Coronary calcification in patients presenting with acute coronary syndromes: insights from the MATRIX trial.

AIMS: The role of coronary calcification on clinical outcomes among different revascularization strategies in patients presenting with acute coronary syndromes (ACSs) has been rarely investigated. The aim of this investigation is to evaluate the role of coronary calcification, detected by coronary angiography, in the whole spectrum of patients presenting with acute ACS. METHODS AND RESULTS: The present study was a post hoc analysis of the MATRIX programme. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, myocardial infarction (MI), or stroke up to 365 days. Among the 8404 patients randomized in the MATRIX trial, data about coronary calcification were available in 7446 (88.6%) and therefore were included in this post hoc analysis. Overall, 875 patients (11.7%) presented with severe coronary calcification, while 6571 patients (88.3%) did not present severe coronary calcification on coronary angiography. Fewer patients with severe coronary calcification underwent percutaneous coronary intervention whereas coronary artery bypass grafting or medical therapy-only was more frequent compared with patients without severe calcification. At 1-year follow-up, MACE occurred in 237 (27.1%) patients with severe calcified coronary lesions and 985 (15%) patients without severe coronary calcified lesions [hazard ratio (HR) 1.91; 95% confidence interval (CI) 1.66-2.20, P < 0.001]. All-cause mortality was 8.6% in patients presenting with and 3.7% in those without severe coronary calcification (HR 2.38, 1.84-3.09, P < 0.001). Patients with severe coronary calcification incurred higher rate of MI (20.1% vs. 11.5%, HR 1.81; 95% CI 1.53-2.1, P < 0.001) and similar rate of stroke (0.8% vs. 0.6%, HR 1.35; 95% CI 0.61-3.02, P = 0.46). CONCLUSION: Patients with ACS and severe coronary calcification, as compared to those without, are associated with worse clinical outcomes irrespective of the management strategy.

A large, prospective, multicentre study of left main PCI using a latest-generation zotarolimus-eluting stent: the ROLEX study.

BACKGROUND: Data on left main (LM) percutaneous coronary interventions (PCI) have mostly been obtained in studies using drug-eluting stent (DES) platforms without dedicated large-vessel devices and with limited expansion capability. AIMS: Our study aimed to investigate the safety and efficacy of LM PCI with the latest-generation Resolute Onyx DES. METHODS: ROLEX (Revascularization Of LEft main with resolute onyX) is a prospective, multicentre study (ClinicalTrials.gov: NCT03316833) enrolling patients with unprotected LM coronary artery disease and a SYNTAX score <33 undergoing PCI with the Resolute Onyx zotarolimus-eluting coronary stent, that includes dedicated extra-large vessel platforms. The primary endpoint (EP) was target lesion failure (TLF): a composite of cardiac death, target vessel myocardial infarction (TVMI) and ischaemia-driven target lesion revascularisation (ID-TLR), at 1 year. All events were adjudicated by an independent clinical event committee. An independent core lab analysed all procedural angiograms. RESULTS: A total of 450 patients (mean age 71.8 years, SYNTAX score 24.5±7.2, acute coronary syndrome in 53%) were enrolled in 26 centres. Of these, 77% of subjects underwent PCI with a single-stent and 23% with a 2-stent technique (8% double kissing [DK] crush, 6% culotte, 9% T/T and small protrusion [TAP] stenting). Intravascular imaging guidance was used in 45% (42% intravascular ultrasound [IVUS], 3% optical coherence tomography [OCT]). At 1 year, the primary EP incidence was 5.1% (cardiac death 2.7%, TVMI 2.7%, ID-TLR 2.0%). The definite/probable stent thrombosis rate was 1.1%. In a prespecified adjusted subanalysis, the primary EP incidence was significantly lower in patients undergoing IVUS/OCT-guided versus angio-guided PCI (2.0 vs 7.6%; hazard ratio [HR] 0.28, 95% confidence interval [CI]: 0.13-0.58; p<0.001). CONCLUSIONS: In this large, multicentre, prospective registry, LM PCI with the Resolute Onyx DES showed good safety and efficacy at 1 year, particularly when guided by intracoronary imaging.

