Bleeding management in computed tomography-guided liver biopsies by biopsy tract plugging with gelatin sponge slurry

To evaluate the safety and impact of biopsy tract plugging with gelatin sponge slurry in percutaneous liver biopsy. 300 consecutive patients (158 females, 142 males; median age, 63 years) who underwent computed tomography-guided core biopsy of the liver in coaxial technique (16/18 Gauge) with and without biopsy tract plugging were retrospectively reviewed (January 2013 to May 2018). Complications were rated according to the common criteria for adverse events (NCI-CTCAE). The study cohort was dichotomized into a plugged (71%; n = 214) and an unplugged (29%; n = 86) biopsy tract group. Biopsy tract plugging with gelatin sponge slurry was technically successful in all cases. Major bleeding events were only observed in the unplugged group (0.7%; n = 2), whereas minor bleedings (4.3%) were observed in both groups (plugged, 3.6%, n = 11; unplugged, 0.7%, n = 2). Analysis of biopsies and adverse events showed a significant association between number of needle-passes and overall (P = 0.038; odds ratio: 1.395) as well as minor bleeding events (P = 0.020; odds ratio: 1.501). No complications associated with gelatin sponge slurry were observed. Biopsy tract plugging with gelatin sponge slurry is a technically easy and safe procedure that can prevent major bleeding events following liver biopsy.

478 Clinical outcomes of patients at very high stroke risk undergoing watchman implantation

Aims Left atrial appendage occlusion (LAAO) with the Watchman device is an effective alternative to oral anticoagulation in patients with non-valvular atrial fibrillation at high thromboembolic risk. We sought to evaluate the safety and effectiveness of LAAO for stroke and bleeding prevention in patients at very high stroke risk. Methods and results Data were extracted from a prospective database of 488 AF patients who underwent LAA closure with a Watchman device. Periprocedural complications, thromboembolic (TE), and bleeding event rates among patients with a CHA2DS2-VASc ≥ 5 were reported. Predicted annual rates of TE or major bleeding events were compared to the annualized observed risk of the population. Overall, 209 patients with a CHA2DS2-VASc ≥5 (CHA2DS2-VASc: 6.0 ± 1.0; HAS-BLED: 3.7 ± 1.1) were included in the study. The mean age was 78 ± 6 years and 52.2% (n = 109) were males. Watchman implantation was successful in all patients. Overall procedure-related complication rate was 3.3% (n = 7). Two major complications were observed (1.0%): one pericardial tamponade requiring surgery and one major bleeding event at 3 days post-procedure. The incidence of minor complications was 2.3% (n = 5). Specifically, two patients experienced a pericardial effusion that required drainage and three had a groin hematoma. During a mean follow-up duration of 12 ± 5 months (193 pt/years), six TE events (2.9%/annualized rate: 3.1%) were documented after a median of 6.3 months (IQR: 2.2–9.6). Based on the estimated annual TE risk according to the CHA2DS2-VASc score (8.5%), the % risk reduction after LAAO was 63.5%. Four major bleeding events [1.9% (median time to event: 2.1 months; IQR: 1.0–3.4)] and five minor bleeding events occurred (2.5%) during follow-up. Compared to the expected rate of bleeding events as assessed by the HAS-BLED of the population (8.03%), LAAO led to a 42% reduction of bleeding risk. Conclusions In a population at very high TE risk, LAAO with the Watchman device was a safe and effective approach, and led to a 63.5% of stroke risk.

473 Propensity-matched comparison of left atrial appendage occlusion and direct oral anticoagulation for thromboembolic prevention in octogenarians

