent VTE | 83/2468 (3.4) | 81/2453 (3.3) | - |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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