Antiplatelet Therapy with Cangrelor in Patients Undergoing Surgery after Coronary Stent Implantation: A Real-World Bridging Protocol Experience.

Objective The aim of the study is to describe the real-world use of the P2Y 12 inhibitor cangrelor as a bridging strategy in patients at high thrombotic risk after percutaneous coronary intervention (PCI) and referred to surgery requiring perioperative withdrawal of dual antiplatelet therapy (DAPT). Materials and Methods We collected data from nine Italian centers on patients with previous PCI who were still on DAPT and undergoing nondeferrable surgery requiring DAPT discontinuation. A perioperative standardized bridging protocol with cangrelor was used. Results Between December 2017 and April 2019, 24 patients (mean age 72 years; male 79%) were enrolled. All patients were at high thrombotic risk after PCI and required nondeferrable intermediate to high bleeding risk surgery requiring DAPT discontinuation (4.6 ± 1.7 days). Cangrelor infusion was started at a bridging dose (0.75 µg/kg/min) 3 days before planned surgery and was discontinued 6.6 ± 1.5 hours prior to surgical incision. In 55% of patients, cangrelor was resumed at 9 ± 6 hours following surgery for a mean of 39 ± 38 hours. One cardiac death was reported after 3 hours of cangrelor discontinuation prior to surgery. No ischemic outcomes occurred after surgery and up to 30-days follow-up. The mean hemoglobin drop was <2 g/dL; nine patients received blood transfusions consistent with the type of surgery, but no life-threatening or fatal bleeding occurred. Conclusion Perioperative bridging therapy with cangrelor is a feasible approach for stented patients at high thrombotic risk and referred to surgery requiring DAPT discontinuation. Larger studies are warranted to support the safety of this strategy.

A rare but serious complication of ticagrelor therapy: a case report.

BACKGROUND: Ticagrelor is a widely used P2Y12 inhibitor and represents a fundamental therapeutic agent in acute coronary syndrome treatment and selected post-percutaneous coronary intervention (PCI) cases. Dyspnoea and bradycardia are the most common side effects but the latter has been reported to be of trivial clinical significance. CASE SUMMARY: A 51-year-old gentleman underwent PCI to left anterior descending and obtuse marginal for unstable angina receiving a loading dose of ticagrelor (180 mg). During hospital stay, whilst on telemetry monitoring, a 16 s long, symptomatic, asystolic ventricular standstill was recorded prompting ticagrelor interruption and a switch to prasugrel. DISCUSSION: Despite ventricular pauses have been reported in dedicated analyses of Phase III trials, no apparent clinical consequences were documented. However, several reports have shown that significant brady-arrhythmic events might be linked to ticagrelor administration presenting both as sino-atrial and atrio-ventricular conduction disturbances. We report a case of asystole occurring 36 h after the administration of a loading dose.

Downstream or upstream administration of P2Y12 receptor blockers in non-ST elevated acute coronary syndromes: study protocol for a randomized controlled trial.

BACKGROUND: The optimal timing to administer a P2Y12 inhibitor in patients presenting with a non-ST elevation acute coronary syndrome remains a topic of debate. Pretreatment with ticagrelor before coronary anatomy is known as a widely adopted strategy. However, there is poor evidence on how this compares with administration of a P2Y12 inhibitor after defining coronary anatomy (i.e., downstream administration). Moreover, there are limited head-to-head comparisons of the two P2Y12 inhibitors-ticagrelor and prasugrel-currently recommended by the guidelines. STUDY DESIGN: DUBIUS is a phase 4, multicenter, parallel-group, double randomized study conducted in NSTE-ACS patients designed to compare a pretreatment strategy (including only ticagrelor) versus a downstream strategy (including prasugrel or ticagrelor) and to compare downstream prasugrel with downstream ticagrelor. A total of 2520 patients will be randomly assigned to pretreatment with ticagrelor or to no pretreatment. The PCI group of the downstream arm will be further randomized to receive prasugrel or ticagrelor. The two primary hypotheses are that the downstream strategy is superior to the upstream strategy and that downstream ticagrelor is non-inferior to downstream prasugrel, both measured by the incidence of a composite efficacy and safety endpoint of death from vascular causes, non-fatal MI, or non-fatal stroke, and Bleeding Academic Research Consortium (BARC) type 3, 4, and 5 bleedings. CONCLUSIONS: The DUBIUS study will provide important evidence related to the benefits and risks of pretreatment with ticagrelor compared with a strategy of no pretreatment. Moreover, the clinical impact of using downstream ticagrelor compared with downstream prasugrel will be assessed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02618837 . Registered on 1 December 2015.

