Grigorios Tsigkas

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).

Eosinophilic responses to stent implantation and the risk of Kounis hypersensitivity associated coronary syndrome

The use of drug eluting stents constitutes a major breakthrough in current interventional cardiology because it is more than halves the need of repeat interventions. It is incontrovertible that coronary stents, in general, have been beneficial for the vast majority of patients. A small increase in thrombosis, following DES implantation, is offset by a diminished risk of complications associated with repeat vascularization. However, late and, especially, very late stent thrombosis is a much feared complication because it is associated with myocardial infarction with increased mortality. Despite that stent thrombosis is thought to be multifactorial, so far clinical reports and reported pathology findings in patients died from coronary stent thrombosis as well as animal studies and experiments, point toward a hypersensitivity inflammation. The stented and thrombotic areas are infiltrated by interacting, via bidirectional stimuli inflammatory cells including eosinophils, macrophages, T-cells and mast cells. Stented regions constitute an ideal surrounding for endothelial damage and dysfunction, together with hemorheologic changes and turbulence as well as platelet dysfunction, coagulation and fibrinolytic disturbances. Drug eluting stent components include the metal strut which contains nickel, chromium, manganese, titanium, molybdenum, the polymer coating and the impregnated drugs which for the first generation stents are: the antimicrotubule antineoplastic agent paclitaxel and the anti-inflammatory, immunosuppressive and antiproliferative agent sirolimus. The newer stents which are called cobalt-chromiun stents and elute the sirolimus analogs everolimus and zotarolimus both contain nickel and other metals. All these components constitute an antigenic complex inside the coronary arteries which apply chronic, continuous, repetitive and persistent inflammatory action capable to induced Kounis syndrome and stent thrombosis. Allergic inflammation goes through three phases, the early phase, the late phase and the chronic phase and these three phases correspond temporally with early (acute and sub acute), late and very late stent thrombosis. Bioabsorbable allergy free poly lactic acid self expanding stents, nickel free stainless steel materials, stent coverage with nitric oxide donors and antibodies with endothelial progenitor cell capturing abilities as well as stents eluting anti-inflammatory and anti-allergic agents might be the solution of this so feared and devastating stent complication.

Transulnar Compared With Transradial Artery Approach as a Default Strategy for Coronary Procedures A Randomized Trial The Transulnar or Transradial Instead of Coronary Transfemoral Angiographies Study (The AURA of ARTEMIS Study)

Background—The ulnar artery is rarely selected for coronary angiography or percutaneous coronary intervention despite the expanding use of the transradial approach. We aimed to establish noninferiority of a default transulnar relative to transradial approach in terms of feasibility and safety. Methods and Results—This was a prospective, randomized, multicenter, parallel-group study involving 902 patients at 5 sites eligible to undergo diagnostic coronary angiography and percutaneous coronary intervention. Patients were randomized in a 1:1 ratio to either transradial approach (reference intervention) or transulnar approach (experimental intervention) regardless of the Allen test results. The primary end point was a composite of cross-over to another arterial access, major adverse cardiovascular events, and major vascular events of the arm at 60 days. The study was prematurely terminated after the first interim analysis because of inferiority of the transulnar approach. Although the difference in the primary end point became inconclusive after adjustment for operator clustering (24.30%; 99.99% confidence interval [CI], −7.98% to 56.58%; P=0.03 at &agr;=0.0001), need for cross-over in the transulnar group remained inferior to transradial access site with a difference of 26.34% (95% CI, 11.96%–40.69%; P=0.004). Conclusions—As a result of higher cross-over rates, a first-line transulnar strategy was proven inferior to the transradial approach for coronary procedures. At present, the transulnar route should not be regarded as an acceptable alternative to the transradial access site. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01364532.

White blood cell counts, leukocyte ratios, and eosinophils as inflammatory markers in patients with coronary artery disease.

Inflammation is a key feature of atherosclerosis and its clinical manifestations. The leukocyte count has emerged as a marker of inflammation that is widely available in clinical practice. Since inflammation plays a key role in atherosclerosis and its end results, discovering new biomarkers of inflammation becomes important in order to help diagnostic accuracy and provide prognostic information about coronary cardiac disease. In acute coronary syndromes and percutaneous coronary intervention, elevated levels of almost all subtypes of white blood cell counts, including eosinophils, monocytes, neutrophils, and lymphocytes, and neutrophil–lymphocyte ratio and eosinophil–leukocyte ratio constitute independent predictors of adverse outcomes. Eosinophil count and eosinophil–leukocyte ratio, in particular, emerge as novel biomarkers for risk stratification in patients with coronary artery disease. Since the presence of eosinophils denotes hypersensitivity inflammation and hypersensitivity associated with Kounis syndrome, this reality is essential for elucidating the etiology of inflammation in order to consider predictive and preventive measures and to apply the appropriate therapeutic methods.

