Percutaneous Coronary Revascularization for Chronic Total Occlusions: A Novel Predictive Score of Technical Failure Using Advanced Technologies.

OBJECTIVES: The aims of this study were to describe the 10-year experience of a single operator dedicated to chronic total occlusion (CTO) and to establish a model for predicting technical failure. BACKGROUND: During the last decade, the interest in percutaneous coronary interventions (PCIs) of chronic total occlusions (CTOs) has increased, allowing the improvement of success rate. METHODS: One thousand nineteen patients with CTO underwent 1,073 CTO procedures performed by a single CTO-dedicated operator. The study population was subdivided into 2 groups by time period: period 1 (January 2005 to December 2009, n = 378) and period 2 (January 2010 to December 2014, n = 641). Observations were randomly assigned to a derivation set and a validation set (in a 2:1 ratio). A prediction score was established by assigning points for each independent predictor of technical failure in the derivation set according to the beta coefficient and summing all points accrued. RESULTS: Lesions attempted in period 2 were more complex in comparison with those in period 1. Compared with period 1, both technical and clinical success rates significantly improved (from 87.8% to 94.4% [p = 0.001] and from 77.6% to 89.9% [p < 0.001], respectively). A prediction score for technical failure including age ≥75 years (1 point), ostial location (1 point), and collateral filling Rentrop grade <2 (2 points) was established, stratifying procedures into 4 difficulty groups: easy (0), intermediate (1), difficult (2), and very difficult (3 or 4), with decreasing technical success rates. In derivation and validation sets, areas under the curve were comparable (0.728 and 0.772, respectively). CONCLUSIONS: With growing expertise, the success rate has increased despite increasing complexity of attempted lesions. The established model predicted the probability of technical failure and thus might be applied to grading the difficulty of CTO procedures.

Impact of left ventricular remodeling and renal function on 24h-ECG recordings and cardiovascular outcome in elderly hypertensive patients.

BACKGROUND: The prognostic role of left ventricular remodeling and renal function in elderly hypertensive patients has been so far scarcely investigated. AIMS: We assessed the impact of left ventricular geometry and renal function on 24h-Holter electrocardiogram (ECG) recordings and outcome in elderly hypertensive patients. METHODS: We enrolled 251 asymptomatic hypertensive elderly patients (>65year-old). Left ventricular remodeling was evaluated by 2-D echocardiogram. Lown's class, mean QTc and standard deviation of all normal R-R intervals (SDNN) were assessed by 24-h Holter-ECG recordings. Data on all-cause and cardiovascular mortality were collected for 2years. RESULTS: Mean age was 76.2±11.4years. High Lown's classes were more frequently observed in the presence of left ventricular hypertrophy (LVH) (57.3% vs. 23.7%; p<0.001). Mean QTc was 444.8±34.8ms and resulted directly correlated with indexed left ventricular mass (r=0.228; p=0.001). Patients with Chronic Kidney Disease (CKD) showed lower SDNN as compared with those with preserved renal function (92.02±36.11ms vs. 103.84±33.96ms, respectively; p=0.017). At 2years, all-cause and cardiovascular mortality rates were 38.0% and 21.1%, respectively. Diabetes mellitus (HR: 2.40; 95% C.I.1.16 to 4.99; p=0.019), CKD (HR: 2.22; 95% C.I.1.10 to 4.52; p=0.028), prolonged QTc (HR: 2.18; 95% C.I.1.07 to 4.41; p=0.030) and SDNN<96ms (HR: 1.98; 95% C.I.1.03 to 4.13; p=0.048) were independent predictors of cardiovascular death at 2year follow-up. CONCLUSIONS: CKD and left ventricular remodeling predicted altered ventricular batmotropism. Diabetes, CKD, heart rate variability and QTc are important predictors of cardiovascular death in elderly hypertensive patients.

Fatal derecruitment of occluded left anterior descending collaterals after left circumflex revascularization.

Coronary arteries are not definitely functionally terminal arteries, as previously thought; indeed, they are linked and interconnected by a rich network of collaterals. Chronic total occlusions (CTOs) represent a subset of frequent lesions encountered in everyday catheterization laboratory practice, generally associated with a developed system of collateral connections. These latter have the capacity to prevent myocardial necrosis and may even uphold metabolic supply to the ischemic territory to maintain its contractile capacity. Authors have reported a rapid and progressive reduction of collateral function and their decline after antegrade flow restoration, resulting in higher myocardial susceptibility to ischemia in the CTO territory. Here, we report the case of a fatal derecruitment of collaterals for a left anterior descending CTO not reopened, after left circumflex subocclusion revascularization.

