Acute Major Bleeding Research Articles

Association of cardiac amyloidosis with periprocedural complications in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis

Abstract Introduction Cardiac amyloidosis (CA) has been frequently observed in patients with aortic stenosis (AS). While transcatheter aortic valve replacement (TAVR) may be an option, the association of CA with risk of periprocedural complications has not been well evaluated. Purpose This study aimed to evaluate the association of CA with periprocedural complications after TAVR in patients with severe AS. Methods A literature search was performed for studies evaluating patients with severe AS undergoing AVR, comparing periprocedural safety endpoints for patients with and without CA. The primary endpoints were vascular complications and bradyarrhythmias post-TAVR requiring permanent pacemaker (PPM) implantation. Secondary endpoints included periprocedural acute kidney injury (AKI), cerebrovascular accidents (CVA), and major bleeding events. Endpoints were defined using the Valve Academic Research Consortium-2 criteria. The search was not restricted to time or publication status. Results 6 studies with 1,138 patients with severe AS (150 with CA, 988 without CA) met inclusion criteria. Mean age was 82 years, 52.4% were men, all except 1 study assessed only patients with ATTR CA. Echocardiographic mean aortic valve parameters included valve area of 0.718 cm2, mean gradient of 40.8, and peak velocity of 4.13 m/s. The mean left ventricular ejection fraction was 55.2%. The presence of CA was not associated with an increased risk of periprocedural vascular complications (OR 0.69, 95% CI 0.25-1.88; p=0.47). While a trend toward higher risk of periprocedural PPM implantation was observed in patients with CA, this finding did not reach statistical significance (OR 1.51; 95% CI 0.77-2.94; p=0.23). The presence of CA was not associated with increased risk of periprocedural AKI, CVA, or major bleeding (OR 1.3, 95% CI 0.32-5.3; p=0.72, OR 0.65, 95% CI 0.17-2.41; p=0.52; OR 0.55, 95% CI 0.16-1.87; p=0.34). Conclusion In the context of patients with severe AS undergoing TAVR, the presence of cardiac amyloidosis did not increase the risk of periprocedural complications, including vascular complications, AKI, CVA, or major bleeding. Although a trend toward a higher risk of bradyarrhythmias requiring PPM implantation was noted in patients with CA, further studies are warranted to confirm this observation. Overall, these findings contribute valuable insight into the safety profile of TAVR in the patients with CA.Figure 1Figure 2

Comparative effectiveness and safety of direct oral anticoagulants and warfarin in atrial fibrillation patients with dementia.

Developing an effective stroke prevention strategy is crucial for elderly atrial fibrillation (AF) patients with dementia. This is due to the limited and inconsistent evidence available on this topic. In this nationwide, population-based cohort study, we aim to compare the effectiveness and safety of direct oral anticoagulants (DOACs) and warfarin in AF patients with dementia. We identified AF patients with dementia, aged 50 years or older, from Taiwan's National Health Insurance Research Database between 2010 and 2019. The primary outcome was a composite of hospitalizations due to ischemic stroke, acute myocardial infarction, intracranial hemorrhage, or major bleeding, as well as all-cause mortality. We used 1:1 propensity score matching and Cox proportional hazard models to adjust for confounding factors when comparing outcomes between warfarin and DOAC (apixaban, dabigatran, edoxaban, or rivaroxaban) users or warfarin and each individual DOAC. There were 2952 patients in the DOAC-warfarin matched cohort. The apixaban-, dabigatran-, edoxaban-, and rivaroxaban-warfarin matched cohorts had 2346, 2554, 1684, and 2938 patients, respectively. The DOAC group, when compared to warfarin, was associated with a lower risk of both the composite outcome (hazard ratio (HR), 0.81; 95% confidence interval (CI) 0.69-0.95) and ischemic stroke (HR 0.65; 95% CI 0.48-0.87). Apixaban (HR 0.79; 95% CI 0.66-0.94), dabigatran (HR 0.64; 95% CI 0.53-0.77), and rivaroxaban (HR 0.82; 95% CI 0.70-0.97) were also associated with a lower risk of the composite outcome. Compared to warfarin, DOACs, whether as a group or apixaban, dabigatran, or rivaroxaban individually, were associated with a reduced risk of the composite outcome in elderly patients with concurrent AF and dementia.

Interactive Media-Based Approach for an Exception From Informed Consent Trial Involving Patients With Trauma

Exception From Informed Consent (EFIC) research requires community consultation (CC) and public disclosure (PD). Traditional methods of conducting CC and PD are slow, expensive, and labor intensive. To describe the feasibility and reach of a novel interactive, media-based approach to CC and PD and to identify the similarities and differences between trial sites in website views, survey responses, online community forum attendance, and opt-out requests. This survey study analyzed the CC and PD campaigns conducted for the TAP trial (Evaluation of BE1116 in Patients With Traumatic Injury and Acute Major Bleeding to Improve Survival), an EFIC trial of the early administration of prothrombin complex concentrate in patients with trauma. The CC and PD campaigns consisted of social media advertisements, linked websites, community surveys, and online community forums. These activities were coordinated from a central site and approved by a central institutional review board. This study focused on the first 52 of 91 TAP trial sites (level I trauma centers) in the US to have completed their CC and PD campaigns. Community members in the catchment areas of the participating trauma centers were targeted. Data analysis was conducted between October 2023 and February 2024. Social media advertisements, surveys, and online community meetings conducted as part of the CC and PD campaign for the TAP trial. Social media campaign reach and engagement, web page views, survey results, online community forum attendance, and opt-out requests. Fifty-two trial sites were approved for participant enrollment. Social media advertisements were displayed 92 million times, reaching 11.8 million individuals. The median (IQR) number of people reached in each location was 210 317 (172 068-276 968). Site-specific websites were viewed 144 197 times (median [IQR] viewings per site, 2984 [1267-4038]). A total of 17 206 fully or partly completed surveys were received, and survey respondents had a median (IQR) age of 40.1 (15-65) years and included 10 444 females (60.7%). Overall, 60.6% survey respondents said they would want to be entered into the trial even if they could not give consent, 87.7% agreed that emergency care research was necessary, and 88.0% agreed that the TAP trial should be conducted in their community. Online community forums were attended by a median (IQR) number of 38 (20-63) people. Four opt-out requests were received. The interactive media-based approach to CC and PD for the ongoing TAP trial showed the feasibility and benefits of executing an efficient, coordinated, centrally run series of locally branded and geographically targeted CC and PD campaigns for a large EFIC study.

