Gochanour, Benjamin R.

Introduction: Bioprosthetic valve thrombosis is a recognized cause of bioprosthetic valve dysfunction. It was found to be associated with accelerated bioprosthetic degeneration and higher rates of valve re-replacement. Hypothesis: Warfarin for 3 months after transcatheter aortic valve replacement (TAVR) protects against accelerated valve degeneration and is therefore associated with better outcomes compared to dual antiplatelet (DAPT) and single antiplatelet therapies (SAPT). Methods: Adult patients who underwent TAVR (2012-2019) were identified retrospectively (n=1,501). Patients with atrial fibrillation were excluded (n=657). Patients were classified into warfarin, DAPT, and SAPT groups based on antithrombotic regimen. Structural valve degeneration (SVD) was considered when patients developed new ≥ moderate trans-prosthetic regurgitation, increase in mean gradients ≥10 mmHg from baseline, or when gradients exceeded 20 mmHg. Discharge date was considered time zero. Results: Overall, 844 patients [mean age 80 (±9), 43% females, mean Society of Thoracic Surgeons risk score 6.7 (±5.0)] were included. Warfarin was used in 633 (75%) patients, DAPT in 164 (19%), and SAPT in 47 (6%). Median follow-up time was 2.5 (IQR 1.2-3.9) years. There was no difference in outcomes of ischemic stroke, death, valve re-intervention, SVD, their composite endpoint, or hemorrhagic stroke and hemorrhagic stroke/RBC transfusion events (Figures 1 & 2), even after adjustment for confounders. Conclusion: Warfarin after TAVR was not associated with better clinical or hemodynamic outcomes or with worse adverse events compared to DAPT and SAPT.

Abstract Objective: Upper tract urothelial cancers (UTUC) can be difficult to characterize, and non-invasive surveillance tools are lacking. UTUC are often treated with nephroureterectomy (NU). To address these gaps, we sought to discover and validate methylated DNA markers (MDMs) for detection of UTUC. Methods: Archival formalin fixed paraffin embedded (FFPE) tissue samples from NU were pathologically reviewed and punched prior to DNA extraction. Reduced representation bisulfite sequencing (RRBS) was used to identify candidate MDMs that discriminated between UTUC and age-balanced control urothelial tissues (uninvolved ureter/renal pelvic of renal cell carcinoma at radical nephrectomy). Highest ranked (fold-change and p-value) candidate MDMs were biologically validated by quantitative methylation specific PCR in a 2nd independent set of UTUC and age-balanced controls. DNA from healthy donor urine and buffy coat samples was used to assess MDM background signal. Discrimination between UTUC and controls was assessed as the area under the receiver operator characteristic curve (AUC) with corresponding 95% confidence intervals. Results: RRBS assessed 33 UTUC and 26 ureter/renal pelvis controls. 3.01 x 106 CpGs mapped to the reference genome with at least 10X read depth. From 358 candidates, 20 MDMs were selected for biological validation in independent patient samples which included 20 renal pelvis & 16 ureter UTUC and 17 renal pelvis & 15 ureter control specimens. Of UTUC and control patients, 36% and 65% of were men, respectively. Median AUC for comparison of UTUC vs control tissue was 0.87 (IQR 0.81-0.88); AUCs with corresponding 95% CIs are shown for the 10 most accurate MDMs (Table) across all control types. Conclusion: We report discovery and validation of highly sensitive and specific MDMs with potential for accurate non-invasive screening supported by low background in urine and blood. AUCs (95% CI) for selected methylated DNA markers for UTUC vs control tissue, urine, and blood UTUC vs Marker Control Tissue Control Urine Control Buffy C2orf55 0.92 (0.84-1) 0.93 (0.87-1) 0.96 (0.91-1) ANKRD35 0.91 (0.84-0.99) 0.93 (0.86-1) 0.98 (0.94-1) DLX6 0.91 (0.84-0.98) 0.78 (0.66-0.9) 0.97 (0.93-1) Chr8.9998 0.90 (0.82-0.97) 0.91 (0.84-0.97) 0.98 (0.96-1) SP9 0.88 (0.8-0.97) 0.95 (0.9-1) 0.99 (0.98-1) Chr13.1127 0.88 (0.8-0.97) 0.94 (0.89-1) 0.92 (0.85-1) Septin9.r2 0.88 (0.79-0.97) 0.95 (0.88-1) 0.98 (0.94-1) LBX2 0.88 (0.79-0.97) 0.94 (0.88-1) 0.96 (0.91-1) SIM2.r1 0.88 (0.79-0.97) 0.91 (0.82-1) 0.94 (0.86-1) Chr14.1037 0.88 (0.78-0.97) 0.93 (0.85-1) 0.96 (0.9-1) Citation Format: Ojas Bhagra, William R. Taylor, Benjamin R. Gochanour, Patrick H. Foote, Calise K. Berger, Xiaoming Cao, Douglas W. Mahoney, Sara S. Then, Anna M. Gonser, Karen A. Doering, Kelli N. Burger, John C. Cheville, Matthew T. Gettman, John B. Kisiel. Discovery and validation of methylated DNA markers of upper tract urothelial tract cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3349.

Abstract Background Bioprosthetic valve thrombosis is currently a well-recognized cause of bioprosthetic valve dysfunction. It was found to be associated with accelerated degeneration of the bioprosthesis with higher rates of valve re-replacement, even after treatment with anticoagulation. We hypothesized that the use of warfarin for three months after transcatheter aortic valve replacement (TAVR) protects against accelerated valve degeneration and is therefore associated with better outcomes compared to dual antiplatelet therapy (DAPT). Methods Consecutive adult patients who underwent TAVR in our clinic between 2012 and 2019 were identified retrospectively. Patients with atrial fibrillation were excluded. Subsequently, patients who received DAPT were propensity matched to up to 2 patients who received three months of warfarin as part of their anti-thrombotic regimen. Matching was performed for variables that were significantly different at baseline between the two groups and included diabetes mellitus, prior myocardial infarctions, chronic lung disease, peripheral arterial disease, hemoglobin at time of TAVR, kidney function [creatinine>2], use of angiotensin-converting enzyme inhibitors / angiotensin II receptor blockers, beta blockers, the Society of Thoracic Surgeons (STS) score [STS ≥8, STS 4–8, STS<4], and valve size. The two groups were then compared for outcomes of ischemic stroke, death, valve re-replacement/intervention, the composite endpoint of the aforementioned three outcomes, as well as the three-month outcome of hemorrhagic strokes. Kaplan Meier was used for outcome analysis, and discharge date was considered time zero. Patients who had their anti-thrombotic therapy interrupted were censored at that time point. Results A total of 1,373 patients who underwent TAVR were identified. Of these, 576 patients with atrial fibrillation were excluded. Baseline characteristics were compared between 633 patients who received three months of warfarin and 164 patients who received DAPT after TAVR. After matching the two groups, 435 patients were included in the final analysis [warfarin in 281, DAPT in 154; median time to last follow up 2.61 years], Table 1. There was no difference in matched (Figure 1) or unmatched analysis (not shown) in outcomes of ischemic stroke, death, valve re-replacement/intervention, their composite endpoint, or hemorrhagic strokes (p>0.05 for all). Conclusion Antithrombotic regimen including three months of warfarin after TAVR was not associated with better outcomes of ischemic strokes, deaths, and valve re-replacement/intervention or with increased risk of hemorrhagic strokes compared to DAPT. Funding Acknowledgement Type of funding sources: None.