Wysokiński, Waldemar E.

Objective Previous studies have postulated a causal role of patent foramen ovale (PFO) in the aetiology of embolic stroke in the general population. We hypothesised that the presence of concomitant PFO and atrial fibrillation (AF) will add incremental risk of ischaemic stroke to that linked to AF alone. Methods We analysed data on 3069 consecutive patients (mean age 69.4±12.2 years; 67.1% men) undergoing transoesophageal echocardiography-guided electrical cardioversion (ECV) for AF between May 2000 and March 2012. PFO was identified by colour Doppler and agitated saline contrast study. All patients were followed up after ECV for first documentation of ischaemic stroke. Outcomes were compared using Cox regression models. Results The prevalence of PFO was 20.0% and the shunt direction was left-to-right in the majority of patients (71.4%). Patients with PFO had a higher frequency of obstructive sleep apnoea (21.7% vs 17.1%, p=0.01) and higher mean peak left atrial appendage emptying velocity (38.3±21.8 vs 36.1±20.4 cm/s; p=0.04) compared with those without PFO. Otherwise, baseline characteristics were similar between groups. During a mean follow-up period of 7.3±4.6 years, 214 patients (7.0%) had ischaemic stroke. Multivariable analysis showed no significant association between PFO and ischaemic stroke (HR, 0.82 (95% CI 0.57 to 1.18)). PFO shunt direction was strongly associated with stroke: HR, 1.91 (95% CI 1.16 to 3.16) for right-to-left shunt and HR, 0.58 (95% CI 0.36 to 0.93) for left-to-right shunt. Conclusions The presence of concurrent PFO in this largely anticoagulated group of patients with AF was not associated with increased risk of ischaemic stroke.

Background: Randomized controlled trials leading to the approval of apixaban and rivaroxaban for venous thromboembolism (VTE) did not include patients with UE-DVT. Limited observational data has been published on outcomes in this setting and no direct comparison to traditional anticoagulation has been performed. Objective: Evaluate the safety and effectiveness of rivaroxaban and apixaban for the treatment of acute UE-DVT compared to low-molecular weight (LWMH) and warfarin. Methods: Consecutive patients with VTE were enrolled into the Mayo Clinic VTE Registry, between March 1, 2013 and July 22, 2019, were followed prospectively. Clinical, demographic and imaging data were collected at the time of study recruitment. Patients with a diagnosis of acute UE-DVT who received either rivaroxaban, apixaban, LMWH or warfarin within the first 14 days after diagnosis and who completed at least 3 months of anticoagulant therapy or had an outcome event in that period were included into the analysis. Recurrent VTE, major bleeding, clinical relevant non-major bleeding (CRNMB), and death were assessed at 3 months, in person whenever feasible, or by mailing a written questionnaire or a scripted phone interview. The study was approved by Mayo Clinic Institutional Review Board. Results: One hundred and thirty-four patients with acute UE-DVT were included. Forty-one were treated with apixaban, 32 with rivaroxaban, and 61 with LWMH and/or warfarin. The mean age was 58.3 years, mean BMI was 28.2, and 59% were male (Table 1). Patients treated with LMWH / warfarin were older (61.3 vs 55.8, p=0.04) and had a lower BMI (27.1 vs 29.0, p=0.0496). Twenty-six (19%) patients had catheter-associated UE-DVT, 93 (69.4%) had a diagnosis of malignancy, and 16 (11.9%) had concurrent pulmonary embolism, which were similar between groups. More patients on apixaban /rivaroxaban were receiving chemotherapy (53.4% vs 47.5%, p=0.04) and had recent surgery (13.7% vs 3.3%, p=0.04) compared to LMWH / warfarin. At 3 months of follow up, 1 recurrent VTE occurred in patients treated with LMWH /warfarin and none of those treated with apixaban /rivaroxaban (p=0.27). Major bleeding occurred in 2 patients treated with LMWH /warfarin and in none of those treated with apixaban /rivaroxaban (p=0.12). CRNMB occurred in 1 patient treated with LWMH /warfarin and 5 patients treated with apixaban / rivaroxaban (p=0.15). Two of the CRNMBs occurred with rivaroxaban and 3 occurred with apixaban. Death occurred in 5 patients treated with LMWH /warfarin and in none of the apixaban /rivaroxaban treated patients (p=0.01). Conclusion: This single institution prospective study adds to the limited experience with apixaban and rivaroxaban for acute UE-DVT. Treatment of UE-DVT with rivaroxaban and apixaban appears to be as safe and effective as LMWH/warfarin after 3 months of anticoagulation. Disclosures McBane: BMS: Research Funding.