Timing of Oral P2Y12 Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: Although oral P2Y12 inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined. OBJECTIVES: The purpose of this study was to compare downstream and upstream oral P2Y12 inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment. METHODS: We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit). RESULTS: We randomized 1,449 patients to downstream or upstream oral P2Y12 inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment). CONCLUSIONS: Downstream and upstream oral P2Y12 inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y12 Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837).

An Uncommon Case of Spontaneous Hemopericardium in a Patient Treated with Rivaroxaban.

We describe a case of an 88-year-old woman with a severe bluntly ematic pericardial effusion. Radiological and laboratory examinations excluded all the most common causes of hemopericardium, and the diagnosis of spontaneous hemopericardium associated with the treatment with rivaroxaban was made. This is the first case report describing a hemopericardium in a patient treated with rivaroxaban who did not take other herbal products or drugs that may significantly increase rivaroxaban blood levels. This report emphasizes the need for the careful use of new oral anticoagulants, and the importance of taking in mind uncommon side effects. Spontaneous hemopericardium should be considered in these patients.

Impact of angiographic coronary artery disease complexity on ischemic and bleeding risks and on the comparative effectiveness of zotarolimus-eluting vs. bare-metal stents in uncertain drug-eluting stent candidates.

BACKGROUND: The impact of coronary artery disease (CAD) extension/complexity on outcomes and on the comparative benefits/risks of zotarolimus-eluting stent (ZES) versus bare-metal stents (BMS) remains unclear in patients at high risk of bleeding or thrombosis or at low restenosis risk. METHODS: We performed a post-hoc analysis of the ZEUS trial. The impact of coronary anatomic complexity measured by the SYNTAX score on the differences in outcomes following ZES and BMS was assessed at 1 year. RESULTS: The mean SYNTAX score was 16.3 ±â€¯13.1 with a median of 12 (IQR: 7 to 22). We stratified patients according to SYNTAX tertiles (0-8: n = 563; >8-19 n = 532; >19: n = 511), and observed that the higher the score, the correspondingly higher was the rate of the primary endpoint of major adverse cardiovascular events (MACE) and other ischemic events, but not bleeding after adjustment. The superior efficacy of ZES versus BMS for MACE was consistent across SYNTAX tertiles (tertile 1: HR 0.71, 95% CI 0.44-1.13; tertile 2: HR 0.71, 95% CI 0.46-1.09; tertile 3: HR 0.83, 95% CI 0.61-1.10) without significant heterogeneity (p for trend = 0.55). This between-groups difference mainly reflected a reduction in MI and TVR without effect on mortality. There was no significant interaction between the SYNTAX score and allocated stent type with respect to ischemic and bleeding endpoints. CONCLUSIONS: The SYNTAX score was predictor of major adverse cardiovascular events but not bleeding and ZES provided superior efficacy and safety than BMS across the whole spectrum of CAD complexity. SYNTAX score may be routinely used for the assessment of the ischemic risk (but not bleeding) after PCI and should not guide the decision-making for DES versus BMS in patients undergoing PCI.

Radial versus femoral access and bivalirudin versus unfractionated heparin in invasively managed patients with acute coronary syndrome (MATRIX): final 1-year results of a multicentre, randomised controlled trial.

