Treating patients with anticoagulants and antiplatelet drugs is always a balance between risk for thrombosis vs. risk for bleeding

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia and is associated with an increased risk of cardioembolic stroke. Oral anticoagulation reduces the risk of thromboembolism in patients with AF by about two-thirds compared with placebo but this comes at some cost of an increased risk of bleeding.1,–4 In this issue of the journal, Dr. Benz and co-workers from Canada aimed to systematically assess the effects of antiplatelets on clinical outcomes in patients with atrial fibrillation (AF), treated and not treated with oral anticoagulation. A total of 18 trials including 21 518 participants met the pre-specified eligibility criteria. The authors concluded that in patients with AF not receiving oral anticoagulation, antiplatelet therapy modestly reduced stroke. There was a corresponding signal for harm when used on top of anticoagulation. Irrespective of background anticoagulation use, antiplatelet therapy significantly increased bleeding, moderately reduced myocardial infarction, and did not affect mortality. Patients with acute ST-segment elevation myocardial infarction (STEMI) have an elevated risk of stroke, most of which are cardio-embolic in origin because of left ventricular (LV) thrombus formation. Current guidelines recommend the use of vitamin K antagonist (VKA) for up to 3–6 months for treatment of left ventricular (LV) thrombus post-acute myocardial infarction (AMI). However, treatment with direct oral anticoagulants (DOACs) may be another treatment option.5,6 Dr. Alcalai et al. from Israel aimed to assess the efficacy of apixaban vs. warfarin in treating LV thrombus after MI. Thirty-five patients were enrolled and the primary outcome was the presence and size of LV thrombus 3 months after initiation of anticoagulation. Thrombus completely resolved in 14 of 15 patients in the warfarin group and in 16 of 17 in the apixaban group. Two patients had major bleeding in the warfarin group while no major bleeding events were recorded in the apixaban group. The authors concluded that their small study suggested that apixaban is non-inferior to warfarin for treatment of patients with LV thrombus after acute MI. Mechanical prosthetic valve thrombosis (MPVT) is a serious and often fatal complication after heart valve replacement surgery.7 Thrombolysis is an alternative to surgery for MPVT. Dr. De Caterina and co-workers has performed an open-label, pilot randomized clinical trial randomized adult patients (n = 120) with acute obstructive MPVT to an ultraslow thrombolytic regimen [25 mg of recombinant tissue-type plasminogen activator (rtPA) infused in 25 h] and a fast thrombolytic regimen (50 mg of rtPA infused in 6 h). If thrombolysis failed, a repeated dose of 25 mg of rtPA for 6 h was administered in both groups up to a cumulative dose of 150 mg or the occurrence of a complication. Complete thrombolysis success was achieved in 85.0% in the ultraslow-regimen group and 78.3% in the fast-regimen group. The authors concluded that ultraslow thrombolytic regimen conferred a high thrombosis resolution rate without major complications. Such findings should be replicated in more adequately powered trials. Unfortunately the Covid period is not over yet. The clinical impact of different prophylactic anticoagulation regimens among hospitalized patients with COVID-19 remains unclear.8 A very distinguished group of authors lead by Dr. Angiolillo, have pooled evidence from available randomized controlled trials (RCTs) to provide insights on this topic. Seven RCTs were identified, including 5154 patients followed on average of 33 days. Compared with standard-dose prophylactic anticoagulation, escalated-dose prophylactic anticoagulation was not associated with a reduction of all-cause death. Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is the guideline recommended treatment to prevent future thromboischaemic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). The evidence on the impact of prior antiplatelet therapy on the clinical outcomes of patients admitted with an ACS remains limited.9,10 Dr. Kastrati et al. from Germany aimed to assess whether the efficacy and safety of ticagrelor vs. prasugrel in patients with acute coronary syndromes (ACS) are influenced by pre-admission treatment with aspirin and/or clopidogrel. Patients (n = 4018) were categorized into two groups: pre-admission aspirin and/or clopidogrel group (n = 1455), and no pre-admission aspirin or clopidogrel group (n = 2563). The study group reported that in patients with ACS, pre-admission therapy with aspirin and/or clopidogrel has no influence on the relative efficacy and safety of ticagrelor and prasugrel. In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher-dose edoxaban (60/30 mg) and lower-dose edoxaban (30/15) were non-inferior to warfarin for stroke/systemic embolism (SEE) and significantly reduced major bleeding in AF patients in the ENGAGE-AF TIMI 48 trial.11 Thus the advantage of DOAC treatment has been less clear in AF patients with comorbid PAD.12–14 Dr. Bonaca and co-workers from USA have examined whether the efficacy and safety of these dosing strategies vs. warfarin are consistent in patients with AF and PAD in the ENGAGE-AF TIMI 48 trial. Of 21 105 patients with AF randomized to warfarin, edoxaban 60/30 mg or edoxaban 30/15 mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACEs), SSE, and major bleeding. The authors found that patients with AF and PAD are at heightened risk of MACE and CV death vs. those without PAD. The efficacy and safety of edoxaban 60/30 mg vs. warfarin in AF is consistent regardless of PAD; however, edoxaban 30/15 mg is inferior for stroke prevention in AF patients with PAD. Ticagrelor in monotherapy has been tested in different settings after PCI.15,16 The TWILIGHT study (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial, that randomized high-risk PCI patients after 3 months of dual antiplatelet therapy (DAPT) with the potent P2Y12 inhibitor ticagrelor to either aspirin or placebo in addition to ticagrelor. The main trial findings showed that this approach reduces the risk of clinically relevant bleeding while preserving antithrombotic efficacy.17 The prevalence of chronic kidney disease (CKD) and diabetes mellitus (DM) is very common and the two conditions often co-exist as a single entity, namely diabetic kidney disease. Dr. Mehran and co-workers from USA aimed to evaluate the treatment effects of ticagrelor monotherapy in the very high-risk cohort of patients with concomitant diabetes mellitus (DM) and chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI) in the TWILIGHT. They found that irrespectively of the presence of DM, CKD, and their combination, ticagrelor monotherapy reduced the risk of bleeding without a significant increase in ischaemic events compared with ticagrelor plus aspirin. The optimal duration of DAPT after PCI still remains under discussion.18–20 Dr. Ullah and co-workers from USA identified relevant randomized control trials (RCTs). ED-DAPT, high-potency (HP) DAPT, shorter duration (SD) DAPT, and low-dose (LD) DAPT were compared with DAPT-12. A trial sequential, bivariate, influential, and frequentist network meta-analysis (NMA) was performed to determine the pooled estimates. A total of 30 RCTs comprising 81 208 (40 839 experimental, 40 369 control arm) patients with CAD were included in the quantitative analysis. The author group concluded that DAPT for 3 months followed by ticagrelor-only and use of aspirin + clopidogrel after a short period of high potency DAPT appears to be a safe strategy for treating post-PCI patients. However, given the methodological limitations and inclusion of a small number of trials in novel de-escalation strategies, these findings need validation by future large scale RCTs. A strategy of dual-pathway inhibition (DPI), achieved by selective anti-Xa inhibition using rivaroxaban at a vascular dose regimen in adjunct to a single antiplatelet agent, reduces the risk of ischaemic recurrences in patients with atherosclerotic disease manifestations.21,22 However, in most studies the antiplatelet agent of choice used in adjunct to a vascular dose of rivaroxaban was aspirin, and data with a P2Y 12 inhibitor and how this DPI regimen compares with standard dual antiplatelet therapy (DAPT) is limited. Dr. Galli and co-workers from USA studied 40 patients with stable atherosclerotic disease enrolled from a larger prospective, open-label, parallel-group pharmacodynamics (PD) study. PD measures explored key pathways involved in thrombus formation and included markers of: (1) P2Y 12 reactivity, (2) platelet-mediated global thrombogenicity, (3) cyclooxygenase-1 activity, (4) TRAP induced platelet aggregation; (5) tissue factor (TF)-induced platelet aggregation, and (6) thrombin generation. The conclusion of the authors was that compared with DAPT with aspirin and a P2Y 12 inhibitor, the use of a P2Y 12 inhibitor in adjunct to a vascular dose of rivaroxaban as part of a DPI strategy is associated with similar effects on platelet-mediated global thrombogenicity but reduced thrombin generation. A DPI strategy with ticagrelor is associated with enhanced antithrombotic efficacy, the clinical implications of which warrant larger scale investigations. The ESC WG on Cardiovascular Pharmacotherapy has previously published several papers with issues we need to take into account when the study protocol is designed and the results are interpreted.23–26 Another issue is more seldom discussed. Racial and ethnic differences in clinical studies. In this issue we publish a review paper from our working group entitled ‘Racial and ethnic differences in pharmacotherapy to prevent coronary artery disease and thrombotic events’ Dr. Hasegawa and Dr. Tamargo have led this work.