Fabio Mangiacapra

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.

Fractional Flow Reserve for the Assessment of Nonculprit Coronary Artery Stenoses in Patients With Acute Myocardial Infarction

OBJECTIVES We investigated the reliability of fractional flow reserve (FFR) of nonculprit coronary stenoses during percutaneous coronary intervention (PCI) in acute myocardial infarction. BACKGROUND Assessing the hemodynamic severity of the nonculprit coronary artery stenoses at the acute phase of a myocardial infarction could improve risk stratification and shorten the diagnostic work-up. METHODS One hundred one patients undergoing PCI for an acute myocardial infarction (n = 75 with ST-segment elevation myocardial infarction [STEMI], and n = 26 with non-ST-segment elevation myocardial infarction) were prospectively recruited. The FFR measurements in 112 nonculprit stenoses were obtained immediately after PCI of the culprit stenosis and were repeated 35 ± 4 days later. In addition, left ventricular ejection fraction, quantitative coronary angiographic measurements of the nonculprit stenoses, Thrombolysis In Myocardial Infarction (TIMI) flow, corrected TIMI frame count (cTFC), and the index of microcirculatory resistance (n = 14) of the nonculprit vessels were assessed in the acute phase and at control angiogram. RESULTS The FFR value of the nonculprit stenoses did not change between the acute and follow-up (0.77 ± 0.13 vs. 0.77 ± 0.13, respectively, p = NS). In only 2 patients, the FFR value was higher than 0.8 at the acute phase and lower than 0.75 at follow-up. The TIMI flow, cTFC, percentage diameter stenosis, minimum lumen diameter, and index of microcirculatory resistance did not change. Left ventricular ejection fraction increased significantly in patients with STEMI (from 54 ± 13% to 57 ± 13%, p = 0.03). CONCLUSIONS During the acute phase of acute coronary syndromes, the severity of nonculprit coronary artery stenoses can reliably be assessed by FFR. This allows a decision about the need for additional revascularization and might contribute to a better risk stratification.

Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention

AIMS Although platelet reactivity during P2Y12-inhibitors is associated with stent thrombosis (ST) and bleeding, standardized and clinically validated thresholds for accurate risk stratification after percutaneous coronary intervention (PCI) are lacking. We sought to determine the prognostic value of low platelet reactivity (LPR), optimal platelet reactivity (OPR), or high platelet reactivity (HPR) by applying uniform cut-off values for standardized devices. METHODS AND RESULTS Authors of studies published before January 2015, reporting associations between platelet reactivity, ST, and major bleeding were contacted for a collaborative analysis using consensus-defined, uniform cut-offs for standardized platelet function assays. Based on best available evidence for each device (exploratory studies), LPR-OPR-HPR categories were defined as <95, 95-208, and >208 PRU for VerifyNow, <19, 19-46, and >46 U for the Multiplate analyser and <16, 16-50, and >50% for VASP assay. Seventeen studies including 20 839 patients were used for the analysis; 97% were treated with clopidogrel and 3% with prasugrel. Patients with HPR had significantly higher risk for ST [risk ratio (RR) and 95% CI: 2.73 (2.03-3.69), P < 0.00001], yet a slight reduction in bleeding [RR: 0.84 (0.71-0.99), P = 0.04] compared with those with OPR. In contrast, patients with LPR had a higher risk for bleeding [RR: 1.74 (1.47-2.06), P < 0.00001], without any further benefit in ST [RR: 1.06 (0.68-1.65), P = 0.78] in contrast to OPR. Mortality was significantly higher in patients with HPR compared with other categories (P < 0.05). Validation cohorts (n = 14) confirmed all results of exploratory studies (n = 3). CONCLUSIONS Platelet reactivity assessment during thienopyridine-type P2Y12-inhibitors identifies PCI-treated patients at higher risk for mortality and ST (HPR) or at an elevated risk for bleeding (LPR).