Appropriateness of percutaneous revascularization of coronary chronic total occlusions: an overview.

Coronary chronic total occlusions (CTOs) are commonly encountered in patients undergoing coronary angiography. Several observational studies have demonstrated that successful CTO revascularization is associated with better cardiovascular outcomes and enhanced quality of life (QOL). However, in the absence of randomized trials, its prognostic benefit for patients remains debated. Over the past decade, the interest of the interventional community in CTO percutaneous coronary intervention (PCI) has exponentially grown due to important developments in dedicated equipment and techniques, resulting in high success and low complication rates. Both European and American guidelines have assigned a class IIa (level of evidence B) recommendation for CTO PCI. In the current review, we focus on the impact of CTO revascularization on clinical outcomes and QOL and on appropriate patient selection, and we provide a critical assessment of the current guidelines and recommendations on CTO PCI.

Management strategies in patients affected by chronic total occlusions: results from the Italian Registry of Chronic Total Occlusions.

BACKGROUND: Through contemporary literature, the optimal strategy to manage coronary chronic total occlusions (CTOs) remains under debate. OBJECTIVES: The aim of the Italian Registry of Chronic Total Occlusions (IRCTO) was to provide data on prevalence, characteristics, and outcome of CTO patients according to the management strategy. METHODS: The IRCTO is a prospective real world multicentre registry enrolling patients showing at least one CTO. Clinical and angiographic data were collected independently from the therapeutic strategy [optimal medical therapy (MT), percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG)]; a comparative 1-year clinical follow-up was performed. RESULTS: A total of 1777 patients were enrolled for an overall CTO prevalence of 13.3%. The adopted therapeutic strategies were as follows: MT in 826 patients (46.5%), PCI in 776 patients (43.7%), and CABG in the remaining 175 patients (9.8%). At 1-year follow-up, patients undergoing PCI showed lower rate of major adverse cardiac and cerebrovascular events (MACCE) (2.6% vs. 8.2% and vs. 6.9%; P < 0.001 and P < 0.01) and cardiac death (1.4% vs. 4.7% and vs. 6.3%; P < 0.001 and P < 0.001) in comparison with those treated with MT and CABG, respectively. After propensity score-matching analysis, patients treated with PCI showed lower incidence of cardiac death (1.5 vs. 4.4%; P < 0.001), acute myocardial infarction (1.1 vs. 2.9%; P = 0.03), and re-hospitalization (2.3 vs. 4.4% P = 0.04) in comparison with those managed by MT. CONCLUSIONS: Our data showed how CTO PCI might significantly improve the survival and decrease MACCE occurrence at 1 year follow-up in comparison with MT and/or CABG.

Retrograde Recanalization of Chronic Total Occlusions in Europe: Procedural, In-Hospital, and Long-Term Outcomes From the Multicenter ERCTO Registry.

BACKGROUND: A retrograde approach improves the success rate of percutaneous coronary interventions (PCIs) for chronic total occlusions (CTOs). OBJECTIVES: The authors describe the European experience with and outcomes of retrograde PCI revascularization for coronary CTOs. METHODS: Follow-up data were collected from 1,395 patients with 1,582 CTO lesions enrolled between January 2008 and December 2012 for retrograde CTO PCI at 44 European centers. Major adverse cardiac and cerebrovascular events were defined as the composite of cardiac death, myocardial infarction, stroke, and further revascularization. RESULTS: The mean patient age was 62.0 ± 10.4 years; 88.5% were men. Procedural and clinical success rates were 75.3% and 71.2%, respectively. The mean clinical follow-up duration was 24.7 ± 15.0 months. Compared with patients with failed retrograde PCI, successfully revascularized patients showed lower rates of cardiac death (0.6% vs. 4.3%, respectively; p < 0.001), myocardial infarction (2.3% vs. 5.4%, respectively; p = 0.001), further revascularization (8.6% vs. 23.6%, respectively; p < 0.001), and major adverse cardiac and cerebrovascular events (8.7% vs. 23.9%, respectively; p < 0.001). Female sex (hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.33 to 3.18; p = 0.001), prior PCI (HR: 1.73; 95% CI: 1.16 to 2.60; p = 0.011), low left ventricular ejection fraction (HR: 2.43; 95% CI: 1.22 to 4.83; p = 0.011), J-CTO (Multicenter CTO Registry in Japan) score ≥3 (HR: 2.08; 95% CI: 1.32 to 3.27; p = 0.002), and procedural failure (HR: 2.48; 95% CI: 1.72 to 3.57; p < 0.001) were independent predictors of major adverse cardiac and cerebrovascular events at long-term follow-up. CONCLUSIONS: The number of retrograde procedures in Europe has increased, with high percents of success, low rates of major complications, and good long-term outcomes.

