Significant Increase In Bleeding Risk Research Articles

Milvexian: A Focus on a New Oral Anticoagulant that Targets Factor XIa for Thromboembolism Prophylaxis.

Drugs that target factor XI and/or XIa have been evaluated as alternatives to existing anticoagulants, in light of studies that indicate that a decrease in Factor XI/XIa levels or activity may result in a lower risk of thrombosis without a significant increase in bleeding risk. Milvexian is an investigational small-molecule factor XIa inhibitor that has recently completed phase 2 clinical trials. Preclinical studies were suggestive of its potential to prevent arterial and venous thrombosis. It was well-tolerated in healthy participants, as well as in participants with mild or moderate hepatic impairment and moderate or severe renal impairment. Notably, patients who received milvexian after knee arthroplasty had a dose-proportional lower incidence of venous thromboembolism compared to patients who received postoperative enoxaparin, and they had a lower incidence of clinically relevant bleeding. A separate phase 2 trial was conducted that assessed the use of milvexian for secondary stroke prevention in patients who had ischemic stroke or transient ischemic attack. It failed its primary objective of establishing a dose-response relationship between milvexian and a composite endpoint of symptomatic ischemic stroke or covert brain infarction. The trial did, however, show a reduction in the relative risk of symptomatic ischemic stroke across most of the treatment groups receiving various dosages of milvexian compared to placebo. The efficacy of milvexian in secondary stroke prevention will be further assessed in an upcoming phase 3 trial. Additional upcoming phase 3 trials will also assess its efficacy in stroke prevention in patients with atrial fibrillation as well as in event reduction in patients with acute coronary syndrome.

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<0.01). Patients on prophylaxis had a higher rate of IMiD-based therapy (63.8% vs. 46.7%, p<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.

Chinese stroke patients with atrial fibrillation used Robert's age-adjusted warfarin loading protocol obtained good INR results within therapeutic range

To assess whether Roberts’ age-adjusted warfarin loading protocol is effective in Chinese patients and whether the SAMeTT2R2 score can predict international normalized ratio (INR) control. Roberts’ protocol for warfarin titration was applied to patients with non-valvular atrial fibrillation (NVAF) complicated with ischemic stroke at the Department of Neurology between 2014 and 2019. Clinical and sociodemographic variables were recorded. A minimum of 1-year follow-up was used to calculate the time in therapeutic range (TTR) of the INR. A total of 94 acute ischemic stroke patients with NVAF were included in the study. Seventy-seven (81.9%) of the patients had attained stable INR (2.0–3.0) at the fifth dose, and 90.0% of the patients had achieved stable INR on the ninth day. Seventeen (18.1%) of the patients had an INR > 4 during dose-adjustment period. Patients with INR > 4 had significantly lower body weight (53.8 vs. 63.1 kg, P = 0.014), lower rate of achievement of stable INR (35.3% vs. 92.2%, P = 0.000), and lower rate of TTR ≥ 65% (23.5% vs. 70.1%, P = 0.001), but with no significant increase in bleeding risk. A total of 89 patients underwent long-term INR follow-up, of which 58 (65.2%) patients achieved TTR ≥ 65%. Patients with poor TTR had significantly lower body weight (56.3 vs. 63.7 kg, P = 0.020) and lower rate of stable INR achievement (64.5% vs. 89.7%, P = 0.002). All 94 patients had SAMeTT2R2 score ≥ 2. There was no linear association between SAMeTT2R2 score and the rate of TTR ≥ 65% (Ptrend = 0.095). Chinese ischemic stroke patients with NVAF on warfarin can safely and quickly achieve therapeutic INR using Roberts’ age-adjusted protocol and can obtain a good TTR. Lower body weight may be a predictor of poor TTR and INR > 4. Patients who have not attained stable INR after adjusting the dose five times are at high risk for poor TTR. SAMeTT2R2 score may not predict TTR in Chinese ischemic stroke patients with NVAF.

Low-Dose Alteplase versus Conventional Anticoagulation to treat Submassive Pulmonary Embolism in Hispanic Patients.