BACKGROUND: The Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) programme was designed to assess the comparative safety and effectiveness of radial versus femoral access and of bivalirudin versus unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors in patients with the whole spectrum of acute coronary syndrome undergoing invasive management. Here we describe the prespecified final 1-year outcomes of the entire programme. METHODS: MATRIX was a programme of three nested, randomised, multicentre, open-label, superiority trials in patients with acute coronary syndrome in 78 hospitals in Italy, the Netherlands, Spain, and Sweden. Patients with ST-elevation myocardial infarction were simultaneously randomly assigned (1:1) before coronary angiography to radial or femoral access and to bivalirudin, with or without post-percutaneous coronary intervention infusion or unfractionated heparin (one-step inclusion). Patients with non-ST-elevation acute coronary syndrome were randomly assigned (1:1) before coronary angiography to radial or femoral access and, only if deemed eligible to percutaneous coronary intervention after angiography (two-step inclusion), entered the antithrombin type and treatment duration programmes. Randomisation sequences were computer generated, blocked, and stratified by intended new or current use of P2Y12 inhibitor (clopidogrel vs ticagrelor or prasugrel), and acute coronary syndrome type (ST-elevation myocardial infarction, troponin-positive, or troponin-negative non-ST-elevation acute coronary syndrome). Bivalirudin was given as a bolus of 0·75 mg/kg, followed immediately by an infusion of 1·75 mg/kg per h until completion of percutaneous coronary intervention. Heparin was given at 70-100 units per kg in patients not receiving glycoprotein IIb/IIIa inhibitors, and at 50-70 units per kg in patients receiving glycoprotein IIb/IIIa inhibitors. Clinical follow-up was done at 30 days and 1 year. Co-primary outcomes for MATRIX access and MATRIX antithrombin type were major adverse cardiovascular events, defined as the composite of all-cause mortality, myocardial infarction, or stroke up to 30 days; and net adverse clinical events, defined as the composite of non-coronary artery bypass graft-related major bleeding, or major adverse cardiovascular events up to 30 days. The primary outcome for MATRIX treatment duration was the composite of urgent target vessel revascularisation, definite stent thrombosis, or net adverse clinical events up to 30 days. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01433627. FINDINGS: Between Oct 11, 2011, and Nov 7, 2014, we randomly assigned 8404 patients to receive radial (4197 patients) or femoral (4207 patients) access. Of these 8404 patients, 7213 were included in the MATRIX antithrombin type study and were randomly assigned to bivalirudin (3610 patients) or heparin (3603 patients). Patients assigned to bivalirudin were included in the MATRIX treatment duration study, and were randomly assigned to post-procedure infusion (1799 patients) or no post-procedure infusion (1811 patients). At 1 year, major adverse cardiovascular events did not differ between patients assigned to radial access compared with those assigned to femoral access (14·2% vs 15·7%; rate ratio 0·89, 95% CI 0·80-1·00; p=0·0526), but net adverse clinical events were fewer with radial than with femoral access (15·2% vs 17·2%; 0·87, 0·78-0·97; p=0·0128). Compared with heparin, bivalirudin was not associated with fewer major adverse cardiovascular (15·8% vs 16·8%; 0·94, 0·83-1·05; p=0·28) or net adverse clinical events (17·0% vs 18·4%; 0·91, 0·81-1·02; p=0·10). The composite of urgent target vessel revascularisation, stent thrombosis, or net adverse clinical events did not differ with or without post-procedure bivalirudin infusion (17·4% vs 17·4%; 0·99, 0·84-1·16; p=0·90). INTERPRETATION: In patients with acute coronary syndrome, radial access was associated with lower rates of net adverse clinical events compared with femoral access, but not major adverse cardiovascular events at 1 year. Bivalirudin with or without post-procedure infusion was not associated with lower rates of major adverse cardiovascular events or net adverse clinical events. Radial access should become the default approach in acute coronary syndrome patients undergoing invasive management. FUNDING: Italian Society of Invasive Cardiology, The Medicines Company, Terumo, amd Canada Research Chairs Programme.

Bivalirudin or Heparin in Patients Undergoing Invasive Management of Acute Coronary Syndromes.