Percutaneous Coronary Interventions for Chronic Total Occlusions: More Benefit for the Patient or for the Interventionist's Ego?

Chronic total occlusions (CTOs) represent a common lesion subset observed in patients who undergo coronary angiography. During the past decade, the interest of the interventionist community in CTOs has exponentially grown with fast advancement in dedicated equipment and techniques, which has resulted in high rates of procedural success and low rates of complications. Although different observational studies have shown that CTO revascularization was associated with good clinical outcome, its real benefit for patients remains to be determined, particularly in the absence of randomized trials. In addition, compared with non-CTO lesions, the American and European guidelines downgraded percutaneous coronary intervention in the setting of CTOs. In this viewpoint, we try to identify patients who would benefit from CTO recanalization, and discuss the issues that might improve the appropriateness of CTO percutaneous coronary intervention.

Incidence, treatment, and in-hospital outcome of bifurcation lesions in patients undergoing percutaneous coronary interventions for chronic total occlusions.

BACKGROUND: Bifurcation lesions represent a distinct lesion subset associated with an increased risk of procedural complications. Data on the incidence, treatment, and outcome of bifurcation lesions associated with chronic total occlusions are limited. METHODS: Among chronic total occlusion procedures performed by a single experienced operator, patients with a bifurcation lesion within the chronic total occlusion vessel and a side branch reference diameter greater than or equal to 2.0 mm were enrolled. RESULTS: A total of 905 patients (mean age 61.1±9.5 years, men 89.4%) were treated for 922 chronic total occlusion lesions. Among these, 244 bifurcation lesions were observed (26.5%). The procedural time was significantly longer in bifurcation lesions (139±67 vs. 124±68 min; P=0.003), with greater use of contrast load (470±193 vs. 436±227 ml; P=0.04) and higher number of stents (3.1±1.5 vs. 2.9±1.4; P=0.035). Overall, an angiographic success was achieved in 91.1% of cases with a higher rate in nonbifurcation lesions (92.5 vs. 87.3%; P=0.04). Coronary perforations were more often observed in bifurcation lesions (4.9 vs. 1.7%; P<0.001), resulting in more tamponades (2.4 vs. 0.2%; P<0.001). True bifurcations were encountered in the majority of cases (86.8%) and required more two-stent techniques than false bifurcations (50 vs. 18.8%; P=0.001). CONCLUSION: The incidence of bifurcation lesions in chronic total occlusions is higher than that reported in continuous lesions. The presence of a bifurcation lesion increases the complexity of the procedure and may lead to less angiographic success and more periprocedural complications.

Coronary vasomotion dysfunction after everolimus-eluting stent implantation.

First generation drug-eluting stent can cause a paradoxical "in-segment" coronary vasoconstriction. This phenomenon was seen with sirolimus, paclitaxel, and, more recently, also with zotarolimus-eluting stent. For the first time, we describe a case of coronary-induced vasoconstriction by everolimus-eluting stents (EES).

Impact of renal function on clopidogrel-induced antiplatelet effects in coronary artery disease patients without diabetes mellitus.

Diabetes mellitus (DM) is the most important predictor of chronic kidney disease (CKD), and pharmacodynamic (PD) studies have shown that DM patients with impaired renal function are characterized by reduced clopidogrel response. However, post-hoc PD studies conducted in unselected cohorts, composed of both DM and non-DM patients, have reached controversial findings on the effects of CKD on clopidogrel response, likely attributed to patient heterogeneity. The impact of renal function on clopidogrel response in non-DM patients remains unexplored and represented the aim of this prospective investigation. We conducted a prospective PD investigation in non-DM patients with and without CKD defined as an estimated glomerular filtration rate (eGFR) below or above 60 mL/min, respectively. All patients had known coronary artery disease and were on maintenance aspirin therapy. PD assessments were assessed at baseline and 2 and 24 h after a 600 mg loading dose of clopidogrel. PD assays included light transmission aggregometry (LTA) using 5 and 20 µmol ADP with and without PGE1 and flow cytometric assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP) to determine the platelet reactivity index. A total of 60 patients were studied (n = 30 eGFR ≥60 mL/min; n = 30 eGFR <60 mL/min). At baseline there were no differences between groups. Following clopidogrel loading dose administration, levels of on-treatment platelet reactivity were similar between groups at 2 and 24 h as measured with LTA and VASP. Accordingly, there were no differences in rates of high on-treatment platelet reactivity between groups. In non-DM patients with CAD, the presence of impaired renal function is not associated with differences in clopidogrel-induced antiplatelet effects compared with patients with preserved renal function.

Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation.

Platelets from patients with diabetes mellitus (DM) are hyper-reactive and whether cangrelor, a potent intravenous P2Y(12) receptor blocker, has differential pharmacodynamic (PD) effects according DM status is unknown. The aim of this investigation was to evaluate the in vitro PD effects of cangrelor in coronary artery disease (CAD) patients with and without DM. This prospective study enrolled 120 clopidogrel-naïve patients with CAD on aspirin therapy. PD assessments using cangrelor (500 nmol/l) in vitro included vasodilator-stimulated phosphoprotein assay to obtain the P2Y(12) reactivity index (PRI), and multiple electrode aggregometry (MEA). In a 20 patients subgroup, dose-dependent response was assessed following exposure to escalating concentrations (baseline, 5, 50, 500 and 5,000 nmol/l); thrombin generation processes were evaluated by thromboelastography (TEG). PD data were evaluable in 103 patients. No differences in baseline PD parameters were observed in DM (n = 48) and non-DM (n = 45) subjects. Cangrelor reduced PRI values irrespective of DM status (p < 0.0001), yielding no difference in patients with and without DM (16.1 ± 12.3 vs. 16.8 ± 11.3; p = 0.346). All MEA values were significantly reduced, although this was of greater magnitude with purinergic compared to non-purinergic agonists. A trend analysis showed a dose-dependent effect on platelet inhibition, with no interaction due to DM status, whereas no significant dose-dependent effect was observed for TEG-derived parameters. Therefore, in vitro cangrelor provides potent and dose-dependent blockade of the platelet P2Y(12) receptor, with no differential effect in DM and non-DM patients. In addition, in vitro cangrelor exerts moderate inhibitory effects on non-purinergic platelet signaling pathways, without modulating platelet-derived thrombin generation processes.

Prasugrel.

Prasugrel is a third-generation thienopyridine which selectively inhibits the platelet P2Y(12) receptor more rapidly, more potently, and with less interindividual response variability compared with the second-generation thienopyridine clopidogrel. Large-scale phase III clinical testing showed that in high-to moderate-risk acute coronary syndrome patients undergoing percutaneous coronary intervention, prasugrel translates into a greater reduction in ischemic events, including stent thrombosis, in the short and long term compared to clopidogrel. Prasugrel, however, is associated with an increased risk of major bleeding, which is more pronounced in certain patient subgroups. The ideal patient population for prasugrel use are those patients without prior transient ischemic attack/stroke, <75 years of age and >60 kg in whom the greatest ischemic benefit is achieved without a significant increase in major bleeding risk. Dose modifications in specific populations or at given time-points may represent an avenue to minimize bleeding risk and therefore maximize the clinical benefit of prasugrel. Ongoing clinical studies with prasugrel will better define the safety and efficacy profiles of this agent and potentially set the basis for new indications for use.

Pharmacodynamic effects of prasugrel dosing regimens in patients on maintenance prasugrel therapy: results of a prospective randomized study.

OBJECTIVES: The purpose of this study is to assess the pharmacodynamic effects of different prasugrel dosing regimens in patients on maintenance prasugrel therapy. BACKGROUND: There are a growing number of patients on chronic prasugrel therapy regimens, leading to questions about the dosing regimen of prasugrel to administer if percutaneous coronary intervention is required. METHODS: This is a prospective pharmacodynamic study in patients (n = 64) receiving maintenance prasugrel therapy who were randomly allocated to a 10 mg, 30 mg, or 60 mg dose of prasugrel. Pharmacodynamic assessments using multiple assays were conducted at 3 timepoints (baseline and 1 h and 4 h after dosing). RESULTS: Intragroup comparisons showed that a 60 mg dose reduced the platelet reactivity index (PRI) after 1 h (p = 0.004) and 4 h (p < 0.001, primary endpoint; p = 0.002 between 1 h and 4 h). A 30 mg dose also reduced PRI levels at 1 h (p = 0.006) and 4 h (p < 0.001; p = 0.044 between 1 h and 4 h). A 10 mg dose was associated with modest pharmacodynamic effects. Intragroup comparisons showed similar findings with VerifyNow-P2Y12 and light transmission aggregometry. Intergroup comparisons showed that a 60 mg dose achieved lower PRI levels than 30 mg at 4 h (p = 0.05), and a numerical trend toward better pharmacodynamic effects at 1 h (p = 0.171). Intergroup comparisons were similar with VerifyNow-P2Y12, but not light transmission aggregometry. CONCLUSIONS: For patients on maintenance prasugrel therapy, a 60 mg dosing strategy is associated with faster and higher platelet inhibition compared with lower doses, as assessed by P2Y(12) specific assays. (Impact of Prasugrel Re-load on Platelet Aggregation in Patients on Chronic Prasugrel Therapy; NCT01201772).