Ten Year Time Trends of Amputation Surgery in Peripheral Arterial Disease in Germany: Before and During the COVID-19 Pandemic

Peripheral arterial disease (PAD) has been associated with suboptimal treatment, high mortality, and high amputation rates. It is unclear how the COVID-19 (coronavirus disease 2019) pandemic affected this development in a long term context. This is a registry based, retrospective, nationwide cohort study including patients hospitalised with PAD as a main or secondary diagnosis and amputation surgery between 2012 - 2021 in Germany. Primary endpoints were population wide major and minor amputation rates, in hospital death, and in hospital mortality rates. Secondary endpoints were same admission revascularisations and in hospital death in the event of complications, i.e., failure to rescue (FTR). Pre-pandemic and pandemic trends, focusing on lockdown periods, were analysed. A total of 365 926 patient records with PAD and amputation surgery were analysed. The median patient age was 75 years and 28.8% were female. Overall population wide amputation and in hospital mortality rates (monthly decrease -0.002/100 000, p < .001, and -0.001/100 000, p< .001, respectively) and in hospital mortality rate (8.0% for 2012 - 2014 vs. 6.5% for 2020 - 2021; p < .001) declined between 2012 and 2020. Concurrently, same admission revascularisations increased (41.0% for 2012 - 2014 vs. 47.0% for 2020 - 2021; p < .001), while FTR decreased in a subset of complications (acute ischaemia, major bleeding, compartment syndrome, and mesenterial ischaemia). In the first pandemic lockdown, there was a temporary trend changeto higher major amputations rates (+0.02/100 000; p < .001) and higher in hospital mortality rates (+0.007/100 000; p < .001), which changed to a decrease as of the second lockdown (-0.03/100 000, p= .034, and -0.010/100 000, p < .001, respectively) in an interrupted time series analysis. There was no statistically significant change in observed amputation rates during lockdowns, while observed in hospital mortality rates decreased by 12.0% in the first lockdown (0.22/100 000 vs. 0.25/100 000; p= .005) compared with reference periods of the two previous years. Between 2012 and 2021, pre-pandemic trends toward decreasing population wide overall amputation rates, fewer major amputations, more amputation related revascularisation procedures, and lower in hospital mortality were maintained despite a temporary trend to increased major amputations and in hospital mortality during the first COVID-19 related lockdown in Germany.

Impact of perioperative low-molecular-weight heparin therapy on clinical events of elderly patients with prior coronary stents implanted > 12 months undergoing non-cardiac surgery: a randomized, placebo-controlled trial

BackgroundLittle is known about the safety and efficacy of discontinuing antiplatelet therapy via LMWH bridging therapy in elderly patients with coronary stents implanted for > 12 months undergoing non-cardiac surgery. This randomized trial was designed to compare the clinical benefits and risks of antiplatelet drug discontinuation via LMWH bridging therapy.MethodsPatients were randomized 1:1 to receive subcutaneous injections of either dalteparin sodium or placebo. The primary efficacy endpoint was cardiac or cerebrovascular events. The primary safety endpoint was major bleeding.ResultsAmong 2476 randomized patients, the variables (sex, age, body mass index, comorbidities, medications, and procedural characteristics) and percutaneous coronary intervention information were not significantly different between the bridging and non-bridging groups. During the follow-up period, the rate of the combined endpoint in the bridging group was significantly lower than in the non-bridging group (5.79% vs. 8.42%, p = 0.012). The incidence of myocardial injury in the bridging group was significantly lower than in the non-bridging group (3.14% vs. 5.19%, p = 0.011). Deep vein thrombosis occurred more frequently in the non-bridging group (1.21% vs. 0.4%, p = 0.024), and there was a trend toward a higher rate of pulmonary embolism (0.32% vs. 0.08%, p = 0.177). There was no significant difference between the groups in the rates of acute myocardial infarction (0.81% vs. 1.38%), cardiac death (0.24% vs. 0.41%), stroke (0.16% vs. 0.24%), or major bleeding (1.22% vs. 1.45%). Multivariable analysis showed that LMWH bridging, creatinine clearance < 30 mL/min, preoperative hemoglobin < 10 g/dL, and diabetes mellitus were independent predictors of ischemic events. LMWH bridging and a preoperative platelet count of < 70 × 109/L were independent predictors of minor bleeding events.ConclusionsThis study showed the safety and efficacy of perioperative LMWH bridging therapy in elderly patients with coronary stents implanted > 12 months undergoing non-cardiac surgery. An alternative approach might be the use of bridging therapy with half-dose LMWH.Trial registrationISRCTN65203415.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers After Transcatheter Aortic Valve Replacement: A Meta-Analysis

