Increased Risk Of Bleeding Research Articles

Risk-based and individualised management of bleeding and thrombotic events in adults with primary immune thrombocytopenia (ITP).

Although bleeding is one of the main symptoms of primary immune thrombocytopenia (ITP), risk factors for bleeding have yet to be fully established. Low platelet count (PC; <20-30 × 109 /L) is generally indicative of increased risk of bleeding. However, PC and bleeding events cannot be fully correlated; many other patient- and disease-related factors are thought to contribute to increased bleeding risk. Furthermore, even though ITP patients have thrombocytopenia and are at increased risk of bleeding, ITP also carries higher risk of thrombotic events. Factors like older age and certain ITP treatments are associated with increased thrombotic risk. Women's health in ITP requires particular attention concerning haemorrhagic and thrombotic complications. Management of bleeding/thrombotic risk, and eventually antithrombotic therapies in ITP patients, should be based on individual risk profiles, using a tailored, patient-centric approach. Currently, evidence-based recommendations and validated tools are lacking to support decision-making and help clinicians weigh risk of bleeding against thrombosis. Moreover, evidence is lacking about optimal PC for achieving haemostasis in invasive procedures settings. Further research is needed to fully define risk factors for each event, enabling development of comprehensive risk stratification approaches. This review discusses risk-based and individualised management of bleeding and thrombosis risk in adults with primary ITP.

Anticoagulant Prescribing Patterns in New-Onset Atrial Fibrillation After Cardiac Surgery

BackgroundPostoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and is associated with an increased risk of thromboembolic stroke. Recommendations regarding the optimal anticoagulant, timing of initiation, and duration of therapy remain uncertain. MethodsAdministrative databases were used to include adult patients who presented with POAF after cardiac surgery between January 1, 2015, and December 31, 2020. Key exclusion criteria included preexisting atrial fibrillation, mechanical valve replacement, or anticoagulant prescription fill within 6 months before the index admission. ResultsA total of 3214 of patients were included, and 878 (27.3%) were prescribed an oral anticoagulant (OAC) on discharge, with 536 (61%) prescribed warfarin and 342 (39%) prescribed a direct OAC. More than half of the patients (56.1%) stopped their OAC by 6 months. There was no difference in stroke or systemic embolism at 30 days, 3 months, or 6 months between those with and without anticoagulation prescribed. However, those on any OAC had higher rates of any bleeding at all time points. ConclusionsA minority of patients who presented with POAF after cardiac surgery were prescribed OAC, with warfarin being the most common agent. OAC initiation was associated with increased bleeding risk, warranting special consideration when assessing a patient’s risk of stroke with the increased risk of bleeding, particularly in the postoperative period.

How much do oral NSAIDs increase bleeding risk in patients on anticoagulation therapy?

How much do oral NSAIDs increase bleeding risk in patients on anticoagulation therapy?

COMPARISON OF CLINICAL OUTCOMES IN ACUTE CORONARY SYNDROME PATIENTS WHO UNDERGO PERCUTANEOUS CORONARY INTERVENTION USING DIFFERENT P2Y12 INHIBITORS: A SMS HOSPITAL BASED OBSERVATIONAL STUDY

Background: To compare the safety, and efficacy of contemporary P2Y12 inhibitors, prescription rates, drug defaulter and switch over rates in acute coronary syndrome (ACS) patients following percutaneous coronary intervention (PCI). Methods:In this prospective observational study, we studied195 ACS patients who underwent PCI in SMS Hospital,Jaipur. We compared prescription rates, bleeding, and major adverse cardiac events (MACEs: cardiac death, nonfatal myocardial infarction, or stroke) according to ticagrelor, prasugrel, or clopidogrel use. Results: The prescription rates of ticagrelor, prasugrel, and clopidogrel were 29.5%, 4.3%, and 66.2% respectively. Bleeding occurred in total 6 patients (2.9%) out of which 3 patients (2.2%) in clopidogrel group, 1 patient (11.1%) in prasugrel group and 2 patients (3.2%) in ticagrelor group (p=0.29)), respectively, with higher incidence in ticagrelorand prasugrel users than in clopidogrel users but statistically not significant. After six month follow up, all-cause mortality was total 5 cases (2.4%) out of which 4 death (2.9%) occurred in clopidogrel group while 1 death (1.6%) occurred in ticagrelor group(p=0.76). no mortality was recorded in prasugrel group. Repeat myocardial infarction (Re MI) occurred in total 4 patients (1.9%) with 2 patients in clopidogrel and ticagrelor group each. A total 5 patients (2.4%) switch over to another p2y12 inhibitor,mostly from ticagrelor group(p=0.045). During this follow up period, a total of 4 patients (1.9%) were drug defaulter (0.622). Conclusions: As clopidogrel based DAPT was prescribed more in our centre because of free institutional supply and found no significant difference in clinical outcomes, although slight increase in bleeding risk in ticagrelor or prasugrel based DAPT, demonstrate clopidogrel based DAPT regime can be preferably prescribed safely in our population. Drug defaulter rates in first six month following PCI are low in all groups but more switch over from ticagrelor group to other groups significantly shows importance of low cost and free institutional supply in drug adherence.