BACKGROUND: Contrasting evidence exists on the comparative efficacy and safety of bivalirudin and unfractionated heparin (UFH) in relation to the planned use of glycoprotein IIb/IIIa inhibitors (GPIs). OBJECTIVES: This study assessed the efficacy and safety of bivalirudin compared with UFH with or without GPIs in patients with acute coronary syndrome (ACS) who underwent invasive management. METHODS: In the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX) program, 7,213 patients were randomly assigned to receive either bivalirudin or UFH with or without GPIs at discretion of the operator. The 30-day coprimary outcomes were major adverse cardiovascular events (MACEs) (a composite of death, myocardial infarction, or stroke), and net adverse clinical events (NACEs) (a composite of MACEs or major bleeding). RESULTS: Among 3,603 patients assigned to receive UFH, 781 (21.7%) underwent planned treatment with GPI before coronary intervention. Bailout use of GPIs was similar between the bivalirudin and UFH groups (4.5% and 5.4%) (p = 0.11). At 30 days, the 2 coprimary endpoints of MACEs and NACEs, as well as individual endpoints of mortality, myocardial infarction, stent thrombosis or stroke did not differ among the 3 groups after adjustment. Compared with the UFH and UFH+GPI groups, bivalirudin reduced bleeding, mainly the most severe bleeds, including fatal and nonaccess site-related events, as well as transfusion rates and the need for surgical access site repair. These findings were not influenced by the administered intraprocedural dose of UFH and were confirmed at multiple sensitivity analyses, including the randomly allocated access site. CONCLUSIONS: In patients with ACS, the rates of MACEs and NACEs were not significantly lower with bivalirudin than with UFH, irrespective of planned GPI use. However, bivalirudin significantly reduced bleeding complications, mainly those not related to access site, irrespective of planned use of GPIs. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX [MATRIX]; NCT01433627).

Radial versus femoral access in patients with acute coronary syndromes with or without ST-segment elevation.

Aims: To assess whether radial compared with femoral access is associated with consistent outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods and results: In the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) programme patients were randomized to radial or femoral access, stratified by STEMI (2001 radial, 2009 femoral) and NSTE-ACS (2196 radial, 2198 femoral). The 30-day co-primary outcomes were major adverse cardiovascular events (MACE), defined as death, myocardial infarction, or stroke, and net adverse clinical events (NACE), defined as MACE or major bleeding In the overall study population, radial access reduced the NACE but not MACE endpoint at the prespecified 0.025 alpha. MACE occurred in 121 (6.1%) STEMI patients with radial access vs. 126 (6.3%) patients with femoral access [rate ratio (RR) = 0.96, 95% CI = 0.75-1.24; P = 0.76] and in 248 (11.3%) NSTE-ACS patients with radial access vs. 303 (13.9%) with femoral access (RR = 0.80, 95% CI = 0.67-0.96; P = 0.016) (Pint = 0.25). NACE occurred in 142 (7.2%) STEMI patients with radial access and in 165 (8.3%) patients with femoral access (RR = 0.86, 95% CI = 0.68-1.08; P = 0.18) and in 268 (12.2%) NSTE-ACS patients with radial access compared with 321 (14.7%) with femoral access (RR = 0.82, 95% CI = 0.69-0.97; P = 0.023) (Pint = 0.76). All-cause mortality and access site-actionable bleeding favoured radial access irrespective of ACS type (Pint = 0.11 and Pint = 0.36, respectively). Conclusion: Radial as compared with femoral access provided consistent benefit across the whole spectrum of patients with ACS, without evidence that type of presenting syndrome affected the results of the random access allocation.

Is Bare-Metal Stent Implantation Still Justifiable in High Bleeding Risk Patients Undergoing Percutaneous Coronary Intervention?: A Pre-Specified Analysis From the ZEUS Trial.

