We present a genome-wide association study of a quantitative trait, "progression of systolic blood pressure in time," in which 142 unrelated individuals of the Genetic Analysis Workshop 18 real genotype data were analyzed. Information on systolic blood pressure and other phenotypic covariates was missing at certain time points for a considerable part of the sample. We observed that the dropout process causing missingness is not independent of the initial systolic blood pressure; that is, the data is not missing completely at random. However, after the adjustment for age, the impact of systolic blood pressure on dropouts was no longer significant. Therefore, we decided to impute missing phenotype values by using information from individuals with complete phenotypic data. Progression of systolic blood pressure (∆SBP/∆t) was defined based on the imputed phenotypes and analyzed in a genome-wide fashion. We also conducted an exhaustive genome-wide search for interaction between single-nucleotide polymorphisms (7.14 × 1010 tests) under an allelic model.The suggested data imputation and the association analysis strategy proved to be valid in the sense that there was no evidence of genome-wide inflation or increased type I error in general. Furthermore, we detected 2 single-nucleotide polymorphisms (SNPs) that met the criterion for genome-wide significance (p≤5 × 10−8), which was also confirmed via Monte-Carlo simulation. In view of the rather small sample size, however, the results have to be followed-up in larger studies.

Background Anticoagulation therapy with vitamin K antagonists (e.g. warfarin) has recently been shown to contribute to the accelerated vascular calcification and worsening of renal function. Therefore, it is compelling to investigate the impact of different oral anticoagulants (OACs) on kidney function in non-valvular atrial fibrillation (NVAF) patients. Common co-morbidities in these patients are chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM), which might be presented at the OAC therapy initiation. Purpose The overall objective of the CALLIPER study was to evaluate the effectiveness and safety of the reduced dose rivaroxaban (15 mg once daily) as compared to warfarin in NVAF patients with renal dysfunction in real-world setting. In particular, we evaluated the risk of worsening of renal function in NVAF patients with CKD stage 3 and 4 at baseline (1 year prior to the cohort entry). Additionally, a sub-group analysis of patients with T2DM was performed. We defined worsening of renal function as progression to CKD stage 5, kidney failure or need for dialysis. Methods Individual level data of warfarin- and rivaroxaban-naïve NVAF patients from the MarketScan database for the years 2012 through 2017 were used. Patients with moderate-to-severe CKD (stage 3 and 4) were included in the study cohort and were followed until progression to CKD 5, kidney failure or dialysis, OAC discontinuation/switch, insurance disenrollment or end of data availability. A comparative analysis evaluating the hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) under warfarin or rivaroxaban treatment was performed using Cox regression. A stabilized inverse probability of treatment weighting was used to adjust for imbalances in baseline patient characteristics. Results We identified 5,906 warfarin- and 1,466 rivaroxaban-naïve patients with NVAF and CKD stage 3 and 4, of which 60% were male, median (25–75% range) age=79 (71- 84) years, CHADS2 score=2.67 (2.00- 3.50), CHA2DS2-VASc score=4.43 (3.40–5.62), modified HAS-BLED score=3.00 (2.40 - 3.65). T2DM was present in more than 50% of patients (Table), namely, in 3,160 warfarin- and 746 rivaroxaban-users. Hazard ratios and 95% CI for worsening of renal function were evaluated at 0.53 (0.35; 0.78) in the main cohort and 0.50 (0.30; 0.83) in the T2DM sub-group, meaning that rivaroxaban was associated with a significant 47% and 50% risk reduction of this outcome in NVAF patients with CKD stage 3 and 4 with and without T2DM, respectively. Conclusion The reduced dose of rivaroxaban has appeared to lower significantly the risk of worsening of renal function versus warfarin in NVAF patients with CKD stage 3 and 4 present at the OAC therapy initiation. The conclusion holds true for the patients with the co-morbid T2DM. This evidence was generated by the CALLIPER study using one of the largest US administrative claims database. Acknowledgement/Funding CI Coleman has received research grants from Bayer AG

Background Data on the effectiveness and safety of Factor-Xa non-vitamin-K oral anticoagulants in patients with non-valvular atrial fibrillation (NVAF) and renal disease is scarce. Among others, our study aimed to investigate the risk of renal function worsening in new users of NOACs vs. phenprocoumon with renal disease. Methods We conducted a new user cohort study (one year washout period) in patients with NVAF overall and additionally with renal disease defined by either an extended list of ICD-10 codes (definition 1) or chronic kidney disease (CKD) stages 3 or 4 (definition 2). German claims data between January 1st, 2013 and June 30th, 2017 were utilized and a multiple Cox-regression was performed to calculate confounder-adjusted hazard ratios (HRs) for the risk of end stage renal disease (ESRD)/dialysis and acute kidney injury in new users of NOACs (rivaroxaban, apixaban and edoxaban) vs. new users of phenprocoumon. Results In the overall population 22,339 patients initiating rivaroxaban, 16,201 patients initiating apixaban, 2,828 patients initiating edoxaban and 23,552 patients initiating phenprocoumon were included. NOAC patients with renal disease (definition 1) initiating reduced doses comprised 2,121 initiators of rivaroxaban, 2,507 of apixaban and 292 of edoxaban. 7,289 patients of phenprocoumon were identified. Patients with CKD (definition 2) initiating reduced doses of Factor-Xa inhibitors comprised 1,216 initiators of rivaroxaban, 1,522 of apixaban, 166 of edoxaban and 3,513 of phenprocoumon. In the confounder-adjusted analysis, a beneficial effect for both, rivaroxaban and apixaban over phenprocoumon was seen for the risk of ESRD/dialysis for all populations (overall, renal definition 1 and renal definition 2). In addition, in the CKD population we found a statistically significant risk reduction related to acute kidney injury only for rivaroxaban initiators (44%). There was not sufficient data to conduct the analyses for edoxaban. Figure 1 Conclusion This is the first observational retrospective database study evaluating the effect of renal function worsening in Germany. Results indicate a beneficial effect for both, reduced doses of rivaroxaban and apixaban related to renal function worsening over time when compared to phenprocoumon. This effect was more pronounced for the risk reduction with rivaroxaban related to ESRD /dialysis and specifically also related to a significant risk reduction for AKI. Acknowledgement/Funding The study was funded by Bayer AG

BackgroundTo combine results from a randomized controlled study (RCT) and an observational study (OS) to evaluate discontinuation rate of a levonorgestrel-containing intrauterine contraceptive device (LNG IUD) in a real-life setting.MethodsWe included 253 parous and nulliparous women aged 21–40 years from our own phase II RCT. A total of 1607 women of all ages (including adolescents, < 20 years) were recruited from an OS. We applied the cross design synthesis (CDS) method recommended by the United States General Accounting Office. This method combines the different strengths of RCTs and OSs into one single estimate.ResultsCombined continuation rates for parous vs nulliparous women could be estimated more precisely as well as overall continuation rates after one (86.6%) and two years (78.5%), irrespective of age and parity.ConclusionCross design synthesis allowed more precise estimation of continuation rates of an intrauterine device.