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Rivaroxaban for High-Risk Patients with Stable Coronary Artery Disease: NICE Recommendation by Montasir Ali and Nadir Elamin

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Rivaroxaban for High-Risk Patients with Stable Coronary Artery Disease: NICE Recommendation by Montasir Ali and Nadir Elamin Available online at www.bcs.com ‘Promoting excellence in cardiovascular care’ BCS Editorial Rivaroxaban for high-risk Take Home Messages patients with stable coronary • Patients with stable coronary artery disease artery disease: NICE remain a challenge to treat as they remain at recommendation increased risk of further cardiovascular events. • NICE have recently recommended the combined Montasir H Alia MBBS, MRCP, PGCert use of low dose Rivaroxaban and Aspirin to prevent Nadir Elaminb MBBS, MRCP atherothrombotic events in patients with stable coronary artery disease or in patients with aCore Medical Trainee, bSpecialist Registrar in Cardiology symptomatic peripheral artery disease at high risk of Northern General Hospital ischemic events. Sheffield, United Kingdom • Clinicians may take time to apply the new Editor Deputy Editor Gershan Davis Ahmed Adlan recommendation, particularly in primary care. 18th February 2020 Introduction Rivaroxaban as an additional treatment option to Aspirin alone for high-risk patients with stable Rivaroxaban is a direct oral anticoagulant (DOAC) cardiovascular disease (CVD) to prevent recurrent that works as a direct factor Xa inhibitor. thrombotic events.2 Traditionally, Rivaroxaban has been used to reduce the risk of stroke and systemic embolization in patients with nonvalvular atrial fibrillation (AF) and Secondary prevention in established in the treatment of deep vein thrombosis and cardiovascular disease pulmonary embolism. Cardiovascular diseases continue to cause a major In a large recent randomised controlled trial (RCT) health concern worldwide. An estimated 17.9 widely known as the COMPASS trial million deaths from CVDs occurred in 2016, (Cardiovascular Outcomes for People Using representing 31% of deaths globally that year.3 Data Anticoagulation Strategies), Eikelboom et al (2017) from the United Kingdom in 2017 showed that evaluated whether Rivaroxaban alone or in 168,421 people died of CVD, accounting for 27.7% combination with Aspirin was more effective than of all deaths that year.4 The REACH (Reduction of Aspirin alone for secondary cardiovascular Atherothrombosis for Continued Health) registry prevention in patients with stable atherosclerotic showed that 5-10% of patients with established vascular disease.1 Based on the COMPASS trial, the CVD continued to have new atherothrombotic National Institute for Health and Care Excellence events each year despite optimal medical therapy.5 (NICE) recently published a new Technology These results suggest that Aspirin alone is not Appraisal Guidance recommending the use of sufficient for secondary cardiovascular prevention.1 About the author Dr Montasir Ali graduated from medical school with first-class honours and three academic prizes. He is currently a Core Medical Trainee working in Yorkshire and the Humber Deanery and plans to pursue a career in Cardiology. 2 Rivaroxaban for high-risk patients with stable coronary artery disease: NICE recommendation by Montasir Ali and Nadir Elamin Coronary artery disease is an area in medicine that of increased risk of serious bleeding complications witnessed significant advancement in both diagnosis including intracranial haemorrhage (ICH).9 Table 1 and management during the past few decades.6 provides a summary of the prominent trials over the However, the progress in preventing the thrombotic last 25 years which looked at secondary prevention events is relatively slow despite the extensive of cardiovascular events. numbers of patients researched in this field.7 Since 1950, several trials have studied the use of A previous trial known as ATLAS ACS 2-TIMI 51 combined oral anticoagulants and antiplatelets (such (Anti-Xa Therapy to Lower cardiovascular events in as thienopyridines and glycoprotein IIb/IIIa Addition to Standard therapy in subjects with Acute inhibitors) with or without Aspirin in the context of Coronary Syndrome–Thrombolysis in Myocardial cardiovascular prevention.8 Evidence from RCTs Infarction-51) compared the combination of has shown that the combination of warfarin and Rivaroxaban and dual antiplatelet therapy (DAPT) aspirin is more effective than aspirin alone in versus placebo in the context of acute coronary preventing cardiovascular events but at the expense syndrome (ACS). Results from this study showed Table 1. Outlines from prominent trials looking at the prevention of secondary cardiovascular events Year published Abbreviated Name Type Conclusion 1988 ISIS-211 Meta-analysis Proved the value of Aspirin