Alexios Karagiannis

Mechanisms of Very Late Bioresorbable Scaffold Thrombosis : The INVEST Registry

BACKGROUNDnVery late scaffold thrombosis (VLScT) occurs more frequently after bioresorbable scaffold (Absorb BVSxa01.1, Abbott Vascular, Santa Clara, California) implantation than with metallic everolimus-eluting stents.nnnOBJECTIVESnThe purpose of this study was to elucidate mechanisms underlying VLScT as assessed by optical coherence tomography (OCT).nnnMETHODSnThe INVEST (Independent OCT Registry on Very Late Bioresorbable Scaffold Thrombosis) registry is an international consortium of investigators who used OCT to examine patients with VLScT.nnnRESULTSnBetween June 2013 and May 2017, 36 patients with 38 lesions who had VLScT underwent OCT at 19 centers. VLScT occurred at a median of 20xa0months (interquartile range: 16 to 27xa0months) after implantation. At the time of VLScT, 83% of patients received aspirin monotherapy and 17% received dual-antiplatelet therapy. The mechanisms underlying VLScT were (in descending order) scaffold discontinuity (42.1%), malapposition (18.4%), neoatherosclerosis (18.4%), underexpansion or scaffold recoil (10.5%), uncovered struts (5.3%), and edge-related disease progression (2.6%). Discontinuity (odds ratio [OR]: 110; 95% confidence interval [CI]: 73.5 to 173; pxa0< 0.001), malapposed struts (OR: 17.0; 95% CI: 14.8 to 19.7; pxa0< 0.001), and uncovered struts (OR: 7.3; 95% CI: 6.2 to 8.8; pxa0< 0.001) were more frequent in the thrombosed than the nonthrombosed scaffold regions. In 2 of 16 patients with scaffold discontinuity, intercurrent OCT before VLScT provided evidence of circularly apposed scaffold struts with minimal tissue coverage.nnnCONCLUSIONSnThe leading mechanism underlying VLScT was scaffold discontinuity, which suggests an unfavorable resorption-related process, followed by malapposition and neoatherosclerosis. It remains to be determined whether modifications in scaffold design and optimized implantation can mitigate the risk of VLScT. (Independent OCT Registry on Very Late Bioresorbable Scaffold Thrombosis [INVEST]; NCT03180931).

Effects of Ticagrelor, Prasugrel, or Clopidogrel at Steady State on Endothelial Function

Ticagrelor is a nonthienopyridine direct and reversible P2Y12 platelet receptor antagonist, and unlike prasugrel or clopidogrel inhibits, at least partially, the sodium-independent equilibrative nucleoside transporter 1 [(1)][1]. This ticagrelor-mediated off-target effect has potential to improve

Effects of Ticagrelor, Prasugrel, or Clopidogrel on Endothelial Function and Other Vascular Biomarkers: A Randomized Crossover Study

OBJECTIVESnThe study sought to assess whether treatment with ticagrelor, as compared with prasugrel and clopidogrel, improves endothelium-dependent dilation throughout the course of the treatment and other vascular biomarkers, including systemic adenosine plasma levels.nnnBACKGROUNDnThe inxa0vivo off-target effects of ticagrelor in post-acute coronary syndrome (ACS) patients remain poorly characterized.nnnMETHODSnFifty-four stable post-ACS patients were sequentially exposed to each of the 3 oral P2Y12 inhibitors following a 3-period balanced Latin square crossover design with 4 weeks per treatment in 5 European centers. The primary endpoint was the assessment of endothelial function with pulse amplitude tonometry and expressed as reactive hyperemia index at treatment steady state. Secondary endpoints included reactive hyperemia index after loading or before maintenance regimen, systemic adenosine plasma levels, a wide set of vascular biomarkers, and ticagrelor orxa0AR-C124910XX plasma levels throughout each ticagrelor period. In 9 patients, the evaluation of endothelial function was performed simultaneously by pulse amplitude tonometry and flow-mediated dilation.nnnRESULTSnReactive hyperemia index did not differ after ticagrelor (1.970 ± 0.535) as compared with prasugrel (2.007 ± 0.640; pxa0= 0.557) or clopidogrel (2.072 ± 0.646; pxa0= 0.685), nor did systemic adenosine plasma levels or vascular biomarkers at any time points. P2Y12 platelet reactivity units were lower after ticagrelor as compared with clopidogrel at all time points and after maintenance dose as compared with prasugrel. Flow-mediated dilation did not differ after the maintenance dose of ticagrelor as compared with clopidogrel and prasugrel.nnnCONCLUSIONSnTicagrelor did not improve endothelial function or increased systemic adenosine plasma levels asxa0compared with prasugrel and clopidogrel in stabilized patients who suffered from an ACS. (Hunting for thexa0Off-Targetxa0Properties of Ticagrelor on Endothelial Function in Humans [HI-TECH]; NCT02587260).

