Cristina Giglioli

Cardiovascular Death and Nonfatal Myocardial Infarction in Acute Coronary Syndrome Patients Receiving Coronary Stenting Are Predicted by Residual Platelet Reactivity to ADP Detected by a Point-of-Care Assay A 12-Month Follow-Up

Background— The clinical impact of platelet aggregation assessed by point-of-care assays is unknown. We sought to evaluate whether high residual platelet reactivity (RPR) to ADP during clopidogrel therapy, measured by a point-of-care assay, predicts adverse clinical events in acute coronary syndrome patients undergoing percutaneous coronary intervention. Methods and Results— We used the VerifyNow P2Y12 assay (Accumetrics Inc, San Diego, Calif) to determine RPR to ADP in 683 patients with acute coronary syndrome undergoing dual-antiplatelet therapy who underwent percutaneous coronary intervention with bare-metal or drug-eluting stent implantation. All patients received a single 600-mg clopidogrel loading dose followed by 75 mg of clopidogrel daily and 100 to 325 mg of aspirin daily. The end points of the study at follow-up of 12 months were cardiovascular death, nonfatal myocardial infarction (MI), and target-vessel revascularization. At a 12-month follow-up, we found 51 ischemic events (24 cardiovascular deaths [3.5%], 27 nonfatal MIs [3.9%]) and 40 target-vessel revascularizations (5.8%). By receiver operating characteristic curve (ROC) analysis, the optimal cutoff value in predicting 12-month cardiovascular death and nonfatal MI was P2Y12 reaction unit values ≥240. RPR, defined in the presence of P2Y12 reaction unit values above this cutoff, was found to be a significant and independent predictor of cardiovascular death and nonfatal MI in a model that adjusted for cardiovascular risk factors, renal failure, reduced left ventricular ejection fraction, multivessel disease, total stent length, bifurcation lesions, number of lesions treated, type of stent, and use of glycoprotein IIb/IIIa inhibitors (cardiovascular death: hazard ratio 2.55, 95% CI 1.08 to 6.07, P=0.034; nonfatal MI: hazard ratio 3.36, 95% CI 1.49 to 7.58, P=0.004). No significant association was found between high RPR and the risk of target-vessel revascularization. Conclusions— RPR to ADP with clopidogrel therapy, measured by the point-of-care assay VerifyNow P2Y12, is able to detect acute coronary syndrome patients at risk of 12-month cardiovascular death and nonfatal MI. The optimal cutoff value was identified as being 240 P2Y12 reaction units.

Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients.

Summary.  Background: Two point‐of‐care (POC) systems have been recently proposed as rapid tools with which to evaluate residual platelet reactivity (RPR) in coronary artery disease (CAD) patients. Objectives and Methods: We compared Platelet Function Analyzer‐100 (PFA‐100) closure times (CTs) by collagen/adenosine 5´‐diphosphate (ADP) (C/ADP CT) cartridge and the VerifyNow P2Y12 Assay (VerifyNow) with light transmission aggregation (LTA) induced by 2 and 10 μmol L–1 ADP in 1267 CAD patients on dual antiplatelet therapy who underwent percutaneous coronary intervention. We also performed the vasodilator‐stimulated phosphoprotein (VASP) phosphorylation assay by cytofluorimetric analysis in a subgroup of 115 patients. Results: Cut‐off values for identifying RPR were: ≥ 54% and ≥ 66% for LTA induced by 2 and 10 μmol L–1 ADP respectively, and ≥ 264 P2Y12 Reaction Units (PRU) for VerifyNow. The cut‐off for PFA‐100 C/ADP CT was ≥ 68 s. RPR was detected in 25.1% of patients by 2 μmol L–1 ADP‐induced LTA (ADP‐LTA), in 23.2% by 10 μmol L–1 ADP‐LTA, in 24.4% by PFA‐100, and in 24.7% by VerifyNow. PFA‐100 results did not parallel those obtained with LTA. VerifyNow showed a significant correlation (ρ = 0.62, P < 0.001) and significant agreement (k = 0.34, P < 0.001) with LTA induced by 2 μmol L–1 ADP. The correlation was similar but the agreement was better between VerifyNow and 10 μmol L–1 ADP‐LTA (ρ =  0.64, P < 0.0001; k = 0.43, P < 0.001). Significant relationships were found between VASP platelet reactivity index and both ADP‐LTA and VerifyNow. PFA‐100 C/ADP CT did not significantly correlate with any of the other assays. Conclusions: Our results show a significant correlation between LTA and VerifyNow but not the PFA‐100 C/ADP assay. Clinical validation studies for POC systems are necessary.