in treating acute MI Clopidogrel is more effective than Aspirin in reducing 1996 CAPRIE12 RCT CV death, stroke and MI with equal safety Clopidogrel adds a beneficial effect to Aspirin in 2001 CURE13 RCT patients with acute coronary syndrome than aspirin alone but with higher bleeding risk Clopidogrel plus Aspirin combination is not 2006 CHARISMA14 RCT significantly more effective than Aspirin alone Rivaroxaban reduced risk of CV death, MI and stroke 2012 ATLAS ACS 2–TIMI 5110 RCT but increased risk of bleeding (but not fatal bleed) Vorapaxar reduced risk of CV death and ischaemic 2012 TRA2P TIMI 5015 RCT events but increased risk of severe bleeding including intracranial haemorrhage Prolonged Ticagrelor therapy in addition to Aspirin 2015 PEGASUS-TIMI 5416 RCT reduced risk of CV death, MI and stroke but increased risk of bleeding ATLAS ACS 2–TIMI 51 Anti-Xa Therapy to Lower cardiovascular events in Addition to Standard therapy in subjects with Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 51, CAPRIE Trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events, CV cardiovascular, CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance, CURE Clopidogrel in Unstable Angina to Prevent Recurrent Events, ISIS2 Second International Study of Infarct Survival, MI myocardial Infarction, PEGASUS-TIMI 54 Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54, RCT randomised control trial, TIMI thrombolysis in myocardial infarction, TRA2P TIMI 50 Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events– Thrombolysis in Myocardial Infarction 50 About the author Dr Nadir Elamin is a Cardiovascular Research Fellow at the University of Sheffield and a senior Cardiology Registrar at Sheffield Teaching Hospital. His sub-specialty is Interventional Cardiology and his research interests include being a sub-investigator in clinical trials investigating the management and prevention of coronary artery disease. Rivaroxaban for high-risk patients with stable coronary artery disease: NICE recommendation by Montasir Ali and Nadir Elamin 3 that combining a low dose Rivaroxaban (2.5mg group.1 The study was terminated prematurely after twice daily (bd)) to DAPT significantly reduced the a mean of 23 months by the Independent Data and risk of CV death, MI and stroke in patients with a Safety Monitoring Board in their first interim recent ACS compared to DAPT alone but increased analysis as per the pre-defined termination criteria rates of major bleeding without a significant for the superiority of Rivaroxaban 2.5 mg bd + increase in fatal bleeding or ICH.10 Aspirin group.1 COMPASS Trial Critique As a follow on from the ATLAS trial, the While randomisation in COMPASS was done investigators designed a large, double-blind, particularly well, females were under-represented placebo-controlled RCT known as COMPASS to (22%). This raises the question of extrapolating the investigate the use of Rivaroxaban with or without COMPASS results to female patients.17 Although Aspirin in stable atherosclerotic vascular disease. 1 It primary endpoint results were statistically was conducted in 33 countries at over 600 centres, significant for Rivaroxaban-Aspirin arm, the with a total number of 27, 395 participants. absolute risk reduction and relative risk reduction were modest at 1.3% and 24% respectively The participants were randomly assigned to three translating to a number needed to treat of 76.1,18 The groups; the first group received Rivaroxaban 2.5mg early termination of COMPASS automatically bd + Aspirin 100mg once daily (od); the second raises concerns regarding the overestimation of group received Rivaroxaban 5mg bd + Aspirin efficacy and underestimation of safety 100mg od, and the third group (controls) received endpoints.19,20 Aspirin 100mg od + placebo.1 The net clinical benefit was in favour of The primary efficacy outcome of COMPASS was Rivaroxaban 2.5 mg bd + Aspirin, which according the composite of cardiovascular (CV) death, stroke, to the COMPASS trialists was compatible with the or myocardial infarction (MI). The primary safety findings from the ATLAS ACS TIMI 51 trial.1 outcome was major bleeding defined as per the However, the individual component analysis shows International Society of Thrombosis and that the benefit of Rivaroxaban-Aspirin combination Haemostasis (ISTH) criteria. However, unlike was driven by prevention of stroke (HR 0.58, 0.44- ISTH, the study considered any bleeding resulting 0.76; p<0.0001) rather than the prevention of MI in a hospital admission as major bleeding regardless (HR 0.86, 0.70-1.05; p=0.14). The mechanism for of the need for overnight stay.1 The net clinical this is not fully understood or explained by the trial benefit was the composite of efficacy and safety investigators. In a subsequent analysis of outcomes.1 COMPASS outcomes
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