Matteo Tebaldi

Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome.

OBJECTIVESnThis study sought to investigate the evolving pattern over time of on-clopidogrel platelet reactivity (PR) and its relationship with genotype and clinical outcomes after percutaneous coronary intervention.nnnBACKGROUNDnWhether on-clopidogrel PR and role of genotype differ over time is unknown.nnnMETHODSnOn-clopidogrel PR before percutaneous coronary intervention, and 1 and 6 months thereafter via VerifyNow P2Y12 (Accumetrics Inc., San Diego, California), CYP2C19*2, *17, CYP3A5*3, and ABCB1 polymorphisms were evaluated in 300 patients. Death, stroke, myocardial infarction, and bleedings were assessed up to 1 year.nnnRESULTSnOn-clopidogrel PR varied significantly over time, being higher at baseline than at 1 and 6 months after. From baseline to 1 month, 83 of 300 patients varied their response status. This was mainly due to baseline poor responders becoming full responders (75 of 83). Genotype justifies roughly 18% of this trend. CYP2C19*2 and *17 influence on PR was consistent over time, whereas that of ABCB1 appeared of greater impact at baseline. On-clopidogrel PR at 1 month independently best predicts ischemic and bleeding events. We found a therapeutic window (86 to 238 P2Y₁₂ reactivity units) with a lower incidence of both ischemic and bleeding complications. A risk score was created by combining genotype (ABCB1 and CYP2C19*2), baseline PR, and creatinine clearance to predict 1-month poor responsiveness and 1-year poor prognosis.nnnCONCLUSIONSnIn patients at steady state for clopidogrel undergoing percutaneous coronary intervention, PR decreases from baseline to 1 month. Genotype influences ≈18% of this trend. On-clopidogrel PR at 1 month is the strongest predictor of adverse outcomes, and this can be predicted by combining genotype to baseline phenotype and clinical variables.

Diagnostic Accuracy of Fast Computational Approaches to Derive Fractional Flow Reserve From Diagnostic Coronary Angiography : The International Multicenter FAVOR Pilot Study

OBJECTIVESnThe aim of this prospective multicenter study was to identify the optimal approach for simple and fastxa0fractional flow reserve (FFR) computation from radiographic coronary angiography, called quantitative flow ratio (QFR).nnnBACKGROUNDnA novel, rapid computation of QFR pullbacks from 3-dimensional quantitative coronary angiography was developed recently.nnnMETHODSnQFR was derived from 3 flow models with: 1) fixed empiric hyperemic flow velocity (fixed-flow QFR [fQFR]); 2)xa0modeled hyperemic flow velocity derived from angiography without drug-induced hyperemia (contrast-flow QFR [cQFR]); and 3) measured hyperemic flow velocity derived from angiography during adenosine-induced hyperemia (adenosine-flow QFR [aQFR]). Pressure wire-derived FFR, measured during maximal hyperemia, served as the reference. Separate independent core laboratories analyzed angiographic images and pressure tracings from 8 centers in 7 countries.nnnRESULTSnThe QFR and FFR from 84 vessels in 73 patients with intermediate coronary lesions were compared. Meanxa0angiographic percent diameter stenosis (DS%) was 46.1 ± 8.9%; 27 vessels (32%) had FFRxa0≤ 0.80. Good agreement with FFR was observed for fQFR, cQFR, and aQFR, with mean differences of 0.003 ± 0.068 (pxa0= 0.66), 0.001 ± 0.059 (pxa0= 0.90), and -0.001 ± 0.065 (pxa0= 0.90), respectively. The overall diagnostic accuracy for identifying an FFR ofxa0≤0.80 was 80% (95% confidence interval [CI]: 71% to 89%), 86% (95% CI: 78% to 93%), and 87% (95% CI: 80% to 94%). The area under the receiver-operating characteristic curve was higher for cQFR than fQFR (difference: 0.04; 95% CI: 0.01 to 0.08; pxa0< 0.01), but did not differ significantly between cQFR and aQFR (difference: 0.01; 95% CI: -0.04 to 0.06; pxa0= 0.65). Compared with DS%, both cQFR and aQFR increased the area under the receiver-operating characteristic curve by 0.20 (pxa0< 0.01) and 0.19 (pxa0< 0.01). The positive likelihood ratio was 4.8, 8.4, and 8.9 for fQFR, cQFR, and aQFR, with negative likelihood ratio of 0.4, 0.3, and 0.2, respectively.nnnCONCLUSIONSnThe QFR computation improved the diagnostic accuracy of 3-dimensional quantitative coronary angiography-based identification of stenosis significance. The favorable results of cQFR that does not require pharmacologic hyperemia induction bears the potential of a wider adoption of FFR-based lesion assessment through a reduction in procedure time, risk, and costs.