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.

Nickel allergy, Kounis syndrome and intracardiac metal devices

Metal-induced allergic reactions are not rare in every day practice but nickel, cobalt and chromium are the most common offenders. Other metal anions and metal alloys represent also emerging causes for hypersensitivity reaction in humans. The metal struts of endovascular and intracardiac devices are usually alloys containing nickel and constitute causes for allergic reactions with possible intracardiac and intracoronary mast cell activation resulting in the Kounis hypersensitivity coronary syndrome. Newer intracoronary stents avoid nickel thus making them less allergenic. It is advisable that, before any device implantation, careful history of any metal allergy should be taken and efforts should be made for the development of new devices with better biocompatibility.

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.

Onset of Antiplatelet Action With High (100 mg) Versus Standard (60 mg) Loading Dose of Prasugrel in Patients With ST-Segment–Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention Pharmacodynamic Study

Background—In patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, a suboptimal degree of platelet inhibition for the first 2 hours after the standard 60 mg loading dose of prasugrel has been described. Methods and Results—In a prospective, 3-center, nonrandomized, controlled study, 2 sequential groups of P2Y12 inhibitor-naive consecutive patients were loaded with either 100 mg (n=47) or 60 mg (n=35) of prasugrel. Platelet reactivity was assessed by VerifyNow at hours 0, 0.5, 1, 2, and 4. At hour 2, there was a strong trend for the primary end point of platelet reactivity (in P2Y12 reaction units) to be lower (least squares estimates of the mean difference [95% confidence interval], −45.5 [−91.2 to 0.3]; P=0.051), whereas platelet reactivity percentage inhibition (median, first to third quartile) was higher (75.5% [24%–91.8%] versus 23.5% [0%–78.3%]; P=0.02) in the 100-mg compared with 60-mg loading dose group. At hour 2, prasugrel 100 mg over 60 mg loading dose significantly reduced high platelet reactivity rates from 28.6% to 8.5% (≥230 P2Y12 reaction units threshold; P=0.036) and from 31.4% to 10.6% (≥208 P2Y12 reaction units threshold; P=0.024), whereas resulted in lower rate of ⩽20% platelet inhibition (23.4% versus 51.4%; P=0.009). Conclusions—In patients with ST-segment–elevation myocardial infarction treated with primary percutaneous coronary intervention, a higher (100 mg) than the standard loading dose of prasugrel results in greater and more consistent platelet inhibition, yet this will need to be further validated in additional studies. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01835353.

Long-Term Clinical Outcome After Percutaneous Coronary Intervention in Grafts vs Native Vessels in Patients With Previous Coronary Artery Bypass Grafting

BACKGROUND The long-term clinical outcome of patients with previous coronary artery bypass grafting (CABG), undergoing percutaneous coronary intervention (PCI) is not clear. METHODS Observational, retrospective study of post-CABG patients, who underwent PCI in either a graft or a native vessel. RESULTS Out of 221 consecutive patients, those with PCI in both native vessel and graft (N=16) and missing follow-up data (N=15) were excluded. Out of the remaining 190 patients (age 67.9±9.6 years; 90.0% men), the graft-PCI group (N=88) had more occluded native vessels (2.1±0.8 vs 1.6±0.8; P<0.001), and fewer totally occluded grafts (0.55±0.6 vs 0.75±0.8; P=0.05) compared with the native vessel-PCI group (N=102). On follow-up (median duration 28 months), the incidence of major adverse cardiac events (MACEs), cardiac death, and repeat revascularization was higher in graft-PCI group compared with native vessel-PCI group (43.2% vs 19.6%, log-rank P<0.001; 19.3% vs 6.9%, log-rank P=0.008; and 23.9% vs 12.7%, log-rank P=0.02, respectively). Graft-PCI was independently associated with higher risk for major adverse cardiac events (hazard ratio [HR], 2.84; 95% confidence interval [CI], 1.45-5.57; P=0.002), cardiac death (HR, 3.44; 95% CI, 1.16-10.22; P=0.03) and repeat revascularization (HR, 2.41; 95% CI, 1.02-5.72; P=0.046). CONCLUSIONS Post-CABG patients, undergoing graft compared with native vessel-PCI, have worse long-term clinical outcome. Prospective studies are needed to elucidate the optimal revascularization strategy for such patients.