BackgroundPersistent left ventricular hypertrophy after transcatheter aortic valve replacement (TAVR) has been associated with poor outcomes. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), due to their favorable effects on ventricular remodeling, have been hypothesized to improve outcomes post-TAVR, yet there are no recommendations regarding their use. ObjectivesThis study aimed to compare the outcomes of patients receiving ACEIs/ARBs with those not receiving ACEIs/ARBs after TAVR. MethodsWe performed a literature search on PubMed and Cochrane Library until June 14, 2023, and included all studies comparing clinical outcomes between patients given ACEIs/ARBs and those not given ACEIs/ARBs after TAVR. All-cause mortality was the primary outcome. We used a random effects model with appropriate corrections to calculate relative risk (RR) and CIs, with all analyses carried out using R v4.0.3. ResultsWe included ten studies on the use of ACEIs/ARBs post-TAVR. Patients on ACEIs/ARBs had lower risk of all-cause mortality (RR: 0.74, 95% CI: 0.65-0.86, I2 = 62%, chi-square P < 0.01), cardiovascular mortality (RR: 0.70, 95% CI: 0.56-0.88, I2 = 0%, chi-square P = 0.54), and new-onset atrial fibrillation (RR: 0.71, 95% CI: 0.52-0.96, I2 = 0%, chi-square P = 0.59). Patients on ACEIs/ARBs had a similar risk of myocardial infarction, heart failure, stroke, new permanent pacemaker implantation, acute kidney injury, major bleeding, vascular complications, aortic regurgitation, and mitral regurgitation. ConclusionsWe found that patients receiving ACEIs/ARBs had a lower risk of all-cause mortality, cardiovascular mortality, and new-onset atrial fibrillation. Risk of other outcomes was similar to patients not receiving ACEIs/ARBs. Randomized clinical trials are needed to explore the benefits of ACEIs/ARBs post-TAVR, so that definitive guidelines can be developed.

In-hospital outcomes and trends of patients with autoimmune diseases undergoing percutaneous coronary intervention: A nationwide analysis

BackgroundThe risk of coronary artery disease is exaggerated in patients with autoimmune diseases (AID). A higher risk of complications has been reported during and after percutaneous coronary intervention (PCI) in these patients. We aimed to analyze the in-hospital outcomes and trends of patients with AID, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD) undergoing PCI. MethodWe identified all PCI procedures using the National In-patient Sample database from 2016 to 2020. Stratified them into cohorts with RA, SLE and IBD and compared them to cohorts without AID. The Chi-square test and multivariate logistic regression were used for analysis. A p-value <0.005 was considered statistically significant. ResultWe identified 2,367,475 patients who underwent PCI. Of these, 1.6 %, 0.5 %, and 0.4 % had RA, IBD and SLE respectively. The odds of mortality were lower among patients with IBD (aOR: 0.56; CI 0.38–0.81, p = 0.002) but patients with RA had higher odds of having composite major complications [(MC) including cerebrovascular accident (CVA), cardiac arrest, acute heart failure (AHF), ventricular arrhythmia (VA), major bleeding, and acute kidney injury (AKI)] (aOR: 0.90; CI 0.83–0.98, p = 0.013). Our SLE cohort had higher rates of CVA (p = 0.017) and AKI (p = 0.002). Our cohort with IBD had lower rates of cardiac arrest but had longer hospital length of stay (4.9 days vs 3.9 days) and they incurred higher hospital charges compared to cohort without IBD. ConclusionThis study depicts the immediate adverse outcomes observed in patients with AID undergoing PCI. In contrast to those without AID, our cohorts with RA exhibited worse outcomes, as indicated by the higher odds of major complications. IBD is associated with lower risks of in-hospital adverse outcomes but with higher resource utilization.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity: Prespecified Subgroup Analysis of the ANNEXA-4 Study in Japan.

Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan. This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment. A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events. Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

In-hospital safety outcomes of left atrial appendage occlusion in octogenarians and nonagenarians.

Data on safety outcomes of left atrial appendage occlusion (LAAO) in elderly patients are limited. This study aimed to compare the outcomes of LAAO between octogenarians (age 80-89) and nonagenarians (age ≥90) vs. younger patients (age ≤79). We conducted a retrospective cohort study using the National Inpatient Sample database to identify patients hospitalized for LAAO from 2016 to 2020 and to compare in-hospital safety outcomes in octogenarians and nonagenarians vs. younger patients. The primary outcome was a composite of in-hospital all-cause mortality or stroke. Secondary outcomes included procedural complications, length of stay (LOS), and total costs. Outcomes were determined using logistic regression models. Among 84 140 patients hospitalized for LAAO, 32.9% were octogenarians, 2.8% were nonagenarians, and 64.3% were ≤79 years of age. Over the study period, the volume of LAAO increased in all age groups (all Ptrend < 0.01). After adjustment for clinical and demographic factors, octogenarians and nonagenarians had similar odds of in-hospital all-cause mortality or stroke [adjusted odds ratio (aOR) 1.41, 95% confidence interval (CI) 0.93-2.13 for octogenarians; aOR 1.69, 95% CI 0.67-3.92 for nonagenarians], cardiac tamponade, acute kidney injury, major bleeding, and blood transfusion, in addition to similar LOS and total costs compared with younger patients (all P > 0.05). However, octogenarians and nonagenarians had higher odds of vascular complications compared with younger patients (aOR 1.47, 95% CI 1.08-1.99 for octogenarians; aOR 1.60, 95% CI 1.18-2.97 for nonagenarians). Octogenarians and nonagenarians undergoing LAAO have a similar safety profile compared with clinically similar younger patients except for higher odds of vascular complications.

