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NVAF Study Design

More than 21,000
patients over 2.5 years:
The largest and
longest study in NVAF1,2

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

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Nvaf Study Design Clinical Studies

Objective1

The ENGAGE AF-TIMI 48 study was a multinational, double-blind, noninferiority study comparing the efficacy and safety of SAVAYSA® (edoxaban) 60 mg (or 30 mg dose-reduced), a low-dose edoxaban arm (30 mg or 15 mg dose-reduced), and warfarin (titrated to international normalized ratio [INR] 2.0 to 3.0) in reducing the risk of stroke and systemic embolism (SE) in a diverse range of patients with nonvalvular atrial fibrillation (NVAF). The low-dose edoxaban arm was evaluated but not approved.

Study endpoints1

Primary efficacy

The occurrence of first stroke (either ischemic or hemorrhagic) or of an SE that occurred during treatment or within 3 days from the last dose taken

Primary safety

Major bleeding that occurred during or within 2 days of stopping study treatment

Trial design1,2

The ENGAGE AF-TIMI 48 study was a multinational, double-blind, noninferiority study comparing the efficacy and safety of SAVAYSA 60 mg, a low-dose edoxaban arm, and warfarin in reducing the risk of stroke and SE in patients with NVAF. The low-dose edoxaban arm was evaluated but not approved. A total of 21,105 patients were randomized and followed for a median of 2.8 years and treated for a median of 2.5 years. A total of 21,026 patients received at least 1 dose of study drug (modified intention-to-treat [mITT] population). Patients in the edoxaban treatment arms had their dose halved if 1 or more of the following clinical factors were present: creatinine clearance (CrCl) ≤50 mL/min, low body weight (≤60 kg/132 lb), or concomitant use of specific P-glycoprotein (P-gp) inhibitors (verapamil, quinidine, dronedarone). Patients on antiretroviral therapy (ritonavir, nelfinavir, indinavir, saquinavir) as well as cyclosporine were excluded from the study. According to the approved label for SAVAYSA, no dose reduction is recommended for concomitant P-gp inhibitor use or for low body weight (≤60 kg/132 lb) in patients with NVAF.

Patient characteristics
ENGAGE AF-TIMI 48 enrollment reflects the diverse range of patients you see in your practice

Inclusion/exclusion criteria

Key inclusion criteria1,2

To enter the study, patients ≥21 years of age had to have 1 or more of the following additional risk factors for stroke:

  • A prior stroke (ischemic or unknown type), transient ischemic attack, or non-central nervous system SE, or
  • Two or more of the following risk factors:
    • Age ≥75 years
    • Hypertension
    • Heart failure
    • Diabetes mellitus

Key exclusion criteria2,3

  • Atrial fibrillation due to a reversible disorder
  • An estimated CrCl<30 mL/min
  • A high risk of bleeding
  • Use of dual antiplatelet therapy
  • Moderate-to-severe mitral stenosis or mechanical heart valve
    • Subjects with bioprosthetic heart valves, valve repair, and valvular diseases such as mitral valve prolapse, mitral valve regurgitation, and aortic valve disease, could have been included in the study
  • Other indications for anticoagulation therapy
  • Acute coronary syndromes, coronary revascularization, or stroke within 30 days before randomization

 

Once-daily SAVAYSA and patients with CrCl >95 mL/min1

  • The size and rigor of the ENGAGE AF-TIMI 48 study allowed for analysis based on renal function
  • 22% of study patients had CrCl >95 mL/min. Approximately half of the SAVAYSA dose is eliminated by the kidney; for this reason, these patients with CrCl >95 mL/min showed a smaller effect of SAVAYSA compared to warfarin than would patients with CrCl ≤95 mL/min
  • Therefore, SAVAYSA is indicated to reduce the risk of stroke and SE in patients with NVAF with a CrCl ≤95 mL/min, and should not be used in NVAF patients with CrCl >95 mL/min

Nvaf Study Design - 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 - NVAF Study Design

REFERENCES:

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

2. Giugliano RP, Ruff CT, Braunwald E, et al; for ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.

3. Data on file Daiichi Sankyo, Inc.

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