Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study.

BACKGROUND: Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The frequent genetic functional variant 681 G>A (*2) of cytochrome P450 2C19 (CYP2C19) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel. METHODS: Between April 1, 1996, and April 1, 2008, 259 young patients (aged <45 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. Follow-up was every 6 months. The key secondary endpoint was stent thrombosis proven by angiography. FINDINGS: Median clopidogrel exposure time was 1.07 years (IQR 0.28-3.0). Baseline characteristics were balanced between carriers (heterozygous *1/*2, n=64; homozygous *2/*2, n=9) and non-carriers (n=186) of CYP2C19*2 variant. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs 11 events; hazard ratio [HR] 3.69 [95% CI 1.69-8.05], p=0.0005), as did stent thrombosis (eight vs four events; HR 6.02 [1.81-20.04], p=0.0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation up to the end of follow-up (HR 3.00 [1.27-7.10], p=0.009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4.04 [1.81-9.02], p=0.0006). INTERPRETATION: The CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction.

Long-Term Evolution of Premature Coronary Artery Disease.

BACKGROUND: The long-term evolution of premature coronary artery disease (CAD) is unknown. OBJECTIVES: The objective of this study was to describe the evolution of coronary atherosclerosis in young patients and identify the risk factors of poor outcomes. METHODS: Participants age ≤45 years with acute or stable obstructive CAD were prospectively enrolled and followed. The primary endpoint was all-cause death, myocardial infarction (MI), refractory angina requiring coronary revascularization, and ischemic stroke. RESULTS: Eight hundred-eighty patients with premature CAD were included. They were age 40.1 ± 5.7 years, mainly men, smokers, with a family history of CAD or hypercholesterolemia. At baseline presentation, 91.2% underwent coronary revascularization, predominantly for acute MI (78.8%). Over a follow-up of 20 years, one-third (n = 264) of patients presented with a total of 399 ischemic events, and 36% had at least a second recurrent event. MI was the most frequent first recurrent event (n = 131 of 264), mostly related to new coronary lesions (17.3% vs. 7.8%; p = 0.01; hazard ratio [HR]:1.45; 95% confidence interval [CI]: 1.09 to 1.93 for new vs. initial culprit lesion). All-cause death (n = 55; 6.3%) occurred at 8.4 years (median time). Ethnic origin (sub-Saharan African vs. Caucasian, adjusted hazard ratio [adjHR]: 1.95; 95% CI: 1.13 to 3.35; p = 0.02), inflammatory disease (adjHR: 1.58; 95% CI: 1.05 to 2.36; p = 0.03), and persistent smoking (adjHR: 2.32; 95% CI: 1.63 to 3.28; p < 0.01) were the strongest correlates of a first recurrent event. When considering all recurrent events, the same factors and Asian ethnicity predicted poor outcome, but persistent smoking had the greatest impact on prognosis. CONCLUSIONS: Premature CAD is an aggressive disease despite the currently recommended prevention measures, with high rates of recurrent events and mortality. Ethnicity and concomitant inflammatory disease are associated with poor prognoses, along with insufficient control of risk factors.

Obstructive coronary artery disease in patients hospitalized for severe sepsis or septic shock with concomitant acute myocardial infarction.

PURPOSE: It is difficult to differentiate type 1 acute myocardial infarction (AMI) with obstructive coronary artery disease (OCAD) from type 2 AMI in patients admitted for severe sepsis. The aims of this study were to assess the risk factors and prognosis of OCAD in patients admitted to the intensive care unit for severe sepsis with concomitant AMI. MATERIALS AND METHODS: This is a single-center retrospective cohort study including all consecutive patients who were hospitalized for severe sepsis or septic shock between March 2006 and September 2014 and who underwent coronary angiography in the intensive care unit to identify AMI. RESULTS: Overall, 78 (5.5%) of 1418 patients hospitalized for severe sepsis underwent coronary angiography to identify concomitant AMI. Thirty-two patients (41%) had OCAD. Following multivariate analysis, the risk factors of OCAD were peripheral vascular disease (odds ratio [OR] =5.7; 95% confidence interval [CI], 1.1-30.4; P = .042) and at least 2 cardiovascular risk factors (OR = 6.7; 95% CI, 1.9-23.8; P = .003). Obstructive coronary artery disease was associated with a significant mortality increase at 60 days (OR = 8.1; 95% CI, 1.9-30.2; P = .004). CONCLUSIONS: Obstructive coronary artery disease is a poor prognosis factor in patients hospitalized for severe sepsis with concomitant AMI. In this setting, medical treatment should be considered for patients with peripheral vascular disease or with at least 2 cardiovascular risk factors; the need to perform coronary angiography should be considered carefully.