Adverse Events and Clinical Correlates in Asian Patients with Atrial Fibrillation and Diabetes Mellitus: A Report from Asia Pacific Heart Rhythm Society Atrial Fibrillation Registry.

Aims. To evaluate the adverse events (and its clinical correlates) in a large prospective cohort of Asian patients with atrial fibrillation (AF) and diabetes mellitus (DM). Material and Methods. We recruited patients with atrial fibrillation (AF) from the Asia-Pacific Heart Rhythm Society (APHRS) AF Registry and included those for whom the diabetic mellitus (DM) status was known. We used Cox-regression analysis to assess the 1-year risk of all-cause death, thromboembolic events, acute coronary syndrome, heart failure and major bleeding. Results. Of 4058 patients (mean age 68.5 ± 11.8 years; 34.4% females) considered for this analysis, 999 (24.6%) had DM (age 71 ± 11 years, 36.4% females). Patients with DM had higher mean CHA2DS2-VASc (2.3 ± 1.6 vs. 4.0 ± 1.5, p < 0.001) and HAS-BLED (1.3 ± 1.0 vs. 1.7 ± 1.1, p < 0.001) risk scores and were less treated with rhythm control strategies compared to patients without DM (18.7% vs. 22.0%). After 1-year of follow-up, patients with DM had higher incidence of all-cause death (4.9% vs. 2.3%, p < 0.001), cardiovascular death (1.3% vs. 0.4%, p = 0.003), and major bleeding (1.8% vs. 0.9%, p = 0.002) compared to those without DM. On Cox regression analysis, adjusted for age, sex, heart failure, coronary and peripheral artery diseases and previous thromboembolic event, DM was independently associated with a higher risk of all-cause death (HR 1.48, 95% CI 1.00-2.19), cardiovascular death (HR 2.33, 95% CI 1.01-5.40), and major bleeding (HR 1.91, 95% 1.01-3.60). On interaction analysis, the impact of DM in determining the risk of all-cause death was greater in young than in older patients (p int = 0.010). Conclusions. Given the high rates of adverse outcomes in these Asian AF patients with DM, efforts to optimize the management approach of these high-risk patients in a holistic or integrated care approach are needed.

Balfaxar: Another four-factor PCC for warfarin reversal.

Balfaxar (Octapharma), a human plasma-derived four-factor prothrombin complex concentrate (PCC), has been approved by the FDA for rapid reversal of warfarin anticoagulation in adults who require an urgent surgical/invasive procedure. It is the second four-factor PCC to become available in the US; Kcentra, which has been available since 2013, is approved for the same indication and for urgent reversal of warfarin anticoagulation in adults with acute major bleeding. Balfaxar is marketed in Canada and Europe as Octaplex.

Safety and efficacy of cerebral embolic protection in transcatheter aortic valve implantation: an updated meta-analysis.

The use of cerebral embolic protection devices during transcatheter aortic valve implantation (TAVI) reveals conflicting data. This updated meta-analysis aims to evaluate the efficacy and safety of the SENTINEL Cerebral Protection System. A literature search for relevant studies up to September 2022 was performed. Study outcomes were divided based on time period - overall (up to 30 days) and short (≤7 days). The outcomes studied include stroke (disabling, non-disabling), mortality, neuroimaging findings, transient ischaemic attack, acute kidney injury and major vascular and bleeding complications. A total of 15 studies involving 294,134 patients were included. Regarding overall outcomes, significant reductions were noted for mortality (odds ratio [OR] 0.60, 95% confidence interval [CI]: 0.41-0.88; p=0.008), all stroke (OR 0.64, 95% CI: 0.46-0.88; p=0.006) and disabling stroke (OR 0.42, 95% CI: 0.23-0.74; p=0.003) using the SENTINEL device. No significant differences were noted for other outcomes. There was significant heterogeneity across the studies for mortality (p=0.013) and all stroke (p=0.003). Including only randomised data (n=4), there was only significant reduction in the incidence of disabling stroke (OR 0.39, 95% CI: 0.17-0.89; p=0.026) in the SENTINEL group. In studies reporting ≤7-day outcomes (n=8), use of the SENTINEL device demonstrated significantly lower rates of all stroke (p<0.001), disabling stroke (p<0.001) and major bleeding complications (p=0.02). No differences in neuroimaging outcomes were noted. In this updated meta-analysis, use of the SENTINEL Cerebral Protection System was associated with lower rates of mortality, all stroke and disabling stroke, although significant heterogeneity was noted for mortality and all stroke. Including exclusively randomised data, there was only significant reduction in the incidence of disabling stroke. No significant adverse outcomes with device use were noted.

Dispensing pharmacy chains and direct anticoagulants: Potential associations with patient outcomes.