OBJECTIVES: This study sought to investigate the ischemic and bleeding outcomes of patients fulfilling high bleeding risk (HBR) criteria who were randomized to zotarolimus-eluting Endeavor Sprint stent (E-ZES) or bare-metal stent (BMS) implantation followed by an abbreviated dual antiplatelet therapy (DAPT) duration for stable or unstable coronary artery disease. BACKGROUND: DES instead of BMS use remains controversial in HBR patients, in whom long-term DAPT poses safety concerns. METHODS: The ZEUS (Zotarolimus-Eluting Endeavor Sprint Stent in Uncertain DES Candidates) is a multinational, randomized single-blinded trial that randomized among others, in a stratified manner, 828 patients fulfilling pre-defined clinical or biochemical HBR criteria-including advanced age, indication to oral anticoagulants or other pro-hemorrhagic medications, history of bleeding and known anemia-to receive E-ZES or BMS followed by a protocol-mandated 30-day DAPT regimen. The primary endpoint of the study was the 12-month major adverse cardiovascular event rate, consisting of death, myocardial infarction, or target vessel revascularization. RESULTS: Compared with patients without, those with 1 or more HBR criteria had worse outcomes, owing to higher ischemic and bleeding risks. Among HBR patients, major adverse cardiovascular events occurred in 22.6% of the E-ZES and 29% of the BMS patients (hazard ratio: 0.75; 95% confidence interval: 0.57 to 0.98; p = 0.033), driven by lower myocardial infarction (3.5% vs. 10.4%; p < 0.001) and target vessel revascularization (5.9% vs. 11.4%; p = 0.005) rates in the E-ZES arm. The composite of definite or probable stent thrombosis was significantly reduced in E-ZES recipients, whereas bleeding events did not differ between stent groups. CONCLUSIONS: Among HBR patients with stable or unstable coronary artery disease, E-ZES implantation provides superior efficacy and safety as compared with conventional BMS. (Zotarolimus-Eluting Endeavor Sprint Stent in Uncertain DES Candidates [ZEUS]; NCT01385319).

Cyclosporine A in Reperfused Myocardial Infarction: The Multicenter, Controlled, Open-Label CYCLE Trial.

BACKGROUND: Whether cyclosporine A (CsA) has beneficial effects in reperfused myocardial infarction (MI) is debated. OBJECTIVES: This study investigated whether CsA improved ST-segment resolution in a randomized, multicenter phase II study. METHODS: The authors randomly assigned 410 patients from 31 cardiac care units, age 63 ± 12 years, with large ST-segment elevation MI within 6 h of symptom onset, Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1 in the infarct-related artery, and committed to primary percutaneous coronary intervention, to 2.5 mg/kg intravenous CsA (n = 207) or control (n = 203) groups. The primary endpoint was incidence of ≥70% ST-segment resolution 60 min after TIMI flow grade 3. Secondary endpoints included high-sensitivity cardiac troponin T (hs-cTnT) on day 4, left ventricular (LV) remodeling, and clinical events at 6-month follow-up. RESULTS: Time from symptom onset to first antegrade flow was 180 ± 67 min; a median of 5 electrocardiography leads showed ST-segment deviation (quartile [Q]1 to Q3: 4 to 6); 49.8% of MIs were anterior. ST-segment resolution ≥70% was found in 52.0% of CsA patients and 49.0% of controls (p = 0.55). Median hs-cTnT on day 4 was 2,160 (Q1 to Q3: 1,087 to 3,274) ng/l in CsA and 2,068 (1,117 to 3,690) ng/l in controls (p = 0.85). The 2 groups did not differ in LV ejection fraction on day 4 and at 6 months. Infarct site did not influence CsA efficacy. There were no acute allergic reactions or nonsignificant excesses of 6-month mortality (5.7% CsA vs. 3.2% controls, p = 0.17) or cardiogenic shock (2.4% CsA vs. 1.5% controls, p = 0.33). CONCLUSIONS: In the CYCLE (CYCLosporinE A in Reperfused Acute Myocardial Infarction) trial, a single intravenous CsA bolus just before primary percutaneous coronary intervention had no effect on ST-segment resolution or hs-cTnT, and did not improve clinical outcomes or LV remodeling up to 6 months. (CYCLosporinE A in Reperfused Acute Myocardial Infarction [CYCLE]; NCT01650662; EudraCT number 2011-002876-18).

Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes.

