Differential effect of ticagrelor versus prasugrel on coronary blood flow velocity in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: an exploratory study.

BACKGROUND: Prasugrel and ticagrelor provide a superior anti-ischemic action than clopidogrel, with some of ticagrelor's benefits possibly attributed to adenosine-mediated mechanisms. We aimed to compare the effect of maintenance dose of ticagrelor versus prasugrel on coronary blood flow velocity (CBFV) during increasing doses of intravenously administered adenosine. METHODS AND RESULTS: In a prospective, single-center, single-blind, crossover study, 56 patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention were randomized to receive either ticagrelor 90 mg BID or prasugrel 10 mg OD with a 15-day treatment period. At the end of each treatment period, CBFV by transthoracic Doppler echocardiography was assessed at baseline and under incremental doses (50 µg/kg per minute, 80 µg/kg per minute, 110 µg/kg per minute, and 140 µg/kg per minute) of adenosine infusion. Maximal CBFV area under the curve was higher for ticagrelor-treated than for prasugrel-treated patients, with a least squares mean difference of 7.16 (95% confidence interval, 2.61-11.7; P=0.003). Maximal CBFV/baseline CBFV ratio was higher with ticagrelor than prasugrel at 50, 80, and 110 µg/kg per minute but not at 140 µg/kg per minute adenosine infusion rate, with mean difference (95% confidence interval) of 0.17 (0.08-0.26; P<0.001), 0.21 (0.02-0.41; P=0.03), 0.24 (0.01-0.47; P=0.04), and 0.14 (-0.12 to 0.4; P=0.3), respectively. CONCLUSIONS: In patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention, ticagrelor augments CBFV to a greater extent than prasugrel when incremental doses of adenosine are administered. Although exploratory, these results may represent a pleiotropic action of ticagrelor, possibly contributing to its beneficial effects in such patients.

Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with diabetes.

OBJECTIVE: It has been postulated that prasugrel might be the preferred treatment option in diabetes mellitus (DM) patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We aimed to compare the pharmacodynamic action of ticagrelor versus prasugrel. RESEARCH DESIGN AND METHODS: In a prospective, single-center, single-blind, crossover study, 30 consecutive ACS patients with DM who had been pretreated with clopidogrel were randomized to either 90 mg ticagrelor twice daily or 10 mg prasugrel once daily with a 15-day treatment period. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay, measured in P2Y12 reaction units (PRU). RESULTS: PR was significantly lower after ticagrelor (45.2 PRU [95% CI 27.4-63.1]) compared with prasugrel (80.8 PRU [63.0-98.7]), with a least squares mean difference of -35.6 PRU (-55.2 to -15.9, P = 0.001). High PR rate was 0% for ticagrelor and 3.3% for prasugrel (P = 1.0). CONCLUSIONS: In DM patients with ACS who had been pretreated with clopidogrel and who undergo PCI, ticagrelor achieves a significantly higher platelet inhibition than prasugrel. Both antiplatelet agents effectively treat high PR. The relevance of these findings to the clinical efficacy and safety of ticagrelor and prasugrel in DM patients needs further elucidation.

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.

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).

An optical coherence tomography study of two new generation stents with biodegradable polymer carrier, eluting paclitaxel vs. biolimus-A9.

BACKGROUND: Tissue coverage and strut apposition of drug eluting stents (DES), which can be assessed with optical coherence tomography (OCT), may be associated with late stent thrombosis (LST). METHODS: Prospective observational angiographic and OCT follow-up at 6 months post-implantation of a biolimus-A9 eluting stent (BES) vs. a paclitaxel eluting stent (PES), with biodegradable polymer carriers. The primary outcome was the percent difference of uncovered struts between BESs and PESs. RESULTS: A maximum likelihood model was used for analysis, to account for data clustering. Sixteen patients were treated with BES (28 lesions/4530 struts) and 16 with PES (23 lesions/4450 struts). Overall, BESs compared to PESs had more uncovered [0.41% vs. 0.21%, difference estimate (DE) 0.2 (95% CI, 0.06-0.34), p=0.006], malapposed [0.18% vs. 0.04%, DE 0.14 (95% CI 0.05-0.23), p=0.003], uncovered and malapposed [0.08% vs. 0.026%, DE 0.057 (95% CI 0.015-0.1), p=0.01] and protruding struts [0.23% vs. 0.04%, DE 0.185 (95% CI 0.1-0.27), p<0.001], and significantly lower neointimal thickness (59.3 ± 28.2 µm vs. 201.7 ± 97.5, p<0.001). None of the BESs was totally covered with neointima, in contrast to 5 (21.7%) PESs (p=0.01). Thrombus was detected in 1 (3.6%) BES and 5 (21.7%) PESs (p=0.05); however, no patient experienced clinical stent thrombosis. CONCLUSION: Between two stents with biodegradable polymer, OCT demonstrated that BESs had more uncovered and malapposed struts compared to PESs at 6 months. This difference might be partly attributed to the more potent antiproliferative properties of biolimus-A9; however, its impact on clinical outcome and on the risk of LST is yet to be determined.