Pharmacy chains can differ with respect to the characteristics of their patient populations as well as their nonprescription products, services, and practices, and thus may serve as a surrogate for potential unmeasured confounding in observational studies of prescription drugs. This study evaluates whether a single-source drug can have different patient outcomes based on the dispensing pharmacy chain. Separate analyses for two anticoagulant drugs, rivaroxaban and apixaban, were conducted using Medicare Fee-for-Service claims evaluating the association between dispensing pharmacy chain and outcomes of acute myocardial infarction, ischemic stroke, intracranial hemorrhage, gastrointestinal (GI) bleeding, all-cause mortality, and major GI bleeding. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates across pharmacy chain cohorts, and outcome association was assessed with a Cox Proportional Hazards model. We observed no differences in outcomes across pharmacy chains for apixaban recipients. Rivaroxaban recipients from pharmacy chain C, however, had lower rates of GI bleeding (adjusted HR 0.83; 95% CI 0.69-1.00) and ischemic stroke (adjusted HR 0.57; 95% CI 0.38-0.87) as compared to chain A in primary analyses with a 3-day grace period. The results moved closer to the null when 14- and 30-day grace periods were implemented. These results suggest that dispensing pharmacy chains may have the potential to act as a confounder of associations between drug exposure and outcome in some observational studies. Additional studies of potential confounding by pharmacy chain are needed. Further evaluation of potential pharmacy chain effects on safe use would be of value.

Predictors of Intracranial Hemorrhage Volume Expansion in Patients Receiving Factor Xa Inhibitors in ANNEXA‐4: Time and Severity Matter Most

Background Andexanet alfa, a specific reversal agent for factor Xa inhibitors, resulted in effective hemostasis in 79% of patients with intracranial bleeding in the ANNEXA‐4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) trial (NCT02329327). However, little is known about predictors associated with hematoma expansion in patients with factor Xa inhibitor–associated intracranial hemorrhage (ICrH) receiving andexanet alfa. Methods The ANNEXA‐4 trial was a prospective, single‐arm, open‐label study of andexanet alfa in patients with acute major bleeding within 18 hours after taking a factor Xa inhibitor. Hematoma volumes at baseline and 12 hours after andexanet alfa treatment were measured using a computerized‐assisted volumetric method. Univariable and multivariable logistic regression analyses of clinical and nonclinical parameters were performed to identify factors predictive of different volumes of hematoma expansion. To this end, an ICrH Expansion Scale was developed. Results Overall, 305 ANNEXA‐4 study patients with baseline and follow‐up imaging were included, 15.7% of whom showed evidence of any ICrH expansion ≥6‐mL. Patients with ≥6‐mL ICrH expansion had a significantly ( P&lt; 0.05) higher proportion of ICrH with multiple compartment involvement (36% versus 14.3%); shorter times from symptom onset to baseline computed tomography (median, 1.6 hours [interquartile range (IQR), 1.2–4.3 hours] versus 3.7 hours [IQR, 1.6–7.0 hours]); lower Glasgow Coma Scale scores (14 [IQR, 12–15] versus 15 [IQR, 14–15]); higher systolic blood pressure 15 minutes before andexanet alfa bolus (mean, 151.6 mm Hg [SD, 24.1 mm Hg] versus 143.3 mm Hg [SD, 22.3 mm Hg]); and larger median baseline ICrH volumes (29.3 mL [IQR, 13.3–50.8 mL] versus 8.6 mL [IQR, 2.1–22.4 mL]). Multivariable analysis confirmed shorter symptom onset‐to‐computed tomography time and larger ICrH volume as independent predictors of ≥6‐mL growth and ICrH Expansion Scale change. Lower Glasgow Coma Scale showed a trend ( P = 0.06) as an independent predictor of ≥6‐mL growth but was an independent predictor of ICrH Expansion Scale change. Conclusion Shorter time from symptom onset to computed tomography, larger hematoma volumes, and lower Glasgow Coma Scale score at presentation increased the risk of ICrH expansion in patients with factor Xa inhibitor–associated ICrH treated with andexanet alfa.

Updated Protocol for the Phase 3, Randomized, Double-Blinded Lex-210 Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Factor Xa Inhibitor Therapy

Background and Significance: Despite significantly reduced risk of intracranial hemorrhage compared with vitamin K antagonists, direct oral anticoagulant therapy with factor Xa inhibitors (FXaI) is associated with similar incidences of other major bleeds. Although hemostatic agents such as prothrombin complex concentrates (PCCs) are often used (off-label), the efficacy and safety of PCCs for managing FXaI-related bleeding requires further investigation. This study aims to evaluate superior hemostatic efficacy of high-dose vs low-dose four-factor (4F) PCC (Octaplex®; Octapharma) in adults with FXaI-related major bleeding. Study Design and Methods: LEX-210 (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study. Significant modifications have recently been made to the study design. Patients aged ≥18 years with acute major bleeding (e.g., gastrointestinal, intracranial) and baseline anti-factor Xa activity of ≥100 ng/mL are eligible. To increase rate of recruiting suitable patients into the study, the eligibility criteria have been optimized. For inclusion (full criteria in Table 1), baseline anti-factor Xa activity of ≥100 ng/mL may be either confirmed by locally available tests (including retrospectively by the central laboratory) or suspected by the investigator and later confirmed by the central lab. Prospective written informed consent will be obtained from all patients or patients' legally authorized representative prior to enrolment. If this is not possible, in countries outside the US where it is permitted under local regulations or approved by local ethics committees, deferred consent procedures may be applied. Key exclusion criteria (Table 2) include acute trauma for which FXaI reversal alone would not be expected to control bleeding, and thromboembolic events in the last 3 months. In addition, hypersensitivity to heparin and platelet inhibitors are specified. Patients will be excluded if they score &amp;lt;7 on the Glasgow Coma Scale (with allowances for intubation), or have expected survival of &amp;lt;24 hours. While patients scheduled for surgery in &amp;lt;12 hours are excluded, minor surgeries and invasive procedures for diagnostic or therapeutic reasons are allowed, or if intended to address a second (non-index) bleeding event. Patients will be randomized 1:1 to 50 or 15 IU/kg 4F-PCC. The primary objective is to demonstrate superior hemostatic efficacy of the higher dose in patients with major bleeding associated with FXaI. Hemostatic efficacy through 24 hours after receipt of 4F-PCC will be evaluated by an independent data monitoring and endpoint adjudication committee using objective criteria, with a binary outcome of effective or ineffective. Secondary endpoints include change in endogenous thrombin potential (baseline to 1 hour after 4F-PCC), 30-day rates of thromboembolic events, and all-cause mortality. The study is conducted in accordance with the ethical principles laid down in the Declaration of Helsinki The proportion of patients with an effective outcome will be compared between groups using a one-sided z-test. The primary statistical model will be adjusted for the baseline anti-factor Xa activity as determined retrospectively by the central laboratory. A logistic regression model for the success rate using treatment group (dose level) and the anti-factor Xa activity as fixed effects will be used to determine the one-sided z-statistic. LEX-210 launched in Q4 2021 and will be performed across ~60 sites in North America and the European Continent. Target enrollment is ~260 patients, assuming a 30% dropout rate. So far, 26 sites in the US, Italy, Germany, and Spain have been initiated, with 5 patients enrolled. Study completion is anticipated in Q3 2024.

