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Aims Atherothrombotic events are influenced by systemic hypercoagulability and fibrinolytic activity. The present study evaluated thrombogenicity indices and their prognostic implications according to disease acuity. Methods and results From the consecutive patients undergoing percutaneous coronary intervention (PCI), those with thrombogenicity indices (n = 2705) were grouped according to disease acuity [acute myocardial infarction (AMI) vs. non-AMI]. Thrombogenicity indices were measured by thromboelastography (TEG). Blood samples for TEG were obtained immediately after insertion of the PCI sheath, and TEG tracing was performed within 4 h post-sampling. Major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) were evaluated for up to 4 years. Compared with non-AMI patients, AMI patients had higher platelet-fibrin clot strength [maximal amplitude (MA): 66.5 ± 7.8 vs. 65.3 ± 7.2 mm, P < 0.001] and lower fibrinolytic activity [clot lysis at 30 min (LY30): 0.9 ± 1.8% vs. 1.1 ± 1.9%, P < 0.001]. Index AMI presentation was associated with MA [per one-mm increase: odds ratio (OR): 1.024; 95% confidence interval (CI): 1.013–1.036; P < 0.001] and LY30 (per one% increase: OR: 0.934; 95% CI: 0.893–0.978; P = 0.004). The presence of high platelet-fibrin clot strength (MA ≥68 mm) and low fibrinolytic activity (LY30 < 0.2%) was synergistically associated with MACE occurrence. In the multivariable analysis, the combined phenotype of ‘MA ≥ 68 mm’ and ‘LY30 < 0.2%’ was a major predictor of post-PCI MACE in the AMI group [adjusted hazard ratio (HR): 1.744; 95% CI: 1.135–2.679; P = 0.011], but not in the non-AMI group (adjusted HR: 1.031; 95% CI: 0.499–2.129; P = 0.935). Conclusion AMI occurrence is significantly associated with hypercoagulability and impaired fibrinolysis. Their combined phenotype increases the risk of post-PCI atherothrombotic event only in AMI patients. These observations may support individualized therapy that targets thrombogenicity for better outcomes in patients with AMI. Clinical Trial Registration Gyeongsang National University Hospital (G-NUH) Registry, NCT04650529.

Aims Although platelet reactivity during P2Y(12)-inhibitors is associated with stent thrombosis (ST) and bleeding, standardized and clinically validated thresholds for accurate risk stratification after percutaneous coronary intervention (PCI) are lacking. We sought to determine the prognostic value of low platelet reactivity (LPR), optimal platelet reactivity (OPR), or high platelet reactivity (HPR) by applying uniform cut-off values for standardized devices. Methods and results Authors of studies published before January 2015, reporting associations between platelet reactivity, ST, and major bleeding were contacted for a collaborative analysis using consensus-defined, uniform cut-offs for standardized platelet function assays. Based on best available evidence for each device (exploratory studies), LPR-OPR-HPR categories were defined as < 95, 95-208, and > 208 PRU for VerifyNow, < 19, 19-46, and > 46 U for the Multiplate analyser and < 16, 16-50, and > 50% for VASP assay. Seventeen studies including 20 839 patients were used for the analysis; 97% were treated with clopidogrel and 3% with prasugrel. Patients with HPR had significantly higher risk for ST [risk ratio (RR) and 95% CI: 2.73 (2.03-3.69), P < 0.00001], yet a slight reduction in bleeding [RR: 0.84 (0.71-0.99), P = 0.04] compared with those with OPR. In contrast, patients with LPR had a higher risk for bleeding [RR: 1.74 (1.47-2.06), P < 0.00001], without any further benefit in ST [RR: 1.06 (0.68-1.65), P = 0.78] in contrast to OPR. Mortality was significantly higher in patients with HPR compared with other categories (P < 0.05). Validation cohorts (n = 14) confirmed all results of exploratory studies (n = 3). Conclusion Platelet reactivity assessment during thienopyridine-type P2Y(12)-inhibitors identifies PCI-treated patients at higher risk for mortality and ST (HPR) or at an elevated risk for bleeding (LPR).

This editorial refers to ‘Duration of dual antiplatelet treatment with clopidogrel and aspirin in patients with acute coronary syndrome’, by C. Varenhorst et al. doi:10.1093/eurheartj/eht438 Acute coronary syndromes are associated with injured arterial vessel walls in the setting of a highly prothrombotic state. The stimulus for thrombosis is further heightened by the frequent implantation of a foreign body (a stent) at the site of coronary artery damage. Stenting induces distinct pathological changes in platelet and fibrin deposition together with intense early inflammatory cell infiltration, followed by smooth muscle cell migration and proliferation, and finally complete or incomplete healing. Complete stent endothelialization, the most desired outcome, has been observed within a month with bare metal stent (BMS) implantation, whereas drug-eluting stent (DES) implantation has been associated with highly suppressed early healing and poor endothelial cell coverage that may persist for years.1 We know that compared with aspirin monotherapy, dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor in the non-ST-segment elevation myocardial infarction acute coronary syndrome (NSTEMI ACS) patient is effective in reducing thrombotic events but carries increased risk of bleeding.2 We also know that greater P2Y12 inhibition than derived from clopidogrel therapy in the ACS patient treated with percutaneous coronary intervention (PCI) is associated with less thrombotic event occurrence but more bleeding.3,4 However, the importance of more potent P2Y12 inhibition is a bit less clear in the medically managed ACS patient.5 In the PLATelet inhibition and patient Outcomes (PLATO) trial, the medically managed patient derived a benefit from ticagrelor therapy.3 However, in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY-ACS) trial, an investigation devoted to medical management of NSTEMI ACS, prasugrel-treated patients did not derive a similar benefit from more potent …

