Use Of Novel Anticoagulants Research Articles

Apixaban in bridge to transplant and destination LVAD - rationale and study design: the ApixiVAD trial.

Use of novel anticoagulation in mechanical circulatory support is controversial. We report the rationale and design of the ApixiVad pilot trial, a pilot study testing the safety of apixaban as an anticoagulant in patients bridged to transplant (BTT) or for destination (DT) with Heartmate 3 (HM3) left ventricular assist device (LVAD). Apixaban has been used in small non-randomized cohorts in LVAD patients and shown to be effective in ex vivo studies. The ApixiVAD study examines apixaban use in a multicentre, international, open-label, randomized, controlled trial aiming to include 50 BTT or DT HM3 patients with a 1:1 randomization ratio. This event-driven study has a maximum follow-up period of 24months with interim analysis at 6months. The primary outcome is death, thromboembolic events and major bleeding, including operative bleeding and immediate transplant outcomes. The secondary outcome focuses on patients' quality of life related to anticoagulation. This investigator-driven pilot study is not powered to determine the non-inferiority of apixaban. An increase in primary outcome in the apixaban group of 20% will be considered a signal of harm. A positive outcome in the ApixiVAD study would provide the basis for future, larger, pivotal anticoagulation trials in LVAD patients.

Spontaneous haemorrhagic cholecystitis secondary to the use of novel anticoagulants (rivaroxaban)

Haemorrhagic cholecystitis is a rare complication of acute cholecystitis. It carriesa high risk of morbidity and mortality. Risk factors for haemorrhagic cholecystitis include cholelithiasis, trauma, malignancy and the use of anticoagulants. There have only been a few reported cases of haemorrhagic cholecystitis secondary to the use of novel oral anticoagulants (NOACs). The demographic transition of an ageing population will potentially increase the utilisation of NOACs. Therefore the incidence ofhaemorrhagic cholecystitis secondary to NOACs will likely increase. Awareness and prompt diagnosis is paramount to avoid morbidity and mortality associated with haemorrhagiccholecystitis.

S1236 Outcomes for Patients on DOACs in Compensated and Decompensated Cirrhosis

Introduction: Cirrhotic patients are prone to thromboembolism as well as bleeding. Use of novel anticoagulants is well established in patients with compensated cirrhosis and CTP class A patients however data on the efficacy and safety profile of DOACs in decompensated cirrhotic patients is limited. Our AIM was to determine if the clinical outcomes differed in those with compensated cirrhosis receiving DOACS (apixaban, rivaroxaban, edoxaban, and dabigatran) compared to those with decompensated cirrhosis in terms of thromboembolic events, atrial fibrillation (a fib), bleeding events, and TPA administration Methods: Single center review from 2015-present in all subjects with cirrhosis with/without decompensation at time of DOAC administration. Patients were required to have 90 days of history prior to the DOAC and at least 1 year of follow-up. Decompensation was identified based on ICD codes (ascites, jaundice, gastric and esophageal varices, portal hypertension, hepatorenal syndrome,hepatic encephalopathy). We performed sensitivity analysis for MELD < 11, 11-14 and >14. The cohorts were compared for new onset a fib, bleeding (GI bleed, hemorrhagic stroke, retroperitoneal bleed and other bleeding events), new onset thrombotic events (pulmonary embolism, DVT, occlusive stroke) and new administration of TPA before and after matching for all observable confounders using high dimensionality propensity score matching. Results: 452 decompensated subjects were compared to 321 compensated subjects. The cohorts were similar in age and sex with decompensated cohort having fewer white patients (53.5% vs 64.8%) and higher baseline comorbidity score. While differences were noted in unmatched analyses, no significant differences in outcomes were noted after matching in the variables studied (Table). For each subgroup of MELD scores (MELD < 11, 11-14 and >14) the findings remained consistent Conclusion: In a single site observational analysis we identified no difference in thrombotic events, a fib, bleeding, or administration of TPA when comparing compensated and decompensated liver cirrhosis patients who were on a DOAC. We matched patients on all baseline observable confounders at the time they began DOAC administration. For sensitivity analysis we stratified presenting MELD into low, medium, high and for each subgroup the findings were consistent. Table 1. - Event Outcomes for Compensated and Decompensated Patients on DOACS in Unmatched and Propensity Score Matched Analysis Event Negative Positive (OR 95 CI) P Value Thrombosis Decompensated (unmatched) 308 144 1 (1.000, 1.000) NA Compensated (unmatched) 258 63 0.522 (0.372, 0.733) 0.0001 Decompensated (propensity score matched) 111 39 1 (1.000, 1.00) NA Compensated (propensity score matched) 112 38 0.966 (0.575, 1.62) 0.89 TPA administration Decompensated (unmatched) 447 5 1 (1.0000, 1.00) NA Compensated (unmatched) 319 2 0.561 (0.0531, 3.45) 0.71 Decompensated (propensity score matched) 148 2 1 (1.00000, 1.00) NA Compensated (propensity score matched) 149 1 0.498 (0.00837, 9.66) 1 Atrial Fibrillation Decompensated (unmatched) 254 198 1 (1.000, 1.00) NA Compensated (unmatched) 160 161 1.291 (0.969, 1.72) 0.08 Decompensated (propensity score matched) 65 85 1 (1.000, 1.00) NA Compensated (propensity score matched) 78 72 0.706 (0.448, 1.11) 0.133 Bleeding Events Decompensated (unmatched) 361 91 1(1.000, 1.000) NA Compensated (unmatched) 286 35 0.485 (0.319, 0.739) 0.0005 Decompensated (propensity score matched) 129 211 (1.000, 1.00) NA Compensated (propensity score matched) 130 20 0.945 (0.489, 1.83) 0.87

