Siontis, Konstantinos C.

Background: Stroke prevention using warfarin is challenging in AF patients with CKD, due to high bleeding risk and difficulties in the INR control. NOACs provide alternative options, but all have greater degrees of renal clearance. This study aimed to compare the outcomes of apixaban, dabigatran, rivaroxaban, and warfarin across the range of kidney function in patients with AF. Methods: Using a US administrative database including private insurance or Medicare Advantage patients with linked claims and laboratory data, we identified 34,569 new users of oral anticoagulants with AF and eGFR ≥15 between 10/1/2010-11/29/2017. Stabilized IPTW balanced four treatment groups on 66 baseline characteristics. The primary outcomes included stroke, major bleeding, and mortality. Weighted Cox proportional hazards models compared treatments in the overall population and in each eGFR subgroup, with mortality as a competing risk for stroke and major bleeding. Results: The proportion of patients using warfarin increased as the kidney function declined - 26.5%, 30.4%, 34.6%, 40.5%, and 55.0% of patients were prescribed warfarin in eGFR ≥90, 60-90, 45-60, 30-45, 15-30 groups, respectively. In comparison to warfarin, apixaban was associated with a lower risk of stroke, major bleeding, and mortality; dabigatran was associated with a similar risk of stroke, and a lower risk of major bleeding and mortality; rivaroxaban was associated with a lower risk of stroke, major bleeding, and mortality (Figure). When comparing one NOAC to another NOAC, apixaban and dabigatran were associated with a lower risk of major bleeding than rivaroxaban (HR 0.61 [0.51-0.73], p<0.001 for apixaban versus rivaroxaban; HR 0.67 [0.50-0.90], p=0.007 for dabigatran versus rivaroxaban); dabigatran was associated with a higher risk of stroke than apixaban (HR 1.65 [1.11-2.46], p=0.01); there was no difference in mortality. There was no significant interaction between treatment and eGFR categories for any outcome, but the number of patients with low eGFR was small. Conclusions: In practice, relative to warfarin, NOACs are progressively less commonly used with increasing degree of renal dysfunction. However, each NOAC was consistently associated with at least equivalent effectiveness and safety compared with warfarin across the range of kidney function.

Background: Patients with end-stage kidney disease (ESKD) on dialysis were excluded from clinical trials of direct oral anticoagulants for atrial fibrillation (AF). Recent data have raised concerns regarding the safety of dabigatran and rivaroxaban, but apixaban has not been evaluated despite current labeling supporting its use in this population. The goal of this study was to determine patterns of apixaban use and its associated outcomes in dialysis-dependent patients with ESKD and AF. Methods: We performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System (October 2010 to December 2015). Eligible patients were those with ESKD and AF undergoing dialysis who initiated treatment with an oral anticoagulant. Because of the small number of dabigatran and rivaroxaban users, outcomes were only assessed in patients treated with apixaban or warfarin. Apixaban and warfarin patients were matched (1:3) based on prognostic score. Differences between groups in survival free of stroke or systemic embolism, major bleeding, gastrointestinal bleeding, intracranial bleeding, and death were assessed using Kaplan–Meier analyses. Hazard ratios (HRs) and 95% CIs were derived from Cox regression analyses. Results: The study population consisted of 25 523 patients (45.7% women; 68.2±11.9 years of age), including 2351 patients on apixaban and 23 172 patients on warfarin. An annual increase in apixaban prescriptions was observed after its marketing approval at the end of 2012, such that 26.6% of new anticoagulant prescriptions in 2015 were for apixaban. In matched cohorts, there was no difference in the risks of stroke/systemic embolism between apixaban and warfarin (HR, 0.88; 95% CI, 0.69–1.12; P =0.29), but apixaban was associated with a significantly lower risk of major bleeding (HR, 0.72; 95% CI, 0.59–0.87; P <0.001). In sensitivity analyses, standard-dose apixaban (5 mg twice a day; n=1034) was associated with significantly lower risks of stroke/systemic embolism and death as compared with either reduced-dose apixaban (2.5 mg twice a day; n=1317; HR, 0.61; 95% CI, 0.37–0.98; P =0.04 for stroke/systemic embolism; HR, 0.64; 95% CI, 0.45–0.92; P =0.01 for death) or warfarin (HR, 0.64; 95% CI, 0.42–0.97; P =0.04 for stroke/systemic embolism; HR, 0.63; 95% CI, 0.46–0.85; P =0.003 for death). Conclusions: Among patients with ESKD and AF on dialysis, apixaban use may be associated with a lower risk of major bleeding compared with warfarin, with a standard 5 mg twice a day dose also associated with reductions in thromboembolic and mortality risk.

Background: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. Methods: This was an observational, retrospective, longitudinal cohort study. Results: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9–3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93–1.12), C-index of 0.70 (95% CI, 0.68–0.72), and D-statistic of 1.17 (95% CI, 1.05–1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8–2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96–13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. Conclusions: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.

Dysrhythmias and Death in BiMVPIntroductionBileaflet mitral valve prolapse (BiMVP) is common among survivors of otherwise unexplained sudden cardiac death, but prognostic implications of BiMVP are unknown. This study evaluated whether patients with BiMVP are at higher risk for ventricular dysrhythmias, ICD placement, or death compared to controls with either single‐leaflet mitral valve prolapse (SiMVP) or no mitral valve prolapse (MVP).Methods and ResultsThis retrospective, matched cohort study included 18,786 patients who underwent echocardiography at Mayo Clinic between June 1990 and September 2014. The study included three cohorts: BiMVP, SiMVP, and controls without MVP. We assessed rates of ventricular dysrhythmias, ICD placement, and all‐cause mortality between groups. BiMVP was associated with higher rates of ventricular tachycardia compared to SiMVP and controls (adjusted HR 1.48 [1.14–1.92], P = 0.003 and 1.40 [1.04–1.88], P = 0.026, respectively); however, there were no statistically significant differences in rates of ventricular fibrillation/cardiac arrest or ICD placement between groups. BiMVP was associated with a lower rate of all‐cause mortality compared to SiMVP and controls (adjusted HR 0.86 [0.79–0.94], P = 0.0008, and 0.55 [0.50–0.60], P < 0.0001, respectively).ConclusionAlthough BiMVP is associated with ventricular tachycardia, it is not associated with an increased risk of cardiac arrest/ventricular fibrillation or ICD implantation and is, paradoxically, associated with a better survival compared to SiMVP or matched controls. The findings suggest that, despite its association with ventricular tachycardia, BiMVP in the absence of other risk factors does not seem to portend a poor prognosis at the population level.