Treament with oral anticoagulation is highly effective in reducing the burden of thromboembolic complications in several clinical conditions. The number of patients receiving oral anticoagulation is growing steadily. InSwedenabout 1.5 percent of the population receives treatment. Although the treatment is highly effective in preventing thromboembolic complications, it is also associated with a substantial increase in the risk of bleeding. In clinical practice every physician has to balance the potential benefit of treatment against the risk of bleeding complications in the individual patient. To aid in this decision making, risk scores addressing the likelihood of thromboembolic events, as well as the risk of bleeding complications, have been developed. These scores are imperfect and, to some degree limited by the fact that the risk factors predictive of thromboembolic events are also often associated with bleeding complications. The addition of biomarkers has the potential to increase the predictive ability of risk scores and further enhance the net benefit of oral anticoagulant treatment in the individual patient. In this thesis several potential biomarkers for thromoboembolic and haemorrhagic complications of anticoagulant therapy have been investigated in a longitudinal cohort study of 719 patients with a median follow-up time of 4.2 years. Thrombomodulin is a key component in the generation of activated protein C and hence, a coagulation inhibitor. Conversely, it is also a key component in the inhibition of fibrinolysis by activation of trombin-activated fibrinolysis inhibitor. In warfarin-treated patients we demonstrate that thrombomodulin predicts an increased risk of bleeding complications, but not cardiovascular events. Thus, thrombomodulin has potential as a biomarker specifically for bleeding complications. Von Willebrand factor plays a central and intricate role in the aggregation of platelets and low levels of VWF have been associated with bleeding as a manifestation of von Willebrand’s disease. In our study we noted that high levels of von Willebrand factor predict an increased risk of cardiovascular as well as all-cause mortality, possibly as an expression of endothelial dysfunction. We also noted that high levels of WVF seem to be associated with serious bleeding complications. Decreased renal function is usually measured by an increase in the levels of creatinine and cystatin C, or a decrease in the calculated glomerular filtration rate. A decrease in kidney function is regarded as a marker of an increased risk of bleeding complications. We investigated all the mentioned markers of kidney function and no association with bleeding complications became apparent. However, a clear association between a decrease in kidney function and mortality was noted. Our findings indicate that the emphasis on impaired kidney function as a risk marker needs to be shifted from bleeding complications toward thromboembolic events. Fibrinolysis is important in containing coagulation and several constituents of the fibrinolytic pathway have been shown to predict cardiovascular events and mortality. We found that fibrinolytic factors seem to predict cardiovascular events in patients with oral anticoagulation and that D-dimer also predicts bleeding complications. In conclusion, we have found several biomarkers which exhibit different predictive abilities in patients with oral anticoagulation. It is likely that biomarkers, either alone, in combination, or as ancillary components of risk scores, can contribute to improved risk stratification in patients with oral anticoagulation.

Class of 2015 Abstract / Objectives: Warfarin has historically been the anticoagulant used for the primary prevention of stroke in atrial fibrillation (AF), however three target specific oral anticoagulants, dabigatran, rivaroxaban, and apixaban, have recently been approved for use in this setting. Current literature lacks a comparison of these four drugs in relation to post-stroke outcomes, and this study aims to compare their performance in a natural setting. Methods: This retrospective cohort study identified stroke patients admitted to an academic medical center between January 2013 and December 2014 using the Quintiles, Inc.-American Heart Association Get With The Guidelines-Stroke database; pertinent data was collected from the database and patient electronic medical records. Primary endpoints measured were length of stay, 30-day readmission, and discharge disposition; secondary endpoints included rates of admission to the intensive care unit (ICU) and complications. Results: Of 940 stroke admissions, 53 ischemic stroke patients were identified as receiving an oral anticoagulant for stroke prevention in AF. The warfarin (n=40) and non-warfarin (dabigatran, rivaroxaban, and apixaban; n=13) groups were well matched regarding admission demographics, however patients taking warfarin were more likely to have an elevated INR at hospital admission (P=0.0053) and receive tPA (P=0.047). Patients in the warfarin group were also statistically significantly more likely to receive warfarin on discharge (P=0.004). No endpoints achieved statistical significance. Conclusions: No differences in post-stroke outcomes between warfarin and non-warfarin oral anticoagulants used for stroke prevention in AF were found.

