Elisabetta Ricottini

Short-term, high-dose Atorvastatin pretreatment to prevent contrast-induced nephropathy in patients with acute coronary syndromes undergoing percutaneous coronary intervention (from the ARMYDA-CIN [atorvastatin for reduction of myocardial damage during angioplasty--contrast-induced nephropathy] trial.

Contrast-induced nephropathy (CIN) impairs clinical outcome in patients undergoing angiographic procedures. The aim of this study was to investigate whether short-term high-dose atorvastatin load decreases the incidence of CIN after percutaneous coronary intervention (PCI). Statin-naive patients with acute coronary syndrome undergoing PCI (n = 241) randomly received atorvastatin (80 mg 12 hours before intervention with another 40-mg preprocedure dose, n = 120) or placebo (n = 121). All patients had long-term atorvastatin treatment thereafter (40 mg/day). Primary end point was incidence of CIN defined as postintervention increase in serum creatinine ≥0.5 mg/dl or >25% from baseline. Five percent of patients in the atorvastatin arm developed CIN versus 13.2% of those in the placebo arm (p = 0.046). In the atorvastatin group, postprocedure serum creatinine was significantly lower (1.06 ± 0.35 vs 1.12 ± 0.27 mg/dl in placebo, p = 0.01), creatinine clearance was decreased (80.1 ± 32.2 vs 72.0 ± 26.6 ml/min, p = 0.034), and C-reactive protein peak levels after intervention were decreased (8.4 ± 10.5 vs 13.1 ± 20.8 mg/l, p = 0.01). Multivariable analysis showed that atorvastatin pretreatment was independently associated with a decreased risk of CIN (odds ratios 0.34, 95% confidence interval 0.12 to 0.97, p = 0.043). Prevention of CIN with atorvastatin was paralleled by a shorter hospital stay (p = 0.007). In conclusion, short-term pretreatment with high-dose atorvastatin load prevents CIN and shortens hospital stay in patients with acute coronary syndrome undergoing PCI; anti-inflammatory effects may be involved in this renal protection. These results lend further support to early use of high-dose statins as adjuvant pharmacologic therapy before percutaneous coronary revascularization.

Usefulness of Platelet Response to Clopidogrel by Point-of-Care Testing to Predict Bleeding Outcomes in Patients Undergoing Percutaneous Coronary Intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding Study)

Platelet reactivity predicts ischemic outcomes in patients who undergo percutaneous coronary intervention (PCI), but the correlation of heightened platelet response with bleeding has not been characterized. The aim of this study was to evaluate whether low platelet reactivity by point-of-care measurement after clopidogrel administration correlates with bleeding complications of PCI. A total of 310 patients receiving clopidogrel before PCI were prospectively enrolled. Platelet reactivity was measured with the VerifyNow P2Y12 assay. The primary end point was the 30-day incidence of major bleeding or entry-site complications according to quartile distribution of P2Y12 reaction units (PRU). The primary end point occurred more frequently in patients with preprocedural PRU levels in the lowest quartile compared to those in the highest quartile (10.1% vs 1.3%, p = 0.043), due mainly to entry-site hemorrhages. Absolute PRU levels were lower in patients with major bleeding (171 ± 49 vs 227 ± 68 in patients without, p = 0.002). On multivariate analysis, pre-PCI PRU levels in the first quartile were associated with a 4.5-fold increased risk for major bleeding (odds ratio 4.5, 95% confidence interval 1.9 to 25.9, p = 0.01). By receiver-operating characteristic curve analysis, the optimal cutoff for the primary end point was a pre-PCI PRU value ≤ 189 (area under the curve 0.76, 95% confidence interval 0.66 to 0.87, p = 0.001). In conclusion, this study suggests that an enhanced response to clopidogrel may be associated with higher risk for early major bleeding or entry-site complications in patients who undergo PCI. Point-of-care monitoring of platelet reactivity after clopidogrel administration may help identify patients in whom individualized strategies are indicated to limit bleeding complications after coronary intervention.

A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMYDA-PROVE (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity for Outcome Validation Effort) study.