Eligibility for PCSK9 Inhibitors According to American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines After Acute Coronary Syndromes.

Background The American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) have recently published recommendations for the use of proprotein convertase subtilisin/kexin‐9 (PCSK9) inhibitors in situations of very high risk. We aim to assess in the real world the suitability of PCSK9 inhibitors for acute coronary syndromes. Methods and Results We analyzed a prospective Swiss cohort of 2023 patients hospitalized for acute coronary syndromes between 2009 and 2014 with available data for low‐density lipoprotein cholesterol and lipid‐lowering therapy at 1 year. Clinical familial hypercholesterolemia was defined using the Dutch Lipid Clinic Network algorithm as unlikely, possible, probable, or definite. We simulated a fixed relative reduction of 24% in low‐density lipoprotein cholesterol levels at 1 year in all patients not treated with ezetimibe, irrespective of the low‐density lipoprotein cholesterol levels and statin regimen. At 1 year, 94.3% of patients were treated with statin, 5.8% with ezetimibe, and 35.8% of patients had on‐target low‐density lipoprotein cholesterol levels (<1.8 mmol/L); 25.6% met criteria for possible or probable/definite familial hypercholesterolemia. After a simulation of the lipid‐lowering effect of ezetimibe, the proportion of patients who would be eligible for PCSK9 inhibitors at 1 year was 13.4% using American College of Cardiology criteria and 2.7% using European Society of Cardiology/European Atherosclerosis Society criteria. Patients with possible or probable/definite familial hypercholesterolemia were more eligible for PCSK9 inhibitors compared with their non–familial hypercholesterolemia counterparts: 27.6% versus 8.8% according to American College of Cardiology criteria and 6.6% versus 1.8% according to European Society of Cardiology/European Atherosclerosis Society criteria (P<0.001). Conclusions Recommendations made by the American College of Cardiology guidelines would lead to 5‐fold higher eligibility rates for PCSK9 inhibitors compared to the European Society of Cardiology/European Atherosclerosis Society consensus statement in acute coronary syndrome patients.

Angiographic derived endothelial shear stress: a new predictor of atherosclerotic disease progression

