Benedetta Bellandi

Comparison of Prasugrel and Ticagrelor Loading Doses in ST-Segment Elevation Myocardial Infarction Patients RAPID (Rapid Activity of Platelet Inhibitor Drugs) Primary PCI Study

OBJECTIVES This study sought to compare the action of prasugrel and ticagrelor in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). BACKGROUND It has been documented that prasugrel and ticagrelor are able to provide effective platelet inhibition 2 h after a loading dose (LD). However, the pharmacodynamic measurements after prasugrel and ticagrelor LD have been provided by assessing only healthy volunteers or subjects with stable coronary artery disease. METHODS Fifty patients with STEMI undergoing PPCI with bivalirudin monotherapy were randomized to receive 60 mg prasugrel LD (n = 25) or 180 mg ticagrelor LD (n = 25). Residual platelet reactivity was assessed by VerifyNow at baseline and 2, 4, 8, and 12 h after LD. RESULTS Platelet reactivity units (PRU) 2 h after the LD (study primary endpoint) were 217 (12 to 279) and 275 (88 to 305) in the prasugrel and ticagrelor groups, respectively (p = NS), satisfying pre-specified noninferiority criteria. High residual platelet reactivity (HRPR) (PRU ≥240) was found in 44% and 60% of patients (p = 0.258) at 2 h. The mean time to achieve a PRU <240 was 3 ± 2 h and 5 ± 4 h in the prasugrel and ticagrelor groups, respectively. The independent predictors of HRPR at 2 h were morphine use (odds ratio: 5.29; 95% confidence interval: 1.44 to 19.49; p = 0.012) and baseline PRU value (odds ratio: 1.014; 95% confidence interval: 1.00 to 1.03; p = 0.046). CONCLUSIONS In patients with STEMI, prasugrel showed to be noninferior as compared with ticagrelor in terms of residual platelet reactivity 2 h after the LD. The 2 drugs provide an effective platelet inhibition 2 h after the LD in only a half of patients, and at least 4 h are required to achieve an effective platelet inhibition in the majority of patients. Morphine use is associated with a delayed activity of these agents. (Rapid Activity of Platelet Inhibitor Drugs Study, NCT01510171).

Morphine Is Associated With a Delayed Activity of Oral Antiplatelet Agents in Patients With ST-Elevation Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Background—Morphine is recommended in patients with ST-segment–elevation myocardial infarction, including those undergoing primary percutaneous coronary intervention. Suboptimal antiplatelet effect during and after primary percutaneous coronary intervention is associated with increased thrombotic complications. It was hypothesized a potential drug–drug interaction between morphine and antiplatelet agents. We sought to assess platelet inhibition after a loading dose of the currently recommended antiplatelet agents in ST-segment–elevation myocardial infarction patients according to morphine use. Methods and Results—Three hundred patients undergoing primary percutaneous coronary intervention receiving either prasugrel (n=95) or ticagrelor (n=205) loading dose had platelet reactivity assessed by VerifyNow 1, 2, and 4 hours after loading dose. Patients treated with morphine (n=95; 32%) had a higher incidence of vomit (15% versus 2%; P=0.001). P2Y12 reactivity units 2 hours after the loading dose was 187 (153–221) and 133 (102–165) in patient with and without morphine (P<0.001); the difference persisted after excluding patients with vomit (P<0.0001). High residual platelet reactivity (P2Y12 reactivity units ≥208) at 2 hours was found in 53% and 29% patients with and without morphine (P<0.001) and without difference between prasugrel and ticagrelor patients. The independent predictors of high residual platelet reactivity at 2 hours were morphine use (odds ratio, 2.91 [1.71–4.97]; P<0.0001) and age (odds ratio, 1.03 [1.01–1.05]; P=0.010). Morphine remained associated with high residual platelet reactivity after propensity score adjustment (c-statistic, 0.68; 95% confidence interval, 0.66–0.70; P=0.879 for Hosmer–Lemeshow test). Conclusions—In patients with ST-segment–elevation myocardial infarction, morphine use is associated with a delayed onset of action of the oral antiplatelet agents. This association persisted after adjusting for the propensity to receive morphine and after excluding patients with vomit.

Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study.

In healthy volunteers, 300 mg clopidogrel administered crushed via a nasogastric tube results in faster and greater bioavailability of the drug compared with whole tablets administered orally [(1)][1]. Recently, Crean et al. [(2)][2] reported that ticagrelor tablets could be easily crushed and

Revised clinical diagnostic criteria for Tako-tsubo syndrome: The Tako-tsubo Italian Network proposal

Tako-tsubo syndrome (TTS) or stress cardiomyopathy is a relatively new entity that manifests with a clinical scenariomimicking an acute myocardial infarction [1–6]. TTS accounts for ∼2% of all patients presenting with apparent symptoms of acute myocardial infarction [2]. The clinical characteristics are heterogeneous and the clinical spectrum of presentation somehow wide, a fact that has long proven researchers and physicians in their diagnostic competence. Current TTS diagnostic criteria have been initially proposed by the Mayo Clinic Investigators in 2004 [1], and only slightly modified in 2008 [7], despite the great amount in TTS literature provided in the last 10 years. Of note, TTS patients not correctly identified, but considered common acute coronary syndrome patients, may receive unjustified aggressive therapies resulting in increased complications and costs. Thus, accuracy is needed to differentiate TTC from acute myocardial infarction, because of the different therapeutic and prognostic implications [1–7]. For this purpose, the Tako-tsubo Italian Network (TIN) Investigators, in their multicentre registry including several hundreds of TTS patients, adopted modified TTS diagnostic criteria in order to better detect and treat patients with TTS. The TIN diagnostic criteria that could be considered modified and updated Mayo Clinic diagnostic criteria are summarized in Table 1. The main advantages and novelty of the TIN diagnostic criteria are the following:

Comparison of bivalirudin and unfractionated heparin plus protamine in patients with coronary heart disease undergoing percutaneous coronary intervention (from the Antithrombotic Regimens aNd Outcome [ARNO] trial).

Previous studies have compared bivalirudin and unfractionated heparin (UFH) plus the routine use of glycoprotein IIb/IIIa inhibitors. They have demonstrated that bivalirudin can decrease bleeding complications without a significant increase in ischemic complications, resulting in a better net clinical outcome, as defined by the efficacy (ischemic complications) or safety (bleeding complications) end point. The aim of the present study was to compare bivalirudin and UFH plus protamine in patients undergoing elective percutaneous coronary intervention and pretreated with clopidogrel and aspirin. We randomly assigned 850 patients with stable or unstable coronary artery disease to bivalirudin or UFH followed by protamine at the end of the percutaneous coronary intervention. The primary end point was in-hospital major bleeding. The main secondary end points were the 1-month composite of death, myocardial infarction, unplanned target vessel revascularization; and the 1-month net clinical outcome. The rate of major bleeding (primary end point) was 0.5% in patients randomized to bivalirudin and 2.1% in patients randomized to UFH (p = 0.033). At 30 days, the rate of major bleeding was 0.9% in the bivalirudin arm and 2.8% in the UFH arm (p = 0.043). The composite of death, myocardial infarction, and target vessel revascularization rate and the net clinical outcome rate was 2.8% and 6.4% (p = 0.014) and 3.3% and 7.8% (p = 0.004), respectively, in the bivalirudin and UFH arms. In conclusion, in percutaneous coronary intervention patients pretreated with clopidogrel and aspirin, bivalirudin was associated with less major bleeding and fewer ischemic complications and a better net clinical outcome than UFH.

Comparison of double (360 mg) ticagrelor loading dose with standard (60 mg) prasugrel loading dose in ST-elevation myocardial infarction patients: the Rapid Activity of Platelet Inhibitor Drugs (RAPID) primary PCI 2 study.