OBJECTIVES This study sought to validate the ability of the VerifyNow P2Y12 assay (Accumetrics, San Diego, California) in predicting both ischemic and bleeding events after elective percutaneous coronary intervention (PCI). BACKGROUND High and low levels of platelet reactivity are associated with ischemic and bleeding events, respectively, after PCI. METHODS A total of 732 patients on dual antiplatelet therapy undergoing elective PCI were recruited. Platelet reactivity was measured before PCI. The primary endpoint was the 30-day incidence of net adverse clinical events (NACE), defined as the occurrence of ischemic or bleeding events, in relation to P2Y(12) reaction unit (PRU) distribution. RESULTS At receiver-operating characteristic curve analysis, PRU values could significantly discriminate between patients with and without bleeding events (area under the curve [AUC]: 0.72; 95% confidence interval [CI]: 0.65 to 0.80; p < 0.0001) and those with and without ischemic events (AUC: 0.68; 95% CI: 0.61 to 0.76; p < 0.0001). The optimal cutoffs for bleeding (PRU ≤ 178) and ischemic events (PRU ≥ 239) were used to define 3 groups: low platelet reactivity (LPR) (LPR = PRU ≤ 178), normal platelet reactivity (NPR) (NPR = PRU 179 to 238), and high platelet reactivity (HPR) (HPR = PRU ≥ 239). The incidence of NACE was 14.1% in the LPR group, 7.8% in the NPR group (p = 0.025 vs. LPR group), and 15.4% in the HPR group (p = 0.005 vs. NPR group). At multivariate analysis, PRU values in the NPR group were an independent predictor of reduced risk of 30-day NACE (odds ratio: 0.47, 95% CI: 0.27 to 0.81). CONCLUSIONS A therapeutic window for platelet reactivity measured with the VerifyNow P2Y12 assay can be identified using specific thresholds that define a group of patients at lower risk for both ischemic and bleeding events. Adjunctive measures may be beneficial in patients with higher or lower platelet reactivity in order to improve clinical outcomes after PCI.

Comparison of Platelet Reactivity and Periprocedural Outcomes in Patients With Versus Without Diabetes Mellitus and Treated With Clopidogrel and Percutaneous Coronary Intervention

The effect of periprocedural platelet reactivity and clinical outcomes in diabetic patients taking clopidogrel and undergoing percutaneous coronary intervention (PCI) is unclear. The aim of the present study was to prospectively evaluate the influence of diabetes mellitus (DM) on platelet reactivity measured by the VerifyNow P2Y12 assay and on periprocedural outcomes in patients receiving clopidogrel and undergoing PCI. A total of 285 consecutive clopidogrel-treated patients undergoing elective PCI were included. Platelet function analysis was performed using the VerifyNow P2Y12 assay. High platelet reactivity (HPR) after clopidogrel was defined as a platelet reaction unit value > or =240. Cardiac biomarkers were measured before and 8 and 24 hours after intervention. Patients with DM had significantly higher platelet reactivity before PCI compared to nondiabetics (214 +/- 83 vs 193 +/- 68 platelet reaction units, p = 0.02). HPR was more frequently observed in diabetics (36% vs 22%, p = 0.01) before PCI. Patients with DM had an increased incidence of periprocedural myocardial infarction (MI; 11% vs 4%, p = 0.04). When the entire population was divided by the presence or absence of DM and HPR, patients with DM and HPR presented the highest incidence of periprocedural MI (p for trend = 0.0008). HPR was an independent predictor of periprocedural MI (odds ratio 8.34, 95% confidence interval 2.60 to 26.76, p = 0.0003). In conclusion, patients with DM undergoing PCI have higher platelet reactivity at the time of PCI despite adequate clopidogrel pretreatment and subsequently worse periprocedural outcomes. Point-of-care platelet function testing may help to identify patients at higher risk of periprocedural MI.

Point-of-care assessment of platelet reactivity after clopidogrel to predict myonecrosis in patients undergoing percutaneous coronary intervention.

