Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients wit

Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation: Validation of the R2CHADS2 Index in the ROCKET AF and ATRIA Study Cohorts; Piccini JP, Stevens SR, Chang Y, Singer DE, Lokhnygina Y, Go AS, Patel MR, Mahaffey KW, Halperin JL, Breithardt G, Hankey GJ, Hacke W, Becker RC, Nessel CC, Fox KA, Califf RM; Circulation (Dec 2012)BACKGROUND: We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. METHODS AND RESULTS: In ROCKET AF, 14,264 patients with nonvalvular AF and creatinine clearance (CrCl) ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system (CNS) embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA, an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 (4.0%) patients experienced primary endpoint events. Reduced CrCl was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack (TIA). Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, and vascular disease of the heart and limbs (C-index 0.635). A model including CrCl (R(2)CHADS(2)) improved net reclassification index (NRI) by 6.2% when compared with CHA(2)DS(2)VASc (C-statistic=0.578) and 8.2% when compared with CHADS(2) (C-statistic=0.575). The inclusion of estimated glomerular filtration rate<60 and prior stroke or TIA in a model with no other covariates led to a C-statistic of 0.590. Validation of R(2)CHADS(2) in an external, separate population improved NRI by 17.4% (95% CI 12.1-22.5%) relative to CHADS(2). CONCLUSIONS: In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; Unique identifier: NCT00403767.

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FDA: Don't use dabigatran with mechanical valves

ROCKVILLE, Md -- December 20, 2012 -- The US Food and Drug Administration (FDA) is informing healthcare professionals and the public that the anticoagulant dabigatran etexilate mesylate (Pradaxa) should not be used to prevent stroke or blood clots in patients with mechanical prosthetic heart valves.

A clinical trial in Europe (RE-ALIGN) was recently stopped because dabigatran users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than were warfarin users. There was also more bleeding after valve surgery in the dabigatran group versus the warfarin group.

Dabigatran is not approved for patients with atrial fibrillation caused by heart valve problems.

The FDA is requiring a contraindication of dabigatran in patients with mechanical heart valves. Health care professionals should promptly transition any patient with a mechanical heart valve who is taking dabigatran to another medication.

The use of dabigatran in patients with bioprosthetic valves has not been evaluated and cannot be recommended.

Patients with all types of prosthetic heart valve replacements taking dabigatran should talk to their health care professional as soon as possible to determine the most appropriate anticoagulation treatment.

Data Summary
In the RE-ALIGN trial, patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrolment) were randomised to receive warfarin or dabigatran (150, 220, or 300 mg twice-daily). Initial dosing of dabigatran was determined by renal function. In the warfarin group, the target international normalized ratio (INR) was 2 to 3 or 2.5 to 3.5, depending on the presence of risk factors and the position of the mechanical prosthetic heart valve.

The study was terminated early because the dabigatran arm had significantly more thromboembolic events (valve thrombosis, stroke, and myocardial infarction) and major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) than did the warfarin arm. These bleeding and thromboembolic events were reported in patients who were initiated on dabigatran postoperatively within 3 days after mechanical bileaflet valve implantation and in patients whose valves had been implanted more than 3 months previously.

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