Calr Variant Allele Frequency in Essential Thrombocythemia: Molecular Associations and Impact on Disease Phenotype and Outcome

Background. A mutation in calreticulin ( CALRm) is found in 30-35% of patients (pts) with Essential Thrombocythemia (ET). There are 2 main CALRm mutation types, Type 1/Type 1 like (T1) a 52bp deletion, and Type 2/Type 2 like (T2) a 5bp insertion. Other atypical mutations (T3) occur in a minority of pts. Recent study ( Guglielmelli P et al, BCJ 2023) in pts with myelofibrosis (MF) showed that higher CALR variant allele frequency (VAF) was associated with anemia at diagnosis and during FU, and to features of more advanced disease (CD34 + cell counts, ASXL1 mutation (mut), &amp;gt;2 mutated myeloid genes, and shorter leukocytosis-free survival. Aim. To evaluate whether the CALRm VAF in pts with ET was associated with predefined major clinical outcomes: evolution to MF, transformation to acute leukemia (AML), thrombosis, major bleeding, and survival (OS). Patients and Methods. Diagnosis of ET was strictly according to 2023 WHO and ICC to avoid mis-inclusion of prefibrotic MF. CALRm VAF was determined by capillary gel electrophoresis as the ratio (%) of areas under the curve of CALRm/ CALRm+ CALRwt. A panel of 45 myeloid neoplasm-associated genes was sequenced by NGS. Results. A total of 281 CALRm ET pts were identified from CRIMM (Florence, I), Quebec MPN Research Group centers' (Canada) and Mayo Clinic (Rochester, US) databases; 152 (54%), 101 (36%) and 28 (10%) were T1, T2 and T3 CALRm, respectively. Overall FU was 8.6y (0.3-39.4), median survival was not reached. Rate of death at 10y, 20y and 30y was 8%, 15% and 25%. MF transformation occurred in 50 pts (18%), AML in 2 (0.7%), 25 pts (8.9%) died. A major thrombotic event before or at ET diagnosis occurred in 17 (6.0 %) pts (14 arterial and 3 venous), whereas 28 pts (10.0%) had &amp;gt;1 major thrombosis during follow-up (53.6% arterial, 46.4% venous). Major bleeding occurred in 19 pts (6.8%; 16 at or before diagnosis). Ascertainment of correlation of CALRm VAF with predefined outcomes by continuous variable analysis (ROC curve) highlighted a significant correlation of VAF &amp;gt;60% with MF-free survival (MFS), with HR of 2.85 (95%CI, 1.4-5.6; P= .002. Fig. 1A). On the contrary, there was no impact of CALRm VAF as continuous variable on AML, thrombosis, bleeding and OS. We therefore used a threshold of &amp;gt;60% to compare main clinical and hematologic characteristics at diagnosis and outcomes during FU in pts categorized as CALR-high and CALR-low. Of all pts, 21 (7.5%) harbored a VAF &amp;gt;60%; of these, 52%, 19% and 29% were T1, T2, T3, respectively, compared to 54%, 37%, 8% of CALR-low (P= .008). We found no difference in age, gender, constitutional symptoms, splenomegaly, arterial and venous thrombosis at diagnosis and FU, IPSET revised risk stratification, and bleeding events. Hemoglobin was lower (12.8 g/dL (8.4-14.0) versus 13.6 (10.1-16.0); P=.02), while leukocytes and platelets did not differ. The proportion of pts with additional mutations in myeloid genes was significantly greater in CALR-high pts compared to CALR-low (66.7% vs 30.2%; P=0.01), as it was the proportion of pts with &amp;gt;2 mut myeloid genes (25% vs 11.6%, P=0.04). During FU, 52% of CALR-high pts (n=11) transformed to MF compared to 15% (n=39) of CALR-low (P&amp;lt;.0001); AML and death not differ. Anemia (&amp;lt;10g/dL) during the FU developed in 69% of CALR-high pts vs 18%, leukocytosis (&amp;gt;15x10 9/L) in 46% vs 8% and splenomegaly (greater than 5 cm from LCM) in 50% vs 12% (P&amp;lt;.0001 for all). The HR for anemia-free survival was 2.87 (95%CI, 1.3-6.3), for leukocytosis HR 3.71 (95%CI, 1.3-10.5) and splenomegaly HR 3.40 (95%CI, 1.2-9.2), all P&amp;lt;.01. MFS was significantly shorter in T1 (HR 2.0; P=0.04) or T3 (HR 2.7; P=0.03) using T2 as reference. Finally, we compared C ALR-mut, JAK2V617F mut and triple-negative (TN) ET pts. ROC analysis indicated a JAK2VAF &amp;gt;35% ( JAK2-high) as the best cutoff for shorter MFS. As in Fig. 1B, the MFS survival of CALR-high and JAK2-high was superimposable, and significantly shorter that in CALR/JAK2-low and TN pts. Conclusions. A CALR VAF &amp;gt;60% in pts with ET is associated with greater risk and shorter time to MF progression, development of anemia and splenomegaly. Similar findings in JAK2-high pts reinforce that that accumulation of mutated CALR and JAK2 alleles, evident since diagnosis, is detrimental for evolution to post-ET myelofibrosis. Longitudinal studies after diagnosis might provide further information about the kinetics of allele accumulation.