Aims A significant amount of atrial fibrillation patients does not receive appropriate anticoagulation, owing to contraindications and side effects. Octogenarians have higher competing comorbidities with a remarkable bleeding/thromboembolic (TE) risk. We aimed at analysing the clinical outcomes of LAAO compared with direct oral anticoagulation (DOAC) in octogenarians. Methods and results Data were extracted from two prospective databases including 488 LAAO and 825 DOAC patients. Patients aged 80 years or older accounted for 37.1% (n = 181) and 39.5% (n = 326). In order to attenuate the imbalance in covariates between the groups, a propensity score matching technique was used (covariates: age, sex, CHA2DS2-VASc, and HAS-BLED scores, follow-up duration; tolerance 0.02). This method resulted in matched populations with 108 octogenarian patients per group. The annual stroke/transient ischaemic attack (TIA) risk was estimated based on the CHA2DS2-VASc, and compared to the annualized observed risk, owing to calculate the % risk reduction associated with the two treatment strategies. A total of 216 octogenarians were included in the analysis (84 ± 3 years; CHA2DS2-VASc: 4.9 ± 1.4, HAS-BLED: 3.1 ± 0.9). A Watchman device was successfully deployed in all LAAO ≥ 80 patients; periprocedural adverse events were observed in 2.8% (n = 3) of LAAO patients. During a follow-up of 13 ± 4 months, 3 (2.8%) TE complications (1 stroke, 2 TIA) occurred in LAAO ≥ 80 pts and 4 (3.7%; 1 stroke, 3 TIA) in DOAC ≥ 80 pts (P = 0.99). The annualized risk of stroke/TIA was 2.5% in the first and 3.5% in the second group. Based on the estimated annual TE risk according to the CHA2DS2-VASc score, the % risk reduction after LAAO and DOAC was 54.5% and 36.4%, respectively. Major bleeding events were 3 [1 intracranial, 2 gastrointestinal (GI)] LAAO ≥ 80 pts, and 3 (2 intracranial, 1GI) in DOAC ≥ 80 pts (2.8% in both groups). Minor bleeding events were significantly higher in DOAC ≥ 80 pts [13.0% (n = 14) vs. 2.7% (n = 3); RR: 4.7, 95% CI: 1.4–15.7; P = 0.009]. Conclusions LAAO was safe and similar to DOAC at preventing ischaemic/major bleeding events in a matched population of patients aged ≥80 years. A significantly higher incidence of minor bleeding events was observed in the DOAC group.

High versus Standard Intensity of Thromboprophylaxis in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

Thromboprophylaxis in hospitalized patients with COVID-19 has been associated with a survival benefit and is strongly recommended. However, the optimal dose of thromboprophylaxis remains unclear. A systematic review and meta-analysis (PubMed/EMBASE) of studies comparing high (intermediate or therapeutic dose) versus standard (prophylactic dose) intensity of thrombo-prophylaxis with regard to outcome of hospitalized patients with COVID-19 was performed. Randomized and non-randomized studies that provided adjusted effect size estimates were included. Meta-analysis of 7 studies comparing intermediate versus prophylactic dose of thromboprophylaxis (2 randomized and 5 observational, n = 2009, weighted age 61 years, males 61%, ICU 53%) revealed a pooled adjusted relative risk (RR) for death at 0.56 (95% confidence intervals (CI) 0.34, 0.92) in favor of the intermediate dose. For the same comparison arms, the pooled RR for venous thromboembolism was 0.84 (95% CI 0.54, 1.31), and for major bleeding events was 1.63 (95% CI 0.79, 3.37). Meta-analysis of 17 studies comparing therapeutic versus prophylactic dose of thromboprophylaxis (2 randomized and 15 observational, n = 7776, weighted age 64 years, males 54%, ICU 21%) revealed a pooled adjusted RR for death at 0.73 (95% CI 0.47, 1.14) for the therapeutic dose. An opposite trend was observed in the unadjusted analysis of 15 observational studies (RR 1.24 (95% CI 0.88, 1.74)). For the same comparison arms, the pooled RR for venous thromboembolism was 1.13 (95% CI 0.52, 2.48), and for major bleeding events 3.32 (95% CI 2.51, 4.40). In conclusion, intermediate compared with standard prophylactic dose of thromboprophylaxis appears to be rather safe and is associated with additional survival benefit, although most data are derived from observational retrospective analyses. Randomized studies are needed to define the optimal thromboprophylaxis in hospitalized patients with COVID-19.

Efficacy and Safety of Bivalirudin Versus Heparin Anticoagulation Therapy for Extracorporeal Membrane Oxygenation: Meta-Analysis