OBJECTIVES We sought to evaluate the influence of platelet reactivity after clopidogrel, as assessed by the VerifyNow point-of-care assay (Accumetrics, San Diego, California), on myonecrosis in low-to-intermediate risk patients undergoing percutaneous coronary intervention (PCI). BACKGROUND Inadequate platelet inhibition at the time of PCI is associated with a higher risk of recurrent ischemic events. METHODS A total of 250 consecutive biomarker-negative patients treated with clopidogrel and undergoing elective PCI were enrolled. Cardiac biomarkers (creatine kinase-myocardial band and troponin I) were measured before and 8 and 24 h after intervention. Platelet reactivity after clopidogrel was assessed immediately before PCI by the VerifyNow P2Y12 point-of-care assay. High platelet reactivity (HPR) after clopidogrel was defined as a platelet reaction unit value > or =240. RESULTS Patients with HPR (31% of the overall population) showed more frequent myonecrosis, with statistical significance with regard to creatine kinase-myocardial band elevation (35% vs. 20%; p = 0.011), and by trend with regard to troponin-I elevation (47% vs. 35%; p = 0.059). Incidence of periprocedural myocardial infarction was higher in patients with HPR, both by creatine kinase-myocardial band (13% vs. 4%; p = 0.011) and troponin-I definition (32% vs. 19%; p = 0.019). By multivariable analysis, HPR was an independent predictor of periprocedural myocardial infarction. CONCLUSIONS Easily assessed by a point-of-care assay, HPR after clopidogrel is a frequent finding and is associated with increased risk of myonecrosis in low-to-intermediate risk patients undergoing planned PCI.

Strategies of Clopidogrel Load and Atorvastatin Reload to Prevent Ischemic Cerebral Events in Patients Undergoing Protected Carotid Stenting: Results of the Randomized ARMYDA-9 CAROTID (Clopidogrel and Atorvastatin Treatment During Carotid Artery Stenting) Study

OBJECTIVES This study sought to evaluate whether a strategy with a 600-mg clopidogrel load and a short-term, high-dose atorvastatin reload would improve outcomes in clopidogrel-naïve, statin-treated patients undergoing protected carotid stenting. BACKGROUND Optimal clopidogrel loading dose during carotid stenting has not been investigated; in addition, statin neuroprotection in this setting has not been described. METHODS A total of 156 patients were randomized using a 2 × 2 factorial design to receive either a 600-mg (n = 78) or 300-mg (n = 78) clopidogrel load given 6 h before intervention and either a atorvastatin reload (n = 76; 80 mg + 40 mg initiating 12 h before the procedure) or no statin reload (n = 80). The primary endpoint was the 30-day incidence of transient ischemic attack/stroke or new ischemic lesions on cerebral diffusion-weighted magnetic resonance imaging performed at 24 to 48 h. RESULTS Occurrence of the primary outcome measure was significantly lower in the 600-mg clopidogrel arm (18% vs. 35.9% in the 300-mg group; p = 0.019) and in the atorvastatin reload arm (18.4% vs. 35.0% in the no statin reload group; p = 0.031). High-dose clopidogrel also significantly reduced the transient ischemic attack/stroke rate at 30 days (0% vs. 9%, p = 0.02, secondary endpoint), without an increase in bleeding risk. CONCLUSIONS In patients undergoing carotid stenting, a strategy using both a 600-mg clopidogrel load and a short-term reload with high-dose atorvastatin protects against early ischemic cerebral events. These results, obtained along with routine mechanical neuroprotection, provide new evidence of the optimization of drug therapy before percutaneous carotid intervention. (Clopidogrel and Atorvastatin Treatment During Carotid Artery Stenting [ARMYDA-9 CAROTID]; NCT01572623).

Platelet function and long-term antiplatelet therapy in women: is there a gender-specificity? A ‘state-of-the-art’ paper

Although the female gender is generally less represented in cardiovascular studies, observational and randomized investigations suggest that-compared with men-women may obtain different benefits from antiplatelet therapy. Multiple factors, including hormonal mechanisms and differences in platelet biology, might contribute to such apparent gender peculiarities. The thrombotic and bleeding risks, as well as outcomes after a cardiovascular event, appear to differ between genders, partly in relation to differences in age, comorbidities and body size. Equally, the benefits of antiplatelet therapy may differ in women compared with men in different vascular beds, during primary or secondary prevention and according to the type of an antiplatelet agent used. This document is an attempt to bring together current evidence, clinical practices and gaps of knowledge on gender-specific platelet function and antiplatelet therapy. On the basis of the available data, we provide suggestions on current indications of antiplatelet therapy for cardiovascular prevention in women with different clinical features; no strong recommendation may be given because the available data derive from observational studies or post hoc/subgroup analyses of randomized studies without systematic adjustments for baseline risk profiles.

