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DVT/PE Study Design

Hokusai-VTE: A robust
clinical study of acute
symptomatic DVT and PE1,2

Study originally appeared in the New England Journal of Medicine.2

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DVT - PE Study Design

Objective1

  • SAVAYSA® for the treatment of patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) was studied in a multinational, double-blind study which compared the efficacy and safety of SAVAYSA orally once daily to warfarin (titrated to international normalized ratio [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 (UFH) for at least 5 days

Study endpoints1

Primary efficacy

Symptomatic VTE, defined as the composite of recurrent DVT, new nonfatal symptomatic PE, and fatal PE during the 12-month study period

Primary safety

Clinically relevant bleeding, defined as the composite of major and clinically relevant non-major (CRNM) bleeding that occurred during treatment or within 3 days of stopping study treatment

Trial design1,2

  • Blinded drug treatment was started in the SAVAYSA arm after discontinuation of initial heparin, and in the warfarin arm concurrently with initial heparin therapy1
  • Patients randomized to SAVAYSA received 30 mg once daily if they met 1 or more of the following criteria1:
    • Creatinine clearance (CrCl) 30 to 50 mL/min
    • Body weight ≤60 kg/132 lb
    • Concomitant use of certain P-glycoprotein (P-gp) inhibitors
      • SAVAYSA 30 mg was used for patients who had concomitant use of verapamil or quinidine, or for short-term concomitant administration of azithromycin, clarithromycin, erythromycin, oral itraconazole, or oral ketoconazole
      • In the Hokusai-VTE study, the edoxaban dosage regimen was to be returned to the regular dosage of 60 mg once daily at any time the subject was not taking the concomitant medication, provided no other criteria for dose reduction were met. Other P-gp inhibitors were not permitted in the study

Hokusai-VTE studied a diverse range of patients reflecting many of the patients you treat

Inclusion/exclusion criteria

Key inclusion criteria2

  • 18 years of age or older
  • Objectively diagnosed, acute, symptomatic DVT involving the popliteal, femoral, or iliac veins or acute, symptomatic PE (with or without DVT)

Key exclusion criteria1,2

  • Cancer for which long-term treatment with LMWH was anticipated
  • Required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent
  • CrCl<30 mL/min
  • Significant liver disease
  • Active bleeding
  • Another indication for warfarin therapy
  • Continued to receive treatment with aspirin at a dose of >100 mg daily or dual antiplatelet therapy
  • Concomitant use of ritonavir, nelfinavir, indinavir, saquinavir, or cyclosporine

DVT Safety and Efficacy - Page Navigation

DOSING

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Important Safery Information

INDICATIONS

SAVAYSA® (edoxaban) is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). SAVAYSA should not be used in patients with creatinine clearance (CrCl) >95 mL/min because of an increased risk of ischemic stroke compared to warfarin.

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.

IMPORTANT SAFETY INFORMATION FOR SAVAYSA

BOXED WARNINGS

  • REDUCED EFFICACY IN NVAF PATIENTS WITH CRCL >95 ML/MIN
    SAVAYSA should not be used in patients with CrCl >95 mL/min. In the ENGAGE AF-TIMI 48 study, NVAF patients with CrCl >95 mL/min had an increased rate of ischemic stroke with SAVAYSA 60 mg once daily compared to patients treated with warfarin. In these patients another anticoagulant should be used.
  • PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF ISCHEMIC EVENTS
    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 in the Prescribing Information.
  • SPINAL/EPIDURAL HEMATOMA
    • Epidural or spinal hematomas may occur in patients treated with SAVAYSA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures
    • Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; a history of spinal deformity or spinal surgery
    • Optimal timing between the administration of SAVAYSA and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.

CONTRAINDICATIONS

SAVAYSA is contraindicated in patients with active pathological bleeding.

WARNINGS AND PRECAUTIONS

Bleeding Risk

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). 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 its anticoagulant activity.

