P2Y12 Inhibitor or Aspirin Monotherapy for Secondary Prevention of Coronary Events.

BACKGROUND: Aspirin is the only antiplatelet agent with a Class I recommendation for long-term prevention of cardiovascular events in patients with coronary artery disease (CAD). There is inconsistent evidence on how it compares with alternative antiplatelet agents. OBJECTIVES: This study compared P2Y12 inhibitor monotherapy vs aspirin in patients with CAD. METHODS: We conducted a patient-level meta-analysis of randomized trials comparing P2Y12 inhibitor monotherapy vs aspirin monotherapy for the prevention of cardiovascular events in patients with established CAD. The primary outcome was the composite of cardiovascular death, myocardial infarction, and stroke. Prespecified key secondary outcomes were major bleeding and net adverse clinical events (the composite of the primary outcome and major bleeding). Data were pooled in a 1-step meta-analysis. RESULTS: Patient-level data were obtained from 7 trials. Overall, 24,325 participants were available for analysis, including 12,178 patients assigned to receive P2Y12 inhibitor monotherapy (clopidogrel in 7,545 [62.0%], ticagrelor in 4,633 [38.0%]) and 12,147 assigned to receive aspirin. Risk of the primary outcome was lower with P2Y12 inhibitor monotherapy compared with aspirin over 2 years (HR: 0.88; 95% CI: 0.79-0.97; P = 0.012), mainly owing to less myocardial infarction (HR: 0.77; 95% CI: 0.66-0.90; P < 0.001). Major bleeding was similar (HR: 0.87; 95% CI: 0.70-1.09; P = 0.23) and net adverse clinical events were lower (HR: 0.89; 95% CI: 0.81-0.98; P = 0.020) with P2Y12 inhibitors. The treatment effect was consistent across prespecified subgroups and types of P2Y12 inhibitors. CONCLUSIONS: Given its superior efficacy and similar overall safety, P2Y12 inhibitor monotherapy might be preferred over aspirin monotherapy for long-term secondary prevention in patients with established CAD. (P2Y12 Inhibitor or Aspirin Monotherapy as Secondary Prevention in Patients With Coronary Artery Disease: An Individual Patient Data Meta-Analysis of Randomized Trials [PANTHER collaborative initiative]; CRD42021290774).

Genetic Variation in ADAMTS13 is Related to VWF Levels, Atrial Fibrillation and Cerebral Ischemic Events.

INTRODUCTION: ADAMTS13 cleaves von Willebrand factor (VWF) multimers into less active fragments. Both markers have been related to cardiovascular disease (CVD). We aimed to investigate the influence of ADAMTS13 single nucleotide polymorphisms (SNPs) on levels of ADAMTS13 and VWF, and CVD. METHODS: The c.1342C>G, g.41635A>G and c.2699C>T polymorphisms were determined in patients with chronic coronary syndrome (n = 1000). VWF and ADAMTS13 were analyzed. Clinical endpoints after 2 years (n = 106) were unstable angina pectoris, myocardial infarction, non-hemorrhagic stroke and death. RESULTS: The SNPs did not affect ADAMTS13 levels. The 41635A-allele associated with higher VWF levels (P < .001). Patients with the 1342G-allele had significantly higher frequency of previous atrial fibrillation (n = 26, P = .016) and cerebral ischemic events (n = 47, P = .030). Heterozygous of the 1342CG variant experienced more clinical endpoints compared to homozygous (CC and GG) (P = .028). CONCLUSION: The association between the 41635A-allele and VWF indicates a role for this polymorphism in VWF regulation. ADAMTS13 has previously been linked to atrial fibrillation and ischemic stroke, and our findings suggest that the 1342G-allele may be of significance. The association between the 1342CG genotype and endpoints needs further investigations.Clinicaltrials.gov, ASCET, NCT00222261. https://clinicaltrials.gov/ct2/show/NCT00222261?term=NCT00222261&draw=2&rank=1.

TERT and TET2 Genetic Variants Affect Leukocyte Telomere Length and Clinical Outcome in Coronary Artery Disease Patients-A Possible Link to Clonal Hematopoiesis.