UNLABELLED In ST-elevation myocardial infarction (STEMI) patients, residual platelet reactivity soon after a loading dose (LD) of prasugrel or ticagrelor is higher than that reported for healthy volunteers or subjects with stable coronary artery disease; and the majority of primary percutaneous coronary intervention (PPCI) procedures with bivalirudin monotherapy are performed without proper platelet inhibition. However, ticagrelor LD is just the daily dose, whereas prasugrel LD is 6-fold the long-term daily dose. We hypothesized that an increased ticagrelor LD may result in a faster and more effective platelet inhibition as compared with the standard prasugrel LD. METHODS Fifty patients with STEMI, pretreated with intravenous aspirin, undergoing PPCI were randomized to receive prasugrel 60-mg LD (n = 25) or ticagrelor 360-mg LD (n = 25). Residual platelet reactivity was assessed by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD. RESULTS At the time of LD, 90% of enrolled patients had an aspirin reactivity unit value <550. P2Y12 reaction units 1 hour after the LD (study primary end point) were 236 (129-289) and 248 (115-304) in the prasugrel and ticagrelor group, respectively (P = .899). High residual platelet reactivity (P2Y12 reaction units ≥240) was found in 43% and 56% of patients (P = .386) at 1 hour and in 30% and 32% of patients (P = .907) at 2 hours, respectively. There was no significant difference in bleeding, arrhythmias, or dyspnea episodes in the 2 groups. CONCLUSIONS In patients with STEMI undergoing PPCI, double (360 mg) ticagrelor LD failed to achieve a faster and more intense platelet inhibition as compared with the standard prasugrel LD. Intravenously administered aspirin allowed to achieve a very early inhibition of acid arachidonic pathway.

Abnormal coronary reserve and left ventricular wall motion during cold pressor test in patients with previous left ventricular ballooning syndrome

AIMS To investigate whether and how cold pressor test (CPT) could affect myocardial perfusion and left ventricular (LV) function in patients with previous LV ballooning syndrome (LVBS). METHODS AND RESULTS Cold pressor test (3 min hand immersion in ice-water) was performed in 17 women with previous LVBS and in 7 age- and risk factor-matched women with chest pain and normal coronary arteries. At baseline and peak CPT, global and regional LV function, and myocardial perfusion were quantitatively assessed by real-time three-dimensional echocardiography (RT3DE) and myocardial contrast (SonoVue, Bracco) 2D echocardiography (MCE), respectively (Philips iE33 machine, X3-1 and S5-1 probes). Data were analysed off-line (QLab 6.0 software). Peripheral venous catecholamines were assayed by high performance liquid chromatography with electrochemical detection. Cold pressor test induced similar haemodynamic changes and catecholamine increase in controls and LVBS patients. Left ventricular ejection fraction decreased and transient new mid-ventricular and apical motion abnormalities developed in LVBS patients only (quantitative RT3D analysis), without corresponding perfusion defects (MCE). At peak CPT, coronary blood flow and velocity increased (quantitative MCE analysis) in control subjects only. CONCLUSION Cold pressor test induced LV wall motion abnormalities unmatched to regional coronary flow reduction in LVBS patients only. The reduced coronary reserve in response to CPT suggests microvascular dysfunction in LVBS patients.

Heart rate as an independent prognostic risk factor in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention

BACKGROUND It has been shown that elevated heart rate identified patients with coronary artery disease and left ventricular dysfunction at increased risk of cardiovascular outcomes. OBJECTIVE We sought to assess the prognostic impact of heart rate at presentation in patients with ST-elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS We collected 6-month follow-up data in 2477 consecutive patients with STEMI treated by primary PCI. Patients with atrio-ventricular block (n=64) and atrial fibrillation (n=34) were excluded from the analysis. The association of baseline heart rate with cardiovascular outcomes was analysed using Cox proportional hazard models for groups with a heart rate of 80 beats per min (bpm) or greater (n=799) versus those with a heart rate between 60 and 79 bpm (n=1192) and those with a heart rate less than 60 bpm (n=388). The variables related to mortality were: age (hazard ratio (HR) 1.072, 95% confidence interval (CI) 1.052-1.092, p<0.0001), cardiogenic shock (HR 4.622, 95% CI 2.892-7.387, p<0.0001), previous myocardial infarction (HR 1.724, 95% CI 1.036-2.869, p=0.036), peak creatine-kinase value (HR 1.227, 95% CI 1.142-1.318, p<0.0001), heart rate 80 bpm or greater (HR 2.170, 95% CI 1.414-3.332, p=0.0001), and optimal PCI result (HR 0.126, 95% CI 0.065-0.244, p=0.0001). For every increase of 5 bpm, there were increases in mortality (HR 1.321, 95% CI 1.232-1.415, p=0.0001), but not in reinfarction or in coronary revascularization rates. CONCLUSION In patients with acute myocardial infarction undergoing primary PCI, elevated heart rate (80 bpm or greater) identifies those at increased risk of death. It is unknown whether heart rate reduction will result in improved outcome in this setting of patients.