Bleeding Risk from Anticoagulant Thromboprophylaxis in Patients with Multiple Myeloma

Introduction: Patients with multiple myeloma (MM) have a high risk of venous thromboembolism (VTE) due to unique disease-related (i.e., vascular inflammation, hyperviscosity) and treatment-related factors (i.e., immunomodulatory drugs [IMiDs], high-dose dexamethasone). Thromboprophylaxis is recommended for most patients starting MM therapy. Anticoagulants are preferred over aspirin except in patients at low risk for VTE. However, compliance with prophylaxis guidelines is low. The risk of bleeding from thromboprophylaxis is not well described in these patients so an excessive perceived risk may influence clinicians' practice. We conducted a real-world analysis of bleeding complications from VTE prophylaxis in MM. Methods: The IBM MarketScan Commercial Claims Database was used to identify MM cases between 2013 and 2021. Cases required MM diagnosis from 1 inpatient or 2 outpatient claims, based on ICD-9 or ICD-10 codes, and MM-specific therapy started between 7 days before and 90 days after index diagnosis code, based on HCPCS codes and prescription records. Those with preexisting VTE, atrial fibrillation or stroke were excluded. Thromboprophylaxis was defined as at least 1 prescription for warfarin, low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOAC) within 30 days of diagnosis. Major bleeding was defined as bleeding requiring hospitalization using inpatient ICD codes previously validated (Cunningham algorithm). Patients were followed from end of prophylaxis exposure window (index MM + 30 days) to first major bleeding event, disenrollment (due to death or other reasons) or December 31, 2021. Descriptive statistics were used to calculate rates of bleeding. Cox regression was used to assess the risk of bleeding from thromboprophylaxis and define risk factors associated with major bleeding. Results: We included 6,656 patients diagnosed and treated for MM, with mean age 62.7 years and 55.3% males. Although over 50% of the population would have had a high thrombotic risk based on consensus guidelines, concurrent anticoagulant prophylaxis was prescribed in only 6.6% (436). Prophylaxis agent of choice was warfarin in 23% (102), LMWH in 39% (169), and DOAC in 38% (165), respectively. There was a trend over time favoring DOAC over other agents (25% increase in DOAC use vs. other agents per year on average, p&amp;lt;0.01). Patients on prophylaxis had a higher rate of IMiD-based therapy (63.8% vs. 46.7%, p&amp;lt;0.01) and lower concomitant anti-platelet use (2.1% vs. 4.7%, p=0.01) than those not receiving prophylaxis. There were no differences in age/sex distribution, Charlson comorbidity index (CCI) or history of bleeding between groups. With a median 1.3 years follow-up, the incidence of major bleeding among MM patients receiving VTE prophylaxis was 1.4% or 7.8 bleeding events per 1,000 person-years. This was numerically but not statistically lower than the incident bleeding rate in patients not receiving prophylaxis: 1.8% or 10.1 events per 1,000 person-years. Table 1 shows risk factors for bleeding in this MM population, adjusting for age and sex, including higher age (per 10-year increase, HR 1.38), higher CCI (per SD increment, HR 1.18), history of bleeding (HR 1.54), hypertension (HR 1.87), and renal disease (HR 1.56). IMiD-based MM therapy was associated with decreased risk of bleeding (HR 0.69). Table 2 shows the estimated bleeding risk associated with prophylaxis across several models. No statistically significant association was identified between major bleeding and anticoagulant prophylaxis. Discussion: In a real-world analysis of commercial claims data, the risk of major bleeding associated with VTE prophylaxis in patients with MM undergoing cancer therapy is low and no significant increase in bleeding risk was identified for concurrent anticoagulant use. The rate of major bleeding events appears to be comparable between patients who receive VTE prophylaxis and those who do not. Nevertheless, underutilization of VTE prophylaxis is frequent. Higher CCI, bleeding history, hypertension, and renal disease were clinical factors associated bleeding risk, which may be included in models to help clinicians assess individual patient's risk and guide clinical decisions.

Bleeding Risk Factors in Thrombocytopenic Patients with Hematologic Malignancies

Introduction Despite prophylactic platelet transfusions, World Health Organization (WHO) grade ≥ 2 bleeding occurs in 50 to 70% of patients with hematologic malignancies and hypoproliferative thrombocytopenia secondary to therapy and/or underlying disease (Gernsheimer et al, Blood 2022). Anemia (hematocrit, HCT ≤ 25%), coagulopathy (activated partial thromboplastin time ≥ 30s, international normalized ratio ≥ 1.2), and platelet count ≤ 5000/µl were independently associated with increased risk of bleeding in the PLADO (platelet dose) trial of 1272 patients with hypoproliferative thrombocytopenia treated between 2004 to 2007 (Uhl et al, Blood 2017). Updated data on bleeding outcomes and risk of bleeding is lacking. Methods We performed a post-hoc analysis of bleeding outcomes and bleeding risk factors in 330 patients with hematologic malignancy and hypoproliferative thrombocytopenia from therapy and/or underlying disease randomized at 3 institutions to receive either tranexamic acid (TXA) or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (A-TREAT) (Gernsheimer et al, Blood 2022). Patients received prophylactic platelet transfusions for a platelet count of ≤ 10,000/µl and WHO grade bleeding was assessed daily for 30 days after a platelet count ≤ 30,000/µl and study drug was started. Study drug was discontinued when platelet count was ≥ 30,000/ul for 46 hours without platelet transfusion support or until a maximum of 30 days after treatment activation, whichever came first. Red blood cell (RBC) transfusion was given according to local standard of care. Cox proportional hazards regression with time-varying covariates was used to assess the association of patient characteristics with the risk of a first major (grade 2+) bleeding event. HCT, platelet count, inpatient vs. outpatient status, steroid treatment, and fever were recorded daily. Patients were censored at the first of time of withdrawal, death, or day 30. Results WHO grade ≥ 2 bleeding occurred in 46% of patients overall with no difference between the TXA and placebo groups (TXA 44% versus placebo 47%, p=0.66). Bleeding rates were highest in allogeneic stem cell transplant patients, followed by chemotherapy, followed by autologous stem cell transplant. Overall bleeding rates by organ system showed oral and nasal (18%), skin (17%), gastrointestinal (11%), and genitourinary (11%) bleeding (Table 1). WHO grade ≥ 2 vaginal bleeding occurred in 28% of patients of childbearing potential despite widespread use of hormonal suppression. In a proportional hazards regression model of time to first bleeding event, undergoing allogeneic stem cell transplant was associated with a non-significant increased hazard of bleeding vs chemotherapy (HR 1.32, 95% CI 0.92-1.89), whereas autologous transplant had significantly lower hazard of bleeding vs chemotherapy (HR 0.39, 95% CI 0.20-0.76) (Table 2). HCT &amp;lt; 21% was associated with increased bleeding risk even after adjusting for severe thrombocytopenia (HR 2.71, 29% CI 1.37, 5.36). Platelet count &amp;lt; 5000/µl was also associated with increased risk (HR 3.33, 95% CI 1.67-6.61). Inpatient status, presence of fever, and age did not significantly impact risk of first bleed. Conclusions The overall rate of WHO grade &amp;gt;2 bleeding was similar to historical literature with lower rates of gastrointestinal bleeding than previously reported (31% in PLADO). Vaginal bleeding was common despite standard use of hormonal suppression in patients of childbearing potential. Platelet count &amp;lt; 5000/µl remains a risk factor for bleeding. Regardless of platelet count, bleeding risk increased with HCT &amp;lt; 21% suggesting a red blood cell transfusion threshold higher than 21% is unlikely to mitigate bleeding. More investigation is needed on strategies to reduce bleeding in this patient population.