Background: Incidental pulmonary embolism (PE) is not infrequently found on CT scans with highest incidence reported in patients with cancer. It is unclear whether patients with symptomatic pulmonary embolism (iPE) have different clinical profile or outcomes compared to patients with symptomatic PE (sPE) and whether this is affected by the presence or type of malignancy. Objective: Compare baseline characteristics of patients diagnosed with iPE to patients with sPE with attention to cancer-specific risk factors as well as evaluate clinical outcomes. Methods: Consecutive patients enrolled in the Mayo Thrombophilia Clinic VTE Registry between March 1, 2013 and December 31st, 2018 with PE were followed prospectively. Outcomes of recurrent venous thromboembolism (VTE), major bleeding, clinically relevant non-major bleeding (CRNMB) and mortality data were collected every 3 months. Clinical outcomes were analyzed with specific focus on patients with cancer. Information was collected and managed using REDCap (Research Electronic Data Capture) and data analysis was performed using SAS software (SAS Institute Inc., Cary, North Carolina). Results: Out of a total of 1033 patients with PE in VTE registry, there were 655 patients with PE (284 with incidental and 363 symptomatic) who completed at least 3 months of anticoagulation and were started on treatment within 14 days of diagnosis. Apixaban was used in 220 (34 %), Rivaroxaban 175 (27 %), Enoxaparin 179 (27%), and Warfarin in 81 (12 %) patients. Overall cancer was present in 61% of patients and was more common in patients with iPE compared to sPE (80.2% vs 45.2%, p<0.001). Patients with iPE were less likely to have previous VTE (8.2% vs 25.5%, p< 0.0001) and tended to have lower BMI (mean 28.8 vs 31.4, p<0.0001) Characteristics of the subgroup of only cancer patients with PE are summarized in the Table. Of note, pancreatic and GI cancers were more common in patients with iPE. There were no differences in recurrent VTE, major bleeding and CRNMB in patients with iPE compared to sPE. This also held true for patients with underlying malignancies. Mortality rates were significantly higher in all patients with iPE even when adjusting for presence of malignancy (p=0.03). When adjusting for presence of metastatic malignancy though the difference was no longer present (p=0.33). Conclusion: Patients with iPE were more likely to have an underlying malignancy, potentially due to higher likelihood of undergoing staging imaging studies. Additionally, patients with iPE more often had metastatic disease which was associated with higher mortality. Recurrent VTE and bleeding outcomes were similar in patients with iPE and sPE, this was independent of the presence of underlying malignancy. Disclosures McBane: BMS: Research Funding.

Abstract Background: Currently, low molecular weight heparin is the guideline endorsed treatment of patients with cancer associated venous thromboembolism (VTE). While apixaban is approved for the treatment of acute VTE, there are limited data supporting its use in cancer patients. Methods: Patients with cancer associated acute VTE were randomly assigned to receive either apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily or subcutaneous dalteparin (200 IU/kg for 1 month followed by 150 IU/kg once daily) for 6 months. The primary outcome was major bleeding. Secondary outcomes included VTE recurrence and a composite of major plus clinically relevant non-major bleeding. Results: Of the 300 patients who underwent randomization, 287 were included in the primary analysis. Of these, metastatic disease was present in 65.5% of subjects and 74% were receiving concurrent systemic cancer therapy. Colorectal, lung, pancreas, and breast cancers were the four most prevalent cancer types. Major bleeding occurred in 0 of the 142 patients (0%) in the apixaban group as compared with 3 of the 145 patients (2.1%) in the dalteparin group (p=0.9956). Recurrent VTE occurred in 5 patients (3.4%) in the apixaban group and 20 patients (14.1%) in the dalteparin group (difference in risk -10.7 percentage points) with a Hazard Ratio (HR) 0.26, (95% CI, 0.09 - 0.80, p = 0.0182). Major plus clinically relevant non-major bleeding were similar at 9% for both groups. There were no mortality differences comparing apixaban (15.9%) and dalteparin (10.6%) groups at 6 months (HR 1.36, 95% CI 0.79 - 2.35). Monthly quality of life surveys favored apixaban therapy for many measures including: concern for excess bruising, stress, irritation, burden of delivery, and overall satisfaction with anticoagulant therapy (p<0.05). Monthly bruising questionnaire favored apixaban at each interval (p<0.002). Conclusions: Oral apixaban therapy was associated with very low rates of bleeding and significantly lower VTE recurrence with superior quality of life outcome measures compared to parenteral dalteparin in the treatment of cancer associated VTE. These data support the clinical utility of apixaban for the acute treatment of VTE in this patient population. Table. Table. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Randomized control trials (RCT) have examined the safety and efficacy of direct oral anticoagulants (DOACs) compared to dalteparin in patients with cancer-associated thrombosis (CAT). Increased major bleeding (MB) was seen with edoxaban and increased clinically relevant non-major bleeding (CRNMB) was seen with rivaroxaban and there has been specific concern about increased risk of bleeding among patients with gastrointestinal malignancies (GIM). Results from RCTs comparing apixaban to dalteparin in CAT are pending. Objective: Using the Mayo Clinic VTE registry, we examined the rates of MB, CRNMB, and overall bleeding (MB + CRNMB) in patients with GIM treated with anticoagulation for CAT. Methods: Consecutive patients treated for CAT were enrolled into Mayo Clinic VTE Registry between March 1, 2013 and July 27, 2018 and were followed prospectively for safety and efficacy. Clinical, demographic and imaging data were collected from each participant at the time of study recruitment. Cancer type, stage, and treatment with chemotherapy were recorded. Major and CRNMB events were evaluated at 3-month intervals. Clinical status was assessed by written questionnaire in subjects unable to return at 3 months. Unreturned questionnaires were followed up with a scripted phone interview. The study was approved by Mayo Clinic Institutional Review Board. Results: In the 535 subjects in the registry with CAT, the mean age (64.6 vs. 62.8 years), mean BMI (28.4 vs. 28.8), and percent female (46.4% vs 40.6%) were numerically similar between DOAC and LMWH treatment groups (Table 1). Metastatic disease was present in 53.6% and 60.2% and chemotherapy was being administered in 66.5% and 71.2% of DOAC and LMWH treated patients, respectively. Thrombocytopenia (<100x109/L) at initiation of anticoagulation was present in 6.8% of DOAC treated and 7.5% of LMWH treated patients. Among all cancer patients, 110 (21%) patients had a GIM, 58 (53%) were treated with LWMH and 52 (47%) were treated with a DOAC (42% rivaroxaban or 58% apixaban). In all CAT, the rate of MB was similar in DOAC versus LMWH treated patients (7.8 vs. 5.4 per 100 person-years; HR 1.48, 95% CI 0.72-3.05; Table 2). The rate of CRNMB however, was significantly increased in the DOAC patients compared to LMWH treated patients (6.18 vs. 0.44 per 100 person-years; HR 14.7, 95% CI 1.92, 112.26). In the sub-group of patients with GIM, the rate of MB was non-significantly higher in the DOAC versus LMWH treated patients (11.1 vs. 3.9 per 100 person-years; HR 2.90, 95% CI 0.57, 14.73). In contrast to the overall CAT group, the rate of CRNMB was similar in the DOAC compared to LMWH treated patients (2.10 vs. 1.92 per 100 person-years; HR 1.18, 95% CI 0.07, 20.21). In GIM patients, apixaban compared to rivaroxaban had a numerically higher, but non-significant, rate of major bleeding (23.98 vs. 3.50 per 100 person-years; HR 4.0, 95% CI 0.54-29.87). In the overall group of CAT, the risk of major bleeding was similar between apixaban and rivaroxaban (9.51 vs. 6.77 per 100 person-years). Conclusion: In our registry of subjects with CAT, we identified a significantly increased rate of CRNMB and overall bleeding, but not MB with the use of DOACs. In our data, GIM alone does not appear to account for the increased bleeding risk seen in CAT with DOACs, as we demonstrated no significant increase in major, CRNMB, or overall bleeding compared to LMWH. Direct comparison between apixaban and rivaroxaban was limited by sample size and number of events. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 3404 Background: Appropriate periprocedural management of the chronically-anticoagulated patient with an inherited or acquired thrombophilia is uncertain. Objective: To estimate the 3-month cumulative incidence of thromboembolism (TE) and major bleeding and test thrombophilia as a potential predictor of these outcomes among chronically-anticoagulated patients undergoing a procedure. Methods: 2182 consecutive patients referred to the Mayo Thrombophilia Center for standardized peri-procedural anticoagulation management were followed for TE, major bleeding and survival. The three-month cumulative incidence rates for TE, major bleeding and death were estimated by Kaplan-Meier analyses. For each chronic anticoagulation indication, we tested “strong” thrombophilia (antithrombin, protein C or protein S deficiency, homozygous or combined heterozygous Factor V Leiden or prothrombin G20210A), ”weak” thrombophilia (heterozygous Factor V Leiden or prothrombin G20210A), lupus anticoagulant/antiphospholipid antibodies and bridging heparin as potential predictors of TE and major bleeding using Cox proportional hazards modeling. Results: Patients with thrombophilia tended to be younger with a slight female predominance. Compared to no thrombophilia, thrombophilia patients (n=202; 143 bridged with heparin) had similar rates of venous (0% vs. 0.5%; p=0.34) and arterial (0.5% vs. 0.5%; p=0.94) thromboembolism, major bleeding (2.0% vs. 2.0%; p=0.97) and mortality (1.5% vs. 2.2%; p=0.52). Among thrombophilia patients, the TE and major bleeding rates were similar for strong (n=29) or weak thrombophilia (n=99), or lupus anticoagulant/antiphospholipid antibodies (n=74). Similarly, among thrombophilia patients, bridging heparin did not affect the rates of major bleeding (2.1% vs. 1.7%; p=0.85) or TE (0.7% vs. 0%, p=0.52). Conclusions: Inherited or acquired thrombophilia does not appear to impact the rates of TE, major bleeding or mortality after temporary interruption of chronic anticoagulation for an invasive procedure. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 491 Introduction: Chronically-anticoagulated patients with active cancer (Ca) often require temporary interruption of warfarin for an invasive diagnostic or therapeutic procedure. While such patients may be at increased risk for periprocedural thromboembolism and bleeding, there are virtually no estimates of these outcomes among Ca patients or the most appropriate periprocedural anticoagulation management. The aims of this study were to estimate rates of these outcomes among Ca patients and to test active cancer and “bridging” low molecular weight heparin (LMWH) as potential predictors of these outcomes. Patients and Methods: In a retrospective cohort study, all chronically-anticoagulated patients referred to the Mayo Clinic Thrombophilia Center for periprocedural anticoagulation management over the 11-year period, 1997-2007, were followed forward in time for the outcomes of venous and arterial thromboembolism (VTE; ATE), major bleeding and vital status within 3 months of consultation. Warfarin was stopped 4-5 days prior to the procedure and patients received bridging LMWH according to the estimated risk of thromboembolism and bleeding. All outcome events were centrally adjudicated using pre specified criteria. Results: The total cohort (n=2517) included 500 patients with Ca. Chronic anticoagulation indications included prior VTE (n=1033), mechanical heart valve (n=669), atrial fibrillation (n=530) and other (mainly vascular bypass; n=285). 65% and 64% of patients with and without Ca received bridging LMWH, respectively. Prior VTE was more common among Ca patients compared to those without CA, both in the bridged (56% vs 37%; p<0.001) and the non-bridged (48% vs 39%; p<0.05) groups. The 3 month rate for the composite of VTE, ATE or bleeding was higher among Ca patients compared to patients without Ca (5% vs 2%; p=0.004) due to higher post procedure rates of VTE (1% vs 0.2%; p<0.001) and major bleeding (4% vs 1.7%; p=0.009); the post procedure ATE rates were low in both groups (0.40% vs 0.45%). For the entire cohort, patients receiving bridging LMWH had a significantly higher rate of post procedure bleeding (5% vs 1%; p<0.05). Finally, there were significantly more deaths in Ca patients compared to non-Ca patients (5% vs. 1%; p<0.001). Conclusions: The three-month rates of VTE, major bleeding and death among patients with Ca in whom anticoagulation is temporarily interrupted for an invasive procedure is significantly higher than in patients without Ca, especially the major bleeding rate. Use of heparin increases this rate even farther, suggesting that bridging should be used with caution in patients with active cancer. Disclosures: No relevant conflicts of interest to declare.