BACKGROUND: Conflicting evidence exists on the efficacy and safety of bivalirudin administered as part of percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome. METHODS: We randomly assigned 7213 patients with an acute coronary syndrome for whom PCI was anticipated to receive either bivalirudin or unfractionated heparin. Patients in the bivalirudin group were subsequently randomly assigned to receive or not to receive a post-PCI bivalirudin infusion. Primary outcomes for the comparison between bivalirudin and heparin were the occurrence of major adverse cardiovascular events (a composite of death, myocardial infarction, or stroke) and net adverse clinical events (a composite of major bleeding or a major adverse cardiovascular event). The primary outcome for the comparison of a post-PCI bivalirudin infusion with no post-PCI infusion was a composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events. RESULTS: The rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin (10.3% and 10.9%, respectively; relative risk, 0.94; 95% confidence interval [CI], 0.81 to 1.09; P=0.44), nor was the rate of net adverse clinical events (11.2% and 12.4%, respectively; relative risk, 0.89; 95% CI, 0.78 to 1.03; P=0.12). Post-PCI bivalirudin infusion, as compared with no infusion, did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events (11.0% and 11.9%, respectively; relative risk, 0.91; 95% CI, 0.74 to 1.11; P=0.34). CONCLUSIONS: In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin. The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion. (Funded by the Medicines Company and Terumo Medical; MATRIX ClinicalTrials.gov number, NCT01433627.).

Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial.

BACKGROUND: It is unclear whether radial compared with femoral access improves outcomes in unselected patients with acute coronary syndromes undergoing invasive management. METHODS: We did a randomised, multicentre, superiority trial comparing transradial against transfemoral access in patients with acute coronary syndrome with or without ST-segment elevation myocardial infarction who were about to undergo coronary angiography and percutaneous coronary intervention. Patients were randomly allocated (1:1) to radial or femoral access with a web-based system. The randomisation sequence was computer generated, blocked, and stratified by use of ticagrelor or prasugrel, type of acute coronary syndrome (ST-segment elevation myocardial infarction, troponin positive or negative, non-ST-segment elevation acute coronary syndrome), and anticipated use of immediate percutaneous coronary intervention. Outcome assessors were masked to treatment allocation. The 30-day coprimary outcomes were major adverse cardiovascular events, defined as death, myocardial infarction, or stroke, and net adverse clinical events, defined as major adverse cardiovascular events or Bleeding Academic Research Consortium (BARC) major bleeding unrelated to coronary artery bypass graft surgery. The analysis was by intention to treat. The two-sided α was prespecified at 0·025. The trial is registered at ClinicalTrials.gov, number NCT01433627. FINDINGS: We randomly assigned 8404 patients with acute coronary syndrome, with or without ST-segment elevation, to radial (4197) or femoral (4207) access for coronary angiography and percutaneous coronary intervention. 369 (8·8%) patients with radial access had major adverse cardiovascular events, compared with 429 (10·3%) patients with femoral access (rate ratio [RR] 0·85, 95% CI 0·74-0·99; p=0·0307), non-significant at α of 0·025. 410 (9·8%) patients with radial access had net adverse clinical events compared with 486 (11·7%) patients with femoral access (0·83, 95% CI 0·73-0·96; p=0·0092). The difference was driven by BARC major bleeding unrelated to coronary artery bypass graft surgery (1·6% vs 2·3%, RR 0·67, 95% CI 0·49-0·92; p=0·013) and all-cause mortality (1·6% vs 2·2%, RR 0·72, 95% CI 0·53-0·99; p=0·045). INTERPRETATION: In patients with acute coronary syndrome undergoing invasive management, radial as compared with femoral access reduces net adverse clinical events, through a reduction in major bleeding and all-cause mortality. FUNDING: The Medicines Company and Terumo.

Zotarolimus-eluting versus bare-metal stents in uncertain drug-eluting stent candidates.

BACKGROUND: The use of drug-eluting stents (DES) in patients at high risk of bleeding or thrombosis has not been prospectively studied; limited data are available in patients who have a low restenosis risk. OBJECTIVES: This study sought to compare a hydrophilic polymer-based, second-generation zotarolimus-eluting stent (ZES) with a unique drug fast-release profile versus bare-metal stents (BMS) under similar durations of dual-antiplatelet therapy (DAPT). METHODS: We randomly assigned 1,606 patients with stable or unstable symptