Minor Bleeding Events Research Articles

DNA methylation of ADAMTS7 gene promoter in direct oral anticoagulant-induced bleeding in patients with atrial fibrillation

Abstract Introduction Direct Oral Anticoagulants (DOACs) are recommended as first-line treatment in atrial fibrillation (AF) patients. Despite their benefits and effectiveness, several patients experience bleeding events. No studies have addressed how epigenetic modifications may affect DOAC treatment. To fill this gap, we are conducting a study aiming to follow in time changes of DNA methylation patterns in naïve AF patients starting DOAC therapy. Herein, we present our findings regarding DNA methylation analysis of ADAM Metallopeptidase with Thrombospondin Type 1 Motif 7 (ADAMTS7), a protease that acts on the cardiovascular system. Methods A total of 76 AF patients treated with dabigatran, rivaroxaban, or apixaban and 22 non-AF controls were included. Genomic DNA has been isolated at baseline (t0, controls and patients), and for patients at 7 (t1) and 28 (t2) days of DOAC treatment. Blood genomic DNA was isolated and bisulfite converted prior to methylation analysis. Promoter DNA methylation of ADAMTS7 was analyzed with qMSP-PCR. Results In our study, no major bleeding or thrombotic events were recorded. A total of 16 minor bleeding events occurred. The percentage of ADAMTS7 methylation at baseline did not differ between patients and controls (16,8% vs. 14,8%, p=0,138). In patient cohort, DOAC therapy did not alter ADAMTS7 methylation at different timepoints (16,8% at t0, 15,7% at t1 and 14,3% at t2, p=0,293 from t0 to t1, p=0,06 from t0 to t2 and p=0,205 from t0 to t1). When patients were categorized into experiencing bleeding events (cases) or not (controls), ADAMTS7 was demethylated from t0 to t2 (-3,7% in cases vs. -1.2% in controls, p=0.015) and from t1 to t2 (-2,1% in cases vs. -1,1% in controls, p=0.034). In adjusted regression analysis, bleeding was associated with ADAMTS7 demethylation (β=-2,973, 95%CI -5,481, -0,466, p=0,021). Conclusion This is the first study of DNA methylation on DOACs. Our findings suggest that the methylation of the promoter of ADAMTS7 is reduced when DOAC-related bleeding occurs, increasing its expression levels, and may subsequently promote hemostasis and endothelium remodeling through different pathways.

Risk factors for serious adverse events related to vitamin K antagonists in children with congenital or acquired heart disease: a prospective cohort study

ObjectivesTo assess the occurrence of thrombosis and major bleeding in children with congenital or acquired heart disease (CAHD) treated with VKA and to identify risk factors for these serious adverse events (SAE). Study designAll children enrolled in our VKA dedicated educational program between 2008 and 2022 were prospectively included. The time in therapeutic range (TTR) was calculated to evaluate the stability of anticoagulation. Statistical analysis included Cox proportional hazard models. ResultsWe included 405 patients. Median follow-up was 18.7 (9.3–49.4) months. The median TTR was 83.1 % (74.4 %–95.3 %). No deaths occurred because of bleeding or thrombotic events. The incidences of thrombotic and major bleeding events were 0.9 % (CI95 % [0.1–1.8]) and 2.3 % (CI95 % [0.9–3.8]) per patient year, respectively. At 1 and 5 years, 98.3 % (CI95 % [96.2 %–99.2 %]) and 88.7 % (CI95 % [81.9 % 93.1 %]) of patients were free of any SAE, respectively. Although the mechanical mitral valve (MMV) was associated to major bleeding events (HR = 3.1 CI95 % [1.2–8.2], p = 0.02) in univariate analysis, only recurrent minor bleeding events (HR = 4.3 CI95 % [1.6–11.7], p < 0.01) and global TTR under 70 % (HR = 4.7 CI95 % [1.5–15.1], p < 0.01) were independent risk factors in multivariable analysis. In multivariable analysis, giant coronary aneurysms after Kawasaki disease (HR = 7.8 [1.9–32.0], p = 0.005) was the only risk factor for thrombotic events. ConclusionOverall, VKA therapy appears to be safe in children with CAHD. Suboptimal TTR, regardless of the indication for VKA initiation, was associated with bleeding events.

Abstract 17536: Real World Analysis from the "Fast STEMI" Registry on Adherence and Discontinuation of Statin Therapy Within 6 Months After ST-Elevation Myocardial Infarction on First Year Follow-Up: Prognostic Impact and Predictors of Adherence