Efficacy and Safety of Extended Duration Postoperative Thromboprophylaxis with Low-Molecular-Weight-Heparin Among Subgroups of Patients Undergoing Surgical Resection of Colorectal Cancer: A Post-Hoc Analysis of the Periop-01 Trial

Background: Clinical practice guidelines suggest the use of extended duration of postoperative thromboprophylaxis to prevent venous thromboembolic (VTE) complications after any cancer-related major abdominal or pelvic surgeries. However, recent trials including patients undergoing surgical resection of colorectal cancer have reported relatively low rates of symptomatic VTE. Hence, the risk and benefits of extended postoperative thromboprophylaxis need to be carefully assessed in this patient population. We sought to determine the impact of extended duration thromboprophylaxis with low-molecular-weight-heparin on VTE and bleeding events among different subgroups of patients undergoing surgical resection of localized colorectal cancer. Methods: This is a pre-planned post-hoc analysis of the PERIOP-01 randomized controlled trial which compared extended (up to 6 weeks) to standard duration (in hospital only) of perioperative thromboprophylaxis with tinzaparin (4500 IU SC daily) in patients undergoing surgical resection of localized colorectal cancer. Subgroup analyses were performed based on different baseline characteristics. The primary efficacy and safety outcomes were objectively documented major VTE and combination of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) events, respectively. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using the Cox proportional hazards model to compare the treatment effect accounting for clustering at study center level. Results: A total of 614 patients were randomized in the PERIOP-01 trial (307 in the extended and 307 in the standard duration thromboprophylaxis groups). Overall, the mean age of the participants was 61 years, 41% of them were women, and most patients were white (90%). Type of primary cancer was well-balanced with 311 patients having rectal cancer (51%), whereas 303 (49%) had primary colon cancer. During the study period, major VTE events occurred in 2% and 1% of the extended- and standard-duration prophylaxis groups, respectively (P=0.8). Combination of MB and CRNMB events occurred in 3% of each group. No specific characteristics were found to be associated with a decreased risk of major VTE among patients on extended duration thromboprophylaxis (Figure 1). Patients with colon cancer resection receiving extended thromboprophylaxis were at an increased risk of bleeding complication compared to patients with rectal cancer (HR 2.57, 95%CI 1.25-5.3) (Figure 1). Other characteristics that may be associated with an increased risk of bleeding among patient on extended thromboprophylaxis included age &amp;gt;= 75 (HR 2.37, 95%CI 0.47-11.98) and male sex (HR 2.13, 95%CI 0.2-23.17), although these characteristics were not statistically significant. Conclusions: In the PERIOP-01 trial, extended thromboprophylaxis didn't reduce the risk of major VTE in any subgroups of patients. On the other hand, extended duration of thromboprophylaxis may be associated with an increased bleeding risk among male, elderly patients, and those with colon cancer.

Impact of Cancer Diagnosis on Appropriate Use of Antithrombotic Medications in Individuals with Cardiovascular Diseases