Inherited and acquired mutations in hematopoietic stem cells can cause clonal expansion with increased risk of cardiovascular disease (CVD), a condition known for the clonal hematopoiesis of indeterminate potential (CHIP). Inherited genetic variants in two CHIP-associated genome loci, the telomerase gene telomerase enzyme reverse transcriptase (TERT) (rs7705526) and the epigenetic regulator ten−eleven translocation 2 (TET2) (rs2454206), were investigated in 1001 patients with stable coronary artery disease (CAD) (mean age 62 years, 22% women), with regards to cardiovascular outcome, comorbidities, and leukocyte telomere length. Over 2 years, mutated TERT increased the risk two-fold for major clinical events (MACEs) in all patients (p = 0.004), acute myocardial infarction (AMI) in male patients (p = 0.011), and stroke in female patients (p < 0.001). Mutated TET2 correlated with type 2 diabetes (p < 0.001), the metabolic syndrome (p = 0.002), as well as fasting glucose, HbA1c, and shorter telomeres (p = 0.032, p = 0.003, and p = 0.016, respectively). In conclusion, our results from stable CAD patients highlight TERTs' role in CVD, and underline TET2s' role in the epigenetic regulation of lifestyle-related diseases.

vWF/ADAMTS13 is associated with on-aspirin residual platelet reactivity and clinical outcome in patients with stable coronary artery disease.

BACKGROUND: The mechanisms behind residual platelet reactivity (RPR) despite aspirin treatment are not established. It has been shown that coronary artery disease (CAD) patients with high on-aspirin RPR have elevated levels of von Willebrand factor (vWF). ADAMTS13 is a metalloprotease cleaving ultra large vWF multimers into less active fragments.Our aim was to investigate whether ADAMTS13 and vWF/ADAMTS13 ratio were associated with high RPR, and further with clinical endpoints after 2 years. METHODS: Stable aspirin-treated CAD patients (n = 999) from the ASCET trial. RPR was assessed by PFA-100. ADAMTS13 antigen and activity were analysed using chromogenic assays. Endpoints were a composite of acute myocardial infarction, stroke and death. RESULTS: The number of patients with high RPR was 258 (25.8%). Their serum thromboxane B2 (TxB2) levels were low, indicating inhibition of COX-1. They had significantly lower levels of ADAMTS13 antigen compared to patients with low RPR (517 vs 544 ng/mL, p = 0.001) and significantly lower ADAMTS13 activity (0.99 vs 1.04 IU/mL, p = 0.020). The differences were more pronounced when relating RPR to ratios of vWF/ADAMTS13 antigen and vWF/ADAMTS13 activity (p < 0.001, both). We found an inverse correlation between vWF and ADAMTS13 antigen (r = -0.14, p < 0.001) and ADAMTS13 activity (r = -0.11, p < 0.001). No correlations between TxB2 and ADAMTS13 antigen or activity, were observed, implying that ADAMTS13 is not involved in TxB2 production. Patients who experienced endpoints (n = 73) had higher vWF level (113 vs 105%, p = 0.032) and vWF/ADAMTS13 antigen ratio (0.23 vs 0.20, p = 0.012) compared to patients without. When dichotomizing vWF/ADAMTS13 antigen at median level we observed that patients above median had higher risk for suffering endpoints, with an adjusted OR of 1.86 (95% CI 1.45, 2.82). CONCLUSION: These results indicate that ADAMTS13 is of importance for RPR, and that it in combination with vWF also is associated with clinical endpoints in stable CAD patients on aspirin. TRIAL REGISTRATION: Clinicaltrials.gov NCT00222261. Registered 13.09.2005. Retrospectively registered.

High On-Aspirin Platelet Reactivity and Clinical Outcome in Patients With Stable Coronary Artery Disease: Results From ASCET (Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial).