Bakgrund Förmaksflimmer är en arytmi som uppkommer av att sinusknutan slutar styra hjärtrytmen och impulser initieras istället på flera olika ställen i förmaken. Detta orsakar en snabb och oregelbunden kontraktion med försämrad cirkulation som resultat. Förmaksflimmer är den vanligaste orsaken till stroke och en viktig del i behandlingen av förmaksflimmer är därför att förebygga stroke genom antikoagulerande läkemedel. Warfarin har länge varit förstahandsval, men nya läkemedel, så kallade icke vitamin K antagonist oral antikoagulantia (NOAK) har de senaste åren godkänts som förebyggande behandling vid indikationen förmaksflimmer. Syftet med arbetet var att undersöka effekt, blödningsrisk och kostnad av NOAK som förebyggande behandling av stroke och systemisk emboli hos patienter med förmaksflimmer.  Metod och material Arbetet utfördes som en litteraturstudie där fem kliniska studier från databasen PubMed analyserades. I fyra studier jämfördes de tre faktor Xa-hämmarna apixaban, edoxaban och rivaroxaban, samt trombinhämmaren dabigatran med warfarin. I en studie jämfördes apixaban med Aspirin®.  Resultat Alla NOAK visades reducera risken att drabbas av stroke och emboli minst likvärdigt med warfarin. Dabigatran 150 mg och edoxaban 60 mg visades även vara effektivare än warfarin (RR=0,66; P<0,001, respektive RK=0,79; P<0,001). Apixaban reducerade risken för stroke och systemisk emboli med mer än 50 % i jämförelse med Aspirin® (RK= 0,45; P<0,001). Uppkomst av större blödning var likvärdigt förekommande i jämförelse mellan NOAK och warfarin. Dabigatran 110 mg, edoxaban 30 mg, edoxaban 60 mg och apixaban 5 mg visade på lägre risk för större blödning. Apixaban och Aspirin® visades vara likvärdiga avseende uppkomst av större blödning. Slutsats Icke vitamin K antagonist oral antikoagulantia är effektiva som förebyggande behandling av stroke och emboli hos patienter med förmaksflimmer, med lägre blödningsrisk än warfarin, men till en högre kostnad. / Atrial fibrillation is an arrhythmia characterized by rapid and uncontrolled contraction of the atria. The irregular contractions leads to incomplete circulation, accumulation of blood in the atria and increases the risk of stroke and embolism. An important part in the treatment of atrial fibrillation is to prevent the risk of stroke by use of anticoagulants. The first line treatment is the vitamin K antagonist warfarin. The drug has many side effects such as risk of bleeding, difficulties to adjust the dose and interactions with both drugs and food. In recent years, new drugs, called non vitamin K antagonist oral anticoagulants (NOAC), have been approved as preventive treatment of stroke in patients with atrial fibrillation. These include three factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban, and one thrombin inhibitor: dabigatran. In this study, the efficacy, risk of bleeding and cost of NOAK was investigated for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The study was conducted as a literature study where five clinical trials from the database PubMed was analyzed. In four studies, the three factor Xa inhibitors apixaban, edoxaban and rivaroxaban, and the thrombin inhibitor dabigatran were compared with warfarin. In one study apixaban was compared with Aspirin®. In all studies the prevention of stroke and systemic embolism and risk of bleeding was investigated. All NOAC reduced the risk of stroke and embolism at least equal to warfarin. Dabigatran 150 mg and edoxaban 60 mg was also more effective than warfarin. Apixaban reduced the risk of stroke and systemic embolism with more than 50 % compared with aspirin. The occurrence of major bleeding was similar in comparison of Dabigatran 150 mg, respectively rivaroxaban 20 mg and warfarin. Dabigatran 110 mg, edoxaban 30 mg, edoxaban 60 mg and apixaban 5 mg showed a lower risk of major bleeding than warfarin. Apixaban and Aspirin® appeared to be equivalent regarding the occurrence of major bleeding. Non Vitamin K antagonist oral anticoagulants are effective in the prevention of stroke and embolism in patients with atrial fibrillation, with lower risk of bleeding than warfarin, but with a higher cost.