Introduction: Cancer and Cardiovascular disease (CVD) often coexist and CVD is the leading cause of non-cancer mortality in people with cancer. Antithrombotic medications used to manage CVD are associated with increased bleeding risk, particularly in people with cancer. Appropriate management of CVD is therefore essential in individuals with cancer, both to decrease recurrent CVD as well as to prevent bleeding. In this study, we assessed utilization patterns of antithrombotic medications for CVD following a new diagnosis of cancer. Methods: Among people receiving primary care at the University of Vermont Medical Center from 2010 to 2019, we identified a cohort of 4,010 subjects with baseline CVD, identified from problem lists or billing codes within the first year of follow-up. Exclusion criteria included baseline cancer diagnosis (cancer known at the time of inclusion in the cohort or within the first year of follow-up) or a known history of venous thrombosis. Incident cancer was defined as new diagnosis of cancer after the first year of follow-up and did not include people with non-melanomatous skin cancers. We used the National Cancer Institute list of ICD-9 and ICD-10 codes for different cancer diagnoses. Patient's use of antithrombotics, prescribed or non-prescribed, were captured using computable phenotypes developed from the electronic outpatient medication reconciliation record and validated using chart review. People with baseline CVD who were diagnosed with cancer after the first year of follow up were matched 1:1 by sex and age with people with CVD and no cancer. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CI) of persistent guideline-directed use of antithrombotic medications for 6 months after a new cancer diagnosis versus a matched time-period in those without incident cancer (use of antiplatelets in those with a history of atherosclerotic CVD and use of anticoagulation in those with a history of atrial fibrillation). Results: We identified 4,010 individuals with baseline CVD, 841 of whom (20%) developed incident cancer during follow-up. Distribution of CVD and antithrombotic use in the age- and sex-matched population are presented in Table 1. 2/3 of the population had coronary artery disease and about 30% had atrial fibrillation or flutter. About 65% of individuals were on any antiplatelet therapy and 18% were on anticoagulation for CVD. 41% of people with baseline CVD, and incident cancer diagnosis were still on antiplatelet therapy 6 months after their cancer diagnosis as opposed to 38 % in the matched population without a cancer diagnosis. 33% of individuals with incident cancer were still on anticoagulation for atrial fibrillation or flutter as opposed to 28% of the matched population without cancer. Both of these differences were statistically significant with OR=1.55 (95% CI, 1.15-2.1) for antiplatelets, and OR=1.56 (95% CI, 1.05,2.31) for anticoagulants, compared to those with no cancer diagnosis (Table 2). Conclusion: Surprisingly, our study found that incident cancer in individuals with baseline CVD was associated with increased adherence to antithrombotic therapy. We had hypothesized that incident cancer would be associated with lower use of antithrombotic therapy. This result could be related to increased interaction with medical specialists following a cancer diagnosis. The impact of increased adherence to antithrombotics on bleeding however, will need to be further investigated.

Outcomes of Oral Anticoagulation with Concomitant NSAID Use: A Registry Based Cohort Study

Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs), available without a prescription, are some of the most commonly used drugs in the United States. For patients on oral anticoagulation (OAC), concomitant NSAID use can increase the risk of bleeding. Patients are often advised to avoid this drug combination, or else consider adding a proton pump inhibitor (PPI) or H2 receptor antagonists (H2RA) for gastroprotection when both NSAIDs and OAC are used. However, there are limited data on how NSAID use impacts thrombotic and hemorrhagic outcomes. Available data may be biased due to selection bias, confounding, misclassification, and variable NSAID exposure. We sought to determine the frequency of NSAID use among patients on OAC, the impact on clinical outcomes, and if gastroprotection may mitigate bleeding risk. We hypothesized that NSAIDs would increase bleeding risk without impacting thrombotic risk. We did not anticipate gastroprotection would mitigate this risk. Methods We conducted a retrospective registry-based cohort study of adults starting a direct oral anticoagulant (DOAC) or warfarin therapy for the indications of venous thromboembolism and/or non-valvular atrial fibrillation between June 2011 and June 2023. As part of the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2), warfarin-treated patients were followed by six anticoagulation clinics, and four of the six clinics contributed data for patients on DOACs. Patients were excluded if they had a history of valvular AF, less than 3 months of follow-up, or on more than one antiplatelet drug. Two propensity matched cohorts (OAC alone vs. OAC+NSAID) of patients were analyzed based on NSAID use at the time of study enrollment, using a 4:1 matching ratio. Both prescribed and over the counter NSAIDs were included, potentially with the former being more frequently captured in the study registry. The primary outcome was any new bleeding event. Secondary outcomes included new episodes of arterial or venous thrombosis, bleeding event type (major, fatal, life threatening, central nervous system, and non-major bleeding), emergency room visits, hospitalizations, transfusions, and death. Random chart audits were done to confirm the accuracy of the abstracted data. Event rates were compared using Poisson regression. Results Of 12,083 patients on OAC, 449 (3.7%) were on concomitant NSAIDs. After propensity matching, we compared 1,796 patients on OAC to 449 patients on OAC+NSAIDs. Patient demographics, co-morbidities, indication for anticoagulation, history of bleeding or clotting, medications, and duration of follow-up were well-balanced after matching. Patients were followed for an average of 30 months (standard deviation 34.2 months). For patients on OAC alone vs. OAC+NSAIDs, bleeding event rates were similar: 25.1 (95% confidence interval [CI] 23.7-26.6) versus 24.3 (95% CI 21.4-27.3) bleeds per 100 patient years ( P=0.56). Rates of non-major, major, life-threatening, central nervous system, and fatal bleeding were also similar. Furthermore, rates of thrombosis, emergency room visits, hospitalizations, transfusion, and death were similar. A pre-defined subgroup analysis comparing patients on OAC+NSAIDs with gastrointestinal prophylaxis (PPIs or H2RAs, N=179) to patients on OAC+NSAIDs without gastrointestinal prophylaxis (N=270) also showed similar rates of bleeding and healthcare utilization. Conclusions Nearly 4% of patients were taking NSAIDs with OAC and outcomes were similar to patients on OAC alone. Study limitations include NSAIDs and gastroprotection were only reliably known at time of enrollment. In addition, the potential for unmeasured or unadjusted confounding inherent to observational studies. Further research is needed to determine if there is a “safe” level of NSAID use for patients on OAC and to better define the role of gastrointestinal prophylaxis.