Background We aimed to compare the efficacy and safety of bivalirudin versus heparin as the anticoagulant in patients undergoing Extracorporeal Membrane Oxygenation (ECMO). Methods We conducted a search in PubMed, Embase and the Cochrane Library for all the studies in which bivalirudin was compared to heparin as the anticoagulant for ECMO. Efficacy outcomes were defined as the time to reach therapeutic levels, time within therapeutic range (TTR), thrombotic events, circuit thrombosis, circuit exchanges. Safety outcomes were reported as Heparin-Induced Thrombocytopenia (HIT), major bleeding events, minor bleeding events. Other outcomes included hospital length of stay (LOS), ICU LOS, mortality, 30-day mortality and in-hospital mortality. Results Ten studies were included, involving 1091 patients (Bivalirudin was administered in 405 patients while 686 patients were treated with heparin). A significant reduction in thrombotic events [OR 0.51, 95%CI 0.36,0.73, p=0.0002, I2=0%], major bleeding events [OR 0.31, 95%CI 0.10,0.92, p=0.04, I2=75%] and in-hospital mortality [OR 0.63, 95%CI 0.44,0.89, p=0.009, I2=0%] treated with bivalirudin were found compared with heparin. There were no significant differences between groups regarding the time to reach therapeutic levels[MD 3.53, 95%CI -4.02,11.09, p=0.36, I2=49%], TTR[MD 8.64, 95%CI -1.72,18.65, p=0.10, I2=77%], circuit exchanges[OR 0.92, 95%CI 0.27,3.12, p=0.90, I2=38%], Heparin-Induced Thrombocytopenia (HIT)[OR 0.25, 95%CI 0.02,2.52, p=0.24, I2=0%], minor bleeding events[OR 0.93, 95%CI 0.38,2.29, p=0.87, I2=0%], hospital LOS[MD -2.93, 95%CI -9.01,3.15, p=0.34, I2=45%], ICU LOS[MD -4.22, 95%CI -10.07,1.62, p=0.16, I2=0%], mortality[OR 1.84, 95%CI 0.58,5.85, p=0.30, I2=60%] and 30-day mortality[OR 0.75, 95%CI 0.38,1.48, p=0.41, I2=0%]. The benefit of bivalirudin over heparin was not significant for patients undergoing ECMO for major bleeding events while ruling out the Rivosecchi’s study (OR 0.44, 95%CI 0.71-1.14). Subgroup analysis by patient’s type revealed that studies in children generated lower rate of thrombotic events and major bleeding events compared with adults. Conclusion Our meta-analysis suggests that bivalirudin use as the anticoagulant for ECMO are associated with lower thrombotic events, major bleeding events and in-hospital mortality. Meanwhile, the differences are more pronounced in children than adults. However, the results should be interpreted with caution and further larger, randomized trials are needed to confirm the results.

A Phase 3, Randomized, Double-Blinded Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Direct Oral Anticoagulant Therapy with Factor Xa Inhibitor: The Lex-210 Study

Introduction: The benefit of direct oral anticoagulants (DOAC; Factor Xa Inhibitors [FXaI]) has been demonstrated in both clinical trials and real-world studies. However, 2% to 3.5% of DOAC-treated patients experience major bleeding annually, and this is associated with substantial morbidity, mortality, and the need for hospitalization. Therefore, reversal/hemostatic agents are used to control FXaI-related bleeding. The efficacy and safety profile of prothrombin complex concentrates (PCCs) as hemostatic agents in patients with FXaI-related bleeding requires further investigation. Methods: The pivotal LEX-210 study (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study to demonstrate the hemostatic efficacy and safety of four-factor PCC (Octaplex®, Octapharma) in patients with acute major bleeding on DOAC therapy with FXaI. LEX-210 will include patients aged ≥18 years who have received or are believed to have received a dose of oral FXaI. Patients must have a baseline anti-factor Xa activity equivalent to at least 100 ng/mL according to the available test (e.g., chromogenic assay) and have acute major bleeding. Key exclusion criteria are bleeding that is immediately life-threatening and acute trauma for which reversal of DOAC therapy with FXaI alone would not be expected to control the bleeding event. The study will enroll approximately 200 patients, with the aim to include at least 91 evaluable patients in each group. Patients will be randomized 1:1 to either of two study groups: low-dose 15 IU/kg body weight vs. high-dose 50 IU/kg body weight PCC. The primary objective of this study is to demonstrate superior hemostatic effectiveness of PCC dosed at 50 IU/kg vs. 15 IU/kg for emergency reversal of the anticoagulant effect of DOACs in patients with major bleeding associated with FXaI. The primary endpoint of LEX-210 is the proportion of patients in whom PCC demonstrates hemostatic effectiveness, i.e., binary outcome of effective (rating of excellent or good) or non-effective (rating of poor or none) in management of major bleeding events within 24 hours after the start of initial management, as assessed by an Independent Data Monitoring and Endpoint Adjudication Committee according to predefined criteria modified from those used by Sarode et al., (see Table 1). Secondary endpoints are the change in endogenous thrombin potential as measured by thrombin generation assay from baseline to 1 hour after PCC administration, the 30-day event rate of thromboembolic events and all-cause mortality, the occurrence of adverse events, and vital signs and laboratory parameters. Results: LEX-210 is planned to start in Q3 2021 and will be performed at approximately 60 sites in North America and Europe. Completion is expected by Q1 2024. Conclusions: The LEX-210 study is designed to confirm the safety and hemostatic efficacy of PCC in the management of FXaI-related major bleeding, offering an effective alternative for the management of major bleeding events in these patients. Figure 1 Figure 1. Disclosures Sarode: Portola: Consultancy; CSL Behring: Consultancy; Octapharma: Consultancy; Cerus: Research Funding; Siemens: Research Funding. Maack: Octapharma: Current Employment. Solomon: Octapharma: Current Employment. Knaub: Octapharma: Current Employment. Schulman: Octapharma: Research Funding; Boehringer-Ingelheim: Research Funding.