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. SAVAYSA is not recommended in these patients.

ADVERSE REACTIONS
  • NVAF: The most common adverse reactions (≥5%) are bleeding and anemia
  • DVT/PE: The most common adverse reactions (≥1%) are bleeding, rash, abnormal liver function tests and anemia
DISCONTINUATION FOR SURGERY AND OTHER INTERVENTIONS

Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures because of the risk of bleeding. SAVAYSA can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established.

DRUG INTERACTIONS
  • Anticoagulants, Antiplatelets, and Thrombolytics: Coadministration of anticoagulants, antiplatelet drugs, and thrombolytics may increase the risk of bleeding
  • P-gp Inducers: Avoid concomitant use of SAVAYSA with rifampin
  • P-gp Inhibitors (DVT/PE only): Coadministration of certain P-gp inhibitor medications requires a dose reduction of SAVAYSA to 30 mg once daily
SPECIAL POPULATIONS
  • Nursing mothers: Discontinue drug or discontinue nursing
  • Impaired renal function (CrCl 15 to 50 mL/min): Reduce SAVAYSA dose to 30 mg once daily
  • Moderate or severe hepatic impairment: Not recommended
  • Pregnancy Category C

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.

Savings Card Terms & Conditions

SAVAYSA® (edoxaban) Savings Card:
Eligibility Criteria and Terms & Conditions

Eligibility Criteria: Residents of US or Puerto Rico, 18 years of age or older, with valid prescription for SAVAYSA. Not valid if enrolled in state or federally funded prescription benefit program, including but not limited to Medicare Part D, Medicaid, Medigap, Veterans Affairs (VA), Department of Defense (DoD) or TRICARE programs, or if prohibited by law. Patients who move from commercial to state or federally funded prescription insurance will no longer be eligible.

Terms & Conditions: For patients with commercial insurance, or patients without insurance, this savings card is applied after the following out-of-pocket expenses are met: $4 for a 30-day prescription or $12 for a 90-day prescription. This card is not insurance and does not cover deductibles. The maximum benefit is $270 per 30-day prescription or $810 per 90-day prescription. For patients with commercial insurance or without insurance, card activation must occur by 12/31/17 and program expiration is 12/31/18. This offer is not conditioned on any past, present, or future purchases, including refills. Patients, pharmacists, and prescribers cannot seek reimbursement from health insurance or any third party for any part of the benefit received by patients through this offer. Patient acceptance (use) of this offer constitutes an acknowledgement that it is not prohibited by the patient’s insurance, and that patient will report the value received if required by the insurance provider. This offer is non-transferrable and no substitutions are permissible. Offer cannot be combined with any other rebate/coupon, free trial, or similar offer for the specified prescription. Reproductions of the card are void.

If your pharmacy does not accept the SAVAYSA Savings Card, visit www.patientrebateonline.com for instructions on how to obtain the savings benefit or call the number below. This is not insurance.
By using this card, you certify you meet the Eligibility Criteria and Terms & Conditions.

Pharmacist & Patient Questions:
Call 1-844-SAVAYSA (1-844-728-2972), 8 AM–8 PM EST, M–F.

Pharmacist Conditions: By using this card, you certify that the Eligibility Criteria are met. Submit transaction to McKesson Corp, using BIN #610524. If primary coverage exists, input card information as secondary coverage and transmit using COB segment of NCPDP transaction. Applicable discounts will be displayed in the transaction response. Acceptance of this card and your submission of claims for the SAVAYSA Savings Card program are subject to SAVAYSA Savings Card program Terms & Conditions posted at www.mckesson.com/mprstnc.

Daiichi Sankyo, Inc., reserves the right to rescind, revoke, or amend this program, at any time, without notice.

Reference - DVT/PE Study Design

REFERENCES:

1. SAVAYSA® [package insert], Parsippany, NJ: Daiichi Sankyo, Inc.; 2016.

2. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med.2013;369(15):1406-1415.

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