AIMSnTo examine the efficacy of angiography derived endothelial shear stress (ESS) in predicting atherosclerotic disease progression.nnnMETHODS AND RESULTSnThirty-five patients admitted with ST-elevation myocardial infarction that had three-vessel intravascular ultrasound (IVUS) immediately after revascularization and at 13u2009months follow-up were included. Three dimensional (3D) reconstruction of the non-culprit vessels were performed using (i) quantitative coronary angiography (QCA) and (ii) methodology involving fusion of IVUS and biplane angiography. In both models, blood flow simulation was performed and the minimum predominant ESS was estimated in 3u2009mm segments. Baseline plaque characteristics and ESS were used to identify predictors of atherosclerotic disease progression defied as plaque area increase and lumen reduction at follow-up. Fifty-four vessels were included in the final analysis. A moderate correlation was noted between ESS estimated in the 3D QCA and the IVUS-derived models (ru2009=u20090.588, Pu2009<u20090.001); 3D QCA accurately identified segments exposed to low (<1u2009Pa) ESS in the IVUS-based reconstructions (AUC: 0.793, Pu2009<u20090.001). Low 3D QCA-derived ESS (<1.75u2009Pa) was associated with an increase in plaque area, burden, and necrotic core at follow-up. In multivariate analysis, low ESS estimated either in 3D QCA [odds ratio (OR): 2.07, 95% confidence interval (CI): 1.17-3.67; Pu2009=u20090.012) or in IVUS (<1u2009Pa; OR: 2.23, 95% CI: 1.23-4.03; Pu2009=u20090.008) models, and plaque burden were independent predictors of atherosclerotic disease progression; 3D QCA and IVUS-derived models had a similar accuracy in predicting disease progression (AUC: 0.826 vs. 0.827, Pu2009=u20090.907).nnnCONCLUSIONSn3D QCA-derived ESS can predict disease progression. Further research is required to examine its value in detecting vulnerable plaques.

Frequency, Reasons, and Impact of Premature Ticagrelor Discontinuation in Patients Undergoing Coronary Revascularization in Routine Clinical Practice: Results From the Bern Percutaneous Coronary Intervention Registry.

Background— Although ticagrelor has improved clinical outcomes among patients with acute coronary syndrome compared with clopidogrel, adherence to this new antiplatelet agent in real-world practice has not been fully investigated. Methods and Results— Between November 2011 and June 2014, 1278 of 4831 consecutive patients (26.5%) undergoing percutaneous coronary intervention at a tertiary care center were treated with ticagrelor. Premature ticagrelor cessation was categorized into (1) change, when ticagrelor was replaced by prasugrel; (2) de-escalation, when ticagrelor was replaced by clopidogrel; and (3) premature discontinuation, when ticagrelor was discontinued without P2Y12 inhibitor replacement. Of 1278 patients treated with ticagrelor, premature treatment cessation occurred in 212 patients (17%). De-escalation to clopidogrel was the most frequent scenario (57%; n=120), followed by premature discontinuation (28%; n=60) and change to prasugrel (15%; n=32). Reasons for ticagrelor cessation included adverse effects (49%), initiation of oral anticoagulation (19%), and unspecified general practitioner preference (10%). Most frequent adverse effects leading to premature ticagrelor cessation were bleeding (41%), dyspnea (29%), and gastrointestinal symptoms (18%). Premature ticagrelor cessation was not associated with an increased risk of cardiac death, myocardial infarction, or stroke (hazard ratio, 0.73; 95% confidence interval: 0.40–1.32; P=0.29). Conclusions— Premature ticagrelor cessation in routine clinical practice occurred in 1 of 6 patients and was primarily related to adverse effects among which bleeding and dyspnea were the most frequent. Although premature ticagrelor cessation was not associated with adverse cardiovascular outcomes, this finding requires careful interpretation in view of the modest sample size. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT02241291.

Adenosine and Ticagrelor Plasma Levels in Patients With and Without Ticagrelor-Related Dyspnea

Dyspnea is a common side effect of ticagrelor, leading to drug discontinuation in roughly one in every 20 treated patients.1, 2 Studies have suggested that ticagrelor inhibits the sodium-independent equilibrative nucleoside transporter-1, which may increase adenosine plasma levels and explain drug-related dyspnea.3 However, the identification of a pattern of periodic breathing associated to increased chemosensitivity to hypercapnia in patients with ticagrelor-related dyspnea4 has reinforced the hypothesis that this side effect may result from direct inhibition of P2Y12 receptors on neurons leading to purinergic stimulation of the chemoreflex system.3, 4 Simultaneous measurements of adenosine and ticagrelor plasma levels in patients with and without dyspnea while on treatment with ticagrelor may help unraveling the mechanism of this common and clinically relevant side effect.