PCBs en el medio ambiente y su toxicidad.

Patients who met each of the inclusion criteria below could enroll:

• Men or women aged ≥18 years with non-valvular atrial fibrillation

• Atrial fibrillation was to be documented by ECG evidence (e.g., 12-lead ECG, rhythm

strip, Holter, pacemaker interrogation) within 30 days before randomization.

o Subjects had 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).

ƒ However, subjects with newly diagnosed atrial fibrillation were eligible

provided that:

• there was evidence that the atrial fibrillation was non-valvular

• cardioversion was not planned

ƒ There was ECG evidence on 2 occasions 24 hours apart demonstrating

atrial fibrillation

• Subject were to have a history of prior ischemic stroke, TIA or non-CNS systemic

embolism believed to be cardioembolic in origin OR had 2 or more of the following risk factors:

• Heart failure and/or left ventricular ejection fraction ≤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 were to be postmenopausal (for at least 2 years), surgically sterile,

abstinent, or, if sexually active, be practicing an effective method of birth control.

2 _{The reason for the somewhat earlier site notification date for South African sites is relates to events in South Africa}

at the expected time of study end. In January 2010, as ROCKET neared its end, it was expected that the study’s event target would be reached in May or June of 2010. This suggested that end-of-study procedures might overlap with the 2010 FIFA (soccer) World Cup, which was held in various locations throughout South Africa from June 11 through July 11, 2010. The sponsor was advised that patients and site personnel in South Africa might “not be available” to complete study-related procedures during the World Cup. Accordingly, site notification in South Africa alone was moved up to April 1 so that end-of-study procedures could be completed prior to the World Cup events.

Reviewer comment: From the inclusion criteria as noted, the ROCKET population was selected to be a group that was at high risk for stroke or non-CNS embolic events as a consequence of their atrial fibrillation. The at-risk nature of the population was further increased by the protocol-driven stipulation that after

enrollment of subjects with only 2 risk criteria (other than subjects with a prior stroke, TIA, or non-CNS systemic embolism) could account for only 10% of the study

population in each region, meaning that 90% of patients were to have either a history of stroke/TIA/systemic embolism or have 3 other risk factor. We learned in a

separate communication that the 10% limit was based on the assumption that there would be 3 regions, each with 4666 enrolled patients: North America; Europe + South America; and Asia. At some point, the globe was split into 5 regions by the sponsor, but the 10% limits were implemented based on the original 3 regions and the original estimates of enrollment in those regions. Thus, the North American limit on patients with 2 (non-stroke/TIA/systemic emboli) risk factors was 10% of 4666, or 467, which was much greater than 10% of North American enrollment.

Medically important patient exclusions were: 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

Criteria Related to Hemorrhage Risk

• Active internal bleeding

• History of or condition associated with increased bleeding risk including, but not

limited to:

o Major surgical procedure or trauma within 30 days before the

randomization visit

o Clinically significant gastrointestinal bleeding within 6 months before the

randomization visit

o History of intracranial, intraocular, spinal, or atraumatic intra-articular

bleeding

o Chronic hemorrhagic disorder

o Known intracranial neoplasm, arteriovenous malformation, or aneurysm

• Planned invasive procedure with potential for uncontrolled bleeding, including

• Platelet count <90,000/μL at the screening visit

• Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg or

diastolic blood pressure ≥100 mmHg Concomitant Conditions and Therapies

• Severe, disabling stroke (modified Rankin score of 3 to 5, inclusive (Attachment

2) 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 antiplatelet therapy within 5 days before randomization

• Fibrinolytics within 10 days before randomization

• Note: Aspirin ≤100 mg monotherapy was allowed and thienopyridine monotherapy was 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

• Known significant liver disease (e.g., acute clinical hepatitis, chronic active

hepatitis, cirrhosis), or ALT >3 x the ULN

Reviewer comment: Enrollment criteria seem appropriate for a study with the stated objectives of ROCKET.