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December Issue 2 - Selecting the right patients for oral anticoagulation treatment in the secondary prevention of acute coronary syndrome

Professor Dan Atar, MD, FESC

Dan Atar, MD, holds a full Professorship in Cardiology at the University of Oslo, Norway, and is Head of Research at Oslo University Hospital Ullevål, Department of Medicine, Oslo, Norway. He also holds a Visiting Associate Professorship at the Johns Hopkins University, Baltimore, Maryland, USA. Professor Atar trained in Denmark, Switzerland and the United States before receiving his board certification in Internal Medicine and Cardiology in 1995. He has written more than 200 articles and book chapters, and holds the fellowship titles FESC, FACC, and inaugural FAHA. Professor Atar is currently chairing an EU-FP7 research consortium (‘Mitocare’) to investigate cardioprotection in ST-elevation myocardial infarction (STEMI) patients. He has also served on a number of European Society of Cardiology (ESC) guideline writing committees, including the 2010 ESC Guideline on Atrial Fibrillation and the 2012 ESC STEMI Guideline. In 2012, Professor Atar was elected as Councillor and Board Member of the ESC. Furthermore, in 2014, he was elected Vice President of the ESC for the 2014–2016 Board.

Welcome to the 2nd December 2014 edition of the Thrombosis Adviser newsletter.

Dear Thrombosis Adviser user,

Acute coronary syndrome (ACS) – myocardial infarction (MI) with or without ST-elevation (STEMI and NSTEMI, respectively) and unstable angina – is linked to over 2.5 million hospital admissions globally every year. After an initial ACS, today’s standard therapy involves, in most cases, dual antiplatelet therapy (acetylsalicylic acid with a P2Y12 inhibitor such as ticagrelor, clopidogrel, ticlopidine or prasugrel). However, even with newer antiplatelet drugs such as prasugrel and ticagrelor, a recurrent major cardiovascular event will occur in around 10% of patients in the year after initial acute ACS. Because the thrombi that cause ACS are formed by a dual pathway process of platelet activation and thrombin generation, various studies have investigated whether the combination of antiplatelet and anticoagulant therapy could improve outcomes. Indeed, in most of these studies, the addition of anticoagulation to antiplatelet therapy resulted in a benefit in terms of preventing recurrent events, although this was offset by a significant increase in serious bleeding compared with antiplatelets alone. In the ATLAS ACS 2 TIMI 51 study, the addition of a 2.5 mg twice-daily dosing regimen of the direct Factor Xa inhibitor rivaroxaban to standard antiplatelet therapy produced a more favourable outcome. The addition of rivaroxaban significantly reduced the incidence of the composite of death from cardiovascular causes, MI or stroke by 16% compared with standard therapy alone. Although there was a significant increase in the incidence of major bleeding events not related to coronary artery bypass grafting and intracranial haemorrhage, no significant increase in the incidence of fatal bleeding was recorded. Additionally, rivaroxaban was associated with a reduction in stent thrombosis. The benefit–risk profile was most favourable in patients with elevated cardiac biomarkers (indicating STEMI or NSTEMI) and in those patients without history of stroke or transient ischaemic attack (TIA). On this basis, rivaroxaban was approved in Europe for use in these patients at a dose of 2.5 mg twice daily in addition to single or dual antiplatelet therapy with acetylsalicylic acid plus or minus clopidogrel or ticlopidine.

The question now facing a European physician who is presented with a patient with recent ACS is whether to add rivaroxaban to standard antiplatelet therapy. Each patient’s benefit–risk profile must be considered individually, but there is some general guidance that can be applied.

  • According the European Medicines Agency (EMA) label, rivaroxaban is only indicated for adult patients after ACS if they have elevated cardiac biomarkers (troponin T or I, or creatinine kinase-MB), indicating myocardial injury
  • Patients in the ATLAS study who had prior TIA or stroke did not benefit from the addition of rivaroxaban to background antiplatelet therapy; therefore, these patients should not receive rivaroxaban
  • If the physician elects to use rivaroxaban in addition to antiplatelet therapy, it should be started as soon as possible once the patient is stabilized after the ACS event, at the time parenteral anticoagulation would normally be stopped, but not earlier than 24 hours after hospital admission
  • Based on the ATLAS study, patients are initially recommended to receive rivaroxaban for 12 months, with the potential to extend treatment to 24 months after physician evaluation of the total ischaemic risk, as well as bleeding risks
  • Subanalyses of the ATLAS data have shown that patients with a stent had a significantly lower incidence of stent thrombosis, and favourable outcomes were seen in patients with stabilized STEMI compared with the overall study population. These results further help to determine the profiles of patients for whom rivaroxaban may be considered
  • General contraindications for rivaroxaban treatment include: a current or recent condition associated with a significant risk of bleeding; concomitant therapy with another anticoagulant, with strong cytochrome P450 3A4 inhibitors such as ritonavir (HIV protease inhibitor) or ketoconazole (azole-antimycotic); creatinine clearance <15 ml/min (caution is advised in patients with creatinine clearance 15–29 ml/min); hepatic disease associated with coagulopathy and clinically relevant bleeding risk (including cirrhotic patients with Child–Pugh B and C); age <18 years; and pregnancy or breast feeding
  • There are no data on the use of rivaroxaban in combination with newer P2Y12 inhibitors, such as prasugrel or ticagrelor. Hence, rivaroxaban should only be used in patients receiving acetylsalicylic acid with or without clopidogrel or ticlopidinePatients with atrial fibrillation receiving rivaroxaban 20 mg once daily (or 15 mg once daily if they have moderate renal impairment) who suffer an ACS or undergo elective percutaneous coronary intervention (PCI) should cease to take rivaroxaban, because its use has not been studied in these settings. A new study, PIONEER AF-PCI, will address the use of rivaroxaban in patients with atrial fibrillation undergoing PCI with stent placementIf a patient receiving rivaroxaban has a recurrent ACS, rivaroxaban should be discontinued and standard therapy for acute ACS should be instigated

If a patient with recent ACS meets the criteria of having elevated biomarkers and no prior stroke/TIA, and does not have other contraindications, the decision to add rivaroxaban to antiplatelet therapy must be based on the individual’s likely risk of recurrent ACS, balanced with their risk of bleeding. Physicians will be faced with many different types of patients with ACS, with a vast array of co-morbidities that may, in turn, affect patients’ risk of further ischaemic events and bleeding.

To help with assessment of the benefit–risk balance of therapy, the European Society of Cardiology guidelines for the management of patients with STEMI and NSTEMI recommend the use of established clinical scores such as the GRACE score to estimate the risk of mortality after an ACS event, and the CRUSADE score to estimate the risk of a major bleeding event in hospital. These, and other risk scores, are intended as a guide only, and the treating physician must ultimately decide on therapy based on the overall clinical and risk profile of each individual patient.

Yours sincerely,

Dan Atar
Oslo, Norway

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