Dimitrios Alexopoulos

Consensus and Update on the Definition of On-Treatment Platelet Reactivity to Adenosine Diphosphate Associated With Ischemia and Bleeding

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary intervention. In an earlier consensus document, we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post-percutaneous coronary intervention ischemic events for various platelet function tests (PFTs). Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention, although routine testing is not recommended (Class III). Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor. Recent prospective randomized trials of PFT did not demonstrate clinical benefit, thus questioning whether treatment modification based on the results of current PFT platforms can actually influence outcomes. However, there are major limitations associated with these randomized trials. In addition, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Therefore, a therapeutic window concept has been proposed for P2Y12 inhibitor therapy. In this updated consensus document, we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events. In addition, we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy.

Angiographic success and procedural complications in patients undergoing retrograde percutaneous coronary chronic total occlusion interventions: A weighted meta-analysis of 3482 patients from 26 studies

BACKGROUNDnThe efficacy and safety profile of retrograde chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study. We sought to perform a weighted meta-analysis of the success and complication rates of retrograde CTO PCI.nnnMETHODSnWe conducted a meta-analysis of 26 studies published between 2006 and April 2013 reporting in-hospital outcomes of retrograde CTO PCI. Data on procedural success, frequency of death, emergent coronary artery bypass graft surgery (CABG), stroke, myocardial infarction (MI), perforation, tamponade, stent thrombosis, major vascular or bleeding events, contrast nephropathy, and radiation skin injury were collected.nnnRESULTSnA total of 26 studies with 3482 patients and 3493 target CTO lesions were included. Primary retrograde CTO PCI was attempted in 52.4%. Pooled estimates of outcomes were as follows: procedural success 83.3% [95% confidence interval (CI): 79.0% to 87.7%]; death 0.7% (95% CI: 0.5% to 1.2%); urgent CABG 0.7% (95% CI: 0.4% to 1.2%); tamponade 1.4% (95% CI: 1.0% to 2.2%); collateral perforation 6.9% (95% CI: 4.6% to 10.4%); coronary perforation 4.3% (95% CI: 1.2% to 15.4%); donor vessel dissection 2% (95% CI: 0.9% to 4.5%); stroke 0.5% (95% CI: 0.2% to 1.0%); MI 3.1% (95% CI: 0.2% to 5.0%); Q wave MI 0.6% (95% CI: 0.4% to 1.1%); vascular access complications 2% (95% CI: 0.9% to 4.5%); contrast nephropathy 1.8% (95% CI: 0.8% to 3.7%); and wire fracture and equipment entrapment 1.2% (95% CI: 0.6% to 2.5%).nnnCONCLUSIONSnRetrograde CTO PCI is associated with high procedural success rate and acceptable risk for procedural complications.

Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: Mid-term efficacy and effect on quality of life

BACKGROUNDnOur group previously showed that colchicine treatment is associated with decreased early recurrence rate after ablation for atrial fibrillation (AF).nnnOBJECTIVEnThe purpose of this study was to test the mid-term efficacy of colchicine in reducing AF recurrences after a single procedure of pulmonary vein isolation in patients with paroxysmal AF. Assessment of quality-of-life (QOL) changes was a secondary objective.nnnMETHODSnPatients with paroxysmal AF who were scheduled for ablation were randomized to a 3-month course of colchicine 0.5 mg twice daily or placebo and were followed for a median of 15 months (with a 3-month blanking period). QOL was assessed with a general-purpose health-related QOL tool (26-item World Health Organization QOL questionnaire) at baseline and after 3 and 12 months.nnnRESULTSnTwo hundred twenty-three randomized patients underwent ablation, and 206 patients were available for analysis (144 male, age 62.2 ± 5.8 years). AF recurrence rate in the colchicine group was 31.1% (32/103) vs 49.5% (51/103) in the control group (P = .010), translated in a relative risk reduction of 37% (odds ratio 0.46, 95% confidence interval 0.26-0.81). The number needed to treat was 6 (95% confidence interval 3.2-19.8). Physical domain QOL scores at 12 months were 63.6 ± 13.8 in the colchicine group and 52.5 ± 18.1 in controls, whereas psychological domain scores were 56.1 ± 13.7 vs 44.7 ± 17.3, respectively (P <.001, for both).nnnCONCLUSIONnColchicine treatment after pulmonary vein isolation for paroxysmal AF is associated with lower AF recurrence rates after a single procedure. This reduction is accompanied by corresponding improvements in physical and psychological health-related QOL scores.

