Kerstin Hogg

Overview of the New Oral Anticoagulants Opportunities and Challenges

The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges.The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges. # Significance {#article-title-32}

Overview of the New Oral Anticoagulants

The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges.The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges. # Significance {#article-title-32}

Should we be looking for and treating isolated calf vein thrombosis

Management of isolated calf deep vein thrombosis is an area of significant international debate and variable clinical practice. Both therapeutic anticoagulation and conservative management carry risk. As clinical care of suspected and confirmed venous thromboembolic disease increasingly becomes the remit of emergency medicine, complex decisions are left to practising clinicians at the front door. We aim to provide a contemporary overview of recent evidence on this topic and associated challenges facing clinicians. Given the lack of high-level evidence, we present this work as a narrative review, based on structured literature review and expert opinion. A decision to manage calf thrombosis is principally dependent on the risk of complications without treatment balanced against the risks of therapeutic anticoagulation. Estimates of the former risks taken from systematic review, meta-analysis, observational cohort and recent pilot trial evidence include proximal propagation 7%–10%, pulmonary embolism 2%–3% and death <1%. Fatal bleeding with therapeutic anticoagulation stands at <0.5%, and major bleeding at approximately 2%. Estimates of haemorrhagic risk are based on robust data from large prospective management studies of venous thromboembolic disease; the risks of untreated calf deep vein thrombosis are based on small cohorts and therefore less exact. Pending further trial evidence, these risks should be discussed with patients openly, in the context of personal preference and shared decision-making. Anticoagulation may maximally benefit those patients with extensive and/or symptomatic disease or those with higher risk for complication (unprovoked, cancer-associated or pregnancy).

Time trends in intracranial bleeding associated with direct oral anticoagulants: a 5-year cohort study

BACKGROUND Over the past 5 years, dabigatran, rivaroxaban and apixaban were approved for stroke prevention. Phase III studies have shown a lower risk of intracranial bleeding with these direct oral anticoagulants than with warfarin; however, there is a lack of real-life data to validate this. We analyzed time trends in atraumatic intracranial bleeding from 2009 to 2013 among patients prescribed oral anticoagulants and those not prescribed oral anticoagulants. METHODS We used ICD-10-CA (enhanced Canadian version of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems) codes to identify all patients with atraumatic intracranial bleeding who presented to our neurosurgical centre (serving a population of more than 1.2 million). Trained researchers extracted data on anticoagulant medications used in the week before diagnosis of the intracranial bleed. Provincial prescription data for oral anticoagulants were obtained from IMS Brogan CompuScript Market Dynamics. The primary outcome was the time trend in incident intracranial bleeds associated with oral anticoagulation during the period 2009-2013. The secondary outcomes were the time trend in intracranial bleeds not associated with oral anticoagulation and the provincial prescribing patterns for oral anticoagulants during the same period. RESULTS A total of 2050 patients presented with atraumatic intracranial bleeds during the study period. Of the 371 (18%) prescribed an anticoagulant in the week before presentation, 335 were prescribed an oral anticoagulant. There was an increasing time trend in intracranial bleeding associated with oral anticoagulants (p = 0.009; 6 additional events per year) and in intracranial bleeding not associated with oral anticoagulation (p = 0.06). During 2013, prescriptions for warfarin decreased to 70% of all oral anticoagulant prescriptions in the province, whereas those for dabigatran and rivaroxaban increased to 17% and 12%, respectively. INTERPRETATION We observed increasing time trends in intracranial bleeding, both associated with and not associated with oral anticoagulants, over the study period. Although aggregate provincial data showed increased prescribing of oral anticoagulants, other more likely explanations for our findings include an aging population or increasing frailty.

Towards evidence-based emergency medicine: Best BETs from the Manchester Royal Infirmary

Best evidence topic reports (BETs) summarise the evidence pertaining to particular clinical questions. They are not systematic reviews, but rather contain the best (highest level) evidence that can be practically obtained by busy practicing clinicians. The search strategies used to find the best evidence are reported in detail in …

BET 1: Which is the best clinical test for diagnosing a full thickness rotator cuff tear?