Background: The impact of statin therapy on cardiovascular outcomes after ST-elevation acute myocardial infarction (STEMI) in real-world patients is understudied. Objectives: to identify predictors of low adherence and discontinuation to statin therapy within 6 months after STEMI and to estimate their impact on cardiovascular outcomes at one year follow-up. Methods: We evaluated real-world adherence to statin therapy by comparing the number of bought tablets to the expected ones at 1 year follow-up through pharmacy registries. A total of 6043 STEMI patients admitted from 2012 to 2017 were enrolled in the FAST STEMI registry and followed up for 4,7±1,6 years; 299 patients with intraprocedural and intrahospital deaths were excluded. The main outcomes evaluated were all-cause death, cardiovascular death, myocardial infarction, major and minor bleeding events, and ischemic stroke. The compliance cut-off chosen was 80% as mainly reported in literature. Results: From a total of 5744 patients, 418 (7,2%) patients interrupted statin therapy within 6 months after STEMI. After univariate and multivariate analysis age over 75 years old, known ischemic cardiopathy and female gender resulted as predictors of therapy discontinuation. Statin discontinuation within 6 months showed an increase of both cardiovascular (5% vs 1.7%; HR 2.23; 95%CI 1.37-3.65; p=0,001) and all-cause mortality (14.8% vs 5.1%, HR 2.32; 95%CI 1.73-3.11; p&lt;0,001) at 1 year follow-up. Regarding cardiovascular outcomes, statin optimal adherence (&gt;80%) reduced ischemic stroke incidence (1% vs 2.5%, p=0.001) and both cardiovascular and all-cause death (0.1% vs 4.6%; 0.3% vs 13.4%; p&lt;0.001) at 1 year follow-up. Age over 75 years old, chronic renal failure, previous atrial fibrillation, vasculopathy, known ischemic cardiopathy were found to be predictors of low statin adherence. Conclusions: In our real-world registry low statin adherence and discontinuation therapy within 6 months after STEMI were independently associated to an increase of cardiovascular and all-cause mortality at 1 year follow-up. Low statin adherence led to higher rates of ischemic stroke. This analysis confirmed the predictive factors of adherence and discontinuation therapy already described in literature.

Analysis of Perioperative Factor Replacement Therapy for Hemophilia

Background Hemophilia is a hereditary bleeding disorder, especially in severe hemophilia, that can lead to spontaneous bleeding. For hemophilia patients with inhibitors, even minor acute bleeding events or surgical procedures can have catastrophic consequences. Some hemophiliacs are forced to make surgical choices. There are many risks in perioperative period when hemophiliacs undergo major surgery. Seeking effective and safe perioperative clotting factor replacement therapy or bypass therapy is the basis of successful surgery. Aims To seek effective and safe perioperative coagulation factor replacement therapy or bypass therapy. Methods HA patients were treated with FVIII preparation during perioperative period. To calculate dosage, multiply the patient ' s weight in kilograms by the FVIII level in IU/dL desired, then multiply by 0.5. Example: 50 kg × 40 (IU/dL level desired) × 0.5 = 1000 IU of FVIII. HB patients were treated with PCC or FIX during perioperative period. To calculate dosage, multiply the patient ' s weight in kilograms by the FIX level in IU/dL desired. Example: 50 kg body weight × 40 (IU/dL level desired) = 2000 IU of plasma-derived FIX. For hemophilia patients with low titer inhibitors, estimate the amount of FVIII required as a neutralizing inhibitor loading dose as recommended by WFH. The following formula is used to estimate the amount of FVIII needed as a loading dose to neutralize the inhibitor: [body weight (kg) × 80 × [(1 − hematocrit) × antibody titer (BU)]. An additional 50 IU/kg above the calculated loading dose is added to achieve a measurable FVIII activity. Patients with hemophilia combined with high titer inhibitors were treated with rFVIIa combined with PCC SCBT regimen. Sequential use refers to alternating rFVIIa and aPCC every 3 hours. Results 69 patients with indications for surgery and/or desire for surgery who underwent different types of surgery with clotting factor replacement therapy or bypass therapy were evaluated (Table 1). There were 37 cases of severe hemophilia and 32 cases of non-severe hemophilia. There were 63 cases of HA, including 50 cases of negative inhibitor and 13 cases of positive inhibitor. After meeting the inclusion and exclusion criteria, 69 patients were evaluated for different types of surgery under clotting factor replacement therapy or bypass therapy during perioperative period. 59 cases underwent major operations, including: 49 cases underwent joint replacement, among which 34 cases underwent single joint replacement and 6 cases underwent double joint replacement and so on. 10 cases underwent minor operations. There were 14 cases of hemophilia with inhibitors, of which 13 were major operations with 175.38 (85.00-270.00) minutes of operation and 2 were minor operations with 45.00 minute of operation. In 12 patients with severe hemophilia and high titer inhibitors, the perioperative consumption of factor FVII was as follows: 447.62 (331.04-738.48)ug/kg on the day of surgery, and the total consumption was 2484.21 (1499.40-4500.00)ug/kg. The perioperative consumption of factor PCC was as follows: 126.10 (0-206.45)ug/kg on the day of surgery, and the total consumption was 1332.84 (529.20-1970.00)ug/kg. The mean preoperative FVIII:C level of the HA patients was 1.19 (0.00~6.00)%, the mean preoperative FIX:C level was 0.022 (0.01~0.07)% of the HB patients.The average intraoperative blood loss of the 69 patients was 537.98 (0-3000) ml. 20 patients received intraoperative transfusion of blood products (red blood cells or fresh frozen plasma) and 49 patients did not receive intraoperative transfusion of blood products. In 55 hemophiliacs without inhibitor, no inhibitor was found after surgery. Conclusion(s) It is safe and effective to adopt different schemes for perioperative alternative therapy for different hemophilia types.

