Laura Gatto

Point-of-Care Measurement of Clopidogrel Responsiveness Predicts Clinical Outcome in Patients Undergoing Percutaneous Coronary Intervention : Results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) Study

OBJECTIVES The aim of this study was to evaluate the correlation of point-of-care measurement of platelet inhibition with clinical outcome in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND Individual variability of clopidogrel response might influence results of PCI. METHODS A total of 160 patients receiving clopidogrel before PCI were prospectively enrolled. Platelet reactivity was measured by the VerifyNow P2Y12 assay (Accumetrics Inc., San Diego, California). Primary end point was 30-day occurrence of major adverse cardiac events (MACE) according to quartile distribution of P2Y12 reaction units (PRU). RESULTS Primary end point occurred more frequently in patients with pre-procedural PRU levels in the fourth quartile versus those in the lowest quartile (20% vs. 3%; p=0.034), and it was entirely due to periprocedural myocardial infarction (MI). Mean PRU absolute levels were higher in patients with periprocedural MI (258+/-53 vs. 219+/-69 in patients without; p=0.030). On multivariable analysis pre-PCI PRU levels in the fourth quartile were associated with 6-fold increased risk of 30-day MACE (odds ratio: 6.1; 95% confidence interval: 1.1 to 18.3, p=0.033). By receiver-operating characteristic curve analysis, the optimal cut-off for the primary end point was a pre-PCI PRU value>or=240 (area under the curve: 0.69; 95% confidence interval: 0.56 to 0.81, p=0.016). CONCLUSIONS This study indicates that high pre-PCI platelet reactivity might predict 30-day events. Use of a rapid point-of-care assay for monitoring residual platelet reactivity after clopidogrel administration might help identify patients in whom individualized antiplatelet strategies might be indicated with 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.

Suboptimal stent deployment is associated with subacute stent thrombosis: Optical coherence tomography insights from a multicenter matched study. From the CLI Foundation investigators: the CLI-THRO study

BACKGROUND Acute or subacute stent thrombosis (ST) is a well-described complication usually causing acute coronary syndromes and, in the worst case scenario, sudden cardiac death. In this study, we aimed at exploring the potential role of optical coherence tomography (OCT) in the understanding of the mechanism of ST. METHODS Twenty-one consecutive patients, after acute coronary syndromes due to a definite subacute ST, were assessed with OCT and matched 1:2 with 42 patients undergoing OCT for scheduled follow-up. Optical coherence tomography assessment was focused on features indicative of nonoptimal stent deployment: underexpansion, malapposition, edge dissection, and reference lumen narrowing. RESULTS Optical coherence tomography revealed a minimum stent area sensibly smaller in the ST group (5.6 ± 2.6 vs 6.8 ± 1.7 mm(2); P = .03) with a higher incidence of stent underexpansion when compared with the control group (42.8% vs 16.7%; P = .05). Dissection at stent edges was more commonly detected in ST group (52.4% vs 9.5%; P < .01). No significant differences between the 2 groups were observed for malapposition (52.4% vs 38.1%; P = .651) and reference lumen narrowing (19.0% vs 4.8%; P = .172). At least 1 OCT finding indicative of suboptimal stent deployment was detectable in 95.2% of patients experiencing ST versus 42.9% of the control group (P < .01). CONCLUSIONS Optical coherence tomography assessment in patients experiencing subacute ST revealed nonoptimal stent deployment in almost all cases with higher incidence of stent underexpansion and edge dissection, potentially explaining the cause of this adverse event. The adoption of an OCT-guided percutaneous coronary intervention protocol could have a potential for the prevention of ST in complex cases.

Identification and quantification of macrophage presence in coronary atherosclerotic plaques by optical coherence tomography

AIMS Vulnerable plaques are characterized by a high macrophage content. We investigated the optical coherence tomography (OCT) capability of identifying coronary plaque macrophage presence using tissue property indexes. METHODS AND RESULTS Fifteen epicardial coronary arteries were imaged by OCT and subsequently analysed by histology. Correlating OCT-histological sections were identified and regions of interest (ROIs) were selected on both atherosclerotic plaques and normal appearing vessel tracts. OCT-derived tissue property indexes named normalized standard deviation (NSD), signal attenuation, and granulometry index were applied on ROIs to identify inflamed ROIs defined as a macrophage percentage >10 by histology. Forty-three paired samples (OCT frame and histology section) were considered suitable as ROIs for analysis. Eleven out of 43 ROIs were considered inflamed and the remaining 32 ROIs were non-inflamed on the basis of histological count of macrophage percentage. All OCT-derived tissue property indexes were positively correlated with macrophage percentage (P = 0.0001 for all). Receiver operating characteristic curve analysis showed that NSD, granulometry index, and signal attenuation had a significant area under the curve (area = 0.906, 0.804, and 0.793, respectively). A two-step algorithm requiring to first apply NSD with a cut-off value of 0.0570 followed by granulometry index was able to identify an inflamed ROI with a sensitivity of 100% and a specificity of 96.8%. CONCLUSION OCT was able to identify and quantify macrophage presence in coronary artery specimens using tissue property indexes. NSD and granulometry index showed the highest accuracy in identifying a significant plaque inflammation, especially if used together in a two-step algorithm.