Novel Oral Anticoagulants Compared to Warfarin for Postoperative Atrial Fibrillation After Isolated Coronary Artery Bypass Grafting

Postoperative atrial fibrillation (POAF) is common after cardiac surgery and contributes to short- and long-term morbidity, particularly thromboembolism. Anticoagulation for sustained or recurrent POAF is suggested to reduce thromboembolism. Novel oral anticoagulants may present a safe alternative to warfarin with further benefits including shorter hospital length of stay and better patient convenience. A retrospective analysis was performed on all isolated cases of coronary artery surgery (CABG) at our institution between January 2015 and December 2018, totalling 960 patients. Rates of POAF were examined with particular focus on preoperative factors, postoperative outcomes, and anticoagulation practices. The incidence of POAF was 31.8% (305 patients) and was higher in older patients (67.6±9.4 yrs vs 63.0±10.7 yrs, p<0.001), those with a history of cerebrovascular disease (14.6% vs 8.7%, p=0.02), those with higher CHADS-VASc scores (2.5±1.3 vs 2.8±1.3, p<0.001) those who had a postoperative return to theatre (2.6% vs 0.8%, p=0.002), and those with new renal failure (4.9% vs 1.8%, p=0.02). Off-pump surgery was associated with lower incidence of POAF (29.8% vs 37.1%, p=0.03). Patients who developed POAF had significantly longer admissions than those without (12.6±10.6 days vs 9.3±16.3 days, p<0.001). In total, 106 patients (11.0%) went home anticoagulated; 77 (72.6%) on warfarin and 29 (27.4% on a NOAC). Readmission for bleeding was higher in patients on anticoagulation (1.0% vs 0.0%, p=0.02), but did not drive readmission for pericardial effusion (0.3% vs 0.6%, p=0.55). No bleeding complications occurred in patients who were discharged on a NOAC. Overall mortality at median of 2 years was 1.8% (17 patients) and no mortality occurred in any patient discharged on anticoagulation. Postoperative atrial fibrillation is a common adverse event and is linked to higher preoperative and postoperative morbidity. Anticoagulation may be safely started in these patients and use of novel anticoagulation does not appear to increase postoperative complications, although overall numbers are low.

Novel Oral Anticoagulants in Peripheral Artery Disease: Current Evidence.