AbstractBackgroundCancer‐associated venous thromboembolism (VTE) carries a high rate of recurrence and death. Guidelines recommend continued anticoagulation therapy as long as active cancer persists. Apixaban 2.5 mg twice daily is the FDA‐approved dose for secondary prevention regardless of VTE causation. Whether this apixaban dose is appropriate for secondary VTE prevention in cancer patients is not clear. The rationale and design of this investigator initiated phase III, multicenter, randomized, double‐blind, trial assessing apixaban 2.5 mg vs 5 mg twice daily for 12 months for the secondary VTE prevention in cancer patients (n = 370) who have completed 6 months (but no more than 12 months) of anticoagulation is provided (NCT03080883).Methods/DesignThe primary study objective is to estimate differences in the combined rate of major plus clinically relevant non‐major bleeding for apixaban 2.5 mg vs 5 mg twice daily. Secondary efficacy outcome is to assess rates of venous or arterial thromboembolism. Participating centers are chosen from the Academic and Community Cancer Research United (ACCRU) consortium.ConclusionWe anticipate these trial results to provide evidence supporting low‐dose apixaban as a safe agent for secondary prevention of cancer‐associated VTE for patients who have already completed 6‐12 months of anticoagulation.

Abstract Renal vein thrombosis (RVT), although uncommon, is associated with considerable morbidity and mortality. Neither the etiology nor the natural history of RVT has been adequately described in a large case series. Objective: To determine whether incident RVT is associated with an increased likelihood of recurrent local and systemic venous thromboembolic disease. Methods: Cases were identified by reviewing the Diagnostic Index for all patients with RVT at our institution between 1981 and 2000. Results: The study group consisted of 240 patients (34% women) with a mean age 55± 19 years. The diagnosis of RVT was made by CT (35%), Duplex Ultrasound (35%), MRI±gadolinium (10%) and either at surgery or autopsy in the remainder. The underlying etiology was deemed to be malignancy in 65% of cases. Of these, renal cell carcinoma (74%) and Wilms tumor (3%) made up the majority. Nephrotic syndrome primarily membranous glomerulonephritis was the second most common underlying etiology (23%). Of those tested, a definable thrombophilia was found in only 13 cases including lupus anticoagulant/antiphospholipid antibody (n=4); deficiencies of protein C or S, (n=2 each); heparin induced thrombocytopenia (n=2); antithrombin deficiency, dysfibrinogenemia and hyperhomocysteinemia (n=1 each). Eighty-one patients (34%) were treated with warfarin. Over a mean follow up of 3 years, the rate of recurrence of venous thrombosis at any site was 5%. The mortality rate over this time period was 49%. Conclusion: RVT represents a distinct clinical entity relative to venous thromboembolism of the lower extremity. The observed low rate of recurrence may be explained by the high mortality rate owing to a high percentage of renal malignancy. RVT should prompt an evaluation for an underlying renal malignancy.