Evolving concepts of angiogram: fractional flow reserve discordances in 4000 coronary stenoses

AIMS The present analysis addresses the potential clinical and physiologic significance of discordance in severity of coronary artery disease between the angiogram and fractional flow reserve (FFR) in a large and unselected patient population. METHODS AND RESULTS Between September 1999 and December 2011, FFR and percent diameter stenosis (DS) as assessed by quantitative coronary angiography were obtained in 2986 patients (n = 4086 coronary stenoses), in whom at least one stenosis was of intermediate angiographic severity. Fractional flow reserve correlated slightly but significantly with DS [-0.38 (95% CI: -0.41; -0.36); P < 0.001]. The sensitivity, specificity, and diagnostic accuracy of a ≥ 50% DS for predicting FFR ≤ 0.80 were 61% (95% CI: 59; 63), 67% (95% CI: 65; 69), and 0.64 (95% CI: 0.56; 0.72), respectively. In different anatomical settings, sensitivity and specificity showed marked variations between 35 to 74% and 58 to 76%, respectively, resulting in a discordance in 35% of all cases for these thresholds. For an angiographic threshold of 70% DS, the diagnostic performance by the Youdens index decreased from 0.28 to 0.11 for the overall population. CONCLUSION The data confirm that one-third of a large patient population shows discordance between angiogram ≥ 50%DS and FFR ≤ 0.8 thresholds of stenosis severity. Left main stenoses are often underestimated by the classical 50% DS cut-off compared with FFR. This discordance offers physiologic insights for future trials. It is hypothesized that the discordance between angiography and FFR is related to technical limitations, such as imprecise luminal border detection by angiography, as well as to physiologic factors, such as variable minimal microvascular resistance.

Outcome Comparison of 600- and 300-mg Loading Doses of Clopidogrel in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Results From the ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) Randomized Study

OBJECTIVES The purpose of this study was to compare 600- and 300-mg clopidogrel loading doses in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Given the high thrombotic risk of patients with STEMI, greater platelet inhibition may improve outcome in those patients receiving percutaneous coronary intervention (PCI). Although observational data suggest that pretreatment with a 600-mg clopidogrel loading dose may be more effective than the 300-mg regimen in primary PCI, this hypothesis has never been tested in a randomized study. METHODS A total of 201 patients undergoing primary PCI for STEMI randomly received a 600-mg (n = 103) or 300-mg (n = 98) clopidogrel loading dose before the procedure. The primary endpoint was the evaluation of the infarct size, defined as the area under the curve of cardiac markers. RESULTS Infarct size was significantly lower in the high-dose regimen: median creatine kinase-myocardial band 2,070 ng/ml (interquartile range [IQR]: 815 to 2,847 ng/ml) versus 3,049 ng/ml (IQR: 1,050 to 7,031 ng/ml) in the 300-mg group, p = 0.0001; troponin-I 255 ng/ml (IQR: 130 to 461 ng/ml) versus 380 ng/ml (IQR: 134 to 1,406 ng/ml), p < 0.0001. In the 600-mg arm, Thrombolysis In Myocardial Infarction flow grade <3 after PCI was less frequent (5.8% vs. 16.3%, p = 0.031), left ventricular ejection fraction at discharge was improved (52.1 ± 9.5% vs. 48.8 ± 11.3%, p = 0.026), 30-day major adverse cardiovascular events were fewer (5.8% vs. 15%, p = 0.049), and bleeding/entry site complications were not increased (secondary endpoints). CONCLUSIONS In STEMI patients, pre-treatment with a 600-mg clopidogrel loading dose before primary PCI was associated with a reduction of the infarct size compared with a 300-mg loading dose, as well as with improvement of angiographic results, residual cardiac function, and 30-day major adverse cardiovascular events; further studies are warranted to evaluate impact of such strategy on survival.

Translesional Pressure Gradients to Predict Blood Pressure Response After Renal Artery Stenting in Patients With Renovascular Hypertension

Background—In previous studies on the effect of renal stenting on arterial hypertension, patients were selected mainly on the basis of angiographic parameters of the renal artery stenosis. The aim of the present study was to evaluate whether translesional pressure gradients could identify the patients with renal artery stenosis who might benefit from stenting. Methods and Results—A total of 53 consecutive hypertensive patients with unilateral RAS scheduled for renal artery intervention were recruited. Transstenotic pressure gradients were measured at baseline and during maximal hyperemia, before renal artery stenting. Twenty-four-hour ambulatory blood pressure measurements were performed in all patients before and 3 months after the intervention. Average reductions in systolic blood pressure and diastolic blood pressure at follow-up were −20±30 mm Hg and −2±12 mm Hg, respectively. At multivariate analysis, dopamine-induced mean gradient was the only independent predictor of the variations of both systolic blood pressure (regression coefficient=−4.03, standard error=1.11; P<0.001) and diastolic blood pressure (regression coefficient=−3.11, standard error=1.20; P=0.009). Patients who showed a decline in systolic blood pressure from the baseline value >20 mm Hg were considered as “responders.” The optimal cutoff for identification of “responders” was a dopamine-induced mean gradient ≥20 mm Hg (area under the curve, 0.77; 95% confidence interval, 0.64 to 0.90; P=0.001). Conclusions—A dopamine-induced mean pressure gradient of ≥20 mm Hg is highly predictive of arterial hypertension improvement after renal stenting, and therefore this measurement is useful for appropriate selection of patients with arterial hypertension.