Peripheral artery disease is a common manifestation of systemic atherosclerosis which strongly correlates to cardiovascular morbidity and mortality. In addition, the progression of peripheral artery disease leads to an increased risk of limb loss. In order to reduce these events, the benchmark of treatment and research over the last years has been the antiplatelet therapy which aims at inhibition of platelet aggregation. Over the last years, new studies combining antiplatelet agents in different therapeutic schemes have been proven efficacious. Unfortunately, patients remain still at high risk of CV events. Novel Oral Anticoagulants have been introduced as alternatives to warfarin, in the prevention and treatment of venous thromboembolism. The rationale of using medication which acts on platelet activation and the coagulation pathway of thrombosis has led investigators to examine the role of Noac's in preventing CV events in patients with peripheral artery disease, stable or unstable. The aim of this study is to review the current evidence with respect to recently published studies concerning the use of Novel anticoagulants in peripheral artery disease. The Compass trial has shown that a combination of rivaroxaban with traditional therapy may produce promising results in reducing amputation rates, stroke, cardiac events, and mortality, however, there are still safety issues with bleeding requiring acute care. The ePAD study has provided us with insight concerning safety and efficacy after peripheral angioplasty or stenting and actually the need for further research. The Voyager Pad study, following the steps of Compass, is studying the effect and safety of the addition of rivaroxaban to traditional therapy in the highest risk population aka patients undergoing peripheral revascularization. The evidence concerning patients with concomitant atrial fibrillation appears to be insufficient, however, recent guidelines propose the use of novel oral anticoagulants. For the time being, novel oral anticoagulants in combination with aspirin may provide an alternative treatment in PAD, however, it is deemed necessary to identify patient subgroups who will benefit the most.

Assessing Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications

In recent years, the use of novel anticoagulants and antiplatelet agents has become widespread. Little is known about the toxicity and bleeding risk of these agents after acute overdose. The primary objective of this study is to evaluate the relative risk of all bleeding and major bleeding in patients with acute overdose of novel antiplatelet and anticoagulant medications. This study is a retrospective study of acute ingestion of apixaban, clopidogrel, ticlopidine, dabigatran, edoxaban, prasugrel, rivaroxaban, and ticagrelor reported to 7 poison control centers in 4 states during a 10-year span. The prevalence of bleeding for each agent was calculated, and hemorrhage was classified as trivial, minor, or major. A total of 322 acute overdoses were identified, with the majority of cases involving clopidogrel (260; 80.7%). Hemorrhage occurred in 16 cases (4.9%), including 7 cases of clopidogrel, 6 cases of rivaroxaban, 2 cases of dabigatran, and 1 case of apixaban. Most cases of hemorrhage were classified as major (n=9). Comparing the novel anticoagulants with the P2Y12 receptor inhibitors, the relative risk for any bleeding with novel anticoagulant was 6.68 (95% confidence interval 2.63 to 17.1); the relative risk of major bleeding was 18.1 (95% confidence interval 3.85 to 85.0). Acute overdose of novel anticoagulants or antiplatelet agents is associated with a small risk of significant hemorrhage. The risk is greater with the factor Xa inhibitors and direct thrombin inhibitors than with the P2Y12 receptor antagonists.

Antiplatelet therapies in patients with an indication for anticoagulation

Triple anticoagulant therapy is necessary in patients who are at increased risk for both arterial (in stent) and venous thrombosis, or have atrial fibrillation. Triple therapy however also poses a very high risk for bleeding events, particularly because this subset of patients is particularly frail due to the high incidence of comorbidities and advanced age. Very little randomized studies have tested the impact of the many possible combinations of anticoagulant/antiaggregant drugs, and surveys among practicing physicians show that the use of off-label therapies is very common. In a recent survey from our group, we observed that physicians are very divided in terms of what therapy should be recommended to patients with indication to anticoagulation and with a history of stenting. The use of novel anticoagulants was as frequent as that of vitamin K antagonists, and the duration of triple therapy was very variable.While these data probably show that decisions are usually taken on an individual basis, considering the patient's risk of ischemia and hemorrhagic events, much of this variability probably depends on the fact that, failing randomized trials, guidelines in this area are relatively less specific than in other ones.

Anticoagulation Prophylaxis in Asparaginase-Based Therapy in Adults with Acute Lymphoblastic Leukemia

