Vortosiran in Atrial Fibrillation

Prior treatment

• Patients with an intracranial or intraocular bleed within the 3 months prior to screening or any history of spontaneous intracerebral haemorrhage at any time in the absence of antithrombotic treatment.
• Any stroke within 14 days before randomisation or a transient ischemic attack within 3 days before randomisation.
• Any history of non-traumatic intracranial haemorrhage when not under treatment with an anticoagulant.
• Anticipated need for chronic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs): Patients with chronic NSAID use, defined as systemic NSAID therapy on \>/=3 days per week for at least 4 consecutive weeks prior to screening, are excluded.
• Treated with a vitamin K antagonist within 3 months prior to screening.
• Known current alcohol and / or illicit drug abuse that may interfere with the participant's safety and / or compliance at the discretion of the Investigator.
• Previous (within 30 days or 5 half-lives of the investigational drug, whichever is longer) or concomitant participation in another clinical trial with investigational medicinal product(s) or device(s). Registries and observational studies are allowed.

Other illness

• AF due to a reversible cause (e.g., cardiac surgery, pulmonary embolism, untreated hyperthyroidism, alcohol use), participants in sinus rhythm after successful ablation or planned for cardioversion or ablation during trial conduct.
• Mechanical heart valve or valve disease that is expected to require mechanical valve replacement intervention (surgical or trans vascular) during the course of the trial.
• Patients with a medical condition other than non-valvular AF for which chronic anticoagulation is indicated.
• History of or planned left atrial appendage closure or left atrial appendage removal.
• Uncontrolled hypertension (systolic blood pressure \>/= 160 mmHg or diastolic blood pressure \>/=100 mmHg) at randomization.
• Major surgery during the last 30 days or planned major surgery or intervention with potential for uncontrolled bleeding within the trial period (e.g., carotid endarterectomy, coronary artery bypass grafting).
• Known allergy, intolerance, or hypersensitivity to any of the trial interventions.
• Patients with a diagnosis of hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) at screening.
• Any other condition or therapy that would make the participant unsuitable for the trial.

Lab values

• Active bleeding, known bleeding disorder, or known anaemia that requires treatment or capillary Hgb \<100 g/L.
• Known significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis) or hepatic insufficiency classified as Child-Pugh B or C, or alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \>2.5 x the upper limit of normal, measured between screening and randomisation.
• Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 from the local lab, determined between screening and randomization.

Other

• Known presence of an atrial myxoma or left ventricular thrombus.
• Women who are pregnant, currently breastfeeding, or planning pregnancy during the trial or within the defined post-treatment period are not eligible.
• Any contraindication for the use of an anticoagulant or listed in the local labelling for apixaban.
• Male participants who are not willing to use condoms when sexually active with a woman of childbearing potential who is not using highly effective contraception.

• Adult male and female participants, age \>/=45 years.
• Documented diagnosis of non-valvular AF within 12 months of signing the informed consent (paroxysmal, persistent, or permanent) confirmed by ECG evidence (12-lead or other physician-confirmed electronic recording) and currently receiving continuous treatment with a DOAC for stroke prevention for at least the past 3 months.
• Capable of giving signed informed consent. Written informed consent must be obtained before any trial procedure is initiated.
• Postmenopausal women are eligible without additional contraceptive measures. Postmenopausal status is defined as:
  • Age \>/=55 years with \>/=12 months of spontaneous amenorrhea, or
  • Age \<55 years with \>/=12 months of spontaneous amenorrhea and follicle-stimulating hormone in the postmenopausal range, or surgical menopause (bilateral oophorectomy, with or without hysterectomy) documented in the medical history.
• Women of childbearing potential must agree to use highly effective contraception for the duration of trial treatment and for the specified post-treatment period.