Bleeding Associated with Prophylactic Anticoagulation for Hospital Related Venous Thromboembolism Prevention: A Case Series

The use of heparin products for prophylaxis of venous thromboembolism (VTE) have decreased the prevalence of VTE in all hospitalized patients, however the possibility of bleeding from prophylactic heparin cannot be disregarded. While life-threatening bleeding is less common with prophylactic doses, it can occur in the presence of other risk factors for bleeding. We aim to describe characteristics that may increase bleeding risk from prophylactic use of heparin. We present a single-center, retrospective case series of patients who received protamine for bleeding complications from prophylactic heparin administration at our facility between 2016-2020. We assessed patient demographics, medical history, types of heparin formulations administered, and patient outcomes. We observed that all patients were female. Patients who developed bleeding events from VTE prophylaxis had at least two of these attributes; BMI &amp;lt;18.5 kg/m2, weight &amp;lt;50kg, trauma within 1-month, surgery within 1-month or were taking anti-platelet agents. We suggest that the collective presence of two or more of these characteristics should lend consideration to dose adjustment and/or closer monitoring. In the absence of rigorous research comparing alternative doses to standard doses for prophylaxis in these patients, these decisions fall largely to the discretion of individual physicians. Designing larger studies following patients over long periods of time can help conclusively identify risk factors that predispose patients to bleeding.

Tracheostomy in high-risk patients on ECMO: A bedside hybrid dilational technique utilizing a Rummel tourniquet

ObjectiveTraditionally, critically ill patients requiring prolonged mechanical ventilation benefit from a long-term airway, thus necessitating tracheostomy. The widespread application of extracorporeal membrane oxygenation (ECMO) has exponentially increased in recent years, creating a new subset of patients necessitating tracheostomy with significantly increased bleeding risk. We present a hybrid dilational tracheostomy technique utilizing a Rummel tourniquet developed at our institution to mitigate bleeding risk in patients on ECMO necessitating long-term airway. MethodsA total of 24 patients on ECMO underwent bedside hybrid dilational tracheostomy with utilization of a Rummel tourniquet from 06/2020 to 01/2022 at our institution. These patients were followed longitudinally and evaluated for postoperative bleeding. Particular attention was paid to anticoagulation regimens pre- and post-operatively. ResultsThe primary outcome of the study, postoperative bleeding, was observed in four of the 24 study participants (16.67 %). Each of these complications were managed with tightening of the Rummel tourniquet and application of hemostatic packing agents; no operative interventions were required. Anticoagulation was held for a mean time of 4.33 h preoperatively and 5.2 h postoperatively. ConclusionsOur data support this hybrid tracheostomy technique with the addition of a Rummel tourniquet to be a safe and effective adjunct for perioperative hemostasis in high-risk patients necessitating tracheostomy while on ECMO. While this technique was initially developed for critically ill COVID-19 patients, we believe it can be applied to all patients on ECMO to help mitigate perioperative bleeding risk.

Initiation of warfarin is associated with decreased mortality in patients with infective endocarditis: A population-based cohort study

ImportanceThe use of warfarin to prevent thromboembolism in patients with infective endocarditis (IE) remains controversial due to potentially increased bleeding risks. DesignPopulation-based retrospective cohort study. ParticipantsPatients aged 18 or older and diagnosed with IE in Hong Kong between January 1st, 1997 and August 31st, 2020 were included. Patients with use of any anticoagulant 30 days before IE diagnosis were excluded. Patients initiated on warfarin within 14 days of IE diagnosis and patients without warfarin use were matched for baseline characteristics using 1:1 propensity score matching. ExposureWarfarin use within 14 days of IE diagnosis. Main outcomes and measuresPatients were followed up to 90 days for the outcomes of ischemic stroke, all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding. Cox regression was used to determine hazard ratios (HRs) [95 % confidence intervals (CIs)] between treatment groups. Fine-Gray competing risk regression with all-cause mortality as the competing event was performed as a sensitivity analysis. In addition to 90-day analyses, landmark analyses were performed at 30 days of follow-up. ResultsThe matched cohort consisted of 675 warfarin users (57.0 % male, age 59 ± 16 years) and 675 warfarin non-users (53.5 % male, age 61 ± 19 years). Warfarin users had a 50 % decreased 90-day risk in all-cause mortality (HR:0.50 [0.39–0.65]), without significantly different 90-day risks of ischemic stroke (HR:1.04 [0.70–1.53]), intracranial hemorrhage (HR:1.25 [0.77–2.04]), and gastrointestinal bleeding (HR:1.04 [0.60–1.78]). Thirty-day landmark analysis showed similar results. Competing risk regression showed significantly higher 30-day cumulative incidence of intracranial hemorrhage in warfarin users (sub-HR:3.34 [1.34–8.31]), but not at 90-day (sub-HR:1.63 [0.95–2.81]). Results from Fine-Gray regression were otherwise congruent with those from Cox regression. Conclusions and relevanceWarfarin initiated within 14 days of IE diagnosis was associated with significantly decreased risks of mortality but higher risks of intracranial hemorrhage, with similar risks of ischemic stroke and gastrointestinal bleeding, compared with non-use of warfarin with 14 days of IE diagnosis. Key pointsQuestion: Is warfarin, initiated within 14 days of a diagnosis of infective endocarditis (IE), efficacious and safe?Findings: In this propensity score-matched, population-based, prospective cohort study from Hong Kong, warfarin use within 14 days of IE diagnosis was associated with a 50 % decrease in the risk of all-cause mortality, albeit with higher risk of intracranial hemorrhage, and without significant differences in the risk of ischaemic stroke and gastrointestinal bleeding.Meaning: In patients with IE, warfarin use within 14 days of diagnosis may have mortality benefits, despite increased risks of intracranial hemorrhage.

Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants.