Colchicine Treatment for the Prevention of Bare-Metal Stent Restenosis in Diabetic Patients

OBJECTIVESnThis study sought to test the hypothesis that colchicine treatment after percutaneous coronary intervention (PCI) can lead to a decrease in in-stent restenosis (ISR).nnnBACKGROUNDnISR rates are particularly high in certain patient subsets, including diabetic patients, especially when a bare-metal stent (BMS) is used. Pharmacological interventions to decrease ISR could be of clinical relevance.nnnMETHODSnDiabetic patients with contraindication to a drug-eluting stent, undergoing PCI with a BMS, were randomized to receive colchicine 0.5 mg twice daily or placebo for 6 months. Restenosis and neointima formation were studied with angiography and intravascular ultrasound 6 months after the index PCI.nnnRESULTSnA total of 196 patients (63.6 ± 7.0 years of age, 128 male) were available for analysis. The angiographic ISR rate was 16% in the colchicine group and 33% in the control group (p = 0.007; odds ratio: 0.38, 95% confidence interval: 0.18 to 0.79). The number needed to treat to avoid 1 case of angiographic ISR was 6 (95% confidence interval: 3.4 to 18.7). The results were similar for IVUS-defined ISR (odds ratio: 0.42; 95% confidence interval: 0.22 to 0.81; number needed to treat = 5). Lumen area loss was 1.6 mm(2) (interquartile range: 1.0 to 2.9 mm(2)) in colchicine-treated patients and 2.9 mm(2) (interquartile range: 1.4 to 4.8 mm(2)) in the control group (p = 0.002). Treatment-related adverse events were largely limited to gastrointestinal symptoms.nnnCONCLUSIONSnColchicine is associated with less neointimal hyperplasia and a decreased ISR rate when administered to diabetic patients after PCI with a BMS. This observation may prove useful in patients undergoing PCI in whom implantation of a drug-eluting stent is contraindicated or undesirable.

Cefuroxime-induced coronary artery spasm manifesting as Kounis syndrome.

Allergic angina and allergic myocardial infarction (Kounis syndrome) occurring during the course of a drug-induced allergic reaction in the absence of angiographically stenosed coronary arteries, is rare in clinical practice.This paper reports the case of a 70-year-old woman with no significant risk factors for coronary artery disease who developed coronary artery spasm after intravenous injection of cefuroxime.A subsequent coronary angiogram revealed normal coronary arteries (type I variant of the syndrome). The allergic reaction following cefuroxime administration seems to have triggered the development of coronary artery spasm. Susceptible individuals expressing an amplified mast cell degranulation effect may be more vulnerable to coronary artery spasm. The clinical implications of this syndrome are also discussed.

Anti-Inflammatory Treatment With Colchicine in Stable Chronic Heart Failure: A Prospective, Randomized Study