P2Y12 receptor inhibition and effect of morphine in patients undergoing primary PCI for ST-segment elevation myocardial infarction. The PRIVATE-ATLANTIC study.

PRIVATE-ATLANTIC (P2Y12 Receptor Inhibition with VASP Testing using Elisa kit during the ATLANTIC study) is a pre-specified substudy of the randomised, double-blind ATLANTIC trial in patients with ST-segment elevation myocardial infarction, designed to help interpret the main trial results. The primary objective of ATLANTIC was to assess coronary reperfusion prior to percutaneous coronary intervention (PCI) with pre- vs in-hospital ticagrelor 180 mg loading dose (LD). PRIVATE-ATLANTIC assessed platelet inhibition in 37 patients by measurement of vasodilator-associated stimulated phosphoprotein (VASP) platelet reactivity index (PRI) and VerifyNow platelet reactivity units (PRU) before angiogram (T1), immediately after PCI (T2), 1 (T3), and 6 (T4) hours (h) after PCI, and before next study drug administration (T5). The median time difference between the two ticagrelor LD was 41 minutes. Platelet reactivity was unaffected at T1 when measured by VASP-PRI (89.8 vs 93.9 % for pre- and in-hospital ticagrelor, respectively; p = 0.18) or PRU (239 vs 241; p = 0.82). Numerical differences were apparent at T2 and maximal at T3. Morphine administration significantly delayed onset of platelet inhibition at T3 (VASP-PRI 78.2 vs 23.4 % without morphine; p = 0.0116) and T4 (33.1 vs 11.0 %; p = 0.0057). In conclusion, platelet inhibition in ATLANTIC was unaffected by pre-hospital ticagrelor administration at the time of initial angiogram due to the short transfer delay. The maximum difference in platelet inhibition was detected 1 h after PCI (T3). Morphine administration was associated with delayed onset of action of ticagrelor and appeared more important than timing of ticagrelor administration.

Prospective assessment of incidence of Tako-Tsubo cardiomyopathy in a very large urban agglomeration.

BACKGROUND: Tako-Tsubo cardiomyopathy (TTC) is a recently described medical entity and the incidence of TTC in a global population is still uncertain. We sought to prospectively assess the incidence of TTC in a large urban area. METHODS AND RESULTS: We included all consecutive patients referred for coronary angiography in three hospitals located in Paris and its suburbs. We prospectively estimated the percentage of TTC among patients referred for coronary angiography and extrapolated the number of cases of TTC in the greater Paris area (11,598,866 inhabitants) according to the CARDIO-ARHIF registry (government agency). Among 2547 patients (2972 coronary angiographies) including 815 acute coronary syndromes, 20 patients presented with TTC (19 women, mean age 66 ± 13 years). The percentage of TTC among suspected acute coronary syndromes was 2.5% (8.2% in women versus 0.2% in men, p<0.001). In the CARDIO-ARHIF registry, we individualized 51,403 coronary angiographies performed in all catheterization laboratories in one year (13,820 women and 10,246 women ≥ 60 years). In this region, the yearly number of TTC cases is estimated to be 346 (95% CI: 216-520). The annual incidence of TTC is estimated to be 29.8 per 1,000,000 inhabitants (95% CI: 18.6-44.9), 48.2 per 1,000,000 inhabitants (95% CI: 29.7-73.0) among women and 187.4 per 1,000,000 inhabitants (95% CI: 103.3-307.2) among women ≥ 60 years. CONCLUSIONS: Within a large urban agglomeration, the incidence of TTC is high in women ≥ 60 years. The current rate of this recently described cardiomyopathy has been underestimated in previous retrospective studies and will probably rise with the increase of life expectancy.

Myocarditis during acute schistosomiasis in two travelers.

We report two cases of myocarditis complicating acute schistosomiasis in returning travelers. Treatment with corticosteroids led to full recovery in both cases. Although the pathophysiology of this complication remains unclear, we recommend treating such patients with corticosteroids rather than praziquantel, which can be associated with clinical deterioration.