XARELTO^® provides once-daily^* VTE treatment (after BID initiation period of 21 days)¹

EINSTEIN DVT/PE + AMPLIFY^2-4

XARELTO^® was studied in a broader patient population than Eliquis^® for VTE treatment

The Eliquis^®† trial (AMPLIFY) excluded these patients.

*With food. After BID initiation period of 21 days.

^†Eliquis^® (apixaban) is a trademark of Bristol-Myers Squibb Company.

^‡These studies were not used for the FDA approval of the DVT/PE indication.

^§Please see protocols for complete list of inclusion and exclusion criteria.

^॥Patients with active bleeding or at high risk of bleeding were excluded.

BID = twice daily; DVT = deep vein thrombosis; FDA = US Food and Drug Administration; PE = pulmonary embolism; RWE = real-world evidence; ULN = upper limit of normal; US = United States; VTE = venous thromboembolism.

STUDY DESIGN

Randomized
Phase 3
Multicenter
Active-controlled

Open-label
Parallel-group
Event-driven
Noninferiority

Randomized
Phase 3
Multicenter

Active-controlled
Open-label
Parallel-group

Event-driven
Noninferiority

Inclusion criteria

DVT Patients³

Acute
Symptomatic
Objectively confirmed proximal DVT
Without symptomatic PE

PE patients⁴

Acute
Symptomatic PE with objective confirmation
With or without symptomatic DVT

Bleeding definition

Clinically relevant bleeding:
A composite of major and clinically relevant nonmajor bleeding

Clinically relevant nonmajor bleeding:

Overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention
Unscheduled contact with the physician
Interruption or discontinuation of the study drug
Discomfort or impairment of activities of daily life

Major bleeding:

Clinically overt with a decrease in hemoglobin level of ≥2 g/dL
Leads to transfusion of 2 or more units of red cells
Intracranial or retroperitoneal
Occurred in another critical site
Contributed to death

Primary Outcomes⁵

Efficacy:

Symptomatic recurrent fatal or nonfatal VTE, ~98% of patients did not experience another VTE^5*:
2.1% (86/4150) with XARELTO^® vs 2.3% (95/4131) with enoxaparin and warfarin/VKA; HR 0.89 (95% CI: 0.66-1.19)

Composite of CRNM and major bleeding:

Similar rates of the composite of CRNM and major bleeding^5†:
9.4% (388/4130) with XARELTO^® vs 10.0% (412/4116) with enoxaparin and warfarin/VKA; HR 0.93 (95% CI: 0.81-1.06)

Key clinical subgroups^5‡

Patients with cancer: N=430 (5.2%)

Efficacy outcome: Recurrent VTE

2.6% (6/232) with XARELTO^® vs 4.0% (8/198) with enoxaparin and warfarin/VKA

Safety outcome: Major bleeding

2.6% (6/232) with XARELTO^® vs 4.1% (8/196) with enoxaparin and warfarin/VKA^§

*Rate of first occurrence of DVT or PE was 2.1% for XARELTO^® versus 2.3% for enoxaparin and warfarin/vitamin K antagonist. Patients were followed for an average length of treatment of 208 days with rivaroxaban in the EINSTEIN DVT and PE trials.

^†The principal safety outcomes were comparable rates of the composite of major bleeding and CRNM bleeding across treatment groups.

^‡Not adjusted for multiplicity.

^§In the overall population, major bleeding occurred in 1% (40/4130) of patients treated with XARELTO^® and 1.7% (72/4116) of patients treated with enoxaparin and warfarin/VKA.

CRNM = clinically relevant nonmajor; DVT = deep vein thrombosis; HR = hazard ratio; PE = pulmonary embolism; VKA = vitamin K antagonist; VTE = venous thromboembolism.

RWE study⁶:

XARELTO^® vs Eliquis^® in VTE patients with cancer

STUDY DESIGN

Retrospective cohort study comparing treatment VTE in patients with cancer with rivaroxaban vs apixaban

PRIMARY OUTCOME

Composite of recurrent VTE or any bleed resulting in hospitalization at 3 months

SECONDARY OUTCOMES

Recurrent VTE, any bleed resulting in hospitalization, any critical organ bleed, and composites of these outcomes at 3 and 6 months

105,463 patients with primary hospital, ED, or observation unit billing codes for VTE

12.5% were adult patients with a cancer diagnosis
After exclusions
- 2437 patients with active cancer experienced a VTE
  - 1093 treated with rivaroxaban
  - 1344 treated with apixaban
- 69.2% of patients were aged ≥61 years
- 43.7% of patients had a BMI ≥30 kg/m²

Optum^® de-identified electronic health records, from January 1, 2012 through December 31, 2020

Based on clinical guidelines for treatment of VTE in patients with cancer, patients with these cancer types were excluded^7-12:

Esophageal, gastric, unresected colorectal, bladder, noncerebral central nervous system cancers, leukemia
Alternative indication for anticoagulation, anticoagulation treatment in the previous 12 months, or pregnancy.
Patients that were active in the EHR data set for <12 months prior to the index event and did not have a provider visit in the 12 months prior to the acute VTE event.

