Inclusion and Exclusion Criteria: MARINER Study

Inclusion Criteria

  • At least 40 years of age
  • The duration of the index hospitalization must have been at least three and no more than 14 consecutive days.
    • The index hospitalization is defined as a hospitalization that ended on the day of or the day before randomization and is a continuous period of time at an acute care facility (including hospital, observation unit, ER and/or transferring facility, collectively referred to as "hospital"). The first day that the subject spends any part of the day in the hospital will be counted when determining the duration of index hospitalization, but the day the patient leaves the hospital will not be counted.
  • The reason for the index hospitalization must have been a new diagnosis or exacerbation of one of the following medical conditions:
    • CHF
    • Acute respiratory insufficiency or acute exacerbation of COPD
    • Acute ischemic stroke (including spinal cord infarction if no evidence of intramedullary, subdural or epidural hemorrhage)
    • Acute infectious disease
    • Inflammatory disease, including rheumatic disease
  • The subject must be at increased risk for VTE by the total modified IMPROVE VTE Risk Score
    • If total modified IMPROVE VTE Risk Score ≥3, the subject meets this inclusion criterion.
    • If the total modified IMPROVE VTE Risk Score is 2, at least one of these secondary risk factors must be present:
      • D Dimer >2X ULN during index hospitalization (may be obtained locally to assess eligibility for study entry)
      • History of CHF, when CHF was not the primary reason for the index hospitalization
      • History of COPD, when COPD was not the primary reason for the index hospitalization
      • Recent major surgery or serious trauma (i.e., trauma requiring hospitalization) occurring four to 12 weeks prior to index hospitalization
      • Severe varicosities and/or chronic venous insufficiency (as evidenced by the presence of edema, tortuous varicosities and skin hyperpigmentation)
      • Body mass index greater than or equal to 35 kg/m2
  • Life expectancy of at least three months
  • Prescribed thromboprophylaxis with LMWH or UFH during the index hospitalization
  • Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study.

Exclusion Criteria

Bleeding Risk-Related Criteria:

  • Any bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within three months prior to randomization or occurring during index hospitalization that would contraindicate the use of pharmacologic thromboprophylaxis
  • Major surgery, biopsy of a parenchymal organ, ophthalmic surgery, or serious trauma within four weeks before randomization
  • Any planned major surgery or major invasive diagnostic procedure intended during the duration of the trial
  • Subjects with any known coagulopathy or bleeding diathesis, or an INR >1.5 during the index hospitalization without a subsequent value (the last value before randomization) that is ≤1.5.
  • A history of hemorrhagic stroke at any time in the past, evidence of primary intracranial hemorrhage on computed tomography or magnetic resonance imaging scan of brain, or clinical presentation consistent with intracranial hemorrhage. This applies as well to subjects hospitalized for ischemic stroke upon randomization. Subjects with hemorrhagic transformation of an ischemic infarct prior to randomization are not excluded unless there is evidence of parenchymal hemorrhage (types PH-1 and PH-2).
  • Severe head trauma within three months of randomization
  • Subject has history of or current intracranial neoplasm, cerebral metastases, arteriovenous (AV) malformation, or aneurysm.
  • Active gastroduodenal ulcer, defined as diagnosed within three months or currently symptomatic or known AV malformations of the gastrointestinal tract
  • Screening platelet count <75 x 109 cells/L

Concomitant Conditions or Diseases:

  • Active cancer (excluding non-melanoma skin cancer) at time of index hospitalization
  • Any medical condition (e.g., atrial fibrillation) that requires use of any parental or oral anticoagulant(s) (e.g., warfarin sodium or vitamin K antagonists, Factor II or Xa infibitors, fibrinolytics) concomitantly with study medication
  • Bilateral and unilateral above-knee lower extremity amputation
  • Subject has known allergies, hypersensitivity, or intolerance to rivaroxaban or any of its excipients
  • Severe renal insufficiency (baseline CrCl <30 mL/min calculated using the Cockcroft-Gault formula)
  • Known significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis) which is associated with coagulopathy or moderate or severe hepatic impairment
  • Known HIV infection
  • Sustained uncontrolled systolic blood pressure (BP) of ≥180 mmHg or diastolic BP of ≥100 mmHg at randomization despite treatment
  • Current drug or alcohol abuse, based on investigator’s assessment
  • Cardiogenic or septic shock with the need for vasopressor(s) during index hospitalization
  • Presence of inferior vena caval filter
  • Severe bronchiectasis or cavitary tuberculosis or any other pulmonary condition (e.g., vasculitis) at risk for major hemoptysis

Drugs or Procedures:

  • Combined P-gp and strong CYP3A4 inhibitors (such as but not limited to ketoconazole, telithromycin or protease inhibitors) use within four days before randomization, or planned use during the study. Itraconazole use is prohibited within seven days before randomization and during the study.
  • Combined P-gp and strong CYP3A4 inhibitors (such as but not limited to rifampin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John’s Wort) use within two weeks before randomization, or planned use during the study
  • Received fibrinolysis during index hospitalization
  • Planned use of ASA at a dose >162 mg/day clopidogrel >75 mg/day during the study
  • Planned use of dual therapy with two or more antiplatelet agents (dipyridamole is permitted) during the study
  • Childbearing potential without proper contraceptive measures, pregnancy or breastfeeding
  • Before randomization, a woman must be either:
    • Not of childbearing potential: premenarchal, postmenopausal (>45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least six months and a serum follicle stimulating hormone (FSH) level >40 IU/L), permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy), or otherwise be incapable of pregnancy
    • Of childbearing potential and practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: e.g., established use of oral, injected, or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods: condom with spermicidal foam/gel/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/suppository; male partner sterilization (the vasectomized partner should be the sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle of that subject)

      The initiation of hormonal contraception for the purpose of the study is not recommended. A woman of childbearing potential must have a negative serum or urine pregnancy test at screening.

      A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a double-barrier method of birth control [e.g., either condom with spermicidal foam/gel/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/suppository]. All men must also not donate sperm during the study, from the time of first dose to the last dose of the study drug.
  • Participation in another pharmacotherapeutic study or experimental medical device within 30 days before the start of study treatment
  • Planned use of prasugrel or ticagrelor during the study
  • Planned use of nonsteroidal anti-inflammatory agents (NSAID) during the study
  • Subject is unwilling or unable to complete all study visits as well as follow-up visit.
  • Subject is an employee or investigator of study site, with direct involvement in the proposed study or other studies under the direction of that investigator study site, as well as family members of the employees or investigator.
  • Planned use of proton pump inhibitors (PPIs) omeprazole or esomeprazole with clopidogrel during the study. Use of other PPIs is allowed.

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