The use of low-dose tissue plasminogen activator (tPA) in Hispanic patients with submassive pulmonary embolism (PE) is understudied. The purpose of this study is to explore the use of low-dose tPA in Hispanic patients with submissive PE compared with counterparts that received heparin alone. We retrospectively analyzed a single-center registry of patients with acute PE between 2016 and 2022. Out of 72 patients admitted for acute PE and cor pulmonale, we identified six patients that were treated with conventional anticoagulation (heparin alone) and six patients who received low-dose tPA (and heparin afterward). We analyzed if low-dose tPA was associated with differences in length of stay (LOS) and bleeding complications. Both groups were similar in regard to age, gender, and PE severity (based on Pulmonary Embolism Severity Index scores). Mean total LOS for the low-dose tPA group was 5.3 days, compared with 7.3 days in the heparin group ( p = 0.29). Mean intensive care unit (ICU) LOS for the low-dose tPA group was 1.3 days compared with 3 days in the heparin group ( p = 0.035). There were no clinically relevant bleeding complications documented in either the heparin or the low-dose tPA group. Low-dose tPA for submassive PE in Hispanic patients was associated with a shorter ICU LOS without a significant increase in bleeding risk. Low-dose tPA appears to be a reasonable treatment option in Hispanic patients with submassive PE who are not at high bleeding risk (<5%).

Coronary stent and prolonged dual antiplatelet therapy. A longitudinal study.

In current European guidelines for the management of myocardial infarction after coronary stent placement, there is no consensus on dual antiplatelet therapy (DAPT) ideal duration to prevent stent thrombosis-restenosis without significantly increasing the bleeding risk. To report the percentage of major bleeding and presence of major cardiovascular events associated with prolonged DAPT in patients recruited at the National Institute of Cardiology, treated with primary percutaneous coronary intervention and stent. A longitudinal, prospective, observational, non-experimental, descriptive study was carried out. Patients were recruited from November 2016 to December 2017. One hundred and thirty-five patients with a mean age of 57 ± 10 years who completed the three-year follow-up were selected. Obesity and hypertension stood out as the main risk factors. After using DAPT for three years, 3.7% of mortality, 1.48% of major bleeding, and 4.4% of thrombosis-restenosis were recorded. Prolonged use of DAPT would be justified by the high incidence of thrombosis-restenosis, without a significant increase in bleeding risk, as well as a decrease in major cardiovascular events.

Bleeding Risk With Combination Intrapleural Fibrinolytic and Enzyme Therapy in Pleural Infection: An International, Multicenter, Retrospective Cohort Study

Combination intrapleural fibrinolytic and enzyme therapy (IET) has been established as a therapeutic option in pleural infection. Despite demonstrated efficacy, studies specifically designed and adequately powered to address complications are sparse. The safety profile, the effects of concurrent therapeutic anticoagulation, and the nature and extent of nonbleeding complications remain poorly defined. What is the bleeding complication risk associated with IET use in pleural infection? This was a multicenter, retrospective observational study conducted in 24 centers across the United States and the United Kingdom. Protocolized data collection for 1,851 patients treated with at least one dose of combination IET for pleural infection between January 2012 and May 2019 was undertaken. The primary outcome was the overall incidence of pleural bleeding defined using pre hoc criteria. Overall, pleural bleeding occurred in 76 of 1,833 patients (4.1%; 95%CI, 3.0%-5.0%). Using a half-dose regimen (tissue plasminogen activator, 5mg) did not change this risk significantly (6/172 [3.5%]; P= .68). Therapeutic anticoagulation alongside IET was associated with increased bleeding rates (19/197 [9.6%]) compared with temporarily withholding anticoagulation before administration of IET (3/118 [2.6%]; P= .017). As well as systemic anticoagulation, increasing RAPID score, elevated serum urea, and platelets of< 100× 109/L were associated with a significant increase in bleeding risk. However, only RAPID score and use of systemic anticoagulation were independently predictive. Apart from pain, non-bleeding complications were rare. IET use in pleural infection confers a low overall bleeding risk. Increased rates of pleural bleeding are associated with concurrent use of anticoagulation but can be mitigated by withholding anticoagulation before IET. Concomitant administration of IET and therapeutic anticoagulation should be avoided. Parameters related to higher IET-related bleeding have been identified that may lead to altered risk thresholds for treatment.

