Pharmacodynamic effect of prasugrel 5 mg vs clopidogrel 150 mg in elderly patients with high on-clopidogrel platelet reactivity.

BACKGROUND: Elderly patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) frequently exhibit high platelet reactivity (HPR) while on clopidogrel. In the elderly cohort, either prasugrel is not recommended or, if used, halving of the dose has been suggested. We aimed to test the hypothesis that in elderly patients exhibiting HPR after standard treatment with clopidogrel, prasugrel-reduced dose (5 mg) could be more effective than high-dose (150 mg) clopidogrel. METHODS: Consecutive elderly (≥75 years old) patients with ACS undergoing PCI and loaded with clopidogrel were considered for platelet reactivity (PR) assessment at 24 hours after PCI with the VerifyNow assay (Accumetrics Inc, San Diego, CA), measured in P2Y12 reaction units (PRU). Of 63 screened patients, 30 (47.6%) were found with HPR (defined as PRU ≥230) and 27 of them participated in a prospective, randomized, single-center, single-blind, investigator-initiated, crossover study of platelet inhibition by prasugrel 5 mg/d vs clopidogrel 150 mg/d, with a 15-day treatment period. RESULTS: The primary end point of PR at the end of the 2 study periods was lower in patients receiving low-dose prasugrel than those receiving high-dose clopidogrel (least squares estimates 190.8 [95% CI 161.5-220.1] and 240.8 [95% CI 211.0-270.6], respectively; P = .008). The secondary end point of HPR rate at the end of treatment periods was lower for prasugrel (8/24; 33.3%) compared with clopidogrel (16/24; 66.7%), P = .02. CONCLUSIONS: In elderly patients with ACS undergoing PCI and exhibiting HPR after standard clopidogrel treatment, prasugrel 5 mg/d is significantly more efficacious than clopidogrel 150 mg/d in reducing PR and HPR rate.

Predictors of high on-treatment platelet reactivity early after clopidogrel loading in ST-elevation myocardial infarction.

BACKGROUND: Given that platelet inhibition is crucial when ST-elevation myocardial infarction (STEMI) patients undergo primary PCI (PPCI), the identification of factors associated with early high on-treatment platelet reactivity may be important. METHODS AND RESULTS: Consecutive STEMI patients admitted for PPCI were considered for platelet reactivity assessment 2 h after loading with 600 mg clopidogrel using the VerifyNow point-of-care P2Y12 assay. A cut-off of ≥235 P2Y12 reaction units indicated high on-treatment platelet reactivity. Out of 92 STEMI patients, 63 (68.5%) were found to have high on-treatment platelet reactivity. Patients with high on-treatment platelet reactivity had received upstream clopidogrel loading and pantoprazol more frequently, had lower admission hemoglobin and tended to have an impaired renal function compared to those with an adequate response to clopidogrel. On multivariate analysis, upstream clopidogrel loading and creatinine clearance <60 ml/min were independently associated with higher risk for high on-treatment platelet reactivity (relative risk [RR]=1.55, 95% confidence interval [CI]: 1.11-2.17, P=0.01; RR=1.31, 95% CI: 1.008-1.71, P=0.04, respectively). CONCLUSIONS: In patients with STEMI undergoing PPCI, use of upstream clopidogrel and impaired renal function independently predict high on-treatment platelet reactivity assessed as early as 2h following 600 mg of clopidogrel loading dose on point-of-care P2Y12 function assay.

Mechanisms of nonfatal acute myocardial infarction late after stent implantation: the relative impact of disease progression, stent restenosis, and stent thrombosis.