Role of hemodynamic shear stress in cardiovascular disease

Atherosclerosis is the main cause of morbidity and mortality in the Western world. Inflammation and blood flow alterations are new markers emerging as possible determinants for the development of atherosclerotic lesions. In particular, blood flow exerts a shear stress on vessel walls that alters cell physiology. Shear stress arises from the friction between two virtual layers of a fluid and is induced by the difference in motion and viscosity between these layers. Regions of the arterial tree with uniform geometry are exposed to a unidirectional and constant flow, which determines a physiologic shear stress, while arches and bifurcations are exposed to an oscillatory and disturbed flow, which determines a low shear stress. Atherosclerotic lesions develop mainly in areas of low shear stress, while those exposed to a physiologic shear stress are protected. The presence of areas of the arterial tree with different wall shear stress may explain, in part, the different localization of atherosclerotic lesions in both coronary and extracoronary arteries. The measurement of this parameter may help in identifying atherosclerotic plaques at higher risk as well as in evaluating the efficacy of different pharmacological interventions. Moreover, an altered shear stress is associated with the occurrence of both aortic and intracranial aneurysms, possibly leading to their growth and rupture. Finally, the evaluation of shear stress may be useful for predicting the risk of developing restenosis after coronary and peripheral angioplasty and for devising a coronary stent with a strut design less thrombogenic and more conducive to endothelization.

Effects of ULTRAfiltration vs. DIureticS on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart failure: the ULTRADISCO study

To evaluate the clinical, biohumoral, and haemodynamic effects of ultrafiltration vs. intravenous diuretics in patients with decompensated heart failure (HF). Signs and symptoms of volume overload are often present in these patients and standard therapy consists primarily of intravenous diuretics. Increasing evidence suggests that ultrafiltration can be an effective alternative treatment.

Propafenone versus amiodarone in field treatment of primary atrial tachydysrhythmias

Thirty-nine patients with paroxysmal atrial fibrillation or supraventricular tachycardia randomly received amiodarone or propafenone intravenously at home. Fifteen patients received amiodarone and 24 received propafenone; 87.5% of the patients who received propafenone and 40% of the patients who received amiodarone were converted at home to sinus rhythm (P less than .005). The median time of conversion was 10 minutes (range 5 to 35) for propafenone and 60 minutes (range 20 to 130) for amiodarone (P less than 0.005). When either drug failed to terminate atrial tachydysrhythmias at home, the same drug always restored sinus rhythm with subsequent oral treatment during hospitalization. No major side effects were observed after the infusion of either drug. The incidence of minor side effects was not significantly different between the two drugs. Both the drugs are efficacious and safe in the acute management of primary supraventricular tachydysrhythmias. Propafenone showed a greater rapidity of action.

NT-proBNP on admission for early risk stratification in STEMI patients submitted to PCI. Relation with extension of STEMI and inflammatory markers

The prognostic implications of NT-proBNP measured on admission in patients with the ST-elevation myocardial infarction (STEMI) are not so far well elucidated. The present investigation, performed in 198 STEMI patients submitted to percutaneous coronary intervention (PCI), was aimed at assessing the prognostic value of NT-proBNP measured on admission to Intensive Cardiac Care Unit (ICCU) and its relation with the extension of myocardial infarction (indicated by cardiac biomarkers and ejection fraction) and inflammatory markers (C-reactive protein - CRP, erythrocyte sedimentation rate - ESR, leucocytes, fibrinogen). All patients who died during ICCU stay had increased values of NT-proBNP. Each quartile of NT-proBNP resulted directly correlated with age, heart rate, peak Tn I, admission creatinine serum levels, ESR, fibrinogen, and inversely correlated with ejection fraction. At backward logistic regression analysis, NT-proBNP values showed a significative correlation with peak Tn I (OR 1.013; 95% CI 1.001-1.025; p=0.036), and CRP positive (OR 6.450; 95% CI 1.714-24.272; p=0.006); age was close to reaching statistical significance (OR 1.043; 95% CI 0.999-1.089; p=0.055). At long term-follow-up NT-proBNP lacks any prognostic role in predicting adverse events such as hospitalization for rePCI, re-infarction and heart failure. Kaplan-Meier curves showed that all patients dead at follow-up were in the highest NT-proBNP quartiles.