Safety and Efficacy of Apixaban Thromboprophylaxis in Ambulatory Cancer Patients By Renal Function: A Subgroup Analysis of the Avert Trial

Background Patients with cancer have an increased risk of venous thromboembolism (VTE) and associated morbidity and mortality. Renal dysfunction is more common in patients with cancer, leading to heightened risks of bleeding and thrombotic complications. In the AVERT trial, thromboprophylaxis with apixaban resulted in a significantly lower rate of VTE and higher rate of major bleeding compared to placebo among intermediate-to-high-risk ambulatory cancer patients starting chemotherapy. As apixaban depends on some degree of renal clearance, there may be concerns regarding the safety and efficacy of apixaban thromboprophylaxis in patients with renal insufficiency. In this post-hoc analysis of AVERT, we evaluated the efficacy and safety of apixaban thromboprophylaxis according to renal function at randomization. Methods Eligible patients were randomized to apixaban (2.5mg twice daily) or placebo. First dose of study drug was given within 24 hours of the first chemotherapy administration with the intended treatment period of 180 days. For this subgroup analysis, the efficacy and safety of apixaban thromboprophylaxis was evaluated accordingly to renal function (calculated creatinine clearance [CrCl] by Cockcroft-Gault Equation) at randomization. Patients with CrCl < 30 mL/min were excluded from the trial. The primary efficacy outcome was objectively confirmed major VTE (proximal deep vein thrombosis or pulmonary embolism) within 180 days (±3 days) following randomization. The primary efficacy outcome was evaluated by modified intention-to-treat analysis, which included all patients who had undergone randomization and received at least one dose of study medication on or before day 180 (±3 days). The primary safety outcome was major bleeding defined by the International Society on Thrombosis and Haemostasis criteria. The primary safety outcome was evaluated by on-treatment analysis, when events were counted only if they occurred on study drugs or up to two days after discontinuation of the study drugs. Secondary outcomes included clinically relevant non-major bleeding and overall mortality. Results A total of 574 patients underwent randomization, with 563 patients included in the original primary efficacy and safety analysis (288 apixaban and 275 placebo). Upon randomization, 66 (11.5%) patients had CrCl < 60 mL/min and 508 (88.5%) patients had CrCl ≥ 60 mL/min. Patients with CrCl < 60 mL/min were significantly older, more female, had lower weight and fewer with body mass index (BMI) > 35 kg/m 2 and poorer ECOG performance status (Table 1). In patients with CrCl < 60 mL/min, VTE occurred in no patient on apixaban compared to 1 on placebo, and major bleeding episode occurred in 1 on apixaban and 0 on placebo. In patients with CrCl ≥ 60 mL/min, VTE occurred in 13 out of 257 (5.1%) in the apixaban group and 28 out of 242 (11.6%) in the placebo group [HR 0.41 (95% CI 0.26-0.64), p=0.0001] (Table 2). There were no significant differences between apixaban and placebo groups in major bleeding and clinically relevant non-major bleeding events. Overall mortality was significantly lower in the apixaban group (HR 0.25 [95% CI 0.13-0.45], p<0.0001) in patients with CrCl ≥ 60 mL/min. Conclusions In the AVERT trial, patients with CrCl < 60 mL/min were significantly older, more likely to be female, with lower weight or BMI and poorer ECOG performance status. There were very few VTE or major bleeding events in patients with CrCl < 60 mL/min. In patients with CrCl ≥ 60 mL/min, apixaban thromboprophylaxis was associated with a significantly lower rate of VTE and overall mortality compared to placebo, with no significant differences in the rates of major bleeding or clinically relevant non-major bleeding events. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Carrier: Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Servier: Honoraria; Pfizer: Honoraria, Research Funding; Bayer: Honoraria. Wells: Daiichi Sankyo: Honoraria; BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria. OffLabel Disclosure: apixaban for primary thromboporphylaxis in ambulatory cancer patients receiving chemotherapy