▪Background:Venous thromboembolism (VTE) is a well-known complication in adults receiving asparaginase (ASNase) based intensification chemotherapy for acute lymphoblastic leukemia (ALL). We previously reported a high VTE rate in patients receiving a modified Dana Farber Cancer Institute (DFCI) intensification phase, which included weekly ASNase. We report thrombosis rates during induction and the results using two different dosing schedules of enoxaparin as primary VTE prophylaxis in adults treated with the same protocol.Methods:We reviewed pts who received induction chemotherapy, without VTE prophylaxis, using DFCI protocol (containing one dose of ASNase) between 2012-2016. Pts achieving complete remission (CR) subsequently received weekly ASNase-based modified DFCI intensification phase for at least 7 cycles (21 weeks) with VTE prophylaxis, using two dosing schedules in consecutive cohorts: A. Low-dose group received enoxaparin 40 mg subcutaneously (SC) daily for patients weighing < 80 kg and 60 mg daily for those ≥ 80 kg; B. Dose-escalated group received enoxaparin 1 mg/kg SC daily (rounded to the nearest 20 mg).VTE rates were calculated for pts during induction and intensification phase (low-dose and escalated dose prophylaxis). Results were compared to a similar group of 99 pts previously treated with the same DFCI protocol who did not receive VTE prophylaxis during intensification. Patients not achieving CR, relapsing, undergoing alloSCT after induction, not completing at least 21 weeks of intensification phase or developing VTE before induction were not included.Results:The VTE rate during induction (n-=144) was 2.8%. Of 111 pts who received intensification prophylaxis, the overall VTE rate was 19.8% (p<0.001 compared to induction). Of 41 patients who received low-dose prophylaxis, the VTE rate was 26.8%, while the VTE rate in the dose-escalated prophylaxis group was 15.7%. This compared to a 27.3% rate in the historical non-prophylaxis group (Table 1). There was no significant difference among intensification groups (no prophylaxis, low-dose, and dose-escalated) with respect to median age, gender, weight and number of treatment cycles.The actual mean dose of enoxaparin in the low-dose prophylaxis group was 0.62 mg/kg, as compared to 0.90 mg/kg in the dose-escalated group. There were no major bleeding complications observed in the prophylaxis groups. The minor bleeding rate in the entire prophylaxis cohort was 4.5% (5/111), and was similar between the low-dose and escalated dose groups. Sites of VTE in the prophylaxis groups included lower extremity (11 cases), sagittal sinus (3), subclavian line related (5), pulmonary embolism (9), and cardiac thrombus (1); some patients had more than one site involved.Conclusions:Our data confirmed a high VTE rate during intensification, even with prophylaxis. Dose-escalation of enoxaparin to 1 mg/kg was safe with a trend toward reduction in VTE rates, particularly in patients weighing > 80 kg; however, a larger cohort would be needed to determine if this difference is significant. The use of novel anticoagulants in this setting could be considered. [Display omitted] DisclosuresSchuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Schimmer:Novartis: Honoraria.

Use of Novel Anticoagulation to Treat Pulmonary Thromboembolism in an Ulcerative Colitis Patient with Cytomegalovirus Superinfection

Crohn's disease and ulcerative colitis are the two major types of inflammatory bowel disease, and affect mainly the gastrointestinal tract but also have extraintestinal sequelae, such as arterial and venous thromboembolism. Thromboembolic complications, particularly pulmonary thromboembolism, can be life threatening and require prompt management with anticoagulants. Conventional vitamin K antagonists have been used for the treatment of thromboembolic complications, but the development of novel oral anticoagulants has shifted the paradigm. We report a case of a 42-year-old female with ulcerative colitis with complaints of fever, rectal bleeding, abdominal and chest discomfort of 1-week duration. Initial sigmoidoscopy revealed multiple longitudinal ulcerations with a friable mucosa and easy touch bleeding in all colonic fields. Random biopsies and tissue CMV PCR were performed. The results indicated acute and chronic colitis, together with negative CMV immunohistochemistry, but positive CMV PCR. CMV IgG was positive and CMV real-time PCR using whole blood yielded a viral load of 633 copies/mL (19900 IU/mL). Initial chest dynamic computed tomography (CT) and lower-extremity CT showed diffuse deep vein thrombosis from the left common iliac vein to the calf veins of the lower left leg and filling defects in the lobar and segmental branches of the right lung, suggesting pulmonary thromboembolism. She was treated with oral mesalamine, intravenous steroid and ganciclovir and low-molecular-weight heparin, followed by rivaroxaban, a novel oral anticoagulant. Her symptoms resolved after treatment, and no recurrence was noted during a 6-month post-treatment follow-up.Figure 1Figure 2Figure 3We believe that in the near future, NOACs should replace VKAs for treatment of thrombotic complications in IBD patients.