The Incidence of Venous Thromboembolism and Practice of Deep Venous Thrombosis Prophylaxis Among Hospitalized Cirrhotic Patients.

BackgroundPatients with liver cirrhosis have altered hepatic synthetic functions which theoretically result in reduced levels of pro-and anti-coagulant factors as well as thrombocytopenia. Initially, cirrhotic patients were thought to be at an increased risk of bleeding and a reduced risk of thrombosis. Several studies have recently reported an increased occurrence of venous thromboembolism (VTE) in cirrhotic patients. In this study, we aimed to assess the current practice of deep venous thrombosis (DVT) prophylaxis, the incidence and predictors of VTE, and the associated bleeding sequelae in patients with liver cirrhosis.MethodsA retrospective cohort study was performed. We included all adult patients with a diagnosis of liver cirrhosis from January 2010 to June 2019 admitted to the hospital. Our cohort patients were divided into two groups, cirrhotic patients with pharmacological VTE prophylaxis and those with mechanical or no VTE prophylaxis.ResultsWe included 601 cirrhotic patients in our study. The incidence of VTE occurring within the first 6 months of their admission was 1.5%. Seven patients (1.49%) developed VTE with the majority being DVTs while not on pharmacologic prophylaxis, and two patients developed VTE despite being on pharmacologic prophylaxis; however, there was no statistical difference. Alcohol use was the most common underlying cause of liver cirrhosis (40.4%), followed by chronic hepatitis C (21.1%), and nonalcoholic steatohepatitis (11.3%). Out of the 601 patients included, 69 patients received neither pharmacologic nor mechanical VTE prophylactic agent (11.48%), while the remaining majority received either pharmacological or mechanical prophylaxis (88.52%).ConclusionsOur study did not show a statistically significant association between the use of pharmacological VTE prophylactic agents and a reduction in the risk of VTE in cirrhotic patients. The rates of usage of DVT prophylactic agents among our Northwell hospitals during the study period appeared to be no longer suboptimal when compared to prior studies. Low albumin appears to be a predictor factor to develop VTE. There was a statistically significant increase in bleeding risk and transfusion requirement in cirrhotic patients receiving no pharmacological VTE prophylactic agents. Further prospective trials are needed to shed more light on this subject and identify the group of cirrhotic patients who could safely benefit from pharmacologic VTE prophylaxis.

Anticoagulation after intracerebral hemorrhage in patients with atrial fibrillation: between Scylla and Charybdis.

Oral anticoagulants (OAC) are indicated in patients with atrial fibrillation (AF) and high risk of ischemic stroke. However, the introduction of anticoagulation in patients with AF and previous intracerebral hemorrhage (ICH) is controversial. We aimed to better understand the efficacy and safety of OAC in this context and to assess the factors that may influence this decision. In a single-center retrospective observational study, patients with AF and ICH who survived hospitalization at a level A Stroke Unit between 2009 and 2018 were included. Patients were followed for two years after discharge. Data were collected regarding the introduction or not of OAC and the occurrence of major thrombotic/hemorrhagic events and death. Ninety-five patients (75.2 ± 9.9years) were included and 40 patients (42.1%) started OAC. Patients were more likely to initiate anticoagulation if they had: mechanical prosthetic valves, previous AF (p = 0.005) and previous OAC therapy (p < 0001); and less if they had previous hemorrhagic stroke (p < 0.005). During follow-up, 10.5% had at least one major hemorrhagic event (60% anticoagulated), 20% had at least one major thrombotic event (all non-anticoagulated) and 20% died. The only factor associated with the risk of bleeding was ICH score (OR:2.49 per 1-point increase; 95%CI:1.14-5.46). Patients who initiated anticoagulation had lower mortality than non-anticoagulated (OR:0.296; 95%CI:0.090-0-975). Previous ICH and higher CHA2DS2-VASc were associated with higher mortality. In this retrospective series, anticoagulation reduced thrombotic events and overall mortality in patients admitted for ICH and AF, without a significant increase in bleeding risk.

