Carlo Tumscitz

Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting A Randomized Multicenter Trial

Background— The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration–approved drug-eluting or bare-metal stents. Methods and Results— We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74–1.29; P=0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. Conclusions— A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00611286.

Randomized comparison of 6- versus 24-month clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all-comer patients undergoing percutaneous coronary intervention: Design and rationale for the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY)

BACKGROUND The optimal duration of clopidogrel therapy after coronary stenting is debated because of the scarcity of randomized controlled trials and inconsistencies arising from registry data. Although prolonged clopidogrel therapy after bare metal stenting is regarded as an effective secondary prevention measure, the safety profile of drug-eluting stents itself has been questioned in patients not receiving ≥ 12 months of dual-antiplatelet therapy. HYPOTHESIS Twenty-four months of clopidogrel therapy after coronary stenting reduces the composite of death, myocardial infarction, or stroke compared with 6 months of treatment. STUDY DESIGN PRODIGY is an unblinded, multicenter, 4-by-2 randomized trial. All-comer patients with indication to coronary stenting are randomly treated-balancing randomization-with bare metal stent (no active late loss inhibition), Endeavor Sprint zotarolimus-eluting stent (Medtronic, Santa Rosa, CA) (mild late loss inhibition), Taxus paclitaxel-eluting stent (Boston Scientific, Natick, MA) (moderate late loss inhibition), or Xience V everolimus-eluting stent (Abbott Vascular, Santa Clara, CA) (high late loss inhibition). At 30 days, patients in each stent group are randomly allocated to receive 24 or up to 6 months of clopidogrel therapy-primary end point randomization. With 1,700 individuals, this study will have >80% power to detect a 40% difference in the primary end point after sample size augmentation of 5% and a background event rate of 8%. SUMMARY The PRODIGY trial aims to assess whether 24 months of clopidogrel therapy improves cardiovascular outcomes after coronary intervention in a broad all-comer patient population receiving a balanced mixture of stents with various anti-intimal hyperplasia potency.

Two-Year Outcomes After First- or Second-Generation Drug-Eluting or Bare-Metal Stent Implantation in All-Comer Patients Undergoing Percutaneous Coronary Intervention : A Pre-Specified Analysis From the PRODIGY Study (PROlonging Dual Antiplatelet Treatment After Grading stent-induced Intimal hyperplasia studY)

OBJECTIVES This study sought to assess device-specific outcomes after implantation of bare-metal stents (BMS), zotarolimus-eluting Endeavor Sprint stents (ZES-S), paclitaxel-eluting stents (PES), or everolimus-eluting stents (EES) (Medtronic Cardiovascular, Santa Rosa, California) in all-comer patients undergoing percutaneous coronary intervention. BACKGROUND Few studies have directly compared second-generation drug-eluting stents with each other or with BMS. METHODS We randomized 2,013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group received up to 6 or 24 months of clopidogrel therapy. The key efficacy endpoint was the 2-year major adverse cardiac event (MACE) including any death, myocardial infarction, or target vessel revascularization, whereas the cumulative rate of definite or probable stent thrombosis (ST) was the key safety endpoint. RESULTS Clinical follow-up at 2 years was complete for 99.7% of patients. The MACE rate was lowest in EES (19.2%; 95% confidence interval [CI]: 16.0 to 22.8), highest in BMS (32.1%; 95% CI: 28.1 to 36.3), and intermediate in PES (26.2%; 95% CI: 22.5 to 30.2) and ZES-S (27.8%; 95% CI: 24.1 to 31.9) groups (chi-square test = 18.9, p = 0.00029). The 2-year incidence of ST in the EES group (1%; 95% CI: 0.4 to 2.2) was similar to that in the ZES-S group (1.4%; 95% CI: 0.7 to 2.8), whereas it was lower compared with the PES (4.6%, 95% CI: 3.1 to 6.8) and BMS (3.6%; 95% CI: 2.4 to 5.6) groups (chi-square = 16.9; p = 0.0001). CONCLUSIONS Our study shows that cumulative MACE rate, encompassing both safety and efficacy endpoints, was lowest for EES, highest for BMS, and intermediate for PES and ZES-S groups. EES outperformed BMS also with respect to the safety endpoints with regard to definite or probable and definite, probable, or possible ST. (PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY [PRODIGY]; NCT00611286).