Short- Versus Long-Term Duration of Dual Antiplatelet Therapy in Patients Treated for In-Stent Restenosis A PRODIGY Trial Substudy (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia)

OBJECTIVESnThis study sought to investigate the clinical outcome of patients treated with percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) randomized to short (6 months) versus long (24 months) dual antiplatelet therapy (DAPT) regimen.nnnBACKGROUNDnIt is still unclear if patients treated for ISR may benefit from a long DAPT regimen.nnnMETHODSnFor the present purpose, we selected 224 patients undergoing the PCI procedure for ISR enrolled in the PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia) trial and randomized to short (6 months) versus long (24 months) DAPT regimen. The primary objective was the cumulative incidence of death, nonfatal myocardial infarction (MI), or cerebrovascular accident at 24 months. Safety endpoints were moderate and major bleeding complications.nnnRESULTSnOverall, 114 patients were allocated to short DAPT regimen, whereas 110 patients were allocated to long DAPT regimen. Twenty-seven patients reached the primary endpoint (19 in short DAPT regimen vs. 8 in long DAPT regimen; pxa0= 0.02). The cumulative incidence of the primary endpoint at 24 months was 16.7% in the short DAPT regimen group compared with 7.3% in the long DAPT regimen group (pxa0= 0.034). This is principally due to a lower occurrence of death and MI in the long DAPT regimen group as compared to the short DAPT regimen group (6.5%xa0vs.xa015.5%; pxa0= 0.03). There was no difference in the occurrence of bleeding complications between long and short DAPT regimen.nnnCONCLUSIONSnOur study offers preliminary evidence that patients receiving a new PCI procedure for ISR may benefit from long-term administration of aspirin plus clopidogrel. (Synergy Between Stent and Drugs to Avoid Ischemic Recurrences After Percutaneous Coronary Intervention [PRODIGY]; NCT00611286).

Genetic determinants of on-clopidogrel high platelet reactivity

Clopidogrel has been used (alone or in association with aspirin) to prevent vascular complications in atherothrombotic patients, to prevent stent thrombosis (ST) in patients undergoing percutaneous coronary intervention (PCI) and as a long-term prevention of cardiovascular and cerebrovascular events. Unfortunately, it is important to note that there are a number of patients who, during clopidogrel therapy, show and maintain a high platelet reactivity (PR), similar to that observed before the start of antiplatelet therapy. Clopidogrel pro-drug is absorbed in the intestine and this process is influenced by P-glycoprotein-1 (P-GP). Its conversion into 2-oxo clopidogrel is regulated by cytochromes (CYP) called CYP2C19, CYP2B6 and CYP1A2. Whereas, the final transformation into the active metabolite is regulated by CYP called CYP2C19, CYP2C9, CYP2B6, CYP3A4, CYP3A5 and, as recently emerged, by the glycoprotein paraoxonase-1 (PON1). The genes encoding these enzymes are characterized by several polymorphisms. Some of these are able to modify the activity of proteins, reducing the concentration of active metabolite and the values of on-clopidogrel PR. Only one gene polymorphism (CYP2C19*17) increases the clopidogrel metabolization and so the clopidogrel-induced platelet inhibition. Several studies have clearly associated these gene polymorphisms to both ischemic and bleeding complications in patients receiving dual antiplatelet therapy. The aim of this review is to describe the principal gene polymorphisms influencing on-clopidogrel PR and their relationship with long-term clinical outcome.

