Stent thrombosis remains a significant pitfall of percutaneous coronary intervention (PCI). A recent trial observed that an adjusted loading dose (LD) of clopidogrel according to platelet monitoring ...decreases the rate of major adverse cardiovascular events after PCI. We investigated if such a strategy of a tailored clopidogrel LD according to platelet reactivity monitoring could decrease the rate of stent thrombosis. This multicenter prospective randomized study included 429 patients with a low clopidogrel response after a 600-mg LD undergoing PCI. Patients were randomized to a control group (n = 214) and to a vasodilator-stimulated phosphoprotein (VASP)-guided group (n = 215). In the VASP-guided group, patients received up to 3 additional 600-mg LDs of clopidogrel to obtain a VASP index <50% before PCI. The primary end point was the rate of stent thrombosis at 1 month. Secondary end points were rates of major adverse cardiovascular events and bleeding. Patients in the 2 groups had a high body mass index and were often diabetic (control vs VASP-guided group 28 ± 5.1 vs 27.9 ± 4.7 kg/m 2 , p = 0.8, and 39% vs 33%, p = 0.2, respectively). PCI was performed in most patients for acute coronary syndrome in the 2 groups (52.3% vs 50.7%, p = 0.8). Despite a 2,400-mg LD of clopidogrel, 8% of patients in the VASP-guided group remained low responders. The rate of stent thrombosis was significantly lower in the VASP-guided group (0.5% vs 4.2%, p <0.01). The rate of major adverse cardiovascular events was also higher in the control group (8.9% vs 0.5%, p <0.001). There was no difference in the rate of bleeding (2.8% vs 3.7%, p = 0.8). In conclusion, a tailored clopidogrel LD according to platelet reactivity monitoring decreases the rate of early stent thrombosis after PCI without increasing bleeding.
Immune checkpoint inhibitors (ICIs) represent a major advance in the treatment of cancer. Although clinical trials reported a low incidence of immune-related cardiovascular adverse events, the number ...of published life-threatening cases of cardiotoxicity is increasing. In this descriptive observational analysis, we aimed to describe the clinical manifestations, management, and outcomes of patients who developed ICI-related cardiotoxicity.
Objectives The aim of this study was to investigate the relationship between platelet reactivity (PR) after a loading dose (LD) of prasugrel and thrombotic events. Background Post-treatment PR has ...been shown to be strongly associated with the occurrence of major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI) in the clopidogrel era. Prasugrel is a new P2Y12 –adenosine diphosphate receptor with a higher potency on PR. Methods A prospective multicenter study included patients who underwent successful PCI for acute coronary syndromes and received prasugrel therapy. Vasodilator-stimulated phosphoprotein (VASP) index was measured after the prasugrel LD. High on-treatment PR was defined as a VASP index ≥50%. MACE included cardiovascular death, myocardial infarction, and definite stent thrombosis at 1 month. Results Three hundred one patients were enrolled. The mean VASP index after 60 mg of prasugrel was 34.3 ± 23.1%. High on-treatment PR was observed in 76 patients (25.2%). Patients experiencing thrombotic events after PCI had significantly higher VASP indexes compared with those free of events (64.4 ± 14.4% vs. 33.4 ± 22.7%; range: 51% to 64% and 5% to 47.6%, respectively; p = 0.001). Kaplan-Meier analysis comparing good responders and patients with high on-treatment PR demonstrated a significantly higher rate of MACE in patients with suboptimal PR inhibition (log-rank p < 0.001). Receiver-operating characteristic curve analysis found a cutoff value of 53.5% of the VASP index to predict thrombotic events at 1 month (r = 0.86, p < 0.001). Patients with minor or major Thrombolysis In Myocardial Infarction unrelated to coronary artery bypass grafting bleeding and those without had similar VASP indexes (30 ± 17.8% vs. 34.3 ± 23%, p = 0.70). Conclusions Despite the use of prasugrel, a significant number of patients undergoing PCI in the setting of acute coronary syndromes do not achieve optimal PR inhibition. Such patients have a higher risk for MACE after PCI.
Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary ...intervention. In an earlier consensus document, we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post–percutaneous coronary intervention ischemic events for various platelet function tests (PFTs). Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention, although routine testing is not recommended (Class III). Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor. Recent prospective randomized trials of PFT did not demonstrate clinical benefit, thus questioning whether treatment modification based on the results of current PFT platforms can actually influence outcomes. However, there are major limitations associated with these randomized trials. In addition, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Therefore, a therapeutic window concept has been proposed for P2Y12 inhibitor therapy. In this updated consensus document, we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events. In addition, we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy.
Objectives This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration (APC) in acute coronary syndrome (ACS) patients. Background Ticagrelor is a direct-acting P2Y12 ...-adenosine diphosphate receptor blocker. The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non–platelet-directed properties. Animal and in vitro models suggested that the “pleiotropic” properties of ticagrelor may be related to an interaction with adenosine metabolism. Methods We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel. The APC was measured by liquid chromatography. To assess the mechanism of APC variation, we measured adenosine deaminase concentration, adenosine uptake by red blood cells, and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors. The P2Y12 -adenosine diphosphate receptor blockade was assessed by the vasodilator-stimulated phosphoprotein index. Results Patients receiving ticagrelor had significantly higher APC than patients receiving clopidogrel (1.5 μM interquartile range: 0.98 to 1.7 μM vs. 0.68 μM interquartile range: 0.49 to 0.78 μM; p < 0.01). The APC was not correlated with vasodilator-stimulated phosphoprotein (p = 0.16). Serum-containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls (p < 0.01 for both comparisons). Adenosine deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor (p = 0.1). Ticagrelor and clopidogrel had no direct impact on adenosine receptors (p = not significant). Conclusions Ticagrelor increases APC in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells.
The addition of clopidogrel to aspirin treatment reduces ischemic events in a wide range of patients with cardiovascular disease. However, recurrent ischemic event occurrence during dual antiplatelet ...therapy, including stent thrombosis, remains a major concern. Platelet function measurements during clopidogrel treatment demonstrated a variable and overall modest level of P2Y12 inhibition. High on-treatment platelet reactivity to adenosine diphosphate (ADP) was observed in selected patients. Multiple studies have now demonstrated a clear association between high on-treatment platelet reactivity to ADP measured by multiple methods and adverse clinical event occurrence. However, the routine measurement of platelet reactivity has not been widely implemented and recommended in the guidelines. Reasons for the latter include: 1) a lack of consensus on the optimal method to quantify high on-treatment platelet reactivity and the cutoff value associated with clinical risk; and 2) limited data to support that alteration of therapy based on platelet function measurements actually improves outcomes. This review provides a consensus opinion on the definition of high on-treatment platelet reactivity to ADP based on various methods reported in the literature and proposes how this measurement may be used in the future care of patients.
High on-treatment platelet reactivity (HTPR) after a clopidogrel loading dose predicts the risk of thrombotic events after percutaneous coronary intervention. We have demonstrated that HTPR could be ...overcome in most cases using dose adjustment according to PR monitoring resulting in an improved clinical outcome. However, this strategy failed in nearly 10% of patients with HTPR. Cytochrome P450 (CYP) 2C19 polymorphism was a major determinant of the response to clopidogrel and could be responsible for a failure of dose adjustment. We aimed to determine the clinical and genetical predictors of a failure of the dose-adjustment strategy. Seventy-three patients undergoing percutaneous coronary intervention were included in this prospective multicenter study. A vasodilator phosphoprotein index ≥50% after a 600-mg loading dose of clopidogrel defined HTPR. Dose adjustment was performed according to PR monitoring to reach a vasodilator phosphoprotein index <50%. Genetic polymorphism of CYP2C19 was determined by direct sequencing. Clinical predictors of HTPR were body mass index (BMI; p = 0.01), diabetes mellitus (p = 0.03), and acute coronary syndrome (p = 0.02). The mutant 2* allele of CYP2C19 681A > G loss of function polymorphism was also significantly associated with HTPR (p = 0.04). The rate of successful dose adjustment was similar in carriers of the CYP2C19*2 allele and carriers of the wild-type allele. The only independent predictor of a failed dose adjustment was a high BMI (p = 0.01). In conclusion, high BMI, acute coronary syndrome, diabetes mellitus, and CYP2C19*2 are associated with HTPR after a 600-mg loading dose of clopidogrel. Dose adjustment overcomes HTPR in carriers of the CYP2C19*2 allele. BMI is the only independent predictor of failed dose adjustment. Thus, drug underdosage seems to be the main determinant of HTPR.
