In this large prospective study of warfarin genetic dose-determinants, carriage of a single or double CYP2C9 variant, reduced warfarin dose 18-72%, and of a VKORC1 variant by 65%. Genotype-based modeling explained almost one-half of dose-variance. A quantitative dosing algorithm incorporating genotypes for 2C9 and VKORC1 could substantially improve initial warfarin dose-selection and reduce related complications.
Background
Atrial fibrillation (AF) is common and has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke.
Methods
To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 controls. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1×10−3 to <1×10−8 in a prior independent genetic association study.
Results
Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13–1.46; P=1.5×10−4) to 1.67 (25 variants; 95%CI, 1.47–1.90; P=9.3×10−15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629–0.811; maximum ΔC statistic from clinical score alone, 0.009–0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke, versus those in the lowest quartile (95%CI, 1.39–4.58; P=2.7×10−3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20–4.40; P=0.01).
Conclusions
Comprehensive AF genetic risk scores were associated with incident AF beyond clinical AF risk factors, with magnitudes of risk comparable to other clinical risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts to determine whether AF genetic risk may improve identification of subclinical AF or distinguish stroke mechanisms are warranted.
Introduction
The incidence of cardiac implantable electronic device (CIED) infections has risen rapidly since 2004. A commercially available minocycline and rifampin impregnated antibacterial envelope has been associated with a low CIED infection rate. We performed a retrospective cohort study analyzing CIED infection rates in patients receiving an antibacterial envelope.
Methods
Prospectively applied criteria for use of the antibacterial envelope included ≥2 of the following: diabetes, renal insufficiency, anticoagulation, chronic corticosteroid use, fever or leukocytosis at the time of implantation, prior CIED infection, ≥3 leads (cardiac resynchronization therapy or abandoned leads), pacemaker dependence, or early pocket reentry. CIED infection rate was compared to a cohort of patients with matched risk factors and a CIED implanted prior to use of the antibacterial envelope.
Results
A total of 260 antibacterial envelopes were implanted from November 1, 2009 to April 30, 2012. The mean number of CIED infection risk factors was 2.8 ± 1.2. The control cohort (N = 639) was matched for mean number of CIED infection risk factors (2.8 ± 1.2), though individual risk factors differed. After a minimum of 90 days of follow-up, there was one CIED infection among patients who received an antibacterial envelope (0.4%), compared to 19 (3%) in controls (odds ratio [95% confidence interval] 0.13 [0.02–0.95], P = 0.04). This difference persisted after adjustment for covariates (0.09 [0.01–0.73], P = 0.02) and propensity score matching (0.11 [0.01–0.85], P = 0.04).
Conclusions
In patients prospectively identified at high risk for CIED infection, use of a commercially available antibacterial envelope was associated with a marked reduction in CIED infections when compared to a matched control cohort.
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