Abstract Background Congenital/hereditary qualitative platelet disorders (CQPD) can be classified by platelet count (eg, normal or decreased) and platelet size as well as by functional defect. Based on mean platelet volume (MPV), congenital thrombocytopenias (CT) are classified as macro-thrombocytopenias (eg, Bernard-Soulier syndrome [BSS], MYH-9 [myosin heavy chain 9, non-muscle]-associated thrombocytopenias, gray platelet syndrome [GPS], etc.); microthrombocytopenias (eg, Wiskott-Aldrich syndrome and variants); and those with normal platelet size. CQPDs with normal platelet count include Glanzmann thrombasthenia (GT), dense granule storage pool disorders (DG-SPD) including Hermansky-Pudlak syndrome (HPS), platelet secretion disorders and many others. Diagnosis has relied on platelet counting and sizing, blood smear light microscopy, platelet aggregation (agg) and platelet function analyzer (PFA-100) studies. Platelet transmission electron microscopy (PTEM) and flow cytometry can provide supplementary information and molecular analysis is also evolving. The objective of this study was to determine the roles of platelet transmission electron microscopy (PTEM) and flow cytometry in the diagnosis of CQPD and CT. Methods In this retrospective cohort study, after IRB approval, the electronic medical record system was queried for patients (pt) with a confirmed CQPD or CT seen at Mayo Clinic between 2000 and 2015. A detailed chart review was undertaken. Results 54 pt (64% female) met our study criteria; median age was 32 years (range 1 day to 81 years). 18/54 (33%) pt had macrothrombocytopenia: BSS 4 (7%); MYH-9 10 (19%); gray platelet syndrome 4 (7%). 36/54 (66%) had normal MPV: Glanzmann thrombasthenia 6 (11%); storage pool disorders including DG-SPD 10 (19%) and HPS 2 (3%), mild alpha granule deficiency 3 (6%) and York platelet syndrome 4 (7%); platelet secretion disorders 4 (7%); ANKRD26 mutation 3 (6%); congenital amegakaryocytic thrombocytopenia 1 (2%); GATA-1 mutation 1 (2%); RUNX-1 mutation 1 (2%); and Jacobsen syndrome 1 (2%). 44 pt (81%) had a positive bleeding history: epistaxis 52%, cutaneous bleeding 57%, gastrointestinal bleeding 21% and menorrhagia 54%; 10 pt (19%) had a negative bleeding history. Results of standard and esoteric platelet testing are summarized in Table 1. Diagnosis in the 10 pt with glycoprotein deficiency (BSS or GT) was established by agg; flow cytometry was confirmatory but not necessary. Of the 23 pt with SPD, 5 had a negative bleeding history; 4 pt had normal agg and PFA-100 and were diagnosed exclusively by PTEM. In this group, the abnormalities on platelet aggregation and PFA were variable and PTEM allowed for a better definition of the specific abnormalities. For MYH-9 patients, PTEM confirmed leukocyte inclusions that had already been identified on light microscopy. PTEM was the only diagnostic modality able to identify the abnormality in York platelet syndrome. In 5/54 (9%) genetic testing was necessary for diagnosis (GATA-1, ANKRD26 and RUNX-1) Conclusion In this cohort, standard platelet assays established the diagnosis in the large majority of CQPD and CT. PTEM was essential for confirmation in DG-SPD, mild alpha granule deficiency and York platelet syndrome and useful in combination with molecular testing to establish a diagnosis in selected cases. Guidance on selection of patients for such specialized testing requires further study. Table 1. Results of standard and esoteric platelet testing for 54 patients with congenital qualitative platelet disorders and/or thrombocytopenia Disorder n (%) Platelet aggregation PFA PTEM Flow cytometry Confirmation by genetics Done Abnormal Done Abnormal Done Abnormal Done Abnormal Glanzmann thrombasthenia 6 (11) 6 6 5 5 1 0 3 3 0 Bernard-Soulier syndrome & variants 4 (7) 4 4 4 4 3 0 4 4 0 MYH-9 related disorders 10 (19) 7 2 8 3 5 5 4 2 5 Dense granule deficiency and HPS 12 (22) 12 8 12 8 12 12 4 0 0 Alpha granule deficiency* 7 (13) 7 4 7 6 7 7 4 4 1 York platelet syndrome 4 (7) 1 0 1 1 4 4 1 1 0 TXA2 or PG synthesis/receptor defect 4 (7) 4 4 4 3 3 0 3 0 0 CATM 1 (2) 0 - 0 - 0 - 0 - 1 ANKRD26 3 (6) 3 3 3 2 3 3 3 3 3 GATA-1 1 (2) 0 - 1 1 1 1 1 1 1 RUNX-1 1 (2) 1 0 1 1 0 - 0 - 1 Jacobsen syndrome 1 (2) 1 0 1 1 1 1 1 0 1 MYH-9: myosin heavy chain 9, non-muscle (MHY-9) associated thrombocytopenia, HPS: Hermansky-Pudlak Syndrome, TXA2: thromboxane A2, PG: prostaglandin CATM: congenital amegakaryocytic thrombocytopenia. * Includes gray platelet syndrome Disclosures Pardanani: Stemline: Research Funding.