Cigarette smoking is associated with a dose-response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study.

OBJECTIVES: This study sought to assess the presence of a dose-response effect of cigarette smoking and its impact on high on-treatment platelet reactivity (HPR) in patients with diabetes mellitus treated with clopidogrel. BACKGROUND: Cigarette smoking is an inducer of cytochrome P450 1A2, a hepatic enzyme involved in clopidogrel metabolism. If cigarette smoking is associated with a dose-response effect on pharmacodynamic measures in clopidogrel-treated patients is unknown. METHODS: A total of 134 type 2 diabetes mellitus patients on maintenance aspirin and clopidogrel therapy were studied. Patients were divided into 3 groups according to cotinine levels: <3 ng/ml (nonsmokers), 3 to 199 ng/ml (light smokers), and ≥ 200 ng/ml (heavy smokers). Platelet function was assessed by light transmittance aggregometry, VerifyNow P2Y12 assay (Accumetrics, San Diego, California), and vasodilator-stimulated phosphoprotein. Rates of HPR were defined using established cutoff values. RESULTS: A dose-response effect was observed for all pharmacodynamic parameters tested. Serum cotinine levels were inversely associated with platelet reactivity as assessed by light transmittance aggregometry using 5 and 20 µmol/l adenosine diphosphate (p < 0.0001 for all). Accordingly, platelet disaggregation increased with levels of serum cotinine (p < 0.0001). Similar results were found with P2Y(12) reaction units (p < 0.0001) and inhibition of platelet aggregation (p = 0.005) as defined by VerifyNow P2Y12 testing, and platelet reactivity index (p = 0.002) as assessed by vasodilator-stimulated phosphoprotein. Higher serum cotinine levels were significantly associated with lower rates of HPR, as defined according to various pharmacodynamic cutoff measures. CONCLUSIONS: Cigarette smoking is associated with a dose-response effect on clopidogrel-induced antiplatelet effects and lower rates of HPR in diabetes mellitus patients.

Transient impairment of vasomotion function after successful chronic total occlusion recanalization.

OBJECTIVES: The aim of our study was to assess coronary vasomotion after successful revascularization of chronic total occlusion (CTO). BACKGROUND: It is largely unknown whether the recovery of anterograde flow after CTO recanalization with drug-eluting stent implantation affects vascular function in distal coronary segments. METHODS: One hundred consecutive CTOs successfully treated with drug-eluting stents underwent coronary diameter measurement after intracoronary nitroglycerin injection 5, 20, and 35 mm distal to the stented coronary segment using 3-dimensional quantitative coronary angiography. In a subgroup of 14 patients, coronary vasomotion was tested in distal segments: incremental atrial pacing for endothelium-dependent cases; and intracoronary nitroglycerin injection for endothelium-independent cases. In another subgroup of 13 patients, distal vessels were assessed by intracoronary ultrasounds. RESULTS: Vessel diameters significantly increased at follow-up as compared to baseline values (2.0 ± 0.52 mm vs. 2.25 ± 0.50 mm, 1.76 ± 0.49 mm vs. 2.05 ± 0.58 mm, 1.54 ± 0.53 mm vs. 2.04 ± 0.58 mm, at each segment analyzed; p < 0.001). At baseline, distal segments failed to respond to both endothelium-dependent and -independent stimuli. At follow-up, atrial pacing induced vasoconstriction, whereas nitroglycerine administration resulted in significant vasodilation (p < 0.05). Intracoronary ultrasounds failed to show changes of the cross-sectional area of distal segments at follow-up angiography. CONCLUSIONS: Recanalization of CTO is followed by a hibernation of vascular wall at distal coronary segments that fail to respond to endothelium-dependent and -independent stimuli. Distal vessel diameter increases over time in the absence of positive remodeling and in spite of persistent endothelial dysfunction. This severe impairment of vasomotor tone after CTO reopening suggests that intracoronary ultrasound assessment is of paramount importance for the selection of stent size.