Prasugrel overcomes high on-clopidogrel platelet reactivity in chronic coronary artery disease patients more effectively than high dose (150 mg) clopidogrel.

BACKGROUND: High on-treatment platelet reactivity (HTPR) is present in a substantial percentage of patients on chronic clopidogrel treatment and may have prognostic implications. Strategies to optimize platelet inhibition in such patients are not clear. METHODS: We performed a prospective, single-center, single-blinded, investigator-initiated randomized, crossover study of platelet inhibition by prasugrel 10 mg/day versus high-dose 150 mg/day clopidogrel, with a 14 day treatment period, in 31 patients with HTPR (out of 99 screened, 31.3%) while on chronic (≥ 12 months) treatment with clopidogrel. All patients had stable coronary artery disease and 87.1% of them had a prior percutaneous coronary intervention. Platelet reactivity (PR) was assessed by the VerifyNow assay measured in platelet reactivity units (PRU). RESULTS: The primary end point of PR at the end of the two treatment periods was lower in patients receiving prasugrel compared with high dose clopidogrel ( least squares estimate 148.1, 95% CI 127.1-169.2 and 219.8, 95% CI 198.6-240.9 respectively, P < .001). The secondary end point of HTPR rate was lower for prasugrel compared with clopidogrel, 11.5% vs 46.3%, P = .003. CONCLUSIONS: Prasugrel appears more effective than double clopidogrel in inhibiting PR in patients with HTPR following chronic clopidogrel treatment.

Mechanisms of non-fatal stent-related myocardial infarction late following coronary stenting with drug-eluting stents and bare metal stents. Insights from optical coherence tomography.

BACKGROUND: A prospective observational study using optical coherence tomography (OCT) of patients with myocardial infarction (MI), late following drug-eluting (DES) or bare metal stent (BMS) implantation, when the stented segment was considered culprit. METHODS AND RESULTS: Seventeen patients (58.9±8.3 years; 7 DES, 10 BMS) with MI at 50 (3-180) months post-stenting. Patients with BMS sustained a MI later than patients with DES (95 (3-180) vs. 8 (3-62) months, P=0.01]; 5 (71.4%) of the DES patients demonstrated binary angiographic restenosis, in contrast to 8 (80%) with BMS (P=1.0). DES had significantly less thickness of the neointimal hyperplasia compared with BMS (0.08±0.04 vs. 0.36±0.2mm, P=0.003). None of the DES was totally covered with neointimal tissue. The overall percentage of uncovered and malapposed struts (ANCOVA), was significantly higher in DES than BMS (1.96, 95% confidence interval (CI) 1.5-2.4 vs. 0.25, 95%CI 0.1-0.6, P<0.001, and 0.66, 95%CI 0.29-1.03 vs. 0.11, 95%CI 0.19-0.4, P=0.03, respectively). OCT features of atherosclerosis (lipid, neovascularization, or calcification) and possible neointimal rupture were found only in patients with BMS. Thrombus detection was not different between the 2 groups. CONCLUSIONS: Stent-related, non-fatal, late acute MI following stent implantation occurs later in patients with a BMS compared with those with a DES, and the mechanism includes delayed healing (mainly DES), and neointimal hyperplasia with atherosclerotic transformation and subsequent rupture (mainly BMS).

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.

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.

The future of cardiovascular magnetic resonance in Greece: expectations and reality.

INTRODUCTION: The latest advances in cardiovascular magnetic resonance (CMR) have established this technique as the gold standard imaging modality for many cardiac diseases. However, cardiologists seem to be reluctant to use CMR in their everyday clinical practice. METHODS: In an attempt to identify some of the reasons for this discrepancy, we conducted a survey employing a written questionnaire completed by 60 trained cardiologists in the third most populated region of Greece. RESULTS: Cardiologists would refer patients for CMR rarely (71.6%) or never (28.3%). The most frequent indications for CMR were congenital heart disease (46.7%) and aortography (28.3%). Only 13.3% were familiar with cardiac computed tomography and 8.3% with CMR. Participants would like CMR to be able to clarify coronary artery anatomy (81.3%). Only 3% answered correctly all the questions regarding contraindications of CMR. The main reasons for not referring a patient for CMR were non-availability (75%), lack of familiarity (60%), and high cost (55%). The most appropriate physician for conducting/interpreting a CMR examination is a cardiologist (31.7%), radiologist (10%), both (51.7%), or not important (6.7%). The method is going to expand a lot (41.6%), moderately (46.7%), or not at all (1.2%) in the future. CONCLUSIONS: A complex interplay between the lack of trained physicians and technicians, non-availability of scanners for CMR, high costs, and lack of adequate education of cardiologists, leads to a vicious circle with the final odds against CMR. Actions to bypass these issues are required on behalf of all scientists involved in CMR imaging. Training of more physicians and technicians, establishment of dedicated CMR programs, and in-depth education of cardiologists regarding the indications and advantages of CMR over other imaging modalities, will be required if CMR is to become established in everyday clinical practice.