Stress-induced hyperviscosity in the pathophysiology of takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TC) is characterized by transient hypokinesis of the left ventricular apex or midventricular segments with coronary arteries without significant stenosis. It is often associated with emotional or physical stress; however, its pathophysiology is still unclear. In the present study, we analyzed the alterations in blood viscosity and markers of endothelial damage induced by sympathetic stimulation in patients with previous TC. Seventeen women (mean age 71 years) with previous TC, included and investigated in the TC Tuscany Registry, were compared to a control group of 8 age- and risk factor-matched women with chest pain and coronary arteries free of stenosis. All subjects underwent the cold pressor test (CPT). Before and after the CPT, the hemorheologic parameters (whole blood viscosity at 0.512 s(-1) and 94.5 s(-1), plasma viscosity, erythrocyte deformability index, and erythrocyte aggregation), catecholamines, plasminogen activator inhibitor-1 (PAI-1), and von Willebrand factor levels were assessed. The patients with TC had significantly greater baseline PAI-1 levels (p <0.01) and lower erythrocyte deformability index values (p <0.01). After CPT, both the patients with TC and the controls had a significant increase in several hemorheologic parameters, catecholamines, and von Willebrand factor levels and a decrease in erythrocyte deformability index. However, the PAI-1 levels were significantly increased only in the patients with TC. Compared to the controls, the patients with TC had significantly greater values of whole blood viscosity at 94.5 s(-1) (p <0.05), PAI-1 (p <0.01), von Willebrand factor (p <0.05) and lower erythrocyte deformability index values (p <0.01) after CPT. In conclusion, the results of the present study suggest that in patients with TC, the alterations in erythrocyte membranes and endothelial integrity induced by catecholaminergic storm could determine microvascular hypoperfusion, possibly favoring the occurrence of left ventricular ballooning.

Effectiveness of Primary Percutaneous Coronary Interventions for Stent Thrombosis

There are very few (and conflicting) data about the effectiveness of primary percutaneous coronary interventions (PCIs) for stent thrombosis (ST) treatment. We sought to evaluate the prevalence, efficacy, and outcomes of primary PCI in patients with ST-elevation acute myocardial infarction (STEMI) due to ST in 2,464 consecutive patients treated by primary PCI. ST was the cause of STEMI in 67 patients (3%). Patients with ST showed a lower rate of significant collateral circulation (0% vs 6%, p = 0.034) and a higher peak creatine kinase value (2,678 +/- 3,221 vs 2,375 +/- 2,189 U/L, p = 0.003) compared with the other 2,397 patients with STEMI. PCI was successful in 64 patients (96%) in the ST group and consisted of additional stenting (78%) or only balloon angioplasty (22%). Abciximab and rheolytic thrombectomy were used in 75% and 31% of patients, respectively. Procedure (39 +/- 26 vs 32 +/- 19 minutes, p = 0.0001) and fluoroscopy (13 +/- 10 vs 10 +/- 8 minutes, p = 0.0001) times were longer, and contrast medium amount (221 +/- 89 vs 194 +/- 103 ml, p = 0.034) larger in patients with ST compared with patients with de novo STEMI. Six-month death (12% vs 8%, p = 0.216) and nonfatal reinfarction (10% vs 1%, p = 0.0001) rates were higher in patients with ST compared with those without. At 6-month angiographic follow-up (n = 1,843 of 2,269), the restenosis/reocclusion rate was 54% versus 17% (p = 0.0001) in patients with and without ST. In conclusion, the prevalence of primary PCI for ST is low. Additional stenting with or without thrombectomy is effective in restoring vessel patency in patients with ST, but restenosis and reocclusion are frequent. ST treated with successful PCI is associated with a large infarct and poor outcome.