Class of 2016 Abstract / Objectives: To identify common and serious drug-drug interactions involving novel anticoagulant drugs in cancer patients. Subjects: 60 patients who were treated at the Banner University of Arizona Cancer Center between November 1, 2013 and April 1, 2015 with rivaroxaban, dabigatran, or apixaban. Methods: A retrospective chart review was performed for patients who received a NOAC (novel oral anticoagulant) to determine if a medication regimen contained a drug-drug interaction involving the NOAC. Results: When analyzing the DDIs involving rivaroxaban, dabigatran, and apixaban, Micromedex® detected a total of 123 interactions, compared to Lexicomp®, which detected 111 interactions. When using Lexicomp®, there were 59 (32%) instances of no detected interactions, 19 (10%) moderate interactions, 27 (15%) major interactions, and 65 (36%) contraindicated DDIs with rivaroxaban. When using Micromedex®, there were 47 (26%) instances where no interaction was detected, 4 (2%) moderate interactions, and 119 (65%) major interactions, and no interactions were classified as contraindicated with rivaroxaban. Lexicomp® detected 3 (50%) interactions as major, and found no DDIs in 3 (50%) instances for dabigatran, and detected 1 (7%) moderate, 2 (14%) major and 6 (43%) contraindicated interactions for apixaban. Micromedex® detected 3 (50%) interactions as major, and found no DDIs in 3 (50%) instances for dabigatran, and detected 12 (86%) of interactions as major and found no DDIs in 2 (14%) instances for apixaban. Conclusions: There was significant variation in DDI detection between current literature4,5 and the drug information databases, Lexicomp® and Micromedex®, however most interactions detected were major or contraindicated.

Atrial fibrillation (AF) is associated with high risk of systemic thromboembolism leading to significant morbidity and mortality. Warfarin, previously the mainstay for stroke prevention in AF, requires close monitoring because of multiple food and drug interactions. In recent years, food and drug administration has approved several direct oral anticoagulants (DOACs) for use in patients with nonvalvular AF. These agents have not been studied in patients with valvular AF who are at an even higher risk of systemic thromboembolism. DOACs do not require frequent blood testing or changes in dosage except when renal function deteriorates, however, the lack of established antidotes for many of these agents remains a challenge. Also, currently there is no head-to-head comparison between these agents to guide clinical choice. This article discusses the advantages and disadvantages of currently approved oral antithrombotics in nonvalvular AF, with a special emphasis on the DOACs and their individual characteristics.

Purpose:This review summarizes the available evidence concerning direct oral anticoagulant (DOAC) use to treat venous thromboembolism (VTE) in patients with cancer as well as pertinent safety data on the use of DOACs in patients with both cancer and atrial fibrillation. Summary:The introduction of DOACs into clinical practice changed the way thrombotic complications are managed and prevented in diverse patient populations, including VTE and atrial fibrillation. Low-molecular-weight heparins have been the standard of care for treating VTE in cancer patients due to superiority over vitamin K antagonists in preventing recurrent VTE. Therefore, widespread DOAC use for VTE in patients with active cancer has not been adopted. Conclusion:Recent randomized clinical trials (SELECT-D, Hokusai VTE Cancer) have provided evidence that DOACs may have a role in treating VTE in cancer patients.

Yes / Health Services Research and Pharmacy Practice Conference Abstracts: Partnerships in Healthcare: Advancing Sustainable Medicines Optimisation 17–18 April 2023 University of Bradford.

