Problem Atrial fibrilation
Format Double-blinded multi-center RCT
Treatment Rivaroxaban
Control Warfarin
Population 14,264 patients
Inclusion criteria - Men or women aged ≥18 years with non-valvular atrial fibrillation
- Atrial fibrillation must be documented by ECG evidence (e.g., 12-lead ECG, rhythm strip, Holter, pacemaker interrogation) within 30 days before randomization. In addition, subjects must have medical evidence of atrial fibrillation within 1 year before and at least one day before the qualifying ECG evidence. This could be obtained from a notation in the subject's record (e.g., medical chart, hospital discharge summary).
- Subjects with newly diagnosed atrial fibrillation are eligible provided that:
–- there is evidence that the atrial fibrillation is non-valvular
–- cardioversion is not planned
–- there is ECG evidence on 2 occasions 24 hours apart demonstrating atrial fibrillation
- History of prior ischemic stroke, TIA or non-CNS systemic embolism believed to be cardioembolic in origin or has 2 or more of the following risk factors:
–- Heart failure and/or left ventricular ejection fraction â‰_35%
–- Hypertension (defined as use of antihypertensive medications within 6 months before the screening visit or persistent systolic blood pressure above 140 mmHg or diastolic blood pressure above 90 mmHg)
– Age ≥75 years
– Diabetes mellitus (defined as a history of type 1 or type 2 diabetes mellitus or use of antidiabetic medications within 6 months before screening visit)
- Female subjects must be postmenopausal (for at least 2 years), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study; and, for those of childbearing potential, have a negative serum Î_-hCG pregnancy test at screening.
- Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study
- In order to participate in the optional pharmacogenomic component, subjects must have signed the informed consent for DNA research document indicating willingness to participate in the pharmacogenomics component of the study (where local regulations permit)
Exclusion criteria Cardiac-Related Conditions
- Hemodynamically significant mitral valve stenosis
- Prosthetic heart valve (annuloplasty with or without prosthetic ring, commissurotomy and/or valvuloplasty are permitted)
- Planned cardioversion (electrical or pharmacological)
- Transient atrial fibrillation caused by a reversible disorder (e.g., thyrotoxicosis, PE, recent surgery, MI)
- Known presence of atrial myxoma or left ventricular thrombus
- Active endocarditis
Hemorrhage Risk-Related Criteria
- Active internal bleeding
- History of or condition associated with increased bleeding risk including, but not limited to:
–- Major surgical procedure or trauma within 30 days before the randomization visit
–- Clinically significant gastrointestinal bleeding within 6 months before the randomization visit
–- History of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding
–- Chronic hemorrhagic disorder
–- Known intracranial neoplasm, arteriovenous malformation, or aneurysm
- Planned invasive procedure with potential for uncontrolled bleeding, including major surgery
- Platelet count <90,000/Î_L at the screening visit
- Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg 10
Concomitant Conditions and Therapies
- Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within 3 months or any stroke within 14 days before the randomization visit
- Transient ischemic attack within 3 days before the randomization visit
- Indication for anticoagulant therapy for a condition other than atrial fibrillation (e.g., VTE)
- Treatment with:
–- Aspirin >100 mg daily
–- Aspirin in combination with thienopyridines within 5 days before randomization
–- Intravenous antiplatelets within 5 days before randomization
– Fibrinolytics within 10 days before randomization
– Note: Aspirin â‰_100 mg monotherapy is allowed and thienopyridine monotherapy is allowed.
- Anticipated need for chronic treatment with a non-steroidal anti-inflammatory drug
- Systemic treatment with a strong inhibitor of cytochrome P450 3A4, such as ketoconazole or protease inhibitors, within 4 days before randomization, or planned treatment during the time period of the study
- Treatment with a strong inducer of cytochrome P450 3A4, such as rifampin/rifampicin, within 4 days
before randomization, or planned treatment during the time period of the study
- Anemia (hemoglobin <10 g/dL) at the screening visit
- Pregnancy or breast-feeding
- Any other contraindication to warfarin
- Known HIV infection at time of screening
- Calculated CLCR <30 mL/min at the screening visit (refer to Attachment 4 for calculating CLCR)
- Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis), or ALT >3 x the ULN Study Participation and Follow-up-Related Criteria
- Serious concomitant illness associated with a life expectancy of less than 2 years
- Drug addiction or alcohol abuse within 3 years before the randomization visit 11
- Have received an experimental drug or used an experimental medical device within 30 days before the planned start of treatment
- Previous randomization in the present study or other study of rivaroxaban
- Known allergy or hypersensitivity to any component of rivaroxaban, warfarin or placebo excipients (includes lactose, microcrystalline cellulose, magnesium stearate, hypromellose, macrogol, croscarmellose sodium, sodium lauryl sulfate, titanium oxide/ferric oxide red, titanium dioxide/ferric oxide red, anhydrous lactose, pregelatinized starch, FD&C Red #6 barium lake, FD&C Yellow #10 aluminum lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, cornstarch, lactose monohydrate)
- Inability or unwillingness to comply with study-related procedures
- Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator
Follow-up Median 707 days
Primary endpoint Composite of stroke (ischemic or hemorrhagic) and systemic embolism.

Brain imaging was recommended to distinguish hemorrhagic from ischemic stroke. In the presence of atherosclerotic peripheral arterial disease, the diagnosis of embolism required angiographic demonstration of abrupt arterial occlusion.
Secondary endpoint(s) Composite of stroke, systemic embolism, or death from cardiovascular causes; a composite of stroke, systemic embolism, death from cardiovascular causes, or myocardial infarction; and individual components of the composite end points

Safety end point: composite of major and nonmajor clinically relevant bleeding events
Details Non-valvular AF
Brief summary: Rivaroxaban non-inferior for warfarin for bleeding and stroke
PAPER: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
Date 8 Sep 2011
Journal N Engl J Med. 2011 Sep 8;365(10):883-91.
Information Rivaroxaban (vs. Warfarin)
-Noninferior for the prevention of stroke or systemic embolism
-Reduced risk of intracranial and fatal bleeding
-No significant difference in the risk of major bleeding