Myocardial Infarction Caused by Coronary Artery Thromboembolism in a Atrial Fibrillation Patient on Rivaroxaban

SESSION TITLE: Student/Resident Case Report Poster - Cardiovascular Disease II SESSION TYPE: Student/Resident Case Report Poster PRESENTED ON: Tuesday, October 25, 2016 at 01:30 PM - 02:30 PM INTRODUCTION: Myocardial infarction (MI) is usually caused by a sudden occlusion of blood supply to cardiac muscle in the setting of atherosclerosis. Atrial fibrillation can cause a demand-supply mismatch leading to cardiac injury in the setting of rapid ventricular rate, however an embolic event to the coronary arteries secondary to atrial fibrillation is extremely rare, more so in the presence of anticoagulation. We present a unique case of coronary thromboembolic infarction in a patient with atrial fibrillation who failed anticoagulation with rivaroxaban. CASE PRESENTATION: A 58 y/o Caucasian male with a PMH significant for HTN, non-valvular atrial fibrillation and recent embolic stroke on rivaroxaban, biologic aortic valve replacement presented with sudden onset of sub-sternal chest pain. On exam, he was diaphoretic, tachycardic with irregular pulse, and faint crackles were heard over both of his lung bases. His EKG on admission showed atrial fibrillation with RVR and 1mm ST depressions in leads V5-V6 . Troponin I on admission was elevated at 0.08. His initial management included sublingual nitroglycerin, iv metoprolol and rivaroxaban was continued. His troponin levels however trended up to 9.56 at 12hrs. Repeat EKG remained unchanged. Heparin drip was started and subsequent cardiac cath showed a complete occlusion in the distal left circumflex artery with angiographic appearance of an embolus followed by successful embolectomy; he did not have any significant atherosclerotic disease in his other vessels. Given these findings, a post cardiac-cath TEE was done which revealed a new left atrial appendage clot which wasn’t present on a prior TEE done after his ischemic stroke few months ago. He was started on Coumadin and eventually discharged home on dual antiplatelet agents aspirin and clopidogrel. DISCUSSION: Systemic embolism is the most common major complication of atrial fibrillation. It is usually manifested as ischemic stroke, with peripheral embolization accounting for less then 10% of all embolic events1. Our case demonstrates the extremely rare scenario of cardio-cardiac embolization leading to MI. It is further made unique by the demonstration of failure of anticoagulant effect of rivaroxaban. Diagnosis is made by cardiac catheterization and demonstration of embolic clot within the vasculature, with further evidence of the origin of the clot as illustrated by the TEE. Treatment involves embolectomy followed by therapeutic anticoagulation. Our patient was switched to Coumadin and did well with INR maintained between 2 - 3. CONCLUSIONS: Our case elicits the importance of working up non-atherosclerotic causes of MI. Further studies may also be needed to support the use of novel anticoagulants in non-valvular atrial fibrillation. Reference #1: Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685. DISCLOSURE: The following authors have nothing to disclose: Steve Antoine, Dhruv Lowe, Kegan Jessamy, Obiajulu Anozie, Vincent Frechette No Product/Research Disclosure Information

Asian venous thromboembolism guidelines: updated recommendations for the prevention of venous thromboembolism.

The Asian venous thromboembolism (VTE) prophylaxis guidelines were first published in 2012. Since its first edition, the Asian Venous Thrombosis Forum (AVTF) working group have updated the Asian VTE epidemiology and reviewed issues that were not addressed in the previous guidelines. The authors noted that the rising incidence of VTE across Asia may be attributable to aging population, dietary changes, and increasing incidence of obesity and diabetes. The new additions in the guideline include role of thrombophilia in VTE, bleeding risk in Asians, individual risk assessment, updates in the prevention of VTE in medically ill, bariatric surgery, cancer, orthopedic and trauma patients. The influence of primary thrombophilia in perioperative VTE is still unclear. The secondary risk factors, however, are similar between Asians and Caucasians. The group found no evidence of increased risk of bleeding while using pharmacological agents, including the use of novel anti-coagulants. At present, Caprini risk assessment model is widely used for individual risk assessment. Further validation of this model is needed in Asia. In medically ill patients, pharmacological agents are preferred if there is no bleeding risk. Intermittent pneumatic compression device (IPC) is recommended in patients with bleeding risk but we do not recommend using graduated compressive stockings. In bariatric patients, data on VTE is lacking in Asia. We recommend following current international guidelines. A high index of suspicion should be maintained during postbariatric surgery to detect and promptly treat portomesenteric venous thrombosis. Different cancer types have different thrombotic risks and the types of surgery influence to a large extent the overall VTE risk. Cancer patients should receive further risk assessment. In patients with higher thrombotic risk, either due to predisposing risk or concomitant surgery, low molecular weight heparin is indicated. Different countries appear to have different incidence of VTE following trauma and major orthopedic surgery. We recommend mechanical prophylaxis using IPC as the main method and additional pharmacological prophylaxis if the thrombotic risk is high. As for obstetric practice, we propose adherence to the UK Greentop guideline that is widely accepted and utilized across Asia. To improve VTE thromboprophylaxis implementation in the region, we propose that there should be better health education, establishment of hospital-based guidelines and multidisciplinary collaboration.