Fractional flow reserve evaluation and chronic kidney disease: Analysis from a multicenter Italian registry (the FREAK study)

To establish if the presence of chronic kidney disease (CKD) influences fractional flow reserve (FFR) value in patients with intermediate coronary stenosis.

Occurrence, causes, and outcome after switching from ticagrelor to clopidogrel in a real-life scenario: data from a prospective registry

Abstract In randomized clinical trials, ticagrelor has been substituted in roughly one-third of the patients during follow-up. To date, there are no studies addressing safety and modalities of switching from ticagrelor to clopidogrel. The aim of our study is to describe the occurrence, causes, and outcome of the switch from ticagrelor to clopidogrel in a real-life scenario. From June 2013 to March 2015, 586 patients were treated with ticagrelor in our centre. Overall, 101 (17%) patients were switched to clopidogrel through a standardized protocol, and they were followed-up for 12 months. Ischemic and bleeding events were prospectively recorded. The switch from ticagrelor to clopidogrel occurred mostly after discharge (69 ± 40 days), and the most frequent cause was the need of oral anticoagulation treatment, followed by bleeding events. Patients requiring ticagrelor discontinuation were older, more frequently female, with lower body mass index and creatinine clearance if compared to the “non-switched” group. In the 10 days after the switch, we did not observe ischemic adverse events. No definite/probable stent thrombosis was recorded. Before the switch, there was a significant higher occurrence of BARC bleedings in the “switched” group, particularly BARC 1 and 2. Our data confirm that the switch from ticagrelor to clopidogrel is common, and it occurs for several reasons. Our analysis did not demonstrate a significant increase in adverse cardiovascular events in the days following the switch from ticagrelor to clopidogrel, although larger studies are needed to validate our findings.

Use of the Dual-Antiplatelet Therapy Score to Guide Treatment Duration After Percutaneous Coronary Intervention