57-Year-Old Woman With Weakness and Word-Finding Difficulties

57-Year-Old Woman With Weakness and Word-Finding Difficulties

Do we need prophylactic anticoagulation in ambulatory patients with lung cancer? A review.

Venous thromboembolism is a common complication of malignancy. Lung cancer is considered one of the most thrombogenic cancer types. Primary thromboprophylaxis is not currently recommended for all ambulatory patients with active cancer. In the present narrative review we aim to summarize recent data on the safety and efficacy of primary thromboprophylaxis as well as on venous thromboembolism risk assessment, focusing on ambulatory patients with lung cancer. A potential benefit from prophylactic anticoagulation with low molecular weight heparins in terms of venous thromboembolism risk reduction and increased overall survival in patients with lung cancer, without a significant increase in bleeding risk, has been reported in several studies. Recent studies also reveal promising results of direct oral anticoagulants regarding their efficacy as primary thromboprophylaxis in patients with cancer, including those with lung cancer. However, the use of different study methodologies and the heterogeneity of study populations among the trials limit the extraction of definite results. More randomized, controlled trials, restricted to a well-characterized population of patients with lung cancer, are greatly anticipated. The use of risk assessment tools for stratification of venous thromboembolic risk is warranted. The development of an accurate and practical risk assessment model for patients with lung cancer represents an unmet need.

Early Secondary Prevention in Transient Ischemic Attack (TIA) and Minor Stroke.

The purpose of this study was to review recent literature on the early secondary prevention in transient ischemic attack (TIA) and minor stroke. The result of Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events and the secondary analysis of Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) have shown that treatment with clopidogrel and aspirin for 21days reduced the risk of recurrent stroke with no significant increase in bleeding risk. Triple antiplatelet therapy with aspirin, clopidogrel, and dipyridamole resulted in a significant increase in major (including fatal) bleeding with no significant reduction in the recurrent stroke or TIA. The early treatment of patients with TIA or minor stroke with clopidogrel and aspirin for 21days was effective in reducing the risk of recurrent stroke with no significant increase in bleeding risk. Most stroke guidelines have been updated to reflect this recommendation.

Direct oral anticoagulants for extended treatment of venous thromboembolism: insights from the EINSTEIN CHOICE study.

The risk of recurrence of venous thromboembolism (VTE) persists after interruption of the initial anticoagulation therapy. New evidence shows that direct oral anticoagulants are effective for extended treatment of VTE and may reduce the risk of all-cause mortality. The optimal duration of anticoagulation after VTE is, however, controversial and complicated by the need for individualised assessment and balance between thrombosis and bleeding risks. Three direct oral anticoagulants (rivaroxaban, apixaban and dabigatran) have been studied for extended treatment of VTE. Dabigatran was shown to be safer than vitamin K antagonists and similarly effective for the prevention of recurrent VTE. Dabigatran, apixaban and rivaroxaban resulted in significant decreases in the rate of recurrent symptomatic VTE when compared to placebo, without a statistically significant difference in the risk of major bleeding. The latest guidelines of the American College of Chest Physicians suggest the use of low-dose aspirin to prevent VTE recurrence in patients who want to stop anticoagulation. In the randomised, double-blind, phase 3 EINSTEIN CHOICE trial, once-daily rivaroxaban at doses of 20 mg or 10 mg and 100 mg of aspirin were compared in VTE patients for whom there was clinical equipoise for extended anticoagulation. Either a treatment dose (20 mg) or a prophylactic dose (10 mg) of rivaroxaban significantly reduced the risk of VTE recurrence without a significant increase in bleeding risk compared with aspirin. The EINSTEIN CHOICE trial included patients with provoked or unprovoked VTE. Patients with VTE provoked by minor persistent or minor transient risk factors enrolled in this trial had not-negligible VTE recurrence rates. These new findings on extended therapy suggest the possibility of anticoagulation regimens at intensities tailored to the patients' risk profiles and VTE characteristics, with a shift of the risk-benefit balance in favour of extended treatment.