Suboptimal oral anticoagulant treatment among Chinese non-valvular atrial fibrillation patients: the Nanchang Atrial Fibrillation Project.

Suboptimal oral anticoagulant treatment among Chinese non-valvular atrial fibrillation patients: the Nanchang Atrial Fibrillation Project.

PATTERNS AND PREDICTORS OF USE OF ANTICOAGULANTS FOR ACUTE VENOUS THROMBOEMBOLISM

Few studies have identified patterns and predictors of use of novel oral anticoagulants compared to warfarin for acute venous thromboembolism (VTE) in clinical practice. To describe the use of anticoagulants (AC) and to identify patient’s characteristics associated with the choice of rivaroxaban over warfarin for the treatment of VTE. A retrospective cohort was built from outpatient visits and inpatients records of hospitalisation between February 18, 2013, and September 18, 2013 (ie. starting 2 months following the availability of rivaroxaban for the treatment of VTE at our institution). This cohort includes new AC’s users treated in a tertiary care center for VTE. General characteristics and the type of AC prescribed was described using means and proportions and predictors of use of novel AC were analysed using two-tailed Student’s t-test for continuous variables and chi-square test for categorical variables. In an 8-months period, 261 patients were included; 67 (26%) had a diagnosis of cancer, 52 (20%) had at least one previous episode of VTE and 17 (7%) had confirm inherited thrombophilia. The median age was 65 years and 52% of the patients were women. The median body mass index was 28 (data were available for 199 patients) and the median length of stay was 8 days for hospitalisation (118 patients). Overall, 146 (56%) received warfarin, 43 (16%) received rivaroxaban and 72 (28%) received a prescription for long-term low molecular weight heparin at discharge. When compared to patients on warfarin, those who received rivaroxaban at discharge were younger (53 versus 63 years, p=0,001), had a higher mean creatinine clearance (93 versus 79 mL/min, p=0,002), were more likely to have an ambulatory visit rather than a hospitalisation (31% versus 60%, p<0,001) and were more likely to have a deep venous thrombosis than a pulmonary embolism (36% versus 58%, p=0,011). In new users of oral anticoagulants for the management of VTE, more subjects were on warfarin. Patients on rivaroxaban were younger and had a higher renal creatinine clearance. Rivaroxaban was more frequently prescribed in subjects who were not hosiptalized.

Haemorrhagic stroke due to rivaroxaban and use of prothrombin complex concentrate as a reversal agent

Background Oral anticoagulation for stroke prevention in atrial fibrillation significantly reduces the risk of thromboembolism; however, intracranial haemorrhage is a serious complication. The novel oral anticoagulants such as rivaroxaban have been shown to be as efficacious as conventional therapy but with a lower risk of bleeding, specifically intracranial bleeding events. Clinical details A 68-year-old male presented to the emergency department with sudden onset confusion, severe frontal headache, photophobia and word finding difficulty. His blood pressure was 224/169 mmHg on admission and he had an irregularly irregular pulse rate of 99 bpm. A computed tomography of the head confirmed a posterior parietal intracranial haemorrhage, which was attributed to recent (3 weeks prior) commencement of rivaroxaban 15 mg daily for stroke prevention in the context of normal renal function. Outcome Intravenous (IV) hydralazine, oral amlodipine and topical glyceryl trinitrate were given to control blood pressure. Prothrombin complex concentrate was used to reverse the effects of rivaroxaban and prevent further bleeding. The patient made an excellent recovery and was discharged with short-term outpatient rehabilitation services. Aspirin was recommenced for stroke prevention 2 weeks after the initial presentation. Conclusion While the new generation of oral anticoagulants offers many benefits in comparison to warfarin (such as fewer drug interactions, more standardised dosing and the lack of need for International Normalised Ratio (INR) monitoring), there still remains a risk of potentially fatal bleeding. Careful patient selection and regular follow-up are required to reduce these risks. Patients should be counselled on the bleeding risks associated with the use of novel anticoagulants.