OBJECTIVESnThe purpose of this study was to test the efficacy of a 6-month course of anti-inflammatory treatment with colchicinexa0in improving functional status of patients with stable chronic heart failure (CHF).nnnBACKGROUNDnCHF has been shown to be associated with inflammatory activation. Inflammation has been designated as a therapeutic target in CHF.nnnMETHODSnPatients with stable CHF were randomly assigned to colchicine (0.5 mg twice daily) or placebo for 6 months. Thexa0primary endpoint was the proportion of patients achieving at least one-grade improvement in New York Heartxa0Association class.nnnRESULTSnTwo hundred sixty-seven patients were available for final evaluation of the primary endpoint: its rate was 11% in the control group and 14% in the colchicine group (odds ratio: 1.40; 95% confidence interval: 0.67 to 2.93; pxa0= 0.365). The rate of the composite of death or hospital stay for heart failure was 9.4% in the control group, compared with 10.1% in the colchicine group (pxa0= 0.839). The changes in treadmill exercise time with treatment were insignificant and similar in the 2 groups (pxa0= 0.938). C-reactive protein and interleukin-6 were both significantly reduced in the colchicine group (-5.1 mg/l and -4.8 pg/ml, respectively; pxa0< 0.001 for both, compared with the control group).nnnCONCLUSIONSnAccording to this prospective, randomized study, anti-inflammatory treatment with colchicine in patients with stable CHF, although effective in reducing inflammation biomarker levels, did not affect in any significant way patient functional status (in terms of New York Heart Association class and objective treadmill exercise tolerance) or the likelihood of death or hospital stay for heart failure.

Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study

Background— Inflammatory processes have been identified as key mediators of the deleterious effects of ischemia/reperfusion in ST‐segment‐elevation myocardial infarction. Colchicine is a substance with potent anti‐inflammatory properties, suitable for safe use in patients with cardiovascular disease. The purpose of this study was to test the hypothesis that a short course of colchicine treatment could lead to reduced infarct size. Methods and Results— Patients presenting with ST‐segment‐elevation myocardial infarction ≤12 hours from pain onset (treated with primary percutaneous coronary intervention) were randomly assigned to colchicine or placebo for 5 days. The primary outcome parameter was the area under the curve of creatine kinase‐myocardial brain fraction concentration. A subset of patients underwent cardiac MRI with late gadolinium enhancement 6 to 9 days after the index ST‐segment‐elevation myocardial infarction. One hundred fifty‐one patients were included (60 in the MRI substudy). The area under the creatine kinase‐myocardial brain fraction curve was 3144 (interquartile range [IQR], 1754‐6940) ng·h‐1·mL‐1 in the colchicine group in comparison with 6184 (IQR, 4456‐6980) ng·h‐1·mL‐1 in controls (P<0.001). Indexed MRI‐late gadolinium enhancement‐defined infarct size was 18.3 (IQR, 7.6‐29.9) mL/1.73 m2 in the colchicine group versus 23.2 (18.5‐33.4) mL/1.73 m2 in controls (P=0.019). The relative infarct size (as a proportion to left ventricular myocardial volume) was 13.0 (IQR, 8.0‐25.3) % and 19.8 (IQR, 13.7‐29.8) %, respectively (P=0.034). Conclusions— These results suggest a potential benefit of colchicine in ST‐segment‐elevation myocardial infarction, but further clinical trials are necessary to draw secure conclusions, especially considering the fact that the present study was not powered to assess clinical end points. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936285.

Red blood cell and platelet microparticles in myocardial infarction patients treated with primary angioplasty.

BACKGROUNDnRed blood cell and platelet microparticles (RBCm and PLTm, respectively) have drawn research attention as to their potential prothrombotic and vasoconstrictive effects in experimental settings. However, the relevance of circulating microparticles in clinical settings is largely undetermined.nnnMETHODSnCirculating microparticles were quantified with a flow cytometric method in blood samples from consecutive STEMI patients after primary PCI. A matched cohort of healthy volunteers was used to derive reference values for comparison. STEMI patients were followed for 6 months for a composite clinical endpoint.nnnRESULTSnFifty-one STEMI patients (age 59.8 ± 8.8 years) and 50 controls (age 56.2 ± 9.2 years; p=0.155) were enrolled. RBCm concentration was 18,198 ± 6062/μl in the reference cohort versus 33,740 ± 21,169/μl in STEMI patients (p<0.001). RBCm count was not correlated to total RBCs (standardized beta 0.018; p=0.861). PLTm did not differ between groups (17,529 ± 16,292/μl in STEMI patients versus 14,372 ± 6211/μl in controls; p=0.203). RBCm c-statistic was 0.832 (95% confidence interval 0.720 to 0.944), while PLTm prognostic value was not statistically significant (c-statistic 0.614, 95% confidence interval 0.444 to 0.784). In the multivariate analysis, RBCm concentration was independently associated with the occurrence of the clinical endpoint, after adjustment for age, ejection fraction, serum creatinine and presence of diabetes (adjusted p=0.034).nnnCONCLUSIONSnThe present study demonstrates for the first time that erythrocyte microparticles are elevated in patients with STEMI treated with primary PCI, with levels approximately double those measured in a reference population of healthy volunteers, and their concentrations appear to be positively associated with adverse clinical events.