Introduction: Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (RYR2) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between RYR2 and bleeding risk to develop the risk scoring system in patients treated with DOACs. Methods: This study was a retrospective analysis of prospectively collected samples. We selected ten SNPs within the RYR2 gene, and two models were constructed (Model I: demographic factors only, Model II: demographic and genetic factors) in multivariable analysis. Independent risk factors for bleeding were used to develop a risk scoring system. Results: A total of 447 patients were included, and 49 experienced either major bleeding or clinically relevant non-major bleeding. In Model I, patients using rivaroxaban and experiencing anemia exhibited an increased bleeding risk after adjusting for covariates. Upon incorporating genetic factors into Model I, a significant association with bleeding was also observed in cases of overdosing on DOACs and in patients with a creatinine clearance (CrCl) < 30mL/min, in addition to rivaroxaban and anemia (Model II). Among genetic factors, RYR2 rs12594 GG, rs17682073 AA, rs3766871 GG, and rs6678625 T alleles were associated with bleeding complications. The area under the receiver operating characteristic curve (AUROC) of Model I was 0.670, whereas that of Model II increased to 0.803, demonstrating better performance with the inclusion of genetic factors. Using the significant variables in Model II, a risk scoring system was constructed. The predicted bleeding risks for scores of 0, 1-2, 3-4, 5-6, 7-8, and 9-10 points were 0%, 1.2%, 4.6%, 15.7%, 41.7%, and 73.3%, respectively. Conclusion: This study revealed an association between RYR2 and bleeding complications among patients taking DOACs and established a risk scoring system to support individualized DOAC treatment for these patients.

Validation of the PRECISE-DAPT score in a population-based sample of patients undergoing percutaneous coronary intervention with stent implantation

Abstract Background Dual antiplatelet therapy (DAPT) after coronary stenting reduces the risk of recurrent ischemia but increases bleeding risk. The PRECISE-DAPT score was developed using data from clinical trials to identify individuals at high bleeding risk who may benefit from shorter DAPT duration. Although use of the PRECISE-DAPT score is recommended in clinical guidelines, its applicability to patients seen in routine clinical practice is uncertain. Purpose To assess the performance of the PRECISE-DAPT score in a population-based cohort of patients undergoing coronary stenting. Methods We calculated the PRECISE-DAPT score in patients enrolled in the Swedish register of cardiac care (SWEDEHEART) who underwent coronary stenting and received DAPT in an urban region in Sweden between January 1, 2013, and December 31, 2018. Patients were followed from day 30 after discharge after coronary stenting until a bleeding event (TIMI major/minor bleeding using ICD-codes for bleeding and data on changes in hemoglobin levels from healthcare registers), an ischemic event (myocardial infarction/ischemic stroke), discontinuation of DAPT, death, 12 months after stenting, or end of study period. We assessed the score’s discrimination and estimated rates of bleeding and ischemic events in groups of patients categorized using the score’s decision rule for "high bleeding risk" (score ≥25). We then compared bleeding rates in groups of patients categorized based on their score with those observed in the clinical trials used to derive the PRECISE-DAPT score. Results Of the 8,348 patients (mean (SD) age 67 (11) years; 27% women) included in the study, 2,001 (24%) were categorized as "high bleeding risk" (Figure 1). The PRECISE-DAPT score had a moderate discrimination (c-statistic 0.64, 95% CI, 0.56– 0.71) for bleeding. Patients with "high bleeding risk", compared to those not at "high bleeding risk", had a higher rate of bleeding (2.0 vs 0.9 events per 100 patient years; hazard ratio 2.17, 95% CI 1.29–3.65) and a higher rate of ischemic events (12.8 vs 9.0 events per 100 patient years; hazard ratio, 1.33, 95% CI 1.10–1.61). Patients with "high bleeding risk" in our study population had lower rates of bleeding as compared with those at "high bleeding risk" in the clinical trials used to derive the score. Rates of bleeding in other risk categories were largely similar to those in the clinical trials. (Figure 2). Conclusion In a population-based cohort from routine clinical practice in Sweden, the PRECISE-DAPT score identified patients with increased bleeding risk, although those patients also had an increased ischemic risk. Differences in bleeding rates among those categorized as "high bleeding risk" across patient populations may mean that the absolute risk differences in bleeding risk for short vs long DAPT duration demonstrated in the clinical trials used to derive the PRECISE-DAPT score may not be directly applicable to patients seen in routine clinical practice.

The impact of cancer on the risk of hospitalisation for bleeding among acute coronary syndrome patients: an analysis of the Virtual Cardio-Oncology Research Initiative (VICORI) database

Abstract Introduction Cardiovascular disease and cancer are common causes of morbidity and mortality. Significant advancements in treatment strategies for both disease entities have resulted in a growing population who live with both conditions. Myocardial infarction (MI) represents approximately 20% of all cardiovascular disease admissions in cancer patients and 10% of patients who present with an acute MI has cancer. Bleeding is a major concern in patients with cancer and an acute coronary syndrome (ACS). While dual antiplatelet therapy (DAPT) increases a patient’s bleeding risk, cancer patients are at a further increased risk. Cancer is a recognised risk factor associated with an increased bleeding risk after percutaneous coronary intervention (PCI), but blood dyscrasias, liver disease and multiple long-term conditions – all common to cancer patients – further exacerbate this risk. Prescribing DAPT post-ACS and post-PCI remains a challenge when balancing ischaemic and bleeding risks in this population. The VICORI database is the world’s first whole-country cardio-oncology research platform, linking data from the National Cancer Registration and Analysis Service, National Institute for Cardiovascular Outcomes Research and Hospital Episode Statistics [1]. Purpose To investigate the risk of hospitalisation for bleeding among ACS patients stratified by presence or absence of cancer. Methods This is an observational cohort study using linked data from the VICORI programme. We explored the risk of hospitalisation for bleeding following an ACS, in patients with and without cancer, identified between 2006–2019. Patients were followed up for one year from the date of their ACS. We used inverse probability weighting based on propensity scores to produce a balanced cohort of patients with and without cancer. Subgroup analyses were performed on patients with ST and non-ST-elevation MI alongside coronary stenting. Results Of 608,771 patients presenting with ACS, 9861 (1.6%) had cancer and 598,910 (98.4%) did not have cancer. Prostate (n=1753, 17.8%), colorectal (n=1548, 15.7%), lung (n=1543, 15.7%) and breast (n=607, 6.2%) cancers were the most common types of primary cancers. Relating to PCI, cancer patients received stents in only 35.4% (n=3,489) of cases, while non-cancer patients received stents in 55.5% (n=332,566) of cases. Bleeding events were more prevalent in cancer patients compared to non-cancer patients (n=779, 7.9% vs n=28,016, 4.7%). The rate (hazard) of hospitalisation for bleeding in the first year following ACS was higher in patients with cancer than those without (HR:1.46, 95%CI 1.36-1.57). Conclusion In this large real-world observational study, cancer patients had an increased risk of hospitalisation for bleeding after ACS compared to those without. Further work is needed to identify people with cancer who are at a high-risk of bleeding, optimal therapies, and the risk:benefit ratio of bleeding versus subsequent cardiovascular events.Incidence Rate of Bleeding in PatientsHazard Ratios for Bleeding

Ticagrelor or clopidogrel in atrial fibrillation patients undergoing percutaneous coronary intervention for myocardial infarction

Abstract Background Contemporary guidelines recommend clopidogrel as the P2Y12 receptor inhibitor of choice in atrial fibrillation (AF) patients with acute coronary syndrome and/or percutaneous coronary intervention (PCI) who require concomitant oral anticoagulation (OAC). Conversely, the use of ticagrelor or prasugrel in these settings is discouraged. Purpose To examine the efficacy and safety of more potent P2Y12 inhibitors (ticagrelor or prasugrel) versus clopidogrel in patients with AF on OAC undergoing PCI for myocardial infarction. Methods We conducted a Danish, nationwide, registry-based cohort study of patients on an OAC for presumed AF who underwent PCI for myocardial infarction from 2011 through 2019. Only individuals discharged on a P2Y12 inhibitor and an OAC were included, while those receiving a P2Y12 inhibitor prior to hospitalization were excluded. The primary efficacy outcome was major adverse cardiovascular events, defined as a composite of death from any cause, recurrent myocardial infarction, repeat revascularization, or stroke, while the primary safety outcome was bleeding requiring hospitalization. Death from any cause was the main secondary outcome. Absolute and relative risks for outcomes at 1 year were calculated through multivariable logistic regression with average treatment effect modeling. Efficacy outcomes were standardized for the CHA2DS2-VASc score and aspirin use while bleeding outcomes were standardized for the HAS-BLED score and proton-pump inhibitor use. Results A total of 2259 patients were included of whom 1918 (84.9%) were discharged on clopidogrel and 341 (15.1%) on ticagrelor or prasugrel (the latter two were merged into one group because only 38 persons were discharged on prasugrel). Individuals who received the more potent P2Y12 inhibitors were younger (median age 70 vs. 74 years), more often men (76.0% vs. 70.8%), and less often had prior coronary artery disease (5.6% vs. 9.6%) than those who received clopidogrel. The standardized risk of major adverse cardiovascular events was significantly lower in patients discharged on ticagrelor or prasugrel compared with clopidogrel (standardized absolute risk, 15.8% vs. 19.6%; relative risk, 0.81, 95% confidence interval [CI], 0.68 to 0.93; P=0.003), while the risk of bleeding did not differ (standardized absolute risk, 5.2% vs. 5.2%; relative risk, 1.00, 95% confidence interval, 0.69 to 1.32; P=0.99) (Figure). The risk of death was significantly lower in the group of patients who were prescribed ticagrelor or prasugrel compared with clopidogrel (P&amp;lt;0.001). Conclusions In patients with AF on OAC who had undergone PCI for myocardial infarction, discharge on ticagrelor or prasugrel versus clopidogrel was associated with reduced ischemic risk, but not an increased bleeding risk. While these findings appear to support an individualized choice of P2Y12 inhibitor in this population, they should be interpreted with caution given the observational nature of the study.Figure

The efficacy and safety of direct oral anticoagulants compared with vitamin K antagonist in patients with hypertrophic cardiomyopathy and atrial fibrillation: a systematic review and meta-analysis

Abstract Background The benefit-risk profile of direct oral anticoagulants (DOAC) therapy in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) have not been well established yet. Purpose This study aimed to evaluate the efficacy and safety of DOAC compared with vitamin K antagonists (VKA) in patients with HCM and AF. Methods PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov were searched to identify studies comparing DOAC with VKA in patients with HCM and AF. Results Five studies involving 8103 patients were included in this meta-analysis. Compared to the VKA group, the DOAC group displayed a significant lower risk of all-cause death [RR (95%CI): 0.44 (0.35-0.55)]. Meanwhile, DOAC therapy group was similar to VKA therapy in reducing ischemic stroke [RR (95%CI): 0.65 (0.33-1.28)] and thromboembolic events [RR (95%CI): 0.95 (0.74-1.22)]. The incidence of major bleeding [RR (95%CI): 0.69 (0.44-1.07)] were comparable between the two groups. Conclusion In patients with HCM and AF, DOAC therapy were superior or non-inferior to VKA therapy in reducing the risk of all-cause death and thromboembolic events, without increasing bleeding risk. Further RCTs are needed to provide more evidence for DOAC therapy in this population.Efficacy and safety endpoints in DOAC th

