Between Scylla and Charybdis: combining anticoagulants with platelet inhibitors and outcome

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Anticoagulation is an established approach to prevent intravascular clot formation. Unfortunately, whenever we inhibit platelets and/or the coagulation cascade, we not only reduce the risk of thrombosis formation, but also increase the risk of bleeding. Although compared with vitamin K antagonists, novel oral anticoagulants or NOACs are an important step forward,1,2 this is still no free lunch3 as we have had to learn from the most recent GALILEO trial.4 Quite possibly, the novel Factor XI antagonists5 will mean further progress in this matter, but right now we have to use NOACs, as discussed in the Viewpoint ‘Non-vitamin K antagonist oral anticoagulants beyond atrial fibrillation: what did we learn from COMPASS and COMMANDER-HF?’ Gregory Lip and colleagues from the University of Liverpool in the UK6 note that NOACs have been a game changer in our management of many thrombo-embolic conditions. Their relative efficacy, safety, and convenience, rapid onset and offset of action, fewer drug and food interactions, and relatively predictable pharmacokinetics compared with oral vitamin K antagonists or vitamin K antagonists has accelerated their use. Due to their advantages, their use has been investigated in other medical conditions beyond atrial fibrillation7 and venous thrombo-embolism. Most importantly, a combination with aspirin has shown promising results in patients with chronic coronary syndromes, although the risk of bleeding increases. In patients with heart failure, COMMANDER missed its primary endpoint of myocardial infarction, stroke, or death,8 but a subanalysis showed benefit for stroke.9 Thus, the indication for NOACs keeps expanding. Combined inhibition of the coagulation cascade and platelets is appealing as both fibrin and activated thrombocytes are required to form a solid clot leading to acute coronary or cerebrovascular occlusion. The expanding indication of a combination of NOACs with antiplatelet agents has been investigated in the FAST TRACK contribution ‘Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials’ by Marco Valgimigli and colleagues from the University of Bern in Switzerland. The authors performed a systematic review and meta-analysis, and analysed the safety and efficacy of double vs. triple antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome or those who underwent percutaneous coronary intervention or PCI.10 The primary safety endpoint of the International Society of Thrombosis and Hemostasis (ISTH) for major or clinically relevant non-major bleeding was lower with double compared with triple antithrombotic therapy across all bleeding definitions (Figure 1). This was counterbalanced by an increase of stent thrombosis with an odds ratio of 1.59 and a trend towards a higher risk of myocardial infarction with double antithrombotic therapy. There were no significant differences in all-cause and cardiovascular death, stroke, and major adverse cardiovascular events. The comparison of NOAC-based double antithrombotic therapy vs. vitamin K antagonist triple antithrombotic therapy yielded consistent results and a reduction of intracranial haemorrhage of 67%. Thus, double antithrombotic therapy, particularly if consisting of an NOAC instead of vitamin K antagonist and a P2Y12 inhibitor, is associated with a reduction of bleeding, including major and intracranial haemorrhages. This benefit is, however, counterbalanced by a higher risk of cardiac—mainly stent-related—but not cerebrovascular ischaemic occurrences. These clinically relevant findings are put into context in a thought-provoking Editorial by Renato Lopes from the Duke Medical Center in Durham, North Carolina (USA).11 The summary of safety and efficacy endpoints in double vs. triple antithrombotic therapy demonstrating that double antithrombotic therapy is associated with reduction of bleeding events but with a trade-off of cardiac ischaemic complications. Pooled random-effects risk ratios with 95% confidence intervals for safety and efficacy endpoints. CRNM, clinically relevant non-major; DAT, double antithrombotic therapy; ISTH, International Society on Thrombosis and Haemostasis; MACE, major adverse cardiovascular events; TAT, triple antithrombotic therapy; TIMI, thrombolysis in myocardial infarction (from Gargiulo G, Goette A, Tijssen J, Eckardt L, Lewalter T, Vranckx P, Valgimigli M. Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials. See pages 3757–3767). Adding a low-dose NOAC to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease, but increases the risk of major bleeding,12 but the lifetime risk–benefit ratio has not been assessed. In another FAST TRACK entitled ‘Estimating individual lifetime benefit and bleeding risk of adding rivaroxaban to aspirin for patients with stable cardiovascular disease: results from the COMPASS trial’, Frank L.J. Visseren and colleagues from the University Medical Center Utrecht in The Netherlands sought to estimate the individual lifetime treatment benefit and harm of adding rivaroxaban to aspirin in 35 529 patients with stable cardiovascular disease of the COMPASS trial and SMART cohort.13 Predicted individual gain in life expectancy free of stroke