Benefit of Risk Score-Guided Prophylaxis in Pregnant Women at Risk of Thrombotic Events: A Controlled Before-and-After Implementation Study

Management of pregnant women at risk of venous thromboembolism (VTE) and placental vascular complications (PVCs) remains complex. Guidelines do not definitively specify optimal strategies. Our objective was to evaluate the impact of employing risk score-driven prophylaxis strategies on VTE and PVC rates in at-risk pregnant women. This study, conducted in 21 French maternity units, compared VTE and PVC rates before and after implementation of a risk scoring system to determine prophylactic strategies. A total of 2,085 pregnant women at risk of VTE or PVC were enrolled. Vascular events occurred in 190 (19.2%) patients before and 140 (13.0%) after implementation of risk score-driven prophylaxis (relative risk [RR] = 0.68 [0.55; 0.83]). The incidence of deep vein thrombosis during pregnancy was reduced (RR = 0.30 [0.14; 0.67]). PVC comprised mainly pre-eclampsia, occurring in 79 patients before and 42 patients after risk score implementation (RR = 0.52 [0.36; 0.75]). Post-partum haemorrhage occurred in 32 patients (3.2%) before and 48 patients (4.5%) after risk score implementation (RR = 1.38 [0.89; 2.13], p = 0.15). Use of a simple risk scoring system, developed by experts in VTE and PVC research to guide prophylaxis, reduced the risk of thrombotic events during pregnancy without any significant increase in bleeding risk.

Thrombotic and Embolic Complications Associated With Atrial Arrhythmia After Fontan Operation: Role of Prophylactic Therapy

BackgroundThere are limited data about the risk of thrombotic and embolic complication (TEC) in adults with atrial arrhythmia after Fontan operation. ObjectivesThis study sought to determine the risk of TEC in this population and the role of anticoagulation therapy in TEC prevention. MethodsThis was a retrospective review of adults with atrial arrhythmia after Fontan operation who were evaluated at the Mayo Clinic between 1994 to 2014. TEC was classified into 2 groups: systemic TEC, defined as intracardiac thrombus, ischemic stroke, or systemic arterial embolus; and nonsystemic TEC, defined as Fontan conduit/right atrial thrombus or pulmonary embolus. Patients were divided into 3 groups: anticoagulation, antiplatelet, and no therapy cohorts. ResultsWe followed 278 patients, mean age 31 ± 9 years, for 88 ± 14 months (1,464 patient-years). Patient groups included antiplatelet (n = 181), anticoagulation (n = 91), and no therapy (n = 6). There were 97 TEC in 81 patients (29%); 32 were systemic, yielding an event rate of 2.1 systemic TEC per 100 patient-years, and 65 were nonsystemic TEC, yielding an event rate of 4.4 nonsystemic TEC per 100 patient-years. Prevalence of TEC was 18% and 55% at 5 and 10 years, respectively. Atriopulmonary connection was a risk factor for TEC (hazard ratio: 2.31; 95% confidence interval: 1.61 to 4.64), and TEC were associated with higher risk of death and hospitalization (p < 0.0001). Anticoagulation was protective against TEC and resulted in a reduction of TEC risk by 2.5 TEC per 100 patient-years. Anticoagulation was also associated with lower risk of death and hospitalization (p = 0.02). Bleeding complications occurred in 21 (7%) patients and were similar in all groups. ConclusionsAnticoagulation was associated with lower TEC rate and lower risk of death and hospitalization, without a significant increase in bleeding risk. Perhaps anticoagulation should be the preferred preventive strategy.