Dual-antiplatelet therapy (DAPT) with aspirin and oral P2Y12 adenosine diphosphatereceptor inhibitors is an evidence-based, guideline-recommended standard of care in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) (13). The pathobiological rationale for DAPT after PCI is to prevent atherothrombotic manifestations in the stented coronary segments before arterial healing and stent endothelialization are complete. However, although guidelines mandate a minimum course of 1 to 6 months after PCI, depending on clinical presentation and stent type (1, 3), the optimal duration of DAPT in the long term is controversial because the ischemic protection afforded by extended DAPT is largely offset by an increase in bleeding complications (4, 5). Prolonged DAPT has been estimated to prevent 8 myocardial infarctions per 1000 persons treated for 1 year, but at a cost of 6 major bleeding events (6, 7). In view of this tradeoff between efficacy and safety, as well as a possible lack of a mortality benefit due to an increase in noncardiovascular deaths with prolonged DAPT (4, 8), American and European guidelines recommend individualizing the duration of DAPT on the basis of ischemic versus bleeding risks (1, 3). This recommendation is also consistent with the results of a survey assessing contemporary clinical practice (9). The DAPT score is a new standardized tool to identify patients who would derive benefit or harm from prolonged DAPT (10, 11). However, the efficacy and safety of DAPT duration as guided by the score have not been assessed outside the derivation cohort included in the DAPT (Dual Antiplatelet Therapy) Study (ClinicalTrials.gov: NCT00977938), in which all patients received DAPT for 12 months and were then randomly assigned to continue thienopyridine treatment or placebo on a background of aspirin (8). We therefore sought to apply the DAPT score to PRODIGY (Prolonging Dual-Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study), which enrolled a broadly inclusive sample of patients randomly assigned to a prolonged (24 months) versus a short (6 months) DAPT regimen after PCI (12). Methods Details on study design and primary results of PRODIGY have been reported elsewhere (1214). Briefly, unselected patients undergoing PCI (n= 2013) were randomly assigned to receive 1 of 4 types of stent (bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting). At 30 days, 1970 patients were randomly allocated to either 6 or 24 months of DAPT. Randomization was stratified by center, ongoing ST-segment elevation myocardial infarction, presence or absence of diabetes mellitus, and presence or absence of in-stent restenosis. Selection criteria were broad in order to reflect routine clinical practice. The main exclusion criteria were known allergy to antiplatelet drugs, planned surgery within the next 24 months, history of bleeding diathesis, active bleeding or stroke in the previous 6 months, need for concomitant oral anticoagulation, pregnancy, and life expectancy less than 2 years. Treatment Protocol A maintenance dose of clopidogrel (75 mg/d) was administered for up to 6 or 24 months according to randomization. A low dose of aspirin (80 to 160 mg/d) was prescribed indefinitely in all patients. Study End Points The primary efficacy end point for this analysis was the composite of death, myocardial infarction, or cerebrovascular accident. Other efficacy outcomes included each component of the primary efficacy end point, cardiovascular death, and stent thrombosis according to the Academic Research Consortium criteria (15). The primary safety end point was a composite of type 3 or 5 bleeding according to the Bleeding Academic Research Consortium (BARC) definitions, including overt bleeding with a decrease in hemoglobin level of at least 3 g/dL; bleeding requiring transfusion, intravenous vasoactive agents, or surgical intervention for control; bleeding resulting in cardiac tamponade; and intracranial or intraocular bleeding. Other safety end points were BARC type 2, 3, or 5 bleeding as well as bleeding that met the Thrombolysis in Myocardial Infarction (TIMI) and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria. The BARC, TIMI, and GUSTO criteria are detailed in Appendix 1. A clinical events committee blinded to treatment allocation adjudicated all efficacy and safety events. Calculation of the DAPT Score We calculated the DAPT score for each patient included in PRODIGY, as previously reported (10). The score ranges from 2 to 10 and is calculated by assigning points according to characteristics related to the patient (0 for age <65 years, 1 for age 65 and <75 years, 2 for age 75 years, 1 for diabetes mellitus, 1 for current smokers, 1 for prior PCI or myocardial infarction, and 2 for history of congestive heart failure or left ventricular ejection fraction <30%) and the index procedure (1 for acute myocardial infarction at presentation, 2 for PCI of saphenous vein graft, 1 for implantation of a paclitaxel-eluting stent, and 1 for stent diameter <3 mm). Overall, a low score (<2) identifies patients for whom bleeding risks outweigh ischemic benefits, and a high score (2) identifies patients for whom ischemic benefits outweigh bleeding risks. A calculator for the score is available at www.daptstudy.org/for-clinicians/calchome.htm. Statistical Analysis For calculation of the DAPT score, missing values for left ventricular ejection fraction (n= 136) were estimated using multiple imputation (Appendix 2). The reported percentages are KaplanMeier estimates of cumulative incidence at 24 months. Because the randomized treatment between groups began to diverge at 6 months, a landmark analysis was performed between 6 and 24 months by censoring patients if they experienced the event of interest, died, or were lost to follow-up before 6 months (16). The efficacy and safety of prolonged versus short DAPT were assessed in categories of high and low DAPT score. To account for data censoring, the pseudovalue approach was used to calculate absolute risk differences (RDs) and 95% CIs between prolonged and short DAPT (17). The treatment effect of prolonged versus short DAPT between patients with high and low scores was compared using a Z test for interaction (18). The efficacy of prolonged versus short DAPT within the high and low score groups was also explored across stent types, with heterogeneity assessed by the Q statistic. Sensitivity analyses were conducted from 1 to 24 months after patients who received earlier-generation paclitaxel-eluting stents, which are associated with a higher risk for stent thrombosis and myocardial infarction, and those with missing values for left ventricular ejection fraction were excluded. A sensitivity analysis of safety outcomes accounting for the competing risk for death was also conducted (17). All P values were 2-sided, and those less than 0.05 indicated statistical significance. All analyses were done using Stata, version 13 (StataCorp). Further details on the statistical analysis are provided in Appendix 2. Institutional Review Board Approval The ethics committees of the participating centers independently approved the protocol, and all participants gave written informed consent. Role of the Funding Source This study received no funding. Results DAPT Score Distribution and Baseline Characteristics Of 1970 patients enrolled in PRODIGY, 884 (44.9%) had a high DAPT score (2) and 1086 (55.1%) had a low score (<2). The median score was 1 (interquartile range, 0 to 2; mean, 1.3 [SD, 1.5]) (Appendix Figure 1). Patients with high scores were younger and more likely to be male; to be smokers; and to have diabetes, prior myocardial infarction, prior coronary revascularization, congestive heart failure or left ventricular dysfunction, and acute myocardial infarction at presentation. They also were less likely to have arterial hypertension or peripheral artery disease and had higher estimated glomerular filtration rates (Table 1). Patients with high scores more frequently had PCI for saphenous vein graft disease or in-stent restenosis and had a greater mean stent diameter (Table 2). Baseline and periprocedural characteristics were similar within high and low score groups between patients assigned to 24 versus 6 months of DAPT (Appendix Tables 1 and 2). Appendix Figure 1. Distribution of the DAPT score. DAPT = dual-antiplatelet therapy. Table 1. Baseline Characteristics, by DAPT Score Table 2. Angiographic Characteristics, by DAPT Score* Appendix Table 1. Baseline Characteristics, by DAPT Score and Randomized Treatment Appendix Table 2. Angiographic Characteristics, by DAPT Score and Randomized Treatment Efficacy Outcomes With Prolonged Versus Short DAPT, by Score The reduction in the primary efficacy outcome of death, myocardial infarction, or cerebrovascular accident with 24 versus 6 months of DAPT was greater in patients with high scores than those with low scores (P for interaction= 0.030) (Figure, top). Figure. Riskbenefit assessment of a DAPT scoreguided strategy from 6 to 24 mo for the primary efficacy end point (top) and the primary safety end point (bottom). DAPT= dual-antiplatelet therapy. Among patients with high scores, the primary ischemic outcome occurred in 4.2% randomly assigned to 24-month DAPT compared with 6.2% randomly assigned to 6-month DAPT (RD, 2.05 percentage points [95% CI, 5.04 to 0.95 percentage points]) (Table 3 and Appendix Figure 2). Compared with short DAPT, prolonged DAPT was associated with fewer cardiac deaths and myocardial infarctions (RD, 2.01 percentage points [CI, 4.53 to 0.51 percentage points]). Definite, probable, or possible stent thrombosis was also significantly reduced in patients with high scores who received prolonged versus short DAPT (RD, 2.44 percentage points [CI, 4.70 to 0.19 percentage points]). Among patients with low