Antiphospholipid Antibody Syndrome (APS) Pediatric Patient Outcomes on Warfarin

Background: Antiphospholipid antibody syndrome (APS) is an acquired thromboembolism (TE) risk factor and places patients at very high risk of recurrent TE. APS diagnosis requires venous (deep vein thrombosis (DVT) or pulmonary embolism (PE)) or arterial thromboembolism and laboratory diagnosis including persistently positive lupus anticoagulant (LA) or elevated anticardiolipin (aCL) and/or beta 2 glycoprotein I (B2GPI) antibodies tested 12 weeks apart. Vitamin K antagonist (warfarin) is the standard of care anticoagulant to reduce risk of TE recurrence in APS patients. Warfarin is dosed based on the International Normalized Ratio (INR) with established therapeutic ranges for optimal efficacy and safety. The reported time in therapeutic range (TTR) varies greatly across specialties with an average TTR of 50-55%. However, it is often difficult to maintain target INR in APS. Furthermore, there is limited data evaluating pediatric patients with APS and their TTR on warfarin and outcomes. Aim: To evaluate the relationship of APS status to TTR and outcomes of patients &amp;lt; 21 years of age with APS who are on warfarin anticoagulation. Methods: This was a single center analysis of APS patients between July 2019 and May 2022 who were enrolled in a multi-center prospective study of pediatric patients on warfarin therapy, eKITE (electronic KidClot Thrombophilia Education). The study included an online learning series regarding warfarin management. Home INR meters and test strips were provided to all patients to perform INR testing. INR values were reported by patients and recorded. Demographic and clinical data was extracted from the electronic medical record, target INR was set by the treating provider, and TTR was calculated as a surrogate for safe, effective warfarin management. Results: Nine patients (n=9) with APS were identified for this analysis, mean age 16.7 years (range 12-19 years). Demographic and laboratory findings are summarized in Table 1. Most patients had secondary APS due to systemic lupus erythematous (SLE) 78% (n=7) and 22% (n=2) had other primary diagnoses. APS antibody status included single positive in 67% (n=6), double positive in 22% (n=2), and triple positive in 11% (n=1). More specifically, APS criteria were met by persistently elevated LA in 78% (n=7), aCL IgM in 22% (n=2) with overall mean aCL IgM of 34.4 MPL^ (range 9.9-127.9), B2GPI IgG in 11% (n=1) with overall mean B2GPI IgG SGU* of 13.1 (range 0.9-63.3), and B2GPI IgM in 22% (n=2) with overall B2GPI IgM mean of 32.5 SGU (range 3.3-190.9). At time of presentation 67% (n=6) of patients had DVT, 44% (n=4) had PE, 11% (n=1) had arterial TE, and 22% (n=2) presented with DVT &amp; PE. Mean TTR for all patients was 56%. TTR for single positive APS was 66%, double positive APS 39%, and triple positive APS 33%. TTR for secondary APS (SLE) and non-SLE diagnoses was 53% and 68% respectively. Mean dose changes were 11 (range 0-48) with one single positive LA patient requiring 48 dose changes, and two patients with single positive LA not requiring any dose changes. Two patients (22%) developed recurrent clot. One triple positive APS patient developed two DVTs and one non-SLE patient developed recurrent arterial TE. Three patients (33%) had minor bleeding events including mild epistaxis and hematemesis not requiring intervention. One patient (11%) had a major bleeding event, hemoperitoneum from pseudoaneurysm extravasation, while resuming warfarin during post-operative period, and required takeback surgery with sub-therapeutic INR 1.5 at the time of event. Conclusion: The mean TTR for pediatric patients with APS is similar to what is reported in other populations despite the challenge of managing warfarin in this group where the INR may be affected by primary disease modifying medications or disease flares. The risk of recurrent TE remains high in APS patients. Home INR monitors are a safe and effective strategy in managing warfarin anticoagulation in APS patients, reducing time and laboratory monitoring burden for frequent dose changes, which ultimately improves quality of life.Optimizing TTR is important to decrease risk of recurrent TE or bleeding in these high risk APS patients.

Comparison of Aspirin and P2Y12 Inhibitors for Secondary Prevention of Ischaemic Stroke: A Systematic Review and Meta-analysis.