Report by: Stephanie Pugh and Michael Callaghan , Physiotherapists Checked by: Kerstin Hogg , Clinical Lecturer in Emergency Medicine Institution : Manchester Royal Infirmary, Manchester, UK A short-cut review was carried out to establish the best clinical test for diagnosing a full thickness rotator cuff tear. Five studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these studies are shown …

Obstacle course runs: review of acquired injuries and illnesses at a series of Canadian events (RACE).

Background The growing popularity of obstacle course runs (OCRs) has led to significant concerns regarding their safety. The influx of injuries and illnesses in rural areas where OCRs are often held can impose a large burden on emergency medical services (EMS) and local EDs. Literature concerning the safety of these events is minimal and mostly consists of media reports. We sought to characterise the injury and illness profile of OCRs and the level of medical care required. Methods This study analysed OCR events occurring in eight locations across Canada from May to August 2015 (total 45 285 participants). Data were extracted from event medical charts of patients presenting to the onsite medical team, including injury or illness type, onsite treatment and disposition. Results There were 557 race participants treated at eight OCR events (1.2% of all participants). There were 609 medical complaints in total. Three quarters of injuries were musculoskeletal in nature. Eighty-nine per cent returned to the event with no need for further medical care. The majority of treatments were completed with first aid and basic medical equipment. Eleven patients (2% of patients) required transfer to hospital by EMS for presentations including fracture, dislocation, head injury, chest pain, fall from height, and abdominal pain. Conclusions We found that 1.2% of race participants presented to onsite medical services. The majority of complaints were minor and musculoskeletal in nature. Only 2% of those treated were transferred to hospital through EMS. This is consistent with other types of mass gathering events.

BET 2: Acupuncture and fibromyalgia

A shortcut review was carried out to see if acupuncture is an effective pain treatment in fibromyalgia. One Cochrane review and five subsequent papers and conference abstracts were identified. There are no large studies addressing this question and acupuncture has been compared with many different treatment modalities. Acupuncture may be a valid treatment for pain in fibromyalgia, but more research is required to validate this.

TIME TRENDS IN INTRACRANIAL BLEEDING AND NEW ORAL ANTICOAGULANT PRESCRIPTION

Objectives & Background Dabigatran, rivaroxaban and apixaban were approved for stroke prevention in the past 4 years. Phase 3 studies reported a lower risk of intracranial bleeding compared to warfarin however there is little real-life data to validate this. We assessed time trends in oral anticoagulant (OAC) associated intracranial bleeding between 2009 and 2013. We compared bleeding rates to provincial OAC prescription trends. Methods ICD-10 codes were used to identify all atraumatic intracranial bleeds presenting to our neurosurgical centre (covering a population of 1.3 million). Trained researchers extracted data on anticoagulant medication in the week prior to diagnosis of intracranial bleed. Provincial prescription data for OACs were obtained from IMS Brogan CompuScript Market Dynamics. The primary outcome was the incident OAC-associated intracranial bleed time trend between 2009 and 2013. The secondary outcomes were the non-OAC associated intracranial bleed time trend, and the provincial OAC prescription trends. Results 2050 patients presented with atraumatic intracranial bleeds. 371 (18%) patients were prescribed an anticoagulant, of which 335 were OACs. There was an increasing trend over time in the rate of anticoagulant associated bleeding (p=0.009) and non-anticoagulant associated bleeding (p=0.063). Warfarin accounted for a disproportionately large number of all OAC-associated bleeds compared to prescription prevalence. Dabigatran, rivaroxaban and apixaban accounted for a smaller proportion of OAC bleeds when compared to prescription prevalence. Conclusion We found an increasing number of patients treated for intracranial bleeding over time. Warfarin accounted for a disproportionate number of intracranial bleeds and the new oral anticoagulants, fewer than expected.

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Which form of aspirin is the fastest to inhibit platelet aggregation in emergency department patients with non-ST segment elevation myocardial infarction?

A short cut review was carried out to establish whether, in patients with suspected acute coronary syndromes presenting to the emergency department, what form of aspirin has the most rapid onset of action. Papers comparing the speed of onset of chewable aspirin, or soluble aspirin or solid aspirin were included. This summarises all three parts of a combined best evidence topic report (BET). The clinical bottom line is that chewable aspirin may be faster than soluble aspirin at decreasing the amount of time to achieve platelet inhibition in a patient. Soluble aspirin is faster than whole solid aspirin, which is faster than enteric-coated aspirin.