Clopidogrel Loading Dose 300 vs. 600 mg in Patients Undergoing One-Stop Hybrid Coronary Revascularization: A Prospective Single-Center Randomized Pilot Study

Background: The optimal loading dose of clopidogrel in one-stop hybrid coronary revascularization (HCR) remains an “evidence-free” zone. This study aimed to compare the major bleeding and ischemic thrombotic events between different clopidogrel loading doses (300 vs. 600 mg) in one-stop HCR.Methods: In this prospective, single-center, randomized, and parallel pilot study, 100 patients receiving one-stop HCR were randomly assigned to the clopidogrel loading dose 300-mg group or 600-mg group in a 1:1 ratio. Major bleeding events and composite in-hospital ischemic thrombotic and adverse complications were evaluated after the procedure.Results: The results showed that postoperative mean chest drainage of the first 4 days and total drainage were comparable between the two groups. No differences were found in Bleeding Academic Research Consortium (BARC) coronary artery bypass grafting (CABG) related bleeding (4 vs. 2%, P = 1), PLATelet inhibition and patient Outcomes (PLATO) life-threatening bleeding (20 vs. 26%, P = 0.48), and PLATO major bleeding (70 vs. 76%, P = 0.5) in the two groups. The composite ischemic thrombotic and adverse events were also similar.Conclusions: In patients receiving one-stop HCR, clopidogrel 600 mg loading dose did not increase major bleeding events compared with 300 mg. More sufficient data is necessary to evaluate the potential benefits of 600 mg loading dose in one-stop HCR.

Substantially elevated thromboembolic and bleeding risks in patients with AMI following acute/subacute stroke events

Introduction AMI infrequently but concomitantly occurs after stroke events. Current guideline recommends primary PCI with DAPT in the setting of AMI. However, this approach is not necessarily applicable in AMI subjects following acute/subacute stroke events due to its bleeding risk. Clinical management and outcomes of these AMI subjects following remains uncertain. Purpose To characterize management and clinical outcomes in patients with AMI following acute/subacute stroke events (=post-stroke AMI). Methods The current study retrospectively analyzed 2041 AMI patients hospitalized at our institute from 2007 to 2018. Post-stroke AMI was defined as its occurrence within 14 days after ischemic/hemorrhagic stroke. The use of reperfusion and anti-thrombotic therapies, and the occurrence of major adverse cardiovascular events (=CV death, non-fatal MI and non-fatal stroke) and major bleeding events (BARC type 3 or 5) were compared in post-stroke and non-post-stroke AMI patients. Results Post-stroke AMI was identified in 1.1% of entire subjects (=23/2041). Of these, 65% of them (=15/23) had AMI within 3 days from the onset of stoke event. Over 60% of them was due to cardioembolic stroke, followed by hemorrhagic (9%), atherothrombotic ones (8%) and other causes (22%). Post-stroke AMI patients were more likely to exhibit Af (p=0.02) and a history of hemodialysis (p=0.009), and have a lower BMI (p=0.04) and hemoglobin level (p=0.02). They were less likely to receive emergent coronary angiography, and primary PCI was conducted in only 65% of post-stroke AMI patients (Table). Furthermore, they more frequently received thrombectomy (p=0.04) alone rather than stent implantation (p=0.002) (Table). With regard to anti-thrombotic therapy, the proportion of DAPT use was significantly lower in post-stroke AMI subjects (52 vs. 89%, p=0.0001), and 17% of them did not receive any anti-thrombotic agents. Of note, only 48% (p=0.04) and 43% (p=0.0001) of post-stroke AMI patients were treated with other established medical therapies including β-blocker and statin, respectively. During the observational period (median = 2.9 years), post-stroke AMI was associated with a greater likelihood experiencing major adverse cardiovascular events (log-rank p<0.001, Figure), CV death (log-rank p<0.0001) and stroke events (log-rank p<0.0001). Furthermore, the frequency of their major bleeding events was substantially elevated (log-rank p<0.001, Figure). Conclusions In our real-world data, the adoption of guideline-recommended reperfusion and anti-thrombotic therapies were considerably low in AMI subjects following acute/subacute stroke events. Given their elevated risk of cardiovascular and bleeding events, it is required to establish better therapeutic management for mitigating their thrombotic/bleeding risks. FUNDunding Acknowledgement Type of funding sources: None. Table 1 Figure 1