P2Y12 inhibitors have been widely used as an alternative to aspirin in clinical practice for secondary stroke prevention. We aimed to compare the efficiency and safety of P2Y12 inhibitors and aspirin for stroke prevention in patients with previous stroke or transient ischaemic attack (TIA). PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. All randomized trials that compared P2Y12 inhibitors with aspirin among patients with stroke were included. The primary efficacy outcomes of our meta-analysis included stroke, vascular events, and all-cause death. The primary safety outcome was minor or major bleeding events. The search identified 4 randomized clinical trials comparing P2Y12 inhibitors with aspirin for secondary stroke prevention that collectively enrolled 24508 patients (12253 received P2Y12 inhibitor and 12255 received aspirin). Pooled results from the random-effects model showed that there were no significant differences in the risk of any stroke (OR 0.90 (0.78-1.04); I²=56.9%), vascular event (OR 0.91 (0.74-1.13); I²=78.3%), all-cause death (OR 0.98 (0.83-1.17); I²=0%), or minor or major bleeding (OR 1.13 (0.70-1.82); I²=79%) among patients who received a P2Y12 inhibitor or aspirin. P2Y12 inhibitors were associated with a significantly lower risk of recurrent ischaemic stroke (OR 0.84 (0.73- 0.96); I²=25%) than aspirin. This meta-analysis suggests that P2Y12 inhibitors are more effective than aspirin in preventing recurrent ischaemic stroke among ischaemic stroke patients despite the absence of any effect on a new ischaemic or haemorrhagic stroke, a new clinical vascular event, all-cause death, and major or minor bleeding events.

An Update on Betrixaban, the Challenging Anticoagulant Agent for Extended Venous Thromboembolism Prophylaxis.

Venous thromboembolism (VTE), comprising deep-vein thrombosis (DVT) and pulmonary embolism (PE), stands as the third leading cause of vascular-related mortality on a global scale. Anticoagulation prophylaxis undeniably ensures a significant reduction in the risk of DVT, while simultaneously exposing individuals to an elevated likelihood of experiencing both major and minor bleeding events. Betrixaban is a novel oral anticoagulant, a direct factor Xa inhibitor, approved by the Food and Drug Administration (FDA) but not by the European Medicines Agency (EMA) for VTE thromboprophylaxis. The current necessity revolves around the acquisition of a substantial volume of data to dispel the uncertainties associated with this drug due to its non-approval by the EMA. Consequently, we eagerly await the results of post-marketing pharmacovigilance efforts to provide further insights into the performance of betrixaban within the broader population.

Model-Guided Decision-Making for Thromboprophylaxis and Hospital-Acquired Thromboembolic Events Among Hospitalized Children and Adolescents

Rates of hospital-acquired venous thromboembolism (HA-VTE) are increasing among pediatric patients. Identifying at-risk patients for whom prophylactic interventions should be considered remains challenging. To determine whether use of a previously validated HA-VTE prognostic model, together with pediatric hematologist review, could reduce pediatric inpatient rates of HA-VTE. This pragmatic randomized clinical trial was performed from November 2, 2020, through January 31, 2022, at a single-center academic children's hospital (Monroe Carell Jr Children's Hospital at Vanderbilt). All pediatric hospital admissions (aged <22 years) under inpatient status were included and randomized. All patients had an HA-VTE probability automatically calculated daily, which was visible to the hematology research team for patients in the intervention group. Patients with an elevated risk (predicted probability ≥2.5%) underwent additional medical record review by the research team to determine eligibility for thromboprophylaxis. The primary outcome was rate of HA-VTE. Secondary outcomes included rates of prophylactic anticoagulation and anticoagulation-associated bleeding events. A total of 17 427 hospitalizations met eligibility criteria, were randomized, and were included in the primary analysis: patients had a median (IQR) age of 1.7 (0 to 11.1) years; there were 9143 (52.5%) female patients and 8284 (47.5%) male patients, and there were 445 (2.6%) Asian patients, 2739 (15.9%) Black patients, and 11 752 (67.4%) White patients. The 2 groups were evenly balanced in number (8717 in the intervention group and 8710 in the control group) and patient characteristics. A total of 58 patients (0.7%) in the control group and 77 (0.9%) in the intervention group developed HA-VTE (risk difference: 2.2 per 1000 patients; 95% CI, -0.4 to 4.8 per 1000 patients; P = .10). Recommendations to initiate thromboprophylaxis were accepted by primary clinical teams 25.8% of the time (74 of 287 hospitalizations). Minor bleeding events were rare among patients who received anticoagulation (3 of 74 [4.1%]), and no major bleeding events were observed during the study period. Among patients randomized to the control group, the model exhibited high discrimination accuracy (C statistic, 0.799, 95% CI, 0.725 to 0.856). In this randomized clinical trial of the use of a HA-VTE prognostic model to reduce pediatric inpatient rates of HA-VTE, despite the use of an accurate and validated prognostic model for HA-VTE, there was substantial reluctance by primary clinical teams to initiate thromboprophylaxis as recommended. In this context, rates of HA-VTE between the control and intervention groups were not different. Future research is needed to identify improved strategies for prevention of HA-VTE and to overcome clinician concerns regarding thromboprophylaxis. ClinicalTrials.gov Identifier: NCT04574895.

Bleeding Complications in COVID-19 Critically Ill ARDS Patients Receiving VV-ECMO Therapy.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) therapy is rapidly expanding worldwide, yet this therapy has a serious risk of bleeding. Whether coagulation-activating viral infections such as COVID-19 may have an impact on the risk of bleeding is largely unknown. This study conducted a monocentric investigation of severely affected COVID-19 patients receiving VV-ECMO therapy with regard to the occurrence and possible influences of minor and major bleeding and transfusion requirements. Among the 114 included study patients, we were able to assess more than 74,000 h of VV-ECMO therapy. In these, 103 major bleeding events and 2283 minor bleeding events were detected. In total, 1396 red blood concentrates (RBCs) were administered. A statistically significant correlation with the applied anticoagulation or demographic data of the patients was not observed. Contrary to the frequently observed thromboembolic complications among COVID-19 patients, patients with VV-ECMO therapy, even under low-dose anticoagulation, show a distinct bleeding profile, especially of minor bleeding, with a substantial need for blood transfusions. COVID-19 patients show a tendency to have frequent bleeding and require repeated RBC transfusions during VV-ECMO. This fact might not be solely explained by the mechanical alteration of ECMO or anticoagulation.

Comparation of the outcomes between ProGlide based post-closure technique and arteriotomy repair for veno-arterial extracorporeal membrane oxygenation decannulation

PurposeTo compare outcomes between post-closure technique based on ProGlide and arteriotomy repair for veno-arterial extracorporeal membrane oxygenation (VA-ECMO) decannulation in this study. Materials and methodsPatients who received VA-ECMO treatment and successfully removed from its support in Changhai Hospital from January 2018 to December 2021 were included in this study. Patients was divided into post-closure group and surgical repair group according to the artery access closure method used. Clinical data of these patients were retrospectively collected and analyzed. ResultsA total of 58 patients were eventually enrolled in this study, including 26 (44.83%) patients in post-closure group and 32 (55.17%) patients in surgical repair group. Post-closure group had shorter procedure time, less minor bleeding events, estimated blood loss and packed cells transfused compared with the surgical repair group. The intensive care unit (ICU) length of stay after decannulation and the hospital length of stay after ICU in post-closure group were both shorter than surgical repair group. Nine patients (15.52%) died of multiple system organ failure after decannulation in this cohort and there were no significant differences between two groups. ConclusionsOur study showed the post-closure technique based on ProGlide for VA-ECMO decannulation is feasible, safe and effective.

Tranexamic Acid Prevention of Hemorrhagic Complications Following Interpolated Flap Repair: A Single-Center, Retrospective, Cohort Study.

Tranexamic acid (TXA) is increasingly being used to prevent hemorrhagic complications after dermatologic surgery. Interpolated flap repairs following Mohs micrographic surgery are at risk for increased bleeding events and unplanned health care utilization, particularly among patients on antithrombotic medication. To assess bleeding events after interpolated flap repair in patients receiving TXA compared with those who did not. A retrospective review identified interpolated flap repairs in a 5-year period. Hemorrhagic complications were analyzed, defined as major bleeding events, which included all unplanned medical visits, and minor bleeding events, which included any unplanned patient phone calls or messages through electronic medical record. One hundred fifteen patients had interpolated flap repair during the 5-year period, of which 21 (18.3%) received TXA postprocedure. Twenty-seven bleeding events were identified in the non-TXA group compared with 1 event in the TXA-treated group. Patients who received TXA were less likely to have had a bleeding event (28.7% vs 4.8%, p < .01). Patients undergoing interpolation flap repair were less likely to experience a bleeding event after subcutaneous injection of TXA.

Direct Oral Anticoagulants for the Treatment of Venous Thromboembolism in Obesity.

Background: Direct oral anticoagulants (DOACs) are known to have similar efficacy with a decreased risk of bleeding when compared to warfarin for the treatment of venous thromboembolism (VTE). In patients with obesity, there are limited data regarding the safety and efficacy of DOACs. Despite concerns for both under- and over-dosing patients with extremes of body weight, there are no dose adjustment recommendations in the package inserts for any of the DOACs. Objective: To evaluate the safety and efficacy of DOACs versus warfarin for the treatment of VTE in patients with obesity. Methods: This single-center, retrospective cohort study included obese patients initiated on DOAC or warfarin therapy for VTE from January 2015 to January 2022. Patients with cancer, hypercoagulable disorders, end-stage kidney disease, or pregnancy were excluded. The primary endpoint was VTE recurrence. Secondary endpoints included major and minor bleeding. Results: A total of 120 patients met criteria for inclusion. Ninety-two received DOAC therapy and 28 received warfarin. The primary endpoint occurred in 4 patients in the DOAC group and 3 patients in the warfarin group (P = 0.35). Major bleeding occurred in 2 patients. Minor bleeding events occurred in 10 (8.33%) patients. Of those, 6 (6.5%) events occurred in patients receiving a DOAC and 4 (14.3%) events occurred in patients receiving warfarin (P = 0.28). Limitations of this study include the retrospective single-center study design. Conclusions: There was a comparable risk of bleeding and recurrent VTE between DOACs and warfarin in patients initiated on therapy for VTE.