BACKGROUND: Patients with stable coronary artery disease on single-antiplatelet therapy with aspirin are still at risk for atherothrombotic events, and high on-aspirin residual platelet reactivity (RPR) has been suggested as a risk factor. METHODS AND RESULTS: In this randomized trial, the association between platelet function determined by the PFA100 platelet function analyzer system (Siemens Healthcare Diagnostics, Germany) and clinical outcome in 1001 patients, all on single-antiplatelet therapy with aspirin (160 mg/d) was studied. Patients were randomized to continue with aspirin 160 mg/d or change to clopidogrel 75 mg/d. A composite end point of death, myocardial infarction, ischemic stroke, and unstable angina was used. At 2-year follow-up, 106 primary end points were registered. The prevalence of high RPR was 25.9%. High on-aspirin RPR did not significantly influence the primary end point in the aspirin group (13.3% versus 9.9%, P=0.31). However, in post hoc analysis, patients with von Willebrand factor levels or platelet count below median values and high on-aspirin RPR had a statistically significant higher end point rate than that of patients with low RPR (20% versus 7.5%, P=0.014, and 18.2% versus 10.8%, P=0.039, respectively). The composite end point rate in patients with high on-aspirin RPR treated with clopidogrel was not different from that of patients treated with aspirin (7.6% versus 13.3%, P=0.16). CONCLUSIONS: In stable, aspirin-treated patients with coronary artery disease, high on-aspirin RPR did not relate to clinical outcome and did not identify a group responsive to clopidogrel. Post hoc subgroup analysis raised the possibility that high on-aspirin RPR might be predictive in patients with low von Willebrand factor or platelet count, but these findings will require confirmation in future studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov Unique identifier: NCT00222261. (J Am Heart Assoc. 2012;1:e000703 doi: 10.1161/JAHA.112.000703.).

Markers of endothelial and platelet activation are associated with high on-aspirin platelet reactivity in patients with stable coronary artery disease.

INTRODUCTION: Aspirin inhibits the cyclooxygenase-1 (COX-1) mediated thromboxane A2 synthesis. Despite COX-1 inhibition, in patients with coronary artery disease (CAD), platelets can be activated through other mechanisms, like activation by thrombin. MATERIALS AND METHODS: At baseline in this cross-sectional substudy of the ASCET trial, 1001 stable CAD patients, all on single aspirin treatment, were classified by the PFA100® method, as having high on-aspirin residual platelet reactivity (RPR) or not. Markers of hypercoagulability, endothelial and platelet activation as related to RPR, were evaluated to explore the potential mechanisms behind high on-aspirin RPR. RESULTS: Altogether, 25.9% (n=259) of the patients were found to have high on-aspirin RPR. S-thromboxane B(2) levels were very low and did not differ between patients having high on-aspirin RPR or not. Patients with high on-aspirin RPR had significantly higher levels of von Willebrand Factor (vWF) (124 vs 100%, p<0.001, platelet count (236 vs 224 × 10(9)/l, p=0.008), total TFPI (68.4 vs 65.5 ng/ml, p=0.005) and ß-thromboglobulin (ß-TG) (33.3 vs 31.3 IU/ml, p=0.041) compared to patients with low on-aspirin RPR. No significant differences between the groups were observed in levels of endogenous thrombin generation (ETP), pro-thrombin fragment 1+2 (F1+2), D-dimer, soluble TF (sTF) or P-selectin (all p>0.05). CONCLUSIONS: The high on-aspirin RPR as defined by PFA100® seems not to be due to increased thrombin activity as evaluated with ETP, sTF, F1+2 or D-dimer. The elevated levels of platelet count, ß-TG, TFPI and especially vWF might be explained by increased endothelial and platelet activation in these patients.

[Reduction of myocardial infarction size after primary percutaneous coronary intervention]. / Reduksjon av infarktstørrelse etter primaer perkutan koronar intervensjon.

BACKGROUND: Achieving reperfusion as soon as possible is essential in order to reduce myocardial infarction size and thus improve prognosis. An increasing number of patients with myocardial infarction are treated with primary percutaneous coronary intervention (PCI). Technetium 99m-tetrofosmin myocardial perfusion tomography (SPECT) is a valid test for assessing myocardium at risk and final infarct size expressed by a hypoperfusion index (HPI) of the left ventricular mass. MATERIAL AND METHODS: 20 patients with acute ST-elevation myocardial infarction were treated with primary percutaneous coronary intervention within six hours of onset of symptoms. Myocardium at risk and final infarct size were assessed by Technetium 99m-tetrofosmin immediately before and a few hours, one week and six weeks after. RESULTS: The hypoperfusion index immediately before percutaneous coronary intervention was 31%, four to six hours after PCI 25%, one week later 16% and six weeks later 12%, i.e. a relative reduction of 60% (p < 0.01). Anterior wall infarctions had a higher level of myocardium at risk before primary PCI compared to inferior wall infarctions (36% vs. 24%), but anterior wall infarctions had a higher salvage index compared to inferior wall infarctions. INTERPRETATION: This non-controlled study shows a marked reduction in final infarction size in patients with acute ST-elevation myocardial infarction treated with primary PCI.