BACKGROUND: The impact of stent restenosis, stent thrombosis, or progression of disease at another site as responsible mechanisms of acute myocardial infarction (AMI) after stent implantation is not clear. METHODS: By searching our catheterization laboratory database for a 4-year period, 91 cases of nonfatal AMI at least 1 month after stent implantation (32.6% drug-eluting stents) were identified. By detailed comparison of post-AMI with the initial percutaneous coronary intervention angiogram, the mechanism of AMI was analyzed. RESULTS: Acute myocardial infarction was attributed to disease progression at another site in 42 (46.2%), stent restenosis in 35 (38.4%), and stent thrombosis in 10 (11%) cases. The AMI mechanism could be either stent related or disease progression (nonidentifiable culprit lesion) in 4 cases (4.4%). The median time from percutaneous coronary intervention to AMI was 27, 19, and 9 months for disease progression at another site, restenosis, and stent thrombosis group, respectively (P = .03). ST-elevation myocardial infarction occurred in 38.1% of the disease progression, in 20% of the restenosis, and in 60% of the stent thrombosis cases (P = .046). CONCLUSIONS: In a "real world" population, late after stent implantation, a patient has an almost equal probability to have suffered a nonfatal AMI from either stent restenosis/thrombosis or disease progression at another site. Continuous research efforts are necessary to equally address both stent therapy and disease progression.

Timing of clopidogrel loading before percutaneous coronary intervention in clopidogrel-naive patients with stable or unstable angina: a comparison of two strategies.

BACKGROUND: Clopidogrel-naive patients subjected to coronary angiography may be candidates for percutaneous coronary intervention (PCI). Clopidogrel loading with 600 mg at least 2 hours before the procedure is advised for such patients. However, there is no direct evidence that delaying PCI for 2 hours after clopidogrel loading is superior to ad hoc PCI. METHODS: After coronary angiography, clopidogrel-naive patients (N = 199) with stable or unstable angina, candidates for PCI, were loaded with 900 mg of clopidogrel and then randomized to ad hoc PCI (ad hoc group, n = 103) or delayed PCI 2 hours after loading (delayed group, n = 96). Combined primary end point was death/periprocedural myocardial infarction (MI)/stroke/reintervention within 30 days post-PCI. Secondary end points were periprocedural MI; periprocedural creatine kinase-MB elevation >3 x upper limit of normal; any periprocedural increase of creatine kinase-MB, troponin-I, or myoglobin above upper limit of normal; Thrombolysis in Myocardial Infarction flow <3 after PCI; thrombocytopenia with platelet count of <70,000/mL; major bleeding defined according to the Thrombolysis in Myocardial Infarction criteria; and elevation of high-sensitivity C-reactive protein and soluble P selectin. RESULTS: Primary end point occurred in 12.6% ad hoc group versus 15.6% delayed group patients (P = .34). High-sensitivity C-reactive protein increased in both groups post-PCI (analysis of variance P < .0001) without difference between groups (P = .5). Major bleeding occurred in 2.9% ad hoc group versus 3.1% delayed group patients (P = .9). No significant difference was observed in any other secondary end point. CONCLUSIONS: In clopidogrel-naive patients, a strategy of delaying PCI for 2 hours after high-dose clopidogrel loading does not seem to confer any benefit compared to ad hoc PCI.

Intrinsic platelet reactivity and thrombus burden in patients with ST-elevation myocardial infarction.

INTRODUCTION: In patients with ST elevation myocardial infarction (STEMI) increased platelet reactivity has been described to affect the primary percutanuous coronary intervention (PPCI) outcome. We aimed to evaluate the predictive accuracy of intrinsic platelet reactivity for intracoronary thrombus burden in P2Y12 inhibitor- naïve STEMI patients. PATIENTS AND METHODS: In a prospective, observational, cohort study we enrolled 94 consecutive STEMI patients undergoing PPCI, subjected to platelet reactivity assessment prior to any P2Y12 blockade, with visible angiographic thrombus in the infarct related artery (stratified as Grade A, B and C). Platelet-function testing was performed with the VerifyNow point-of-care P2Y12 assay immediately prior to intervention. RESULTS: Intrinsic platelet reactivity was higher with greater thrombus burden: Grade A 158.8±51.1 PRU, Grade B 217.4±62.1 PRU and Grade C 243.4±58.6 PRU, p=0.009 and Spearman r=0.32 (0.12-0.49 95% CI), p=0.002. ROC analysis revealed an AUC=0.7 (Standard error 0.07, p=0.03). An intrinsic platelet reactivity value of >220 PRU had 65% sensitivity (53-76 95%CI), 76% specificity (55-91 95%CI), 88% positive predictive value (76-96 95%CI) and 44% negative predictive value (29-60 95%CI) for detection of high thrombus burden. In multivariate analysis intrinsic platelet reactivity >220 PRU emerged as an independent predictor of high thrombus burden (RR=1.5, 1.15-2.07 95% CI, p=0.004). CONCLUSIONS: In patients admitted with STEMI the intrinsic platelet reactivity -as assessed by a point-of-care assay- is positively associated with the degree of intracoronary thrombus, while having a moderate accuracy in predicting high thrombus burden.

Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction.

BACKGROUND: Ticagrelor and prasugrel provide stronger platelet inhibition compared with clopidogrel. Direct pharmacodynamic comparison between them has not yet been reported in ST-segment-elevation myocardial infarction patients. METHODS AND RESULTS: In a prospective, single-center, single-blind study, 55 out of 117 (47%) screened consecutive ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention were randomized to either ticagrelor 180 mg loading followed by 90 mg bid, or prasugrel 60 mg loading followed by 10 mg od for 5 days. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay and the Multiplate Analyzer at 0, 1, 2, 6, 24 hours, and 5 days postrandomization. The primary end point, PR with VerifyNow at hour 1, did not differ significantly between patients randomized to ticagrelor versus prasugrel (257.3 P2Y12 reaction unit [PRU], 95% CI 230.8-283.8 versus 231.3 PRU, 95% CI 205.3-257.4; P=0.2). PR did not differ at 2, 6, and 24 hours, although at day 5 it was lower with ticagrelor than prasugrel (25.6 PRU, 95% CI 12.3-38.9 versus 50.3 PRU, 95% CI 36.4-64.1; P=0.01). At hour 2, high on-treatment PR rates (cutoff 208 PRU) were 46.2% and 34.6% for ticagrelor and prasugrel, respectively, decreased significantly thereafter, whereas did not differ significantly between the 2 agents at all the time points of the study. CONCLUSIONS: In patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, both ticagrelor and prasugrel exhibit an initial delay in the onset of their antiplatelet action. Ticagrelor did not appear superior to prasugrel in reducing PR during the first 24 hours of ST-segment-elevation myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01463163.

Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study.

OBJECTIVES: The study aimed to compare the antiplatelet action of ticagrelor with prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) while on clopidogrel after percutaneous coronary intervention (PCI). BACKGROUND: Newer P2Y12 inhibitors like prasugrel and ticagrelor provide stronger platelet inhibition compared with clopidogrel. Both agents are efficacious in patients with HTPR while on clopidogrel, but direct comparison between them has not yet been reported. METHODS: In a prospective, single-center, single-blind study, 44 (of 139 screened, 31.7%) ACS patients with HTPR while on clopidogrel 24 h post-PCI were randomized to either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for 15 days with a crossover directly to the alternate treatment for another 15 days. HTPR was defined as platelet reactivity units (PRU) ≥ 235 as assessed by the VerifyNow P2Y12 function assay. RESULTS: The primary endpoint of platelet reactivity at the end of the 2 treatment periods was lower for ticagrelor (32.9 PRU, 95% confidence interval [CI]: 18.7 to 47.2) compared with prasugrel (101.3 PRU, 95% CI: 86.8 to 115.7) with a least squares mean difference of -68.3 PRU (95% CI: -88.6 to -48.1; p < 0.001). The secondary endpoint of HTPR rate was 0% for ticagrelor and 2.4% for prasugrel (1 of 42, p = 0.5). No patient exhibited a major bleeding event at either treatment group. CONCLUSIONS: In patients with ACS exhibiting HTPR while on clopidogrel 24 h post-PCI, ticagrelor produces a significantly higher platelet inhibition compared with prasugrel. (Ticagrelor Versus Prasugrel in Acute Coronary Syndromes After Percutaneous Coronary Intervention; NCT01360437).