Optical coherence tomography evaluation of overlapping everolimus-eluting bioresorbable vascular scaffold implantation guided by enhanced stent visualization system

In a porcine model, implantation of overlapping everolimus-eluting bioresorbable vascular scaffolds (BVS, Abbott Vascular, Santa Clara, California) resulted in delayed strut coverage and higher neointimal response [1] that might lead to important clinical consequences (scaffold thrombosis; in-scaffold restenosis). According to this, any effort to minimize BVS overlap area and the number of overlapping struts is desirable. A bench testing in an in vitro phantom model has shown how to minimize BVS overlap utilizing the platinum markers located at each BVS edge, where the ideal overlap should be achieved when BVS edge markers positioned at 90° to each other, causing the majority of the overlapped struts to be positioned in the cell area between the struts [2]. In the same paper [2], authors stated that trying to intentionally achieve a minimum overlap is highly difficult and that the correct positioning of the BVS markers is practically unachievable during conventional PCI. In fact, the achievement of minimum BVS overlap in daily clinical practice may be difficult mainly because BVS edge markers are poorly visible at normal fluoroscopy. Therefore, the risk of “geographical miss” or long overlap remains high. Enhanced stent visualization (ESV) system guidance has beenwell validated during conventional stent implantation [3]. ESV systems might significantly improve