Comparison of different methods to evaluate the effect of aspirin on platelet function in high-risk patients with ischemic heart disease receiving dual antiplatelet treatment.

Patients with coronary artery disease (CAD) receiving aspirin therapy with a residual platelet reactivity (RPR) may be at increased risk of ischemic vascular events. Point-of-care (POC) methods PFA-100 (Dade-Behring, Marburg, Germany) and VerifyNow (Accumetrics, San Diego, CA) assays have been suggested as rapid tools to evaluate RPR. We compared PFA-100 closure times by collagen/epinephrine and VerifyNow Aspirin assays with light transmission aggregation (LTA) induced by 1 mmol/L of arachidonic acid in 484 patients with CAD undergoing percutaneous coronary intervention and receiving dual antiplatelet therapy. RPR was detected in 30.0% of patients by LTA, in 32.4% by PFA-100, and in 14.3% by VerifyNow. Significant correlations were found among 3 methods (all P < .0001). In relation to the presence or absence of RPR by LTA and PFA-100, by LTA and VerifyNow, and by PFA-100 and VerifyNow, samples were significantly concordant (all P < .0001). Assuming LTA as the reference method, PFA-100 and VerifyNow showed sensitivity of 62.1% and 39.3% and specificity of 80.2% and 96.4%, respectively. The cutoff values for POC methods need to be defined for clinical use.

Residual platelet reactivity is an independent predictor of myocardial injury in acute myocardial infarction patients on antiaggregant therapy.

In this study we sought to evaluate if platelet function measured after percutaneous coronary intervention (PCI) affects the severity of myocardial infarction (MI), measured by markers of cardiac necrosis. We measured platelet function by both a point-of-care assay (PFA-100) and platelet-rich plasma aggregation by two agonists (arachidonic acid -AA- and 2 and 10 microM ADP) in 367 patients with MI after PCI (200 patients on dual antiplatelet agents - group A- and 167 on dual antiplatelet agents plus GpIIb/IIIa inhibitors - group B). One hundred twenty-one (32.9%) patients were found to have a residual platelet reactivity (RPR) by PFA (CT/EPI <203 sec): 74/200 (37%) in group A and 47/167 (28.1%) in group B (p = 0.07). In 129 (35.1%) patients we found a RPR by AA-PA: 80/200 (40%) in group A and 49/167 (29.3%) in group B (p < 0.05). Seventeen out of 367 (4.6%) were found to have a RPR by ADP2-PA [15/200 (7.5%) in group A and 2/167 (1.2%) in group B; p < 0.005] and 88/367 (23.9%) by ADP10-PA [64/200 (32%) in group A and 24/167 (14.4%) in group B, p < 0.0001]. CK-MB and cTnI mean peak values were significantly higher in the first tertile of CT/ADP and CT/EPI distribution with respect to the other tertiles and they were significantly higher in patients with RPR by CT/EPI in both group A and group B patients. CK-MB and cTnI peak values were significantly higher in the third tertile of AA-PA, ADP 2 microM-PA and ADP 10 microM-PA distribution with respect to the other tertiles and were significantly higher in patients with RPR by AA-PA and by ADP 10-PA in both group A and group B patients. Multivariate analysis revealed platelet function as an independent predictor of CK-MB and cTnI peak values in both groups of patients independently of clinical, laboratory ad procedural parameters. In conclusion, we found that the severity of MI in patients with MI undergoing primary PCI is influenced by a persistent platelet activation on multiple antiplatelet therapy.

Gender-related difference in ST-elevation myocardial infarction treated with primary angioplasty: a single-centre 6-year registry

Objective: Still contrasting are data on the impact of sex on outcome in patients with ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI). Design: We sought sex-related differences in management and early outcomes in 1127 STEMI patients submitted to PCI consecutively admitted to our intensive cardiac care unit (ICCU) in Florence from 1 January 2004 to 31 December 2009. Results: Females were significantly older, leaner (p < 0.001, respectively), more hypertensive (p < 0.001), and diabetic (p = 0.016); they showed a higher incidence of neurological impairment (p = 0.002) and chronic obstructive pulmonary disease (p = 0.048). Higher Killip classes were more frequent in females (p = 0.015). Door-to-balloon time was higher in females (p < 0.001) who showed a higher incidence of major bleeding (p < 0.001) and a higher in-ICCU mortality rate (p = 0.037). The use of IIbIIIa glycoprotein inhibitors was lower in females (p < 0.001) who exhibited higher values of admission glycaemia and peak glycaemia (p < 0.001 and p < 0.001, respectively), higher values of fibrinogen (p < 0.001) and erythrocyte sedimentation rate (p < 0.001), and lower eGFR and haemoglobin values (p < 0.001). Conclusions: According to our data, STEMI women show not only a different risk profile (older age, comorbidities, lower haemoglobin values), but also a different gender-related metabolic and inflammatory responses to acute myocardial ischaemia in respect to men. All these factors can account for the higher in-ICCU mortality in women and strongly suggest that STEMI women deserve more intensive care due to a more severe haemodynamic derangement (as indicated by the higher use of inotropes, diuretics, and non-invasive ventilation) and to a more serious metabolic impairment (as inferred by higher glucose values).

High on-treatment platelet reactivity by more than one agonist predicts 12-month follow-up cardiovascular death and non-fatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting

There is some data available on the role of high on-treatment platelet reactivity by ADP whereas, as regards arachidonic acid or other agonists, there is no proof of the best cut-off for identifying populations with a different cardiovascular outcome by the construction of appropriate receiver-operator characteristics (ROC) curves. We enrolled 1,108 acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) with stent implantation and followed them up for 12 months. Platelet reactivity was assessed by light transmission aggregometry (LTA) using 10 microM ADP, 1 mM arachidonic acid (AA) and 2 microg/ml collagen. At a 12-month follow-up, we found 37 cardiovascular deaths (3.3%), 54 non-fatal myocardial infarctions (MI) (4.8%) and 154 target vessel revascularisations (TVR) (13.8%). ROC analysis demonstrated that 10 microM ADP LTA, 1 mM AA and 2 microg/ml collagen LTA were able to distinguish between patients with and without subsequent cardiovascular death and non-fatal MI (area under the curve for 10 microM ADP 0.63 (0.55-0.71), p<0.001; for 1 mM AA 0.68 (0.61-0.76), p<0.0001; for 2 microg/ml collagen 0.62 (0.52-0.73), p<0.0111), whereas no association was demonstrated with the occurrence of TVR. Ten microM ADP LTA>or=55%, 1 mM AA LTA>or=15% and 2 microg/ml collagen LTA>or=31% were identified as the optimal cut-off to predict cardiovascular death and non-fatal MI at 12-month follow-up. The contemporary platelet hyperreactivity to more than one agonist was associated with a higher risk of 12-month cardiovascular death and MI, whereas isolated platelet hyperreactivity to only one agonist had not a predictive value [10 microM ADP LTA>or=55% + 1 mM AA LTA>or=15%: odds ratio [OR]=3.6(2.4-6.1), p<0.0001; ADP LTA>or=55% + 1 mM AA LTA>or=15% + 2 microg/ml collagen LTA>or=31%: OR=4.7(2.9-7.7), p<0.0001]. In this prospective study on a large number of acute coronary syndrome patients undergoing stent implantation, we have found that high on-treatment platelet reactivity measured by LTA induced by more than one agonist--AA, ADP, collagen--is an independent risk factor for 12-month cardiovascular death and non-fatal MI. Isolated platelet hyperreactivity to only one agonist has not a predictive value for clinical recurrences.