BackgroundMyocarditis is a rare but life-threatening adverse event of cancer treatments with immune checkpoint inhibitors (ICIs). Recent guidelines recommend the use of high doses of corticosteroids ...as a first-line treatment, followed by intensified immunosuppressive therapy (IIST) in the case of unfavorable evolution. However, this strategy is empirical, and no studies have specifically addressed this issue. Therefore, we aimed to investigate and compare the clinical course, management and outcome of ICI-induced myocarditis patients requiring or not requiring IIST.MethodsThis case–control study included all patients consecutively admitted to The Mediterranean University Center of Cardio-Oncology (Aix-Marseille University, France) for the diagnosis of ICI-induced myocarditis according to Bonaca’s criteria and treated with or without IIST. In addition, we searched PubMed and included patients from previously published case reports treated with IIST in the analysis. The clinical, biological, imaging, treatment, all-cause death and cardiovascular death data of patients who required IIST were compared with those of patients who did not.ResultsA total of 60 patients (69±12 years) were included (36 were treated with IIST and 24 were not). Patients requiring IIST were more likely to have received a combination of ICIs (39% vs 8%, p=0.01), and developed the first symptoms/signs of myocarditis earlier after the onset of ICI therapy (median, 18 days vs 60 days, p=0.002). They had a significantly higher prevalence of sustained ventricular arrhythmia, complete atrioventricular block, cardiogenic shock and troponin elevation. Moreover, they were more likely to have other immune-related adverse events simultaneously (p<0.0001), especially myositis (p=0.0002) and myasthenia gravis (p=0.009). Patients who required IIST were more likely to die from any cause (50% vs 21%, p=0.02). Among them, patients who received infliximab were more likely to die from cardiovascular causes (OR, 12.0; 95% CI 2.1 to 67.1; p=0.005).ConclusionThe need for IIST was more common in patients who developed myocarditis very early after the start of ICI therapy, as well as when hemodynamic/electrical instability or neuromuscular adverse events occurred. Treatment with infliximab might be associated with an increased risk of cardiovascular death.
Objectives We aimed to investigate the biological impact of a tailored clopidogrel loading dose (LD) according to platelet reactivity monitoring in carriers of the cytochrome (CYP) 2C19*2 ...loss-of-function polymorphism undergoing percutaneous coronary intervention for an acute coronary syndromes. Background CYP2C19*2 polymorphism is associated with reduced clopidogrel metabolism and a worse prognosis after percutaneous coronary intervention. Method A prospective multicenter study enrolling 411 patients with non–ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention was performed. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index, and a cutoff value of ≥50% was used to define high on-treatment platelet reactivity (HTPR). The genetic polymorphism of CYP2C19 was determined by allele-specific polymerase chain reaction. In patients carrying CYP2C19*2 and exhibiting HTPR after a first 600-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 600 mg LDs to obtain a VASP index <50%. Results One hundred thirty-four patients (35.3%) carried at least one 2C19*2 allele (11 homozygotes 2.7% and 123 heterozygotes 32.6%). The VASP index in these patients was significantly higher than in homozygotic patients for the wild-type alleles (61.7 ± 18.4% vs. 49.2 ± 24.2%; p < 0.001). Of the 134 carriers of the loss-of-function polymorphism, 103 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (69.7 ± 10.1% vs. 50.6 ± 17.6%; p < 0.0001). Finally, dose adjustment according to platelet reactivity monitoring, enabled 88% of 2C19*2 carriers exhibiting HTPR to reach a VASP index <50%. Conclusions Increased and tailored clopidogrel loading dose according to platelet reactivity monitoring overcome HTPR in carriers of the loss-of-function CYP2C19*2 polymorphism.
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