Individual patients were assigned weights based on propensity scores. This scoring process involved a stabilized inverse probability of treatment weighting approach.

Various biases may have affected the results. Misclassification bias was attenuated using validated coding algorithms to identify active cancer diagnoses, covariates, and outcomes.

Use of EHR data set provided lab and observation values, reducing reliance on billing codes to identify presence/absence of key covariates (eg, BMI, eGFR, anemia, etc)
Recurrent VTE identification limited to the presence of ≥1 validated sets of VTE-associated billing codes restricted to the primary coding position during inpatient encounter (previously shown positive predictive value ~95%)
Bleeding-related hospitalizations detected using the validated Cunningham algorithm
To address confounding bias risk, this analysis used a stabilized IPTW approach to balance baseline covariates between rivaroxaban- and apixaban-treated patients
Despite use of stabilized IPTW, residual confounding bias from unmeasured covariates in nonrandomized studies cannot be fully ruled out
The EHR data set did not have corresponding claims data for prescriptions used, and researchers were unable to formally assess persistence to rivaroxaban or apixaban
The choice to utilize the anticoagulant used on day 7 as the ITT index anticoagulant therapy was made to prevent early therapy switching within the first 7 days (ie, from a heparin to rivaroxaban or apixaban) from impacting the results
Because a US VTE and cancer population without cancer types associated with high risk of bleeding was utilized, the results and conclusions are most generalizable to that population
While comparing rivaroxaban vs apixaban in patients with VTE and cancer and specific, high-risk bleeding cancers is clinically valuable, available sample sizes were not yet large enough for a robust analysis

BMI = body mass index; ED = emergency department; eFGR = estimated glomerular filtration rate; EHR = electronic health record; IPTW = inverse probability of treatment weighting; ITT = intention-to-treat; RWE = real-world evidence; US = United States; VTE = venous thromboembolism.

RWE: XARELTO^® vs Eliquis^®

Studied in VTE patients with cancer⁶

Recurrent VTE or bleeding-related hospitalization with XARELTO^® vs Eliquis^®

Chart for Recurrent VTE or bleeding-related hospitalization

Secondary outcomes for VTE patients with cancer⁶

Recurrent VTE-Secondary-Outcome for 3 Months

Recurrent VTE-Secondary-Outcome for 6 Months

*Propensity score model for sIPTW included demographics, laboratory values, clinical observations, comorbidities, cancer type, systemic cancer treatments, and concomitant noncancer medications.

ARR = absolute risk reduction; CI = confidence interval; RRR = relative risk reduction; RWE = real-world evidence; sIPTW = stabilized inverse probability of treatment weighting; VTE = venous thromboembolism.

RECOMMENDATIONS: VTE patients with cancer

A DOAC monotherapy option recommended by 5 organizations for the treatment of VTE in patients with cancer^7-10,13

Once-daily XARELTO^®

(After BID initiation period of 21 days)
Carries a lower pill burden than Eliquis^®1,14

Patients take ~175 fewer pills over 6 months during VTE treatment.

*In patients without a high risk of GI or GU bleeding, and with a CrCl >30 mL/min.

^†In patients with CrCl >30 mL/min and without strong drug-drug interactions or GI absorption impairment, and for use with caution in patients with gastrointestinal tract malignancies, especially upper GI tract malignancies.

^‡Patients with gastric or gastroesophageal tumors are at increased risk for hemorrhage with DOACs. Please see full guidelines for additional information.

^§ISTH suggests only XARELTO^® and edoxaban as a primary anticoagulant choice for acute management of VTE in patients with cancer who have a low bleeding risk and no drug-drug interaction with systemic therapy.

ASCO = American Society of Clinical Oncology; BID = twice daily; CrCl = creatinine clearance; DOAC = direct oral anticoagulant; DVT = deep vein thrombosis; ESC = European Society of Cardiology; GI = gastrointestinal; GU = genitourinary; IITC = International Initiative on Thrombosis and Cancer; ISTH = International Society on Thrombosis and Haemostasis; LMWH = low-molecular-weight heparin; NCCN = National Comprehensive Cancer Network^®; PE = pulmonary embolism; RWE = real-world evidence; VTE = venous thromboembolism.

Condition-specific dosing for XARELTO^®

Available Strengths

DVT/PE Dosing

DVT/PE:

DVT initial treatment

15mg strength of dosing

For the first 21 days, 15 mg twice daily with food, at the same time each day in patients with a CrCl ≥15 mL/min

20mg strength of dosing

Starting at day 22, change to 20 mg once daily with food, at the same time each day, for remaining treatment in patients with a CrCl ≥15 mL/min