Long-term follow-up after fractional flow reserve-guided treatment strategy in patients with an isolated proximal left anterior descending coronary artery stenosis

OBJECTIVES This study sought to evaluate the long-term clinical outcome of patients with an angiographically intermediate left anterior descending coronary artery (LAD) stenosis in whom the revascularization strategy was based on fractional flow reserve (FFR). BACKGROUND When revascularization is based mainly on angiographic guidance, a number of hemodynamically nonsignificant stenoses will be revascularized. METHODS In 730 patients with a 30% to 70% isolated stenosis in the proximal LAD and no significant valvular disease, FFR measurements were obtained to guide treatment strategy. When FFR was ≥ 0.80, the patients (n = 564) were treated medically (medical group); when FFR was <0.80, the patients (n = 166) underwent a revascularization procedure (revascularization group; 13% coronary artery bypass graft surgery and 87% percutaneous coronary intervention). A 100% long-term clinical follow-up (median follow-up: 40 months) was obtained. The 5-year survival of the medical group was compared with that of a reference population. For each patient, 4 controls were selected from an age- and sex-matched control population. RESULTS The 5-year survival estimate was 92.9% in the medical group versus 89.6% in the controls (p = 0.74). The mean diameter stenosis was significantly smaller in the medical than in the revascularization group (39 ± 14% vs. 54 ± 13%, p < 0.0001), but there was a large overlap between both groups. The 5-year event-free survival estimates (death, myocardial infarction, and target vessel revascularization) were 89.7% and 68.5%, respectively (p < 0.0001). CONCLUSIONS Medical treatment of patients with a hemodynamically nonsignificant stenosis (FFR ≥ 0.80) in the proximal LAD is associated with an excellent long-term clinical outcome with survival at 5 years similar to an age- and sex-matched control population.

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.

High residual platelet reactivity after clopidogrel: extent of coronary atherosclerosis and periprocedural myocardial infarction in patients with stable angina undergoing percutaneous coronary intervention.

OBJECTIVES We tested the hypothesis that residual platelet reactivity after clopidogrel correlates with the extent and severity of coronary atherosclerosis in patients undergoing elective percutaneous coronary intervention (PCI). BACKGROUND Platelets are actively involved in vascular atherosclerosis. METHODS We prospectively enrolled 338 patients undergoing PCI for stable angina, loaded with 600-mg clopidogrel. Platelet reactivity was assessed 12 h later by measuring P2Y12 reactivity unit (PRU) with VerifyNow P2Y12 assay (Accumetrics, San Diego, California). High platelet reactivity (HPR) was defined as PRU value >or=240. Presence of multivessel disease (MVD) and total stent length (TSL) were used as surrogate markers of atherosclerosis severity and extension. RESULTS Patients with MVD showed higher PRU compared with single-vessel disease (SVD) patients (222 +/- 85 vs. 191 +/- 73; p < 0.001). The PRU increased with the number of stenotic coronaries (1-vessel disease: 191 +/- 73; 2-vessel disease: 220 +/- 88; 3-vessel disease: 226 +/- 80; p = 0.002). The PRU was higher in the third TSL tertile compared with first tertile (217 +/- 83 vs. 191 +/- 73; p = 0.048). The HPR was most frequently observed among MVD patients (40.5% vs. 21.6% in patients with SVD, respectively; p < 0.001) and those in the third TSL tertile (35.8% vs. 22.2% first tertile; p = 0.028). Higher incidence of periprocedural myocardial infarction was observed in patients with HPR (41.2% vs. 26.7% in patients without HPR; p = 0.008) and in those in the third tertile TSL (37.7% vs. 23.1% first tertile; p = 0.020). By multivariate analysis, HPR was the only independent predictor of periprocedural myocardial infarction (p = 0.034). CONCLUSIONS Patients with more extensive coronary atherosclerosis have a higher rate of HPR, which might partly account for higher risk of periprocedural MI.