Friend or Foe? Discussion about Dual Platelet Inhibition as a Salvage Procedure from Imminent Flap Failure

Sir:FigureAntiplatelet drugs and combination therapies are on the rise because or their proven benefits concerning an antithrombotic effect on coronary vessels. Surgeons fear the side effects, including hemorrhage. Nevertheless, both cardiologists and microsurgeons are involved in the patency of small-caliber vessels. In addition, the mechanism of acute coronary syndrome reminds us of the process in microanastomosed and pedicled flaps; similar to myocardium, microsurgical transposed tissue is subjected to ischemia, thrombosis, and endothelial injury. Therefore, the idea suggests transforming the foe into a friend and making use of antiplatelet drugs in microsurgery. This idea is promoted by data acquired through animal models. In animal models, a potential benefit of antiplatelet therapy has been proved in randomized, controlled, double-blind studies.1 Antiplatelet drugs have been shown to result in a significant increase in arterial and venous patency and a decrease in anastomotic thrombus formation. Therefore, this knowledge could be used in clinical practice. We present the case report of a 53-year-old patient whose right breast was reconstructed using a pedicled transverse rectus abdominis musculocutaneous flap. After an inconspicuous initial course, epitheliolysis manifested on the fifth postoperative day, with a rapidly increasing livid coloration of the whole flap between days 7 and 11, suggestive of a no-reflow phenomenon. Therefore, on day 11, a salvage attempt was made. The patient was submitted to double-platelet inhibition therapy consisting of acetylsalicylic acid and clopidogrel. One hundred milligrams of of acetylsalicylic acid was administered daily and clopidogrel was given with a loading dose of 225 mg on the first day of treatment, changing to a 75-mg daily dose on the following days. This treatment was maintained for 4 weeks. After this regimen, the vascular changes ceased and the flap recovered appreciably, leaving only a marginal necrosis in zone IV behind (Fig. 1). In addition, no signs of bleeding were recorded.Fig. 1: Imminent loss of a transverse rectus abdominis musculocutaneous flap affiliated with a no-reflow phenomenon. (Left) The obvious livid coloration in almost the whole flap on postoperative day 11, when dual platelet inhibition therapy started. (Right) The imminent flap loss stopped, and after 10 days of dual platelet inhibition, most of the flap appeared salvaged.Whereas the available data1 strongly suggest a potential benefit of antiplatelet drugs in the prevention of flap failure, the question arises of whether this benefit is paid for by an increased bleeding risk. With regard to continued clopidogrel monotherapy in coronary artery bypass grafting, a significant increase in perioperative blood loss, excessive postoperative hemorrhage, increase in transfusion rate and amount of administered blood products, high reoperation rate, and even mortality have been noted.2 Also, in dermatologic surgery, clopidogrel intake has been found to be significantly associated with hemorrhagic complications.3 Thus, operations performed under continued antiplatelet therapy may be associated with a considerable risk of bleeding. However, what about making use of the positive effect of platelet inhibition by administering the drugs postoperatively? Thus, the bleeding risk should be low and the positive effect must be maintained. We can make use of the experience of cardiac surgeons who routinely operate on patients under acetylsalicylic acid therapy, which is combined with clopidogrel therapy 24 to 48 hours postoperatively. Despite the obvious invasiveness of cardiac operations, studies have shown that this postoperative dual platelet inhibition does not cause any significant increase in bleeding risk when compared with acetylsalicylic acid monotherapy.4,5 Keeping in mind the obvious bleeding risks when administered preoperatively, we suggest examining its potential benefits in microsurgery rather than just considering antiplatelet therapy as a foe when administered postoperatively. Stefan Riml, M.D. Heinz Wallner, M.D. Peter Kompatscher, M.D. Department for Plastic, Aesthetic, and Reconstructive Surgery, Academic Hospital Feldkirch, Feldkirch, Austria ACKNOWLEDGMENT The authors thank A. Piontke for excellent photodocumentation. DISCLOSURE The authors have no financial interest to declare in relation to the content of this communication.

Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty

IntroductionThe RECORD programme compared oral rivaroxaban with enoxaparin for prevention of venous thromboembolism after elective total hip or knee replacement. This analysis compared the safety of concomitant use of specified medications with rivaroxaban and enoxaparin by evaluating postoperative bleeding rates from the pooled RECORD1–4 data. Materials and methodsThe co-medications were non-steroidal anti-inflammatory drugs and platelet function inhibitors, including acetylsalicylic acid (no dose restriction). The endpoints evaluated were the composite of major and non-major clinically relevant bleeding and any bleeding occurring after first oral study drug intake. The time relative to surgery was stratified into three time periods: day 1–3, day 4–7 and after day 7. Relative bleeding rate ratios for co-medication use versus non-use were derived using stratified Mantel–Haenszel methods and compared between rivaroxaban and enoxaparin groups. ResultsCo-medication use with rivaroxaban or enoxaparin resulted in non-significant increases in bleeding events. Respective rate ratios were not significantly different between rivaroxaban and enoxaparin for all bleeding endpoints with concomitant use of non-steroidal anti-inflammatory drugs (any bleeding, 1.22 vs 1.22; major and non-major clinically relevant bleeding, 1.28 vs 0.90) and with concomitant use of platelet function inhibitors/acetylsalicylic acid (any bleeding, 1.32 vs 1.40; major and non-major clinically relevant bleeding, 1.11 vs 1.13). ConclusionsThis explorative analysis indicates that there is no significant increase in bleeding risk for rivaroxaban compared with enoxaparin when co-administered with non-steroidal anti-inflammatory drugs or acetylsalicylic acid, although, because of low usage, the experience with platelet function inhibitors (except acetylsalicylic acid) was limited.

Safety and potential anticoagulant effects of nebulised heparin in burns patients with inhalational injury at Singapore General Hospital Burns Centre

Background Nebulised heparin, N-acetylcysteine (NAC) and salbutamol were shown to decrease reintubation rates, incidence of atelectasis and mortality in paediatric patients and reduce lung injury scores in adult burns patients with inhalational lung injury (ILI). Nebulised heparin, NAC and salbutamol treatment protocol was introduced in Singapore General Hospital (SGH) Burns Centre in 2006. However, safety data on the use of nebulised heparin and NAC for burns patients with ILI is not well established. In this study, we investigated the safety and potential anticoagulant effects of nebulised heparin in burns patients with ILI. Methods A retrospective study with historical control was conducted. The treatment group consisted of 52 mechanically ventilated adult patients, with a diagnosis of ILI as confirmed by bronchoscopy, admitted to burn intensive care unit (BICU) from the year 2006 to 2009. The group was treated with nebulised heparin, NAC and salbutamol. The control group consists of 11 mechanically ventilated BICU ILI patients treated from year 2001 to 2005 before protocol initiation. Blood coagulation indices (prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet count) were monitored and bleeding incidences were assessed. Findings Blood coagulation indices did not suggest an increase risk of bleeding with nebulised heparin. The APTT, PT and platelet count followed a similar trend for both groups over 7 days. No clinically significant increase in bleeding risk was found to be associated with nebulised heparin. Conclusion Nebulised heparin was not found to potentiate the risk of bleeding in burns patients with ILI.

Acute Ischemic Coronary Artery Disease and Ischemic Stroke: Similarities and Differences

Although acute myocardial infarction (MI) and acute ischemic stroke share similarities, physicians need to recognize important differences in pathophysiology and how these differences affect acute treatment and prevention to provide optimal patient care. Potential causes of acute ischemic stroke are substantially more heterogeneous than for acute MI, and available acute therapies are substantially more limited. In acute ischemic stroke patients, diagnostic evaluation is paramount in determining eligibility for treatment with the only approved therapy, which must be administered within 3 hours after stroke onset. For patients having acute MI, reperfusion therapy by percutaneous intervention or thrombolytic drug therapy is well established. Because atherosclerosis is a common pathway to acute MI and acute ischemic stroke, modifying associated known risk factors is required for primary and secondary prevention of both conditions. Pharmacologic therapies recommended for secondary prevention include beta-blockers and angiotensin-converting enzyme inhibitors for MI, oral anticoagulants for stroke, and statins and antiplatelet agents for both conditions. Aspirin is recommended for preventing recurrence of both MI and stroke; agents inhibiting the adenosine diphosphate pathway of platelet activation, such as ticlopidine and clopidogrel, are also beneficial. Recent studies suggest the benefits associated with adding aspirin to clopidogrel do not outweigh the significant increase in bleeding risk. The synergistic effects of aspirin plus extended-release dipyridamole make this combination twice as effective than aspirin alone in secondary prevention of ischemic stroke. An ongoing study is directly comparing the combination of aspirin plus extended-release dipyridamole with clopidogrel for the prevention of recurrent stroke.