or myocardial infarction from added low-dose rivaroxaban had a median of 16 months, while predicted individualized lifetime lost in terms of major bleeding had a median of 2 months. Thus, there is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable cardiovascular disease. Using these lifetime models, benefits and bleeding risk can be weighed for each individual patient, which could facilitate treatment decisions in clinical practice. This novel analysis is further discussed in an Editorial by Gregory Lip from the University of Liverpool in the UK.14 Anaemia is a relatively common condition and may be iatrogenic in nature,15,16 or related to multimorbidity, iron deficiency, and heart failure,17 as well as sickle cell disease,18 among others. If moderate to severe, it may require transfusion, but recently this has been used with more caution.19 In a clinical research paper entitled ‘Oral anticoagulation among atrial fibrillation patients with anaemia: an observational cohort study’, Anders Nissen Bonde and colleagues from the Copenhagen University Hospital, Herlev-Gentofte in Denmark investigate the risk of stroke and thrombo-embolism and major bleeding associated with anaemia among 18 734 patients with atrial fibrillation of the Danish registry.20 Among those, 20% had mild anaemia and 14% had moderate to severe anaemia. Moderate to severe anaemia was associated with increased risk of major bleeding and 9.1% lower median time in the treatment range compared with no anaemia (Figure 2). Use of oral anticoagulation was associated with reduced risk of stroke and thrombo-embolism among patients without or with mild anaemia, but not in those with moderate to severe anaemia. Oral anticoagulation was associated with a 5.3% increased standardized absolute risk of major bleeding among atrial fibrillation patients with moderate/severe anaemia. Thus, anaemia is common in patients with atrial fibrillation and associated with major bleeding and poorer anticoagulation control. Oral anticoagulation was associated with more major bleeding, but no reduction in risk of stroke or thrombo-embolism in those with moderate to severe anaemia. These novel findings are put into clinical context in an Editorial by Daniel Duerschmied and Christoph Bode from the University of Freiburg in Germany.21 Risk of major bleeding according to haemoglobin level among atrial fibrillation patients with or without OAC, and risk of stroke/thromboembolism and major bleeding according to use of OAC among atrial fibrillation patients with moderate/severe anaemia. OAC, oral anticoagulation (from Bonde AN, Blanche P, Staerk L, Gerds TA, Gundlund A, Gislason G, Torp-Pedersen C, Lip GYH, Hlatky MA, Olesen JB. Oral anticoagulation among atrial fibrillation patients with anaemia: an observational cohort study. See pages 3782–3790). In a clinical review article entitled ‘Cabins, castles, and constant hearts: the current state of rhythm control therapy in patients with atrial fibrillation’, Paulus Kirchhof and colleagues from the University of Birmingham in the UK note that recent innovations have the potential to improve rhythm control therapy in patients with atrial fibrillation.22 Controlled trials provide new evidence on the effectiveness and safety of rhythm control therapy, particularly in patients with atrial fibrillation and heart failure,23,24 while outcomes in the remaining patients are less clear.25 However, rhythm control certainly improves symptoms and quality of life in patients with symptomatic atrial fibrillation and can be safely delivered in elderly patients with comorbidities. Atrial fibrillation ablation maintains sinus rhythm more effectively than antiarrhythmic drug therapy, but recurrent atrial fibrillation remains common,26,27 highlighting the need for better patient selection. Antiarrhythmic drugs remain effective after atrial fibrillation ablation, underpinning the synergistic mechanisms of action of atrial fibrillation ablation and antiarrhythmic drugs. Atrial fibrillation ablation is safe28 and appears to improve left ventricular function in a subset of patients with atrial fibrillation and heart failure. Data on the prognostic effect of rhythm control therapy are heterogeneous without a clear signal for either benefit or harm. Thus, rhythm control has acceptable safety and improves quality of life in patients with symptomatic atrial fibrillation, including in elderly populations with stroke risk factors. There is a clinical need to better stratify patients for rhythm control therapy. Further studies are needed to determine whether rhythm control therapy, and particularly atrial fibrillation ablation, improves left ventricular function and reduces atrial fibrillation-related complications. This issue also contains two Discussion Forum contributions. In a first one entitled ‘Levetiracetam and non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and epilepsy: a reasonable combination’ Tim von Oertzen and colleagues from the Johannes Kepler Universitat Linz in Linz, Austria comment on ‘The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation’ by Jan Steffel from the University Hospital Zurich, Switzerland, and colleagues.29 Steffel et al. respond to von Oertzen et al. in a separate comment.30 The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.