Initiation of warfarin is associated with decreased mortality in patients with infective endocarditis: a population based cohort study

Abstract Background The use of warfarin as an anticoagulant to prevent thromboembolism in setting of infective endocarditis (IE) remains controversial due to increased bleeding risks. Purpose To study the risks of stroke, mortality and bleeding in warfarin users compared with non-use. Methods Patients aged 18 or older and diagnosed with IE in our city between January 1st 1997 and August 31st 2020 were included. Patients with use of any anticoagulant 30 days before IE diagnosis were excluded. Patients initiated on warfarin within 14 days of IE diagnosis and patients without warfarin use were matched using propensity scores (1:1 ratio). The study outcomes were ischemic stroke, all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding. Cox proportional hazards regression was used to determine the hazard ratios [95% confidence intervals (CIs)] for the predictors of study outcomes at the end of 90-day follow up. Results The matched cohort consisted of 675 warfarin users (57.0% male, age 59±16 years, mean CHA2DS2-VASc score: 1.42±1.72) and 675 warfarin non-users (53.5% male, age 61±19 years, mean CHA2DS2-VASc score: 1.58±1.76). Warfarin use was not associated with ischemic stroke risk (Hazard ratio: 1.04 [95% CI, 0.70-1.53]), but was associated with a 50% decreased risk of all-cause mortality (HR: 0.50 [0.39-0.65]). In terms of bleeding risk, intracranial hemorrhage occurred in 36 (5.3%) warfarin users and in 29 (4.3%) patients warfarin non-users, and gastrointestinal bleeding occurred in 27 (4.0%) warfarin users and in 26 (3.9%) warfarin non-users. Conclusions Warfarin use is associated with decreased risks of mortality but similar risks of ischemic stroke compared with non-use of warfarin in patients with IE.Kaplein Meier curves of study outcomes

Left atrial appendage occlusion indicated by increased thrombotic risk versus increased bleeding risk: a comparison of the stroke despite anticoagulation (STR-OAC) and EWOLUTION cohorts

Abstract Background Left atrial appendage occlusion (LAAO) provides mechanical cardioembolic protection, especially attractive for atrial fibrillation (AF) patients that cannot use oral anticoagulation therapy (OAC). Patients with prior stroke despite OAC are at high risk for recurrence and may also benefit from LAAO as (adjunctive) therapy. Purpose To investigate the efficacy of LAAO in AF patients with prior stroke on OAC compared to LAAO in AF patients with a contra-indication to OAC. Methods The STR-OAC LAAO is an international collaboration combining patients that underwent successful percutaneous LAAO because of a thrombo-embolic event or LAA thrombus on OAC from multiple LAAO registries (n=439). This cohort was compared to patients from the previously published EWOLUTION registry comprising of patients that successfully underwent LAAO because of a contra-indication for long-term OAC (n=1005). Thrombotic endpoints were prespecified and (non-procedural) major bleeding was defined as BARC score&amp;gt;2. Annualized event rates were calculated and compared to historical data based on individual patient risk scores. Results Both cohorts were comparable in terms of age and sex (Table 1). CHA2DS2-VASc and HAS-BLED scores were higher in the STR-OAC cohort. After LAAO indicated by a thrombotic event despite OAC, 33% of patients had a planned lifelong hybrid strategy approach of concomitant LAAO and OAC. Consequently, STR-OAC patients often continued OAC (with or without antiplatelet therapy), whereas EWOLUTION patients were more frequently discharged with antiplatelet therapy only. The annualized event rate (AER) for composite thrombotic events was slightly higher in the STROAC-LAAO compared to the EWOLUTION patients (4.2% versus 2.0%), possibly due to the higher thrombotic risk of this population. Major bleeding occurred more frequently in the EWOLUTION compared to STROAC-LAAO patients (AER 2.6% versus 1.1%, Table 2). In comparison to historically expected event rates, relative risk reduction (RRR) for thrombo-embolic events was 65% in the STR-OAC cohort, and 80% in the EWOLUTION cohort (Fig. 1). Annualized major bleeding rates were reduced with 81% and 46% in the STR-OAC-LAAO and EWOLUTION cohorts, respectively. Conclusions LAAO in AF patients with a thrombotic event despite OAC provides ischemic stroke protection similar to a guideline-recommended population with high bleeding risk. RRR for thrombotic events was more pronounced in the population contra-indicated for long-term OAC, while RRR for major bleeding was more pronounced in the patients that experienced a thrombotic event on OAC. Randomized trial data could endorse thrombotic event despite OAC as an indication for LAAO.Table 1&amp;2Figure 1

Left Atrial Appendage Closure: A Narrative Review.

Atrial fibrillation (AF) is the most commoncardiac arrhythmiaand the cause of thromboembolic events in elderly patients worldwide. AF is associated with a significantly increased risk of morbidity and mortality due to cardiac emboli, primarily from left atrial appendage (LAA) thrombus. Oralanticoagulation therapy is the standard treatment to effectively reduce the risk of thromboembolic events in patients with AF. However, anticoagulation treatment increases bleeding risk. LAA closure (LAAC) has recently been introduced as afeasible mechanical preventive intervention for thromboembolic events while minimizing the risk of bleeding. Transcatheter LAAC devices have evolved in the past decade, and several ongoing trials have demonstrated the improvements of safety and outcomes in newer generation devices. This review summarizes the current perspectives and outcomes regarding LAAC as an alternative to pharmacologic therapy.