Impact of chronic kidney disease on platelet reactivity and outcomes of patients receiving clopidogrel and undergoing percutaneous coronary intervention.

The impact of chronic kidney disease (CKD) on residual platelet reactivity (PR) in patients undergoing percutaneous coronary intervention (PCI) is still debatable. We sought to investigate the interaction between PR and renal function and the related clinical outcomes in patients with coronary artery disease treated with PCI. Immediately before PCI, we measured PR (as P2Y12 reaction units [PRUs]) in 800 patients on clopidogrel with the VerifyNow P2Y12 assay. High PR was defined as a PRU value of ≥240 and low PR as a PRU value of ≤178. Based on a glomerular filtration rate of < or ≥60 ml/min/1.73 m2, patients were respectively grouped into those with or without moderate-to-severe CKD. Primary end point was the incidence of 30-day net adverse clinical events (NACEs). Patients with moderate-to-severe CKD (n=173, 21.6%) and those without showed similar PRU values (208±67 vs 207±75, p=0.819). Yet, NACEs were significantly higher in patients with moderate-to-severe CKD (19.7% vs 9.1%, p<0.001), in terms of both ischemic (12.1% vs 7.2%, p=0.036) and bleeding events (8.7% vs 2.1%, p<0.001). NACEs were significantly higher when moderate-to-severe CKD was associated with either high PR or low PR (25.4%, p for trend<0.001); this association was the strongest predictor of NACE at multivariate analysis (odds ratio 3.4, 95% confidence interval 2.0 to 5.6, p<0.001). In conclusion, we did not find an association between moderate-to-severe CKD and residual PR on clopidogrel. However, the association of moderate-to-severe CKD with either high or low PR was a strong determinant of adverse events after PCI.

The left atrial appendage: from embryology to prevention of thromboembolism

The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches.

Correlation of platelet reactivity and C-reactive protein levels to occurrence of peri-procedural myocardial infarction in patients undergoing percutaneous coronary intervention (from the ARMYDA-CRP study).

The incremental predictive value of high inflammatory status and high on-treatment platelet reactivity (HPR) on the occurrence of periprocedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI) has not been characterized. The aim of this study was to evaluate the correlation of elevated C-reactive protein (CRP) level and/or HPR with the incidence of PMI in patients who undergo PCI. Five hundred consecutive patients treated with clopidogrel who underwent PCI had preprocedural measurement of CRP levels and platelet reactivity using the point-of-care VerifyNow P2Y12 assay. Elevated inflammatory status was defined as CRP >3 mg/L and HPR as P2Y12 reactivity units ≥240. The primary end point was the incidence of PMI in relation to platelet reactivity and/or inflammatory status. Rates of PMI were increased in patients with CRP levels >3 mg/L (10.9% vs 4.6% in those with normal levels, odds ratio 2.4, 95% confidence interval 1.2 to 4.5, p = 0.015) and in patients with HPR (11% vs 5.5% in those without HPR, odds ratio 2.2, 95% confidence interval 1.2-4.4, p = 0.018). The occurrence of PMI was highest in the subgroup with HPR and high inflammatory status (16.6% vs 3.6% in patients with CRP ≤3 mg/L and P2Y12 reactivity units <240, odds ratio 4.3, 95% confidence interval 1.5 to 12.6, p = 0.008). HPR in association with elevated CRP levels resulted in a significant increase in the discriminatory power of a model including clinical and procedural variables in predicting PMI (area under the curve 0.811, p = 0.041). In conclusion, in patients who undergo PCI, baseline stratification according to platelet reactivity and inflammatory status may identify those at higher risk for PMI.