Randomized evaluation of intralesion versus intracoronary abciximab and aspiration thrombectomy in patients with ST-elevation myocardial infarction: The COCTAIL II trial

BACKGROUND Thrombus burden and distal embolization are predictive of no-reflow during primary percutaneous coronary intervention (PCI) in patients with acute ST-elevation myocardial infarction (STEMI). We sought to compare the efficacy of pharmacological and catheter-based strategies for thrombus in patients with STEMI and high atherothrombotic burden. METHODS Between January 2012 and December 2013, 128 STEMI patients undergoing primary PCI at 5 centers were randomly assigned in a 2 × 2 factorial design to intracoronary (IC) abciximab bolus (via the guide catheter) versus intralesion (IL) abciximab bolus, each with versus without aspiration thrombectomy (AT). Study end points were residual intrastent atherothrombotic burden, defined as the number of cross-sections with residual tissue area >10% as assessed by optical coherence tomography, and indices of angiographic and myocardial reperfusion. RESULTS Residual intrastent atherothrombotic burden did not significantly differ with IL versus IC abciximab (median [interquartile range] 6.0 [1-15] vs 6.0 [2-11], P = .806) and with AT versus no aspiration (6.0 [1-13] vs 6.0 [2-12], P = .775). Intralesion abciximab administration was associated with improved angiographic myocardial reperfusion in terms of thrombolysis in myocardial infarction (TIMI) flow (3 [3-3] vs 3 [2-3], P = .040), corrected TIMI frame count (12 ± 5 vs 17 ± 16, P = .021), and myocardial blush grade (3 [2-3] vs 3 [2-3], P = .035). In particular, IL abciximab was associated with higher occurrence of final TIMI 3 flow (90% vs 73.8%, P = .032) and myocardial blush grade 3 (71.6% vs 52.4%, P = .039). Conversely, AT had no significant effect on indices of angiographic or myocardial reperfusion. CONCLUSIONS In patients with STEMI and high thrombotic burden, neither IL versus IC abciximab nor AT versus no aspiration reduced postprocedure intrastent atherothrombotic burden in patients with STEMI undergoing primary PCI. However, IL abciximab improved indices of angiographic and myocardial reperfusion compared to IC abciximab, benefits not apparent with AT.

Thresholds for platelet reactivity to predict clinical events after coronary intervention are different in patients with and without diabetes mellitus

Abstract Patients with diabetes mellitus (DM) have increased baseline platelet reactivity and impaired response to antiplatelet drugs, compared to non-diabetics. Aim of the present study was to investigate whether thresholds for high platelet reactivity (HPR) that predict clinical outcomes after percutaneous coronary intervention (PCI) are similar in diabetic compared to non-diabetic patients. A total of 640 (32.6% with DM) consecutive patients taking aspirin and clopidogrel undergoing elective PCI were recruited. Platelet reactivity was measured immediately before the procedure with the VerifyNow P2Y12 assay. Primary end point was the 30-day incidence of major adverse cardiac events (MACE) in relation to the presence of DM and to P2Y12 reaction units (PRU) distribution. The optimal cut-off to predict 30-day MACE was a PRU value of >256 in diabetics, and a PRU value of >229 in non-diabetics. Accordingly, we redefined HPR on the basis of these two specific thresholds (HPR-ST), now including 60/209 (29%) diabetic patients with PRU >256, and 130/431 (30%) non-diabetic patients with PRU >229. HPR-ST discriminates significantly (p < 0.001) patients with and without MACE, with a diagnostic accuracy of 73%. The combination of DM and HPR-ST resulted in the highest incidence of MACE (23.3%; p for trend <0.001). At multivariate analysis, HPR-ST was the strongest independent predictor of 30-day MACE (odds ratio 4.80, 95% confidence interval 2.58–8.93; p < 0.001). Redefining HPR based on specific thresholds for patients with and without DM significantly improves prediction of MACE post-PCI. Patients with HPR-ST, especially in the presence of DM, are at increased risk for ischemic events and may benefit from more aggressive antiplatelet strategies.