This editorial refers to ‘Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54’[†][1], by M.P. Bonaca et al ., on page 1133. Platelet reactivity to ADP and thromboxane A2, two key secondary agonists, plays a pivotal role in the occurrence of arterial thrombotic events. This foundation positions the platelet as a ‘nidus of evil’ and is the major rationale for dual signalling pathway blockade with a COX-1 and a P2Y12 receptor inhibitor in high-risk patients.1,2 There is good evidence that the potent P2Y12 receptor inhibitors prasugrel and ticagrelor are more efficient in reducing thrombotic events when administered at the time of an acute coronary syndrome (ACS) and continued for 1 year compared with clopidogrel, but also carry a bleeding risk.3,4 Lingering questions remain about the net utility of more prolonged dual antiplatelet therapy (DAPT). In the DAPT study, 11 648 patients who were treated with aspirin and a thienopyridine for 12 months after successful coronary stenting were then randomly assigned to placebo vs. continuation on DAPT for another 18 months. Thirty-one per cent of patients enrolled were stented for acute myocardial infarction (MI). Prolonged DAPT was associated with a significant reduction in major adverse cardiovascular and cerebrovascular events (MACCE) in those with and without MI, but the treatment effect was more pronounced in the ‘clot formers’, i.e. those with MI ( P interaction = 0.03). … [1]: #fn-2

This editorial refers to ‘High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study’†, by J. Silvain et al. , on page 1241 Pathophysiological changes reported in the elderly include increased platelet activation and reactivity, elevated levels of coagulation factors and plasminogen activator inhibitor type-1, and decreased bleeding time—all consistent with an increased risk for thrombosis.1 However, elderly patients with coronary artery disease (CAD) also encounter an increased risk of bleeding during antiplatelet therapy. Thus, we face a challenging treatment dilemma in these patients that is further complicated by frequent co-morbid diseases and polypharmacy. Guideline recommendations for antiplatelet therapy in the elderly are fuzzy due to a lack of dedicated pharmacodynamic and clinical outcome studies in this population. Since the first description of clopidogrel response variability and resistance, much has been learned about numerous factors influencing the metabolism of clopidogrel that directly translate into the pharmacodynamic response ( Figure 1 ).2,3 Non-responsiveness to the world's second most widely used antiplatelet agent, now de facto , has fuelled the development of and widespread interest in new and more pharmacodynamically predictable P2Y12 receptor blockers and laid the cornerstone for personalized antiplatelet therapy.3 Figure 1 Various factors influencing platelet reactivity and clinical events during clopidogrel therapy. ADP, adenosine diphosphate; BMI, body mass index; CAD, coronary artery disease; CCB, calcium channel blocker; CYP, cytochrome P450; DDI, drug–drug interaction; HPR, high on-treatment platelet reactivity; LPR, low on-treatment platelet reactivity; PPI, proton pump inhibitor; SJW, St. John's wort; SNP, single …

Aims CYP3A4-metabolized statins can influence the pharmacodynamic effect of clopidogrel. We sought to assess the impact of switching to a non-CYP3A4-metabolized statin on platelet function among patients receiving clopidogrel and atorvastatin with high on-treatment platelet reactivity (HPR). Methods and results Percutaneous coronary intervention (PCI)-treated patients ( n = 50) with HPR [20 μM adenosine diphosphate (ADP)-induced maximal platelet aggregation (MPA) >50%] were enrolled during chronic administration of atorvastatin (10 mg/day) and clopidogrel (75 mg/day) (≥6 months). They were randomly assigned to a 15-day therapy with either rosuvastatin 10 mg/day ( n = 25) or pravastatin 20 mg/day ( n = 25). Platelet function was assessed before and after switching by conventional aggregometry and the VerifyNow P2Y12 assay. Genotyping was performed for CYP2C19\*2/\*3 , CYP3A5*3 , and ABCB1 C3435T alleles. The primary endpoint was the absolute change in 20 μM ADP-induced MPA. After switching, MPAs after stimuli with 20 and 5 μM ADP were decreased by 6.6% (95% confidence interval: 3.2–10.1%; P < 0.001), and 6.3% (95% confidence interval: 2.5–10.2%; P = 0.002), respectively. Fifty-two P2Y12 reaction units fell (95% confidence interval: 35–70; P < 0.001) and the prevalence of HPR decreased (24%; P < 0.001). Pharmacodynamic effects were similar after rosuvastatin and pravastatin therapy. In addition to smoking status, the combination of calcium channel blocker usage and ABCB1 C3435T genotype significantly affected the change of 20 μM ADP-induced MPA. Conclusions Among PCI-treated patients with HPR during co-administration of clopidogrel and atorvastatin, switching to a non-CYP3A4-metabolized statin can significantly decrease platelet reactivity and the prevalence of HPR. This switching effect appears similar irrespective of the type of non-CYP3A4-metabolized statin.