The efficacy and safety of low-molecular-weight heparin in patients undergoing knee arthroscopic surgery and anterior cruciate ligament reconstruction

PurposeTo inveatigate how effective LMWH was at preventing venous thromboembolism (VTE), major bleeding events, and minor bleeding events after simple knee arthroscopic surgery and anterior cruciate ligament reconstruction (ACLR). MethodsWe conducted a comprehensive search of PubMed, EMBASE, Cochrane Library, and the CNKI database for potentially eligible articles. The outcomes were evaluated in terms of odds ratio (OR) and the associated 95% confidence intervals (CIs). Meta-analysis was performed using the Stata software and subgroup analyses were performed based on the surgical setting including ACLR and simple knee arthroscopic surgery. ResultsA total of eight studies with 2249 patients and 1794 controls were included in this meta-analysis. In patients undergoing simple knee arthroscopic surgery, LMWH prophylaxis did not bring a significant reduction in the risk of symptomatic deep venous thrombosis (DVT), symptomatic pulmonary embolism (PE), symptomatic VTE, and did not increase the risk of major bleeding events, but did have a higher risk of minor bleeding events (OR = 1.95, 95% CI 1.34–2.84, P = 0.000) and a lower risk of asymptomatic DVT (OR = 0.14, 95% CI 0.04–0.53, P = 0.004) in comparison with non-LMWH prophylaxis. In patients undergoing ACLR, LMWH prophylaxis did not bring a significant reduction in the risk of symptomatic DVT, symptomatic PE, symptomatic VTE, and did not increase the risk of major bleeding events and minor bleeding events, but did have a lower risk of asymptomatic DVT (OR = 0.43, 95% CI 0.23–0.78, P = 0.006). ConclusionWhen compared to a control group, this meta-analysis found that LMWH had little potential benefit in preventing major VTE (symptomatic VTE, symptomatic DVT, and symptomatic PE) after simple knee arthroscopy and ACLR. As a result, LMWH should not be considered routinely in patients undergoing knee arthroscopic surgery.

Efficacy and safety of direct oral anticoagulants vs vitamin K antagonists in patients with atrial fibrillation and end-stage renal disease on hemodialysis: A systematic review and meta-analysis

BackgroundThe prevalence of atrial fibrillation (AF) in individuals with end-stage renal disease (ESRD) on chronic hemodialysis is increasing. The optimal anticoagulant choice in this population is unclear since these patients were excluded from the pivotal randomized controlled trials (RCTs) of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) in the general AF population. We aimed to assess the efficacy and safety of DOACs vs. VKAs in patients with AF and ESRD on chronic hemodialysis through a systematic review and meta-analysis of all available evidence. Patients/MethodsWe performed a systematic search in MEDLINE and Scopus for RCTs or observational studies of patients with AF and ESRD on chronic hemodialysis who were treated with DOACs or VKAs. The outcomes of interest included ischemic stroke, the composite of ischemic stroke or systemic embolism, major bleeding, gastrointestinal bleeding, minor bleeding events and all-cause mortality. ResultsAmong 397 studies identified from the literature search, six studies (three RCTs and three observational studies) were included in the meta-analysis. Compared with VKA-treated patients, those treated with DOACs had similar risk of ischemic stroke (RR:0.76, 95% CI:0.41–1.41), ischemic stroke or systemic embolism (RR:0.65, 95% CI:0.38–1.10), major bleeding (RR:0.79, 95% CI:0.49–1.28) and all-cause death (RR:0.79, 95% CI:0.56–1.12). The risk of gastrointestinal bleeding was lower in DOAC- vs VKA-treated patients in three eligible observational studies (RR:0.73, 95% CI: 0.54–0.99, I2 = 79%) but this was not confirmed in two eligible RCTs (RR:0.69, 95% CI: 0.33–1.43, I2 = 0%). ConclusionsAmong AF patients with ESRD on chronic hemodialysis, the risk of ischemic stroke, ischemic stroke or systemic embolism, minor bleeding, major bleeding, and all-cause mortality is similar in patients treated with DOACs compared to VKAs. Given that the meta-analysis of RCTs on gastrointestinal bleeding did not confirm the results of the meta-analysis of the observational studies, it cannot be concluded that gastrointestinal bleeding is lower among DOAC-treated patients. Protocol registrationPROSPERO CRD42023391966

Implications of bleeding on subsequent cardiovascular events in patients with atrial fibrillation after acute coronary syndrome or PCI

IntroductionThe association between bleeding and subsequent major adverse cardiac and cerebrovascular events (MACCE) remains poorly characterized. We aimed to evaluate the impact of hemorrhagic events in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). Materials and methodsA total of 1877 consecutive patients with AF and ACS or undergoing PCI were prospectively recruited. The primary endpoint was MACCE, including all-cause death, myocardial infarction, ischemic stroke, systemic embolism or ischemia-driven revascularization during follow-up. Post-discharge bleeding was graded according to TIMI criteria. Associations between bleeding and subsequent MACCE were examined using time-dependent multivariate Cox regression after adjusting for baseline covariates and the time from bleeding. ResultsDuring a median follow-up of 34.2 months, 341 (18.2 %) had TIMI major or minor bleeding events, of whom 86 (25.2 %) also experienced MACCE. The risk of MACCE was significantly higher in patients with bleeding than those without (8.85 % versus 6.99 % per patient-year; HR, 1.568, 95 % CI, 1.232–1.994). In patients who had both bleeding and MACCE, 65.1 % (56 of 86) bleeding events occurred first. Temporal gradients in MACCE risk after major bleeding was highest within 30 days (HRadj, 23.877; 95 % CI, 12.810–44.506) and remained significant beyond 1 year (HRadj, 3.640; 95 % CI, 1.278–10.366). Minor bleeding was associated with increased risk of MACCE within 1 year. ConclusionsIn patients with AF and ACS or PCI, major and minor bleeding were associated with subsequent MACCE with time-dependency. Our findings may aid in better defining net clinical benefit of optimal antithrombotic therapy.

