The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of-the-art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i.e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID-19-associated coagulopathy is revisited.
Dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor is the standard treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). De-escalation of the potent P2Y12 inhibtor is an appealing concept to balance the ischaemic and bleeding risks after PCI. An individual patient data meta-analysis was performed to compare de-escalation versus standard DAPT in patients with ACS.Electronic databases, including PubMed, Embase, and the Cochrane database, were searched to identify randomised clinical trials (RCTs) comparing the de-escalation strategy with the standard DAPT after PCI in patients with ACS. Individual patient-level data were collected from the relevant trials. The co-primary endpoints of interest were the ischaemic composite endpoint (a composite of cardiac death, myocardial infarction, and cerebrovascular events) and bleeding endpoint (any bleeding) at 1-year post-PCI. Four RCTs (the TROPICAL-ACS, POPular Genetics, HOST-REDUCE-POLYTECH-ACS, and TALOS-AMI trials) including 10 133 patients were analysed. The ischaemic endpoint was significantly lower in the patients assigned to the de-escalation strategy than in those assigned to the standard strategy (2.3% vs. 3.0%, hazard ratio [HR] 0.761, 95% confidence interval [CI] 0.597-0.972, log rank P = 0.029). Bleeding was also significantly lower in the de-escalation strategy group (6.5% vs. 9.1%, HR 0.701, 95% CI 0.606-0.811, log rank P < 0.001). No significant intergroup differences were observed in terms of all-cause death and major bleeding events. Subgroup analyses revealed that compared to guided de-escalation, unguided de-escalation had a significantly larger impact on bleeding endpoint reduction (P for interaction = 0.007); no intergroup differences were observed for the ischaemic endpoints.In this individual patient data meta-analysis, DAPT-based de-escalation was associated with both decreased ischaemic and bleeding endpoints. Reduction in bleeding endpoints was more prominent for the unguided than the guided de-escalation strategy.This study was registered in the PROSPERO (ID: CRD42021245477).
Although current literature indicates both a clinical and a cost-effective benefit of routine genotype-guided treatment of patients treated with clopidogrel, this strategy is not recommended in guidelines. In cardiology, but also in neurology and vascular surgery, the current scientific evidence for this is still insufficient. Nevertheless, the role of pharmacogenetics will gain importance in today's medical world, where the demand for personalised medicine is on the rise. The implementation of genotyping in the clinic will nonetheless be a practical challenge due to a lack of clarity about who will bear the associated costs. In patients with coronary artery disease and a higher bleeding risk, it is valuable to determine the CYP2C19 genotype prior to treatment with clopidogrel. Pending further studies, we recommend that specialists prescribing clopidogrel should determine the CYP2C19 genotype in patients at high risk of recurrent ischemic events.
The population of elderly with cardiovascular diseases and multimorbidity is rapidly growing. For decades, different antithrombotic therapies have been studied to find the most effective therapy in reducing the risk of cardiovascular events. Recently, large trials have investigated a new antithrombotic therapy consisting of a platelet aggregation inhibitor and a low-dose anticoagulant (aspirin plus rivaroxaban). This combination inhibits both primary and secondary haemostasis, and is therefore called 'dual pathway inhibition' (DPI). DPI leads to a further reduction of the risk of ischemic cardiovascular events as compared to aspirin monotherapy, but increases the risk of bleeding. The population at high risk of ischemic events, but without an increased bleeding risk, is expected to experience the highest risk reduction and therefore the highest net clinical benefit of DPI. This population consists of patients with polyvascular disease, heart failure, renal insufficiency, diabetes mellitus and other uncontrolled risk factors.
Abstract Objective We describe the current treatment of elderly patients with non-ST-elevation myocardial infarction (NSTEMI) enrolled in a national registry. Methods The POPular AGE registry is a prospective, multicentre study of patients ≥ 75 years of age presenting with NSTEMI, performed in the Netherlands. Management was at the discretion of the treating physician. Cardiovascular events consisted of cardiovascular death, myocardial infarction and ischaemic stroke. Bleeding was classified according to the Bleeding Academic Research Consortium (BARC) criteria. Results A total of 646 patients were enrolled between August 2016 and May 2018. Median age was 81 (IQR 77–84) years and 58% were male. Overall, 75% underwent coronary angiography, 40% percutaneous coronary intervention, and 11% coronary artery bypass grafting, while 49.8% received pharmacological therapy only. At discharge, dual antiplatelet therapy (aspirin and P2Y 12 inhibitor) was prescribed to 56.7%, and 27.4% received oral anticoagulation plus at least one antiplatelet agent. At 1‑year follow-up, cardiovascular death, myocardial infarction or stroke had occurred in 13.6% and major bleeding (BARC 3 and 5) in 3.9% of patients. The risk of both cardiovascular events and major bleeding was highest during the 1st month. However, cardiovascular risk was three times as high as bleeding risk in this elderly population, both after 1 month and after 1 year. Conclusions In this national registry of elderly patients with NSTEMI, the majority are treated according to current European Society of Cardiology guidelines. Both the cardiovascular and bleeding risk are highest during the 1st month after NSTEMI. However, the cardiovascular risk was three times as high as the bleeding risk.
The cytochrome P450 (CYP) 2C9 enzyme plays a role in the metabolization of clopidogrel. Carriage of a CYP2C9 loss-of-function (LoF) allele has been associated with attenuated pharmacokinetics, leading to a diminished pharmacodynamic response and increased risk for developing stent thrombosis in patients treated with clopidogrel.In this study, we aimed to determine the effect of the CYP2C9*2 and *3 LoF alleles on thrombotic events. Therefore, a post hoc analysis was performed in 878 patients with available CYP2C9 genotype status included in the POPular Genetics and POPular Age trials, which enrolled patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction, respectively. The primary thrombotic outcome was a composite of cardiovascular death, myocardial infarction or stroke.A total of 526 (60%) patients were CYP2C9 LoF allele noncarriers and 352 (40%) were CYP2C9 LoF allele (*2 or *3) carriers. After correction for differences in baseline characteristics, there were no significant differences between CYP2C9 LoF allele carriers and noncarriers for the combined thrombotic outcome (6.3% vs. 5.9%, hazard ratio 1.16 [0.67-2.0], p = 0.60), or the individual thrombotic outcomes. Moreover, no differences were seen in the event rates for clinically relevant bleeding (Bleeding Academic Research Consortium [BARC] 2-5 bleeding) as well as major bleeding (BARC 3 or 5 bleeding).Carriers of a CYP2C9 *2 or *3 LoF allele presenting with acute coronary syndrome and treated with clopidogrel did not have an increased risk for thrombotic events compared with noncarriers. Given the limited number of poor metabolizers, no firm conclusions could be drawn with regard to the thrombotic risk for patients carrying two CYP2C9 LoF alleles.
On 8-9 November 2022, the European Society of Pharmacogenomics and Personalised Therapy organized its sixth biennial congress, in Belgrade, Serbia (congress website: www.sspt.rs). The congress aimed to address the current status and future perspectives of pharmacogenomics, share latest knowledge in the field of precision medicine and showcase the implementation of clinical applications in pharmacogenomics/pharmacogenetics. The 2 day congress consisted of 17 lectures given by key-opinion leaders and included a poster session plus discussions. The meeting was a great success by generating an informal environment and enabling the exchange of information between 162 participants from 16 different countries.