Plasma levels of direct oral anticoagulants in non-valvular atrial fibrillation patients at the time of acute cardioembolic or bleeding events

Abstract Background Direct oral anticoagulants (DOACs) are approved for preventing cardioembolic events in patients with non-valvular atrial fibrillation (NVAF) (1). Unlike Heparin and vitamin K antagonists, DOACs are commonly used without the need for clotting time monitoring, which results in limited data on the correlation between plasma levels and adverse events (2). Objective This study aimed to evaluate, in a real-world cohort of NVAF patients, the relationship between the occurrence of acute cardioembolic or major bleeding events and the plasma levels of DOACs measured at the time of the events. Methods and Results This study included 400 NVAF patients on DOAC therapy from the INSIghT registry who underwent plasma drug level testing at the time of an adverse event (116 cases) or during an elective hospitalization or outpatient visit (284 controls). Out of 116 cases, 74 experienced a cardioembolic event while 42 had a major bleeding. Patients with cardioembolic events presented low (i.e., in the first and second quartiles) DOAC plasma levels (50 vs. 24, p&amp;lt;0.01), while patients with major bleeding events had high (i.e., in the third and fourth quartiles) DOAC plasma levels (25 vs. 14, p&amp;lt;0.01). Conclusions This study highlights the possible association between plasma levels of DOACs and the risk of adverse events, but further research is needed to fully understand the potential benefits DOAC monitoring and individualized dosing.Fig. 1Fig. 2

Outcomes of chronic total occlussion recanalization in patients with prior bypass-surgery: an updated systematic review and meta-analysis of real world registries

Abstract Background Recanalization of chronic total occlusion (CTO) coronary lesions by percutaneous coronary intervention (PCI) in patients with prior coronary artery bypass grafting (CABG) is still considered a challenging scenario due to the complexity of coronary lesions as well as the requirement of CTO PCI advanced techniques. The aim of this study is to compare clinical outcomes of patients undergoing CTO PCI with and without CABG surgery. Methods We conducted a systematic review and meta-analysis of observational studies that compared in-hospital outcomes of CTO PCI in patients with vs. without prior CABG published in Medline from inception until December 2022. The results are synthesized in a quantitative manner with random effects models. Categorical variables were compared using the chi-square test, whereas continuous variables were compared using a 2-sample Student's t-test. Statistical heterogeneity was assessed by I2 statistics: I2 statistic &amp;gt;50% was considered substantial, and I2 &amp;gt;75% was considered considerable. The Review Manager Software version 5.3.5. (The Cochrane Collaboration, 2014) was used to calculate summary statistics (odds ratios [ORs] with 95% confidence intervals [CIs]). Results Eleven observational studies with a total of 35,666 patients were included, of whom 7,005 patients had a history of CABG. Prior CABG patients were older, (68.1 ± 9.0 vs. 64.1 ± 10.7 years; p &amp;lt; 0.001), and had more complex coronary lesions (J-CTO score: 3.2 ± 1.4 vs. 2.5 ± 1.4; p &amp;lt; 0.001). Prior CABG was associated with lower technical success (66.6% vs. 78.5%; OR 0.53 [95% CI: 0.43 to 0.65]; p &amp;lt; 0.00001, I2 = 84%) as well as lower procedural success (OR 0.64 [95% CI: 0.57 to 0.71]; p &amp;lt; 0.00001, I2 = 0%) as compared with patients with no prior CABG (Figure 1A and Figure 1B). Prior CABG patients had a higher incidence of in-hospital mortality (0.7% vs. 0.4%; OR: 2.00 [95% CI: 1.32 to 3.05]; p = 0.001, I2 = 9%, Figure 2A), coronary perforation (3.7% vs. 2.3%; OR: 1.64 [95% CI: 1.15 to 2.33]; p &amp;lt; 0.006, I2 = 74%, Figure 2B), and myocardial infarction (1.7% vs. 0.7%; OR: 2.57 [95% CI: 1.73 to 3.81]; p &amp;lt; 0.00001, I2 = 12%), but a lower incidence of cardiac tamponade (0.2% vs. 0.9%; OR: 0.36 [95% CI: 0.17 to 0.77]; p = 0.09, I2 = 0%, Figure 2C) compared with those without prior CABG. Both groups had a similar incidence of acute cerebrovascular events (0.2% vs. 0.1%; OR: 1.70 [95% CI: 0.75 to 3.88]; p = 0.21, I2 = 0%), major bleeding (1.4% vs. 1.2%; OR: 1.24 [95% CI: 0.96 to 1.61]; p = 0.09, I2 = 0%) and vascular complications (1.4% vs. 0.9%; OR: 1.50 [95% CI: 0.93 to 2.41]; p = 0.10, I2 = 0%). Conclusion Prior CABG patients undergoing CTO PCI presented a higher risk of in-hospital mortality and perioperative procedural complications although the risk of tamponade was lower.Figure 1A and Figure 1BFigure 2A, 2B and 2C