Abstract 3474: Bleeding Complications Associated with Dual Antiplatelet Therapy plus Anticoagulant in Patients Who Underwent Percutaneous Coronary Intervention with Drug-eluting Stents

Backgrounds: Combinations of dual antiplatelet therapy (aspirin with thienopyridine derivatives) plus warfarin sodium are often used in various cardiac conditions. The purpose of this study was to evaluate bleeding complications associated with combinations of dual antiplatelet plus anticoagulant therapy in patients who underwent percutaneous coronary intervention (PCI) with drug eluting stents (DES). Methods and Results : We reviewed 563 PCI cases with DES between August 2004 and March 2007 in our hospital either in the setting of elective situation or acute coronary syndrome. On discharge, 515 patients (91.5%) were prescribed dual antiplatelet therapy alone, while 48 patients (8.5%) were discharged receiving dual antiplatelet plus anticoagulant therapy. Major and minor bleeding complications were observed in 90 patients (17.8%). Rates of bleeding complications were significantly higher among patients receiving triple therapy compared to those with dual antiplatelet alone (37.5% vs. 13.9%, P&lt;0.05). Moreover, incidence of major bleeding was remarkably higher in patients receiving the triple therapy compared to those with dual antiplatelet alone (16.7% vs. 1.9%, P&lt;0.01). Multivariate analysis revealed that chronic kidney disease (CKD) is a strongest predictor of both major and minor bleeding. Conclusions : Triple therapy, dual antiplatelet plus anticoagulant combination, was associated with significant increase in bleeding risk for patients who underwent PCI with DES. Our results also suggest that caution should be paid especially in those patients with CKD, that is a strongest predictor of major bleeding when the triple antithrombotic regimen was prescribed.

P.2.056 Antipsychotic polypharmacy in Germanyand Europe — results from a schizophrenia outpatient treatment observation study (SOHO)

The RECORD programme compared oral rivaroxaban with enoxaparin for prevention of venous thromboembolism after elective total hip or knee replacement. This analysis compared the safety of concomitant use of specified medications with rivaroxaban and enoxaparin by evaluating postoperative bleeding rates from the pooled RECORD1–4 data.The co-medications were non-steroidal anti-inflammatory drugs and platelet function inhibitors, including acetylsalicylic acid (no dose restriction). The endpoints evaluated were the composite of major and non-major clinically relevant bleeding and any bleeding occurring after first oral study drug intake. The time relative to surgery was stratified into three time periods: day 1–3, day 4–7 and after day 7. Relative bleeding rate ratios for co-medication use versus non-use were derived using stratified Mantel–Haenszel methods and compared between rivaroxaban and enoxaparin groups.Co-medication use with rivaroxaban or enoxaparin resulted in non-significant increases in bleeding events. Respective rate ratios were not significantly different between rivaroxaban and enoxaparin for all bleeding endpoints with concomitant use of non-steroidal anti-inflammatory drugs (any bleeding, 1.22 vs 1.22; major and non-major clinically relevant bleeding, 1.28 vs 0.90) and with concomitant use of platelet function inhibitors/acetylsalicylic acid (any bleeding, 1.32 vs 1.40; major and non-major clinically relevant bleeding, 1.11 vs 1.13).This explorative analysis indicates that there is no significant increase in bleeding risk for rivaroxaban compared with enoxaparin when co-administered with non-steroidal anti-inflammatory drugs or acetylsalicylic acid, although, because of low usage, the experience with platelet function inhibitors (except acetylsalicylic acid) was limited.