The primary goal of anticoagulation in atrial fibrillation to prevent stroke and not to offer the apparently cheapest treatment.

Patients with atrial fibrillation (AF) have a particular high risk of cardio-embolic stroke. Cardio-embolic strokes have a high mortality (20%) and >50% of patients remain permanently disabled. Oral anticoagulation with warfarin is highly effective in preventing strokes as long as warfarin is taken. Unfortunately many patients with atrial fibrillation refuse to take warfarin because they are afraid of major bleeding complications in particular intracranial bleeds. In addition long term compliance and adherence with warfarin is terrible due to the need of regular international normalized ratio (INR) monitoring and the many interactions with food and drugs in elderly patients with polypharmacy. Anticoagulation is most effective in old patients who have difficulties to get to a physicians' office or an anticoagulation clinic to get the INR monitored. Just imagine the 86 years old lady with unsteady gate and a walker needing to get to a doctor in winter with ice and freezing temperatures outside. Data from Canadian and German stroke units on admission of patients with AF and a new stroke display shocking facts.1,2 One third of patients with AF and without contraindications for anticoagulation are untreated at the time of stroke. Thirty percent are treated with aspirin which is not effective in secondary stroke prevention in AF.3 Another 30% are treated with warfarin but the INR was <2.0 at the time of stroke. Only 10% of patients were on warfarin and the INR was between 2.0 and 3.0. Reimbursement bodies, however, will consider only the last 10% of patients, namely patients with AF well controlled on warfarin. This does not reflect clinical reality. The most restrictions for the use of novel anticoagulants (NOACs) instead of warfarin prevent the patients in highest need of stroke prevention from a drug that is superior to warfarin and has fewer intracranial bleeds, namely the elderly. In this issue, Bang et al.4 summarized pieces of evidence that NOACs may be particularly helpful for Asian stroke patients. Indeed, Asians are at particular high risk of major bleeds on warfarin. This risk is much lower with novel anticoagulants. Therefore it is not rational to restrict the use of NOACs in Asian patients with AF. My policy would be to offer all patients who had a transient ischemic attack or ischemic stroke and AF a NOAC, because these patients have a particular high risk of a recurrent stroke. In primary prevention I would offer NOACs to untreated patients, patients on aspirin and patients poorly controlled on warfarin. I see no reason to switch well controlled patients on warfarin to NOACs. In summary putting high hurdles on the prescription of NOACs will lead to many strokes with severe disability and tremendous costs for a national health care system.

Abstract 11: Use of Novel Anticoagulants Among Atrial Fibrillation Patients Hospitalized with Ischemic Stroke or Transient Ischemic Attack: A Get With The Guidelines-Stroke Registry Analysis

Background: The FDA recently approved the direct thrombin inhibitor dabigatran (DTI) and factor Xa inhibitor rivaroxaban for atrial fibrillation (AF) stroke prophylaxis based on large randomized trials showing non-inferiority to warfarin for stroke prevention. However, real-world utilization patterns and predictors of use for these novel anticoagulants (NAC) remain poorly characterized. Methods: Using the AHA Get With The Guidelines Stroke Registry, we analyzed patients with AF who were hospitalized for ischemic stroke or transient ischemic attack (TIA) and discharged on warfarin or NAC. The first NAC approved by the FDA was dabigatran in 10/2010, so we chose a 2-year study period from 10/2010-9/2012. We excluded patients with contraindications for anticoagulation. Patient and hospital variables associated with discharge anticoagulant use were evaluated using Pearson chi-square and Wilcoxon tests. Results: Of 61,655 patients meeting inclusion criteria, 6,835 (11.1%) were discharged on NAC, of which 86.7% were prescribed DTI. Warfarin was prescribed in 54,820 (88.9%) patients. For patients discharged on NAC vs. warfarin, 51.8% vs. 53.3% (p=0.016) were female and median age was 77 [IQR 69-84] vs. 79 [IQR 70-85] (p&lt;0.001). The majority of patients discharged on NAC or warfarin were white (82.7% vs. 80.8% respectively, p=0.005). Slightly higher proportions of patients discharged on NAC vs. warfarin had private/HMO insurance (41.7% vs. 37.6%, p&lt;0.001) than Medicare (39.0% vs. 42.3%, p&lt;0.001). Patients discharged on NAC vs. warfarin had less severe ischemic stroke (NIH stroke scale=3 [IQR 1-8] vs. 5 [IQR 2-11], p&lt;0.001), shorter length of stay (3 [IQR 2-5] vs. 4 [IQR 2-6] days, p&lt;0.001), and higher proportions of patients who could ambulate at admission (32.5% vs. 26.1%, p&lt;0.001) and discharge (47.5% vs. 39.2%, p&lt;0.001). CHADS2 scores were lower among those discharged on NAC (Figure). More patients discharged on NAC were discharged to home (65.0%) than a healthcare facility, compared to 52.4% of patients prescribed warfarin being discharged to home (p&lt;0.001). Conclusion: Among patients with AF and acute ischemic stroke or TIA discharged on oral anticoagulants, NAC use remains low and is prescribed to younger, more functional, and lower risk patients.