Interatrial conduction time and incident atrial fibrillation: a prospective cohort study.

BACKGROUNDnAtrial electrical conduction properties have been implicated in atrial fibrillation (AF) pathogenesis.nnnOBJECTIVEnThe purpose of this study was to prospectively assess the potential association of interatrial conduction time (IACT) with incident AF.nnnMETHODSnThe study included persons referred for invasive electrophysiologic study (EPS), aged ≥50 years, without AF history or valvular disease. IACT was defined as the interval between the high right atrium electrogram and the distal coronary sinus atrial electrogram.nnnRESULTSnSix hundred twelve subjects were included (median follow-up 43 months, interquartile range 40-47). AF incidence was 21.7 cases per 1000 person-years. IACT was a significant predictor of AF with a c-statistic of 0.770 (95% confidence interval 0.702-0.838). In time-dependent analysis, IACT was a significant stratifier of AF risk (log-rank 28.0, P <.001). The corresponding incidences of AF in each tertile of IACT were 3, 17, and 46 per 1000 person-years, respectively (all differences between tertiles were significant). IACT remained significant in multivariable Cox regression analysis, after adjustment for age, sex, hypertension, and left atrial diameter, with each millisecond of prolonged IACT corresponding to 7% (95% confidence interval 2%-12%) higher adjusted risk of incident AF.nnnCONCLUSIONnIACT is independently associated with incident AF. The invasive nature of the measurement is a limitation for its use as a clinical risk stratifier (although it could be used in patients referred for EPS), but these results are of interest in themselves because they suggest a strong pathophysiologic connection between atrial conduction times and substrate alterations ultimately leading to AF.

Aldosterone receptor blockade inhibits degenerative processes in the early stage of calcific aortic stenosis

Calcific aortic valve disease is associated with increased morbidity and mortality, especially in the elderly. To date, pharmacological therapies have not proven as effective as surgical intervention. Here, we used a hyperlipidemic rabbit model to investigate the potential effects of selective aldosterone inhibition on the early stages of aortic valve calcification, a pharmacological strategy that has not yet been tested. Forty New Zealand male rabbits fed a standard diet for 4 weeks were separated into three groups: (1) control (n=10), fed a standard diet; (2) vehicle (n=15), fed a hyperlipidemic diet (cholesterol 1%) plus vehicle; and (3) eplerenone (n=15), fed a hyperlipidemic diet plus 100 mg/kg/d eplerenone (last 4 weeks). After 8 weeks, animals were sacrificed and prepared aortic valve sections were examined with Von Kossa silver stain and by immunostaining for mineralocorticoid receptor, macrophages and angiotensin-converting enzyme. The presence of calcium deposits was confirmed by scanning electron microscopy. Eplerenone increased aldosterone levels but did not affect blood pressure, cholesterol or potassium levels. Hyperlipidemia induced macrophage accumulation and angiotensin-converting enzyme expression, as well as calcium deposition in the leaflets. All markers were decreased by eplerenone treatment. Immunohistochemistry for mineralocorticoid (aldosterone) receptors revealed similar expression in the leaflets of both control and hyperlipidemic groups. Collectively, these results indicate that aldosterone receptors are present in rabbit aortic valve leaflets and their selective blockade with eplerenone inhibits formation of the sclerotic lesions induced by a high fat diet.