Direct oral anticoagulants versus aspirin for primary thromboprophylaxis in patients with multiple myeloma undergoing outpatient therapy: A systematic review and updated meta-analysis.

Patients with multiple myeloma (MM) are at an elevated risk of venous thromboembolism (VTE), which is further increased for those undergoing anti-myeloma therapy. Current guidelines suggest low-dose direct oral anticoagulants (DOACs) as an alternative to aspirin for primary thromboprophylaxis in this population, but data comparing these two therapies are limited. We performed a systematic review and meta-analysis to compare DOACs with aspirin for primary thromboprophylaxis in individuals undergoing outpatient anti-myeloma therapy. Studies were selected when comparing DOACs versus aspirin for thrombotic and haemorrhagic outcomes. We included 10 randomised controlled trials and observational studies comprising 1026 patients with MM who received primary thromboprophylaxis with DOACs (n = 337) or aspirin (n = 689). DOAC thromboprophylaxis was associated with a significantly lower incidence of VTE compared with aspirin (OR 0.33; 95% CI 0.16-0.68; p < 0.001). Major, clinically relevant non-major and minor bleeding event rates did not differ significantly between groups. Overall, our meta-analysis suggests that DOACs may be a preferable option to aspirin for the prevention of MM-related thrombosis. However, these results should be interpreted in the context of heterogeneous baseline population characteristics and potential bias from including observational studies. Further research is needed to evaluate the optimal thromboprophylaxis strategy, particularly in high-risk individuals.

Early Discontinuation of Aspirin Among Patients with Chronic Kidney Disease Undergoing Percutaneous Coronary Intervention with a Drug-Eluting Stent: A Meta-Analysis.

Conflicting evidence exists to support whether short duration of dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor monotherapy reduces bleeding complications after coronary artery drug-eluting stent (DES) insertion, compared with standard 12-month DAPT, particularly among patients with CKD who are at increased risk of bleeding. A Medline search identified randomized trials comparing up to 3 months of DAPT followed by P2Y12 inhibitor monotherapy versus twelve months of DAPT after insertion of a DES for any indication. Trials were included if they reported ischemic or bleeding outcomes among patients with CKD. The primary outcome was a composite of all-cause mortality, cardiac or cerebrovascular events, stent thrombosis (MACE), and major or minor bleeding events. Secondary outcomes were the individual components of the primary outcome, and clinically significant bleeding. The relative risk (RR) was estimated using a random-effects model. Seven randomized trials were included for a total of 4,996 patients with CKD (14% of the trial population). Early discontinuation of aspirin was associated with a similar incidence of the primary outcome among patients with CKD compared with twelve-month DAPT (RR 0.97; 95% confidence interval (95% CI) 0.73-1.30). The relative risk of MACE was also similar between the two arms (RR 1.02; 95% CI 0.85-1.23). The risk of clinically significant bleeding was significantly lower with early discontinuation of aspirin (RR 0.60; 95% CI 0.46-0.78). P2Y12 inhibitor monotherapy after a shortened course of DAPT appears to be associated with a similar risk of ischemic events and a lower risk of bleeding events after DES insertion among patients with CKD compared to 12-month DAPT.

Heparin reversal with protamine sulfate after Percutaneous Hepatic Perfusion (PHP): is less more?

PurposePercutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy for unresectable hepatic malignancies. During PHP, high-dose melphalan is infused via the hepatic artery to saturate tumor in the liver with the chemotherapeutic substance. The venous hepatic blood is filtered by an extracorporeal melphalan specific filtration system. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH) in high doses, which might be reversed with protamine sulfate after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine sulfate on complication rates following PHP.Materials and methodsAll patients receiving PHP treatment between 10/2014 and 04/2021 were classified according to their intraprocedural coagulation management: 92 patients/192 PHP received full UFH reversal with protamine (groupPROTAMINE); 13 patients/21 PHP in groupREDUCED_PROTAMINE received a reduced amount of protamine, and 28 patients/43 PHP did not receive UFH reversal with protamine (groupNO_PROTAMINE). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAEv5.0).ResultsThromboembolic events were recorded after 10 PHP procedures (5%) in groupPROTAMINE, six of which (3%) were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in groupREDUCED_PROTAMINE and groupNO_PROTAMINE. Hemorrhagic events were registered after 24 PHP (13%) in groupPROTAMINE, two of which (1%) were major (CTCAE grade 3-4). In groupREDUCED_PROTAMINE, only minor bleeding events were recorded, and one major hemorrhagic event was documented in groupNO_PROTAMINE (2%). There was a significant difference between the percentage of post-interventional thrombopenia in groupPROTAMINE (39%) and groupREDUCED_PROTAMINE (14%) versus groupNO_PROTAMINE (23%) (p=.00024). In groupPROTAMINE one patient suffered from a severe anaphylactic shock after the administration of protamine.ConclusionOur retrospective study implies that there might be a link between the practice of protamine sulfate administration to reverse the full hemodilutive effect of UFH after PHP and the post-interventional risk of thromboembolic events as well as clinically significant thrombopenia. Our data suggest that the standard use of protamine sulfate after PHP in low-risk patients without clinical signs of active bleeding should be critically re-evaluated.