Patients with mechanical heart valves who present with intracranial haemorrhage are initially treated by reversing their coagulopathy. However, these patients will ultimately require that their oral anticoagulant be restarted. The time at which oral anticoagulants are restarted is critical since restarting too early may increase the risk of recurrent bleeding, while withholding anticoagulants increases the patient’s risk of thromboembolic events. The ideal time to restart patients on their oral anticoagulant medication is defined as the time at which all these risks are minimized. This thesis includes a systematic review and meta-analysis of the literature. The main outcomes were recurrent haematoma, valve thrombosis, stroke and peripheral emboli. Results were stratified by types of intracranial haemorrhage. We also conducted a survey to gain insight into current practices of neurosurgeons and thrombosis experts in Canada and USA when they are faced with deciding on anticoagulant restart times in patients with ICH. Results were stratified by type of intracranial bleed and participants’ characteristics and demographics. The systematic review identified that the ideal time for restarting anticoagulant therapy in patients following an ICH is unknown. Meta-analysis was limited by the heterogeneity of the studies. The survey results indicated that physicians had a wide range of practice and that their practice was dependent on the patient’s clinical features, but many physicians would restart oral anticoagulants between 4 and 14 days after the haemorrhage. For this reason we have proposed a multi centre cohort study to investigate the safety and efficacy of restarting patients on anticoagulation therapy between day 5 and 9 post haemorrhage. A full study protocol is presented in this thesis.

Patients with mechanical heart valves who present with intracranial haemorrhage are initially treated by reversing their coagulopathy. However, these patients will ultimately require that their oral anticoagulant be restarted. The time at which oral anticoagulants are restarted is critical since restarting too early may increase the risk of recurrent bleeding, while withholding anticoagulants increases the patient’s risk of thromboembolic events. The ideal time to restart patients on their oral anticoagulant medication is defined as the time at which all these risks are minimized. This thesis includes a systematic review and meta-analysis of the literature. The main outcomes were recurrent haematoma, valve thrombosis, stroke and peripheral emboli. Results were stratified by types of intracranial haemorrhage. We also conducted a survey to gain insight into current practices of neurosurgeons and thrombosis experts in Canada and USA when they are faced with deciding on anticoagulant restart times in patients with ICH. Results were stratified by type of intracranial bleed and participants’ characteristics and demographics. The systematic review identified that the ideal time for restarting anticoagulant therapy in patients following an ICH is unknown. Meta-analysis was limited by the heterogeneity of the studies. The survey results indicated that physicians had a wide range of practice and that their practice was dependent on the patient’s clinical features, but many physicians would restart oral anticoagulants between 4 and 14 days after the haemorrhage. For this reason we have proposed a multi centre cohort study to investigate the safety and efficacy of restarting patients on anticoagulation therapy between day 5 and 9 post haemorrhage. A full study protocol is presented in this thesis.

Patients with mechanical heart valves who present with intracranial haemorrhage are initially treated by reversing their coagulopathy. However, these patients will ultimately require that their oral anticoagulant be restarted. The time at which oral anticoagulants are restarted is critical since restarting too early may increase the risk of recurrent bleeding, while withholding anticoagulants increases the patient’s risk of thromboembolic events. The ideal time to restart patients on their oral anticoagulant medication is defined as the time at which all these risks are minimized. This thesis includes a systematic review and meta-analysis of the literature. The main outcomes were recurrent haematoma, valve thrombosis, stroke and peripheral emboli. Results were stratified by types of intracranial haemorrhage. We also conducted a survey to gain insight into current practices of neurosurgeons and thrombosis experts in Canada and USA when they are faced with deciding on anticoagulant restart times in patients with ICH. Results were stratified by type of intracranial bleed and participants’ characteristics and demographics. The systematic review identified that the ideal time for restarting anticoagulant therapy in patients following an ICH is unknown. Meta-analysis was limited by the heterogeneity of the studies. The survey results indicated that physicians had a wide range of practice and that their practice was dependent on the patient’s clinical features, but many physicians would restart oral anticoagulants between 4 and 14 days after the haemorrhage. For this reason we have proposed a multi centre cohort study to investigate the safety and efficacy of restarting patients on anticoagulation therapy between day 5 and 9 post haemorrhage. A full study protocol is presented in this thesis.