Short-term atorvastatin preload reduces levels of adhesion molecules in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Results from the ARMYDA-ACS CAMs (Atorvastatin for Reduction of MYocardial Damage during Angioplasty-Cell Adhesion Molecules) substudy.

Objectives In patients with stable angina receiving percutaneous coronary intervention (PCI) prevention of periprocedural myocardial infarction by atorvastatin pretreatment was associated with reduction of endothelial activation. This mechanism was not evaluated in patients with acute coronary syndrome (ACS). The aim was to investigate effects of atorvastatin load on adhesion molecules in ACS patients undergoing PCI. Methods In a planned subanalysis of the ARMYDA-ACS trial, a subgroup of 44 patients were blind-tested for measurement of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin plasma levels; 21 patients belonged to the atorvastatin (80 mg 12 h before PCI, with a further 40 mg preprocedure dose) and 23 to the placebo arm. Adhesion molecules were evaluated at randomization (12 h before intervention), immediately before PCI and after 8 and 24 h. Results Reduction of procedural myocardial injury after statin pretreatment was confirmed in this subgroup. ICAM-1, VCAM-1 and E-selectin levels were similar at randomization and before intervention in both arms. At 8 h, ICAM-1 increase was similar in the two arms, whereas 24-h levels were lower in the atorvastatin vs. placebo group (241 ± 25 vs. 261 ± 30 ng/ml; P = 0.019). Significant attenuation of VCAM-1 elevation occurred both at 8 and 24 h in the atorvastatin group (509 ± 56 vs. 545 ± 59 ng/ml; P = 0.044 and 561 ± 58 vs. 600 ± 53 ng/ml; P = 0.025). E-selectin levels were not different at any time-point in the two arms. Conclusion In ACS patients undergoing PCI, reduction of procedural myocardial injury after atorvastatin load is associated with attenuation of endothelial inflammatory response. This may contribute to mechanisms of statin cardioprotection in this setting.

Clinical Impact of Suboptimal Stenting and Residual Intrastent Plaque/Thrombus Protrusion in Patients With Acute Coronary Syndrome: The CLI-OPCI ACS Substudy (Centro per la Lotta Contro L'Infarto-Optimization of Percutaneous Coronary Intervention in Acute Coronary Syndrome).

Background—Clinical consequences of optical coherence tomographic (OCT) high-definition visualization of plaque/stent structures in acute patients remain undefined. In this retrospective substudy, we assessed the prognostic impact of postprocedural culprit lesion OCT findings in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Methods and Results—In the CLI-OPCI (Centro per la Lotta Contro L’Infarto-Optimization of Percutaneous Coronary Intervention) database collecting cases from 5 independent OCT-experienced centers, we retrospectively analyzed postprocedural OCT findings in acute coronary syndrome patients and explored its possible impact (specifically that of residual intrastent plaque/thrombus protrusion) on outcome. From 2009 to 2013, 507 patients (588 lesions) were evaluated. Patients experiencing device-oriented cardiovascular events showed more frequently the features of suboptimal stent implantation defined as the presence of significant residual intrastent plaque/thrombus protrusion (hazard ratio [HR], 2.35; P<0.01), in-stent minimum lumen area (MLA) <4.5 mm2 (HR, 2.72; P<0.01), dissection >200 µm at distal stent edge (HR, 3.84; P<0.01), and reference lumen area <4.5 mm2 at either distal (HR, 6.07; P<0.001) or proximal (HR, 8.50; P<0.001) stent edges. Postprocedural OCT assessment of treated culprit lesion revealed at least one of these parameters in 55.2% of cases, with an associated increased risk of device-oriented cardiovascular events during follow-up (17.9% versus 4.8%; P<0.001). Both the presence of at least one of these parameters (HR, 3.69; P=0.002) and the residual intrastent plaque/thrombus protrusion (HR, 2.83; P=0.008) were confirmed as independent predictors of device-oriented cardiovascular events. Conclusions—In this retrospective study of acute coronary syndrome patients undergoing percutaneous coronary intervention, a composite of OCT-defined suboptimal stent implantation characteristics at the culprit lesion and residual intrastent plaque/thrombus protrusion was associated with adverse outcome.