Recurrent, Delayed Hemorrhage Associated with Edoxaban after Deep Brain Stimulation Lead Placement

Factor-Xa inhibitors like edoxaban have been shown to have comparable or superior rates of stroke and systemic embolization prevention to warfarin while exhibiting lower clinically significant bleeding rates. The authors report a case of a man who presented with delayed, recurrent intracranial hemorrhage months after successful deep brain stimulator placement for Parkinson disease while on edoxaban for atrial fibrillation. Further reports on the use of novel anticoagulants after intracranial surgery are acutely needed to help assess the true relative risk they pose.

161 Dabigatran Use Associated With Life Threatening Mechanical Valve Thrombosis: A Report Of 2 Cases

Dabigatran etexilate is an oral, reversible direct thrombin inhibitor that has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. It has been recently approved for treatment of non valvular atrial fibrillation and as thromboemolic prophylaxis after orthopedic surgery. It's use as an alternative for Warfarin for other indications has not tested. We report two cases who had been successfully anticoagulated with Warfarin and had never experienced thrombotic or bleeding events. In both cases, one month after being switched from Coumadin to Dabigatran the patients began to experience symptoms and were subsequently diagnosed with mechanical valve thrombosis. Both cases underwent a succefull emergency redo valve replacement. The Use of novel anti-coagulants for unapproved indications can lead to serious and potentially fatal adverse events and represents an important public health concern.

Reversing Anticoagulant Therapy

For more than 50 years, heparin(s) and warfarin have been the most important anticoagulant agents, and clinicians are accustomed to their specific antidotes (protamine sulfate and vitamin K/plasma [or factor concentrates], respectively). Recently, there has been an explosion of novel anticoagulant development: ideally, these newer agents should have advantages over traditional anticoagulants, such as fewer side effects, a more predictable pharmacokinetic profile (and potentially no need for monitoring), minimal drug-drug interactions, and so forth. But, unlike the older agents, the newer anticoagulants do not have specific antidotes. There is increasing focus on the use of nonspecific procoagulants, such as non-activated and activated prothrombin complex concentrates (PCCs) and recombinant factor VIIa (rFVIIa), to manage major bleeding or need for emergency invasive procedures. This paper reviews several of the novel anticoagulants and presents the available evidence for their "reversal". Based on extrapolation from animal models, clinical anecdote, and an understanding of their mechanism of action, we recommend treating major bleeding complications of DTIs, as follows (in descending order of preference): activated PCCs; rFVIIa; and (non-activated) PCCs. For management of fondaparinux-associated bleeding, rFVIIa has some rationale (for which we provide an illustrative case). The increasing use of novel anticoagulants will require physicians to have an understanding of rational approaches to "reverse" their anticoagulant effects when true antidotes do not exist.

Mechanisms of Bleeding and Approach to Patients With Axial-Flow Left Ventricular Assist Devices

Axial-flow LVADs have become an integral tool in the management of end-stage heart failure. Consequently, nonsurgical bleeding has emerged as a major source of morbidity and mortality in this fragile population. The mechanisms responsible for these adverse events include acquired von Willebrand disease, GI tract angiodysplasia formation, impaired platelet aggregation, and overuse of anticoagulation therapy. Because of ongoing concerns for pump thrombosis and thromboembolic events, the thrombotic/bleeding paradigm has led to a difficult clinical dilemma for those managing patients treated with axial flow LVADs. As the field progresses, advances in the understanding of the pathological mechanisms underlying bleeding/thrombosis risk, careful risk stratification, and potential use of novel anticoagulants will all play a role in the management of the LVAD patient.