Late asymptomatic sirolimus-eluting stent fracture in a female with systemic lupus erythematosus.

We report a case of a sirolimus eluting (Cypher, Johnson-Johnson) stent fracture (SF) incidentally depicted 3 years post PCI in an asymptomatic female with systemic lupus erythematosus (SLE). The vessel was assessed with intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Different imaging modalities results are presented. OCT may offer superior imaging of SF compared to fluoroscopy and IVUS and might prove useful for the detailed assessment and tailored treatment of this rare complication.

Simultaneous drug-eluting and bare-metal stent implantation: long-term clinical outcome and findings of clinically indicated coronary angiography.

BACKGROUND: Simultaneous drug-eluting stent (DES) and bare-metal stent (BMS) implantation is occasionally employed in clinical practice, but its long-term clinical and angiographic outcome is not clear. HYPOTHESIS: We aimed to describe the long-term clinical outcome and the findings of clinically indicated coronary angiography in patients subjected to simultaneous DES and BMS implantation ("hybrid stenting"). METHODS: We identified 236 patients (mean age 62.9 ± 11.4 years, 76.7% men) who had undergone percutaneous coronary intervention with at least 1 DES and 1 BMS. At a median follow-up of 42 months (range, 6-89 months) available in 222 patients, 13 (5.9%) patients died from cardiac causes, 13 (5.9%) experienced nonfatal acute myocardial infarction, and 24 (10.8%) experienced unstable angina. Clinically indicated repeat coronary angiography was performed in 64 patients (28.8%). RESULTS: Thirty-one patients (14%) had target lesion revascularization (TLR). The DES demonstrated lower TLR rates (15.9% vs 36.9%, P = 0.002) and lower late loss (0.44 ± 0.5 mm vs 0.68 ± 0.7 mm, P = 0.009) compared with BMS. Use of DES was independently associated with lower risk for binary restenosis (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.19-0.89, P = 0.03) and TLR (HR: 0.26, 95% CI: 0.12-0.54, P<0.001). CONCLUSIONS: Although a hybrid stenting strategy demonstrates a reasonable long-term prognosis even in high-risk patients, DES have a better angiographic outcome compared with BMS under the influence of common patient-related restenosis risk factors.

Evaluation of culprit saphenous vein graft lesions with optical coherence tomography in patients with acute coronary syndromes.

OBJECTIVES: This study sought to assess, with optical coherence tomography (OCT), presumably culprit atherosclerotic lesions of saphenous vein grafts (SVGs) in patients with acute coronary syndromes (ACS). BACKGROUND: Atherosclerotic lesions of SVGs have been studied in vivo with angioscopy and intravascular ultrasound. However, imaging with OCT, which has a higher resolution than intravascular ultrasound and better penetration than angioscopy, has not been conducted systematically. METHODS: Using a nonocclusive OCT technique, we performed angiography and OCT of culprit SVG lesions in patients with unstable angina (UA), ST-segment elevation myocardial infarction (STEMI), and non-STEMI. Fibrous and fatty tissue, calcification, thrombus, and plaque rupture were defined according to OCT objective criteria. RESULTS: Twenty-eight SVGs (average age 14.6 years) in 26 patients were imaged. Lesions on angiography were complex (96.4%), with ulceration in 32.1% and thrombus in 21.4%. OCT disclosed a fibrofatty composition in all lesions, calcification in 32.1%, plaque rupture in 60.7%, and thrombus in 46.4%. Thrombus was progressively more frequent across groups (UA to STEMI, p = 0.003; UA vs. myocardial infarction, p = 0.006). A thin fibrous cap was marginally more frequent in myocardial infarction patients (UA vs. myocardial infarction, p = 0.06; STEMI 100% vs. non-STEMI 53.3% vs. UA 20%, p = 0.03). OCT features of friability were present in 67.9% of SVGs not correlating with clinical presentation. CONCLUSIONS: OCT of culprit lesions of old SVGs in patients with ACS demonstrates fibrofatty composition, relatively thin fibrous cap, plaque rupture, and thrombus, which correlate with the clinical spectrum of ACS. This suggests that similar mechanisms with native vessels' atherosclerosis may be involved in SVG-related ACS.

A giant, free-floating mass in the left atrium in a patient with atrial fibrillation.

A large intracardiac mass is a rare condition and one with an extremely high risk of haemodynamic and embolic complications. Urgent surgical excision is the treatment of choice, and the histological examination reveals the exact nature of the mass, usually a myxoma or a thrombus. We present the case of an 80-year-old woman, with a history of atrial fibrillation, who was admitted because of a seriously impaired level of consciousness, and fever. A large cerebral infarct and a urinary tract infarction were diagnosed. On the transthoracic echocardiogram a giant, free-floating mass was detected in the left atrium, transiently obstructing the mitral valve orifice. Based on the features of the mass and patient's history, it was considered more likely to be a thrombus rather than a tumour. Given the patient's extremely unfavourable neurological status, cardiac surgery was considered to be contraindicated and the patient was administered unfractionated heparin intravenously. Unfortunately, after a few hours the patient suffered a cardiac arrest and died.

Neointimal coverage and stent strut apposition six months after implantation of a paclitaxel eluting stent in acute coronary syndromes: an optical coherence tomography study.

OBJECTIVES: Prospective optical coherence tomography (OCT) study of strut apposition and neointimal hyperplasia thickness (NIH) of a paclitaxel eluting stent (PES), (Infinium, Sahajanand Medical Technologies Pvt Ltd.). BACKGROUND: Few data exist concerning neointimal coverage of PES. Uncovered and malapposed struts are more common following stenting in acute coronary syndromes (ACS) than in non-ACS lesions. METHODS: All consecutive patients with ACS, treated with the above PES for single native coronary lesions between August 2008 and January 2009, who consented to invasive follow-up with OCT at six months (N=13), were included. RESULTS: At 6 months no patient demonstrated angiographic restenosis. 3180 struts from 20 stents were analyzed, and 91.3% were covered with neointima (NIH 204.8 ± 159.5 µm). Standard statistics and least squares estimates (LSE) derived from a hierarchical ANCOVA model to take into account clustering effects are presented. Rate of uncovered struts was 8.6%, LSE 7.39 (95% CI 3.05-11.73), malapposed struts 2.2%, LSE 1.76 (95% CI 0.05-3.58), and protruding struts 2.9%, LSE 2.8 (95% CI 1.35-4.65). The proportion of uncovered malapposed struts was significantly higher compared to uncovered embedded struts (55.7% vs. 6.8%, p<0.01). In total, 5 (25%) PES were fully covered by neointima. No intracoronary thrombus or clinical events were detected. CONCLUSIONS: Six months after implantation of a specific PES in patients with ACS, most of the stents were only partially covered with neointima, especially at sites of strut malapposition or protrusion. These findings emphasize the need for optimal stent apposition during implantation and for prolonged dual antiplatelet therapy.

Double-barrel stenting of distal left main stenosis in a patient with acute coronary syndrome: intravascular ultrasound and optical coherence tomography follow-up at six months.

A 58-year-old man presented with frequent episodes of angina at rest. A diagnosis of anterior non-ST elevation myocardial infarction was made. Coronary angiography performed on the day of admission revealed a significant stenosis (50% to 60%) of the distal left main stem (LMS) extending to the ostia of the left anterior descending and left circumflex arteries. Coronary artery bypass graft surgery was advised; however, the patient consistently declined this option. Kissing balloon predilation was performed at the LMS bifurcation, and two stents of the same diameter and length (4.0 mm × 18 mm) were simultaneously deployed at the same high pressure (18 atm) spanning the entire length of the LMS, and extending into the left anterior descending and left circumflex arteries beyond the bifurcation lesion. Six months later, intravascular ultrasound and optical coherence tomography revealed neointimal hyperplasia, especially in the artificial septum.