| Dabigatran32,33 |
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| Inclusion Criteria |
Exclusion Criteria |
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RE-LY
AF ≤ 6 months before randomization plus one additional risk factor:
Previous stroke, TIA, or systemic embolism Ejection fraction less than 40% in the last 6 months Symptomatic heart failure, NYHA class 2 or higher in the last 6 months Age at least 75 years Age at least 65 years and one of the following:
DM on treatment Documented coronary artery disease (any of prior myocardial infarction, positive stress test, positive nuclear perfusion study, prior bypass surgery or PCI, angiogram showing at least 75% stenosis in a major coronary artery) HTN requiring medical treatment
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History of heart valve disorder (i.e., prosthetic valve or hemodynamically relevant valve disease) Severe, disabling stroke within the previous 6 months, or any stroke within the previous 14 days Conditions associated with an increased risk of bleeding:
Major surgery within the previous month Planned surgery or intervention within the next 3 months History of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intra-articular bleeding Gastrointestinal hemorrhage within the previous year Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days Hemorrhagic disorder or bleeding diathesis Need for anticoagulant treatment of disorders other than AF Fibrinolytic agents within 48 hours of study entry Uncontrolled HTN (systolic BP above 180 mm Hg and/or diastolic BP greater than 100 mm Hg) Recent malignancy or radiation therapy (within 6 months) and not expected to survive 3 years
Contraindication to warfarin treatment Reversible causes of AF (e.g., cardiac surgery, pulmonary embolism, untreated hyperthyroidism) Scheduled for pulmonary vein ablation or surgery for cure of AF Severe renal impairment (estimated CrCl of 30 mL/minute or less) Active infective endocarditis Active liver disease, including but not limited to:
persistent ALT, AST, alkaline phosphatases greater than twice the ULN active hepatitis C (positive HCV RNA) active hepatitis B (HBs antigen–positive, anti-HBc IgM–positive) Active hepatitis A
Women who are pregnant or of childbearing age who refuse to use a medically acceptable form of contraception throughout the study Anemia (Hb < 100 g/L) or thrombocytopenia (platelet count < 100 × 109/L) Patients with transaminase elevations (ALT, AST) upon exposure to ximelagatran (Exanta) Patients who received an investigational drug in the past 30 days Patients considered unreliable by the investigator or who may have a life expectancy less than the expected duration of the trial because of concomitant disease or who have any condition that, in the opinion of the investigator, would not allow safe participation in the study (e.g., drug addiction, alcohol abuse)
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| Rivaroxaban35 |
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| Inclusion Criteria |
Exclusion Criteria |
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ROCKET-AF
Nonvalvular AF History of prior ischemic stroke, TIA, or non-CNS systemic embolism believed to be cardioembolic in origin or two or more of the following risk factors:
Heart failure and/or left ventricular ejection fraction ≤35% HTN (defined as use of antihypertensive medications within 6 months before the screening visit or persistent systolic BP above 140 mm Hg or diastolic BP above 90 mm Hg) Age ≥75 years DM (defined as a history of type-1 or type-2 DM or use of anti-diabetic medications within 6 months before screening visit) Female subjects must be postmenopausal (for at least 2 years); surgically sterile; abstinent; or, if sexually active, must be practicing an effective method of birth control before entry and throughout the study. Females of childbearing age must have a negative serum β-hCG pregnancy test at screening.
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Hemodynamically significant mitral valve stenosis Prosthetic heart valve (annuloplasty with or without prosthetic ring; commissurotomy and/or valvuloplasty permitted) Planned cardioversion (electrical or pharmacological) Transient AF caused by a reversible disorder (e.g., thyrotoxicosis, pulmonary embolism, recent surgery, MI) Known presence of atrial myxoma or left ventricular thrombus Active endocarditis 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 intraarticular 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/μL at screening visit Sustained uncontrolled HTN: systolic BP ≥180 mm Hg or diastolic BP ≥100 mm Hg Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within 3 months or any stroke within 14 days before the randomization visit TIA within 3 days before the randomization visit Indication for anticoagulant therapy for a condition other than AF (e.g., venous thromboembolism) Treatment with:
aspirin >100 mg daily aspirin in combination with thienopyridines within 5 days before randomization IV antiplatelet drugs within 5 days before randomization Fibrinolytic agents within 10 days before randomization Note: aspirin ≤100 mg monotherapy allowed and thienopyridine monotherapy allowed.
Anticipated need for chronic treatment with NSAIDs Systemic treatment with a strong inhibitor of CYP3A4, 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 CYP3A4, such as rifampin/rifampicin, within 4 days before randomization, or planned treatment during the time period of the study Anemia (Hb < 10 g/dL) at screening visit Pregnancy or breastfeeding Any other contraindication to warfarin Known HIV infection at time of screening Calculated CrCl < 30 mL/minute at the screening visit Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis), or ALT > 3 × ULN
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| Apixaban31,34 |
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| Inclusion Criteria |
Exclusion Criteria |
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AVERROES
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Valvular disease requiring surgery Need for anticoagulation or aspirin Serious bleeding event 6 months or less before enrollment High risk for bleeding (e.g., active PUD, platelet count < 100,000/mm3, Hb < 10 g/dL, stroke within previous 10 days, blood dyscrasias) Current alcohol use or psychological problems Life expectancy < 1 year Severe renal insufficiency (Sr.Cr > 2.5 mg/dL or CrCl < 25 mL/minute) AST or ALT >2 × ULN, or total bilirubin >1.5 × ULN Allergy to aspirin
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ARISTOTLE
AF (≤12 months prior to enrollment) plus one additional risk factor:
Prior stroke, TIA, or systemic embolism Age ≥ 75 years Arterial HTN (requiring treatment) DM Symptomatic HF or LVEF ≤ 40% within previous 3 months
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AF due to reversible causes Moderate-to-severe mitral stenosis Comorbid conditions requiring anticoagulation Stroke within previous 7 days Concomitant aspirin administration at doses > 165 mg Concomitant aspirin and clopidogrel administration Renal insufficiency (Sr.Cr > 2.5 mg/dL or CrCl < 25 mL/minute)
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