Fractional flow reserve evaluation and chronic kidney disease: Analysis from a multicenter Italian registry (the FREAK study)

To establish if the presence of chronic kidney disease (CKD) influences fractional flow reserve (FFR) value in patients with intermediate coronary stenosis.

On-treatment platelet reactivity in patients with chronic obstructive pulmonary disease undergoing percutaneous coronary intervention

Patients with chronic obstructive pulmonary disease (COPD) show a poor prognosis after myocardial infarction (MI) and percutaneous coronary intervention (PCI). We evaluated on-treatment platelet reactivity (PR) and several gene polymorphisms related to PR in 130 patients undergoing PCI with and without COPD. Those with concomitant COPD showed higher on-treatment PR values both at the time of PCI and 1u2005month after. This finding may contribute to explain the poor prognosis of COPD patients after MI and PCI.

Prognostic value of serial platelet reactivity measurements on long-term clinical outcome in patients with ST-elevation myocardial infarction undergoing primary PCI.

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Occurrence, causes, and outcome after switching from ticagrelor to clopidogrel in a real-life scenario: data from a prospective registry

Abstract In randomized clinical trials, ticagrelor has been substituted in roughly one-third of the patients during follow-up. To date, there are no studies addressing safety and modalities of switching from ticagrelor to clopidogrel. The aim of our study is to describe the occurrence, causes, and outcome of the switch from ticagrelor to clopidogrel in a real-life scenario. From June 2013 to March 2015, 586 patients were treated with ticagrelor in our centre. Overall, 101 (17%) patients were switched to clopidogrel through a standardized protocol, and they were followed-up for 12 months. Ischemic and bleeding events were prospectively recorded. The switch from ticagrelor to clopidogrel occurred mostly after discharge (69 ± 40 days), and the most frequent cause was the need of oral anticoagulation treatment, followed by bleeding events. Patients requiring ticagrelor discontinuation were older, more frequently female, with lower body mass index and creatinine clearance if compared to the “non-switched” group. In the 10 days after the switch, we did not observe ischemic adverse events. No definite/probable stent thrombosis was recorded. Before the switch, there was a significant higher occurrence of BARC bleedings in the “switched” group, particularly BARC 1 and 2. Our data confirm that the switch from ticagrelor to clopidogrel is common, and it occurs for several reasons. Our analysis did not demonstrate a significant increase in adverse cardiovascular events in the days following the switch from ticagrelor to clopidogrel, although larger studies are needed to validate our findings.

Coagulation Factors and Recurrence of Ischemic and Bleeding Adverse Events in Patients with Acute Coronary Syndromes

In the last years, management and prognosis of patients with acute coronary syndromes (ACS) are significantly improved. Nowadays antithrombotic (antiplatelet plus anticoagulant drugs) therapy represents the main treatment of ACS patients. Anticoagulant drugs are particularly helpful in the acute phase of ACS, whereas in the chronic phase are maintained only in selected cases. Many studies demonstrate that exists a significant variability in the coagulation factor levels between patients affected by ACS. This variation on coagulation factors levels is due to environmental (smoking, inflammation, sex, oral contraceptive, triglycerides, diabetes mellitus) and genetic determinants. Particularly several gene polymorphisms have been selected and clearly associated with significant variations in the coagulation factors values. The heightened levels of tissue factor, factor VII and fibrinogen are related with a hypercoagulable status and with a higher occurrence of ischemic complications after ACS and/or PCI. On the contrary, less data are available regarding the relationship between coagulation factors levels (or their gene polymorphisms) and bleeding complications. Recently, new anticoagulant drugs have been developed. They show less side effects and a better tolerability and, probably, their selected use in patients with a hypercoagulable status may improve the clinical outcome after ACS. In this review we analyze the current available data and we discuss how this finding may be useful for planning future studies to optimize the treatment of ACS patients.

Effects of pre-hospital clopidogrel administration on early and late residual platelet reactivity in ST-segment elevation myocardial infarction patients undergoing primary intervention.

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