A novel de-escalation antiplatelet therapy for patients with acute coronary syndrome undergoing percutaneous coronary intervention.

To investigate the effect of different DAPTs in patients with ACS undergoing PCI, and to identify the most efficient DAPT to reduce the risk of ischemia and bleeding after PCI. Between March 2017 and December 2021, 1598 patients with ACS who underwent PCI were included in the study. The DAPT protocol included the clopidogrel group (aspirin 100 mg + clopidogrel 75 mg), ticagrelor group (aspirin 100 mg + ticagrelor 90 mg), de-escalation Group 1 (reduced dose of ticagrelor [from 90 mg to 60 mg]) after 3 months of oral DAPT [aspirin 100 mg + ticagrelor 90 mg]), and de-escalation Group 2 (switched from ticagrelor to clopidogrel after 3 months of oral DAPT [aspirin 100 mg + ticagrelor 90 mg]). All patients received a 12-month follow-up. The primary endpoint was net adverse clinical events (NACEs) that included the composite endpoints of cardiac death, myocardial infarction, ischemia-driven revascularization, stroke, and bleeding events. There were 2 secondary endpoints, major adverse cardiovascular and cerebrovascular events (MACCEs) and bleeding. No statistically significant difference was found in the incidence of NACEs between the 4 groups at the average 12-month follow-up (15.7% vs 19.2% vs 16.7% vs 20.4%). Cox regression analysis revealed that DAPT ticagrelor group regimen (hazard ratio [HR] 0.547; 95% confidence interval [CI]: 0.334-0.896; P = .017) were associated with a lower risk of MACCEs. Age (HR 1.024; 95% CI: 1.003-1.046; P = .022). DAPT de-escalation Group 2 regimen (HR 1.665; 95% CI: 1.001-2.767; P = .049) were marginally associated with a higher risk of MACCEs. Ticagrelor group regimen (HR 1.856; 95% CI: 1.376-2.504; P < .001) was associated with higher risk of bleeding events. Ticagrelor group regimen (HR 1.606; 95% CI: 1.179-2.187; P = .003) were associated with a higher risk of minor bleeding events. For patients with ACS underwent PCI, there were no significant difference in the incidence of NACEs between 3 and 12 months after PCI between de-escalation and non-de-escalation therapies. Compared with ticagrelor-based 12-month DAPT, there was no significant difference in MACCEs and bleeding events in patients receiving de-escalation treatment (ticagrelor reduction from 90 to 60 mg, 3 months after PCI).

Safety and efficacy of apixaban versus low-molecular weight heparin or vitamin-K antagonists for venous thromboembolism treatment in patients with severe renal failure: A systematic review and meta-analysis

IntroductionChronic kidney disease is an independent risk factor for venous thromboembolism (VTE). Traditionally, Low Molecular Weight Heparin (LMWH) followed by warfarin has been the conventional therapy for VTE treatment. Direct oral anticoagulants (DOACs), including apixaban, have shown several advantages over the traditional therapy in individuals with normal kidney function. This meta-analysis aims to review the safety and efficacy of apixaban compared to warfarin or LMWH for the treatment of VTE in severe renal failure. MethodWe conducted literature search in PubMed, Embase, and Cochrane databases. Retrospective observational studies involving clinical effectiveness and safety outcomes of apixaban compared to warfarin in adult patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/m2 or on dialysis were included. ResultsEight studies were included in the analysis. Significant reduction in VTE recurrence observed in apixaban compared to warfarin (RR, 0.65; 95 % CI, 0.43–0.98; P = 0.04; I2 = 78 %). No significant difference in all-cause mortality between apixaban and warfarin (RR, 0.99; 95 % CI, 0.91–1.07; P = 0.74; I2 = 0 %). Apixaban showed a significantly lower rate of major bleeding (RR, 0.72; 95 % CI, 0.62–0.84; P < 0.0001; I2 = 34 %) and minor bleeding events (RR, 0.42; 95 % CI, 0.21–0.86; P = 0.02; I2 = 10 %) compared to warfarin. No significant difference observed in clinically relevant non-major bleeding between apixaban and warfarin (RR, 0.81; 95 % CI, 0.65–1.00; P = 0.05; I2 = 67 %). ConclusionApixaban was favored over warfarin for treating VTE in severe renal failure, reducing VTE recurrence and bleeding risk. No differences were observed in all-cause mortality and CRNMB events. More evidence is required due to limited RCTs and prospective studies.