Preoperative Exchange Transfusion for Patients with SCD Systematic Review

Introduction: Sickle cell disease (SCD) is the most common genetic disease world wide with the highest prevalence in Africa, Middle east, and east Asia. Surgeries in patients with SCD are associated with a higher rate of perioperative complications, however, there is no solid recommendations in the guidelines to advice perioperative transfusion strategies in patients with SCD. This review investigated the current available evidence in the literature to provide a clearer guidance. Methods: PubMed and Embase electronic search identified 655 articles related to randomized controlled trials and observational studies about the safety of perioperative transfusion in SCD. After removing duplicates and non-relevant articles 39 articles were evaluated in full text for eligibility, of which 24 studies were found eligible for inclusion in qualitative analysis and 16 studies with 3486 participants eligible for inclusion in the quantitative analysis. Assessment of quality and risk of Bias was done using the Cochrane tool for RCTs and ROBBINS-I tool for observational non randomized studies. The safety outcomes of perioperative transfusion, including acute chest syndrome (ACS), painful crisis, neurological complications, fever, minor or major bleeding, thrombosis, intensive care unit (ICU) admission, and all-cause mortality were assessed in comparison to SCD patients undergoing surgeries with conservative transfusion strategy. The risk ratio (RR) with 95% confidence intervals (CI) were calculated for the desired outcomes, the data was combined in forest plots and meta-analysis using the random-effects model. Results: Of the 24 studies included, 13 studies had the control arm as no transfusion in comparison to perioperative transfusion, while the remaining studies had conservative strategy guided by hemoglobin level as a control. Sixteen studies reported ACS among SCD patients who received perioperative transfusion (n=1890) versus conservative transfusion strategy (n=1596) (RR= 0.91, 95% CI 0.58-1.41, I2= 58%) (Figure 1-A). Fifteen studies reported painful crisis with perioperative transfusion (n=1856) versus conservative transfusion strategy (n=1532) (RR= 0.94, 95% CI 0.53-1.68, I2= 63%) (Figure 1-B). Neurological complications associated with the perioperative transfusion in SCD (n=1590) compared to conservative transfusion strategy (n=1250) were reported in nine studies (RR= 1.38, 95% CI 0.54-3.57, I2= 0%). Seven studies reported fever as a post-operative complication following perioperative transfusion in SCD (n= 1243) versus conservative transfusion (n= 922) (RR= 1.36, 95% CI 0.94-1.97, I2= 51%). Six studies reported bleeding following perioperative transfusion in SCD (n= 847) versus conservative strategy (n= 477) (RR= 4.32, 95% CI 1.75-10.68, P=0.002, I2= 0%) (Figure 1-C). Three studies reported thrombotic events following the perioperative transfusion in SCD (n= 885) versus conservative transfusion (n= 404) (RR= 0.59, 95% CI 0.06-5.68, I2= 0%). ICU admissions were reported in three studies with perioperative transfusion (n= 53) versus conservative transfusion (n= 147) (RR= 4.99, 95% CI 0.98-25.48, I2= 0%). Mortality was reported in six studies with perioperative transfusion (n= 1320) versus conservative transfusion (n= 977) (RR= 0.67, 95% CI 0.05-8.75, I2= 71%). Conclusion: According to this systematic review and meta-analysis Perioperative transfusion in SCD resulted in significantly higher rate of bleeding compare to conservative strategies while the rates of acute chest syndrome, painful crisis, fever, neurological complications, thrombosis, ICU admission, and mortality remained similar between the two strategies.

Sex-related differences in presentation, treatment, and outcomes of Asian patients with atrial fibrillation: a report from the prospective APHRS-AF Registry

We aimed to investigate the sex-related differences in the clinical course of patients with Atrial Fibrillation (AF) enrolled in the Asia–Pacific-Heart-Rhythm-Society Registry. Logistic regression was utilized to investigate the relationship between sex and oral anticoagulant, rhythm control strategies and the 1-year chance to maintain sinus rhythm. Cox-regression was utilized to assess the 1-year risk of all-cause, and cardiovascular death, thromboembolic events, acute coronary syndrome, heart failure, and major bleeding. In the whole cohort (4121 patients, 69 ± 12 years,34.3% female), females had different cardiovascular risk factors, clinical manifestations, and disease perceptions than men, with more advanced age (72 ± 11 vs 67 ± 12 years, p < 0.001) and dyslipidemia (36.7% vs 41.7%, p = 0.002). Coronary artery disease was more prevalent in males (21.1% vs 16.1%, p < 0.001) as well as the use of antiplatelet drugs. Females had a higher use of oral anticoagulant (84.9% vs 81.3%, p = 0.004) but this difference was non-significant after adjustment for confounders. On multivariable analyses, females were less often treated with rhythm control strategies (Odds Ratio [OR] 0.44,95% Confidence Interval [CI] 0.38–0.51) and were less likely to maintain sinus rhythm (OR 0.27, 95% CI 0.22–0.34) compared to males. Cox-regressions analysis showed no sex-related differences for the risk of death, cardiovascular, and bleeding. The clinical management of Asian AF patients should consider several sex-related differences.