Role of the tricuspid regurgitation after mitraclip and transcatheter aortic valve implantation: a systematic review and meta-analysis

Aims Treatment of tricuspid regurgitation (TR) is common after surgery for mitral and/or aortic valves. The prognostic role of moderate to severe TR in patients undergoing mitraclip or transcatheter aortic valve implantation (TAVI) is not well-defined. Thus, the aim of this article is to perform a systematic review and meta-analysis of articles valuing the prognostic role of TR for patients undergoing mitraclip and TAVI. Methods and results Articles were searched in Pubmed, Cochrane Library, Google Scholar and Biomed Central in September 2016. Inclusion criteria: observational or randomized clinical trials with data on the prognostic role of TR in patients undergoing mitraclip or TAVI. Primary outcome was all-cause mortality expressed as hazard ratio (HR). Six articles fulfilled inclusion criteria, three were on mitraclip and three on TAVI. A total of 2329 patients were analysed (mean age was 78.38 (3.09), 63% male): 1328 treated with TAVI and 1001 with mitraclip. The HR for all-cause mortality of moderate to severe TR was 2.0 (95% CI 1.57-2.55, I2 = 0%). Data were confirmed also after subgroup analysis for mitraclip vs. TAVI. None of the factor considered in meta-regression analyses was affecting the primary outcome. Conclusions The current meta-analysis suggests that the presence of moderate to severe TR in patients undergoing mitraclip or TAVI might be a major determinant of all-cause mortality. New studies are needed to confirm it and to plan possible intervention in order to reduce its impact.

A counseling program on nuisance bleeding improves quality of life in patients on dual antiplatelet therapy: A randomized controlled trial

Background Nuisance bleeding is a major determinant of quality of life and drug discontinuation in patients on dual antiplatelet therapy (DAPT). However, no randomized trial has been focused on the impact of nuisance bleeding on quality of life. Methods BATMAN is an investigator-driven, randomized, controlled, single-center, open trial (NCT02554006). Four hundred and forty-eight consecutive patients with indication to at least 6 months of DAPT were randomized to: i) multimodal counseling program focused on nuisance bleedings (interventional arm); ii) usual discharge process (control arm). The primary endpoint was the one-month health-related quality of life assessed by the EuroQol-5 Dimension (EQ-5D) visual analog scale (VAS) score. Secondary endpoints were EQ-5D at 1 and 6 months, EQ-5D VAS at 6 months, DAPT withdrawal, need of information regarding DAPT and/or nuisance bleedings, 6-month ischemic and bleeding adverse events. Results The EQ5D-VAS was significantly higher in the interventional arm compared to the control arm at 1 and 6 months (81[74–88] vs. 73[64–80], p < 0.001 at 1 month; 82[76–88] vs. 74[65–81], p < 0.001 at 6 months). Patients in the interventional arm had also significantly lower pain/discomfort and anxiety/depression at the EQ-5D both at 1 and 6 months. Patients in the control arm withdrew DAPT significantly more (7 (3%) vs. 1 (0.4%), p = 0.03) and looked for information regarding DAPT and/or about nuisance bleeding more frequently than those in the interventional arm (178 (79%) vs.19 (8%), p < 0.001). Conclusions The systematic utilization of a multimodal counseling program improved quality of life and reduced the DAPT withdrawal rate in patients on DAPT.

Enhanced stent visualization systems during PCI: A case series and review of literature

Enhanced stent visualization systems increase the amount and quality of information during percutaneous coronary interventions. When compared to imaging techniques such as intravascular ultrasound and optical coherence tomography, enhanced stent visualization systems are easy-to-use, as well as time and cost saving. They are useful during stent implantation, overlap, assessment of integrity, and expansion. We review the available data regarding enhanced stent visualization systems and we report 5 cases showing their current applications during percutaneous coronary interventions. <Learning objective: Enhanced stent visualization (ESV) systems are helpful especially during complex percutaneous coronary interventions (PCI). In everyday clinical practice, ESV systems can be used both along with and instead of intracoronary imaging systems. The present case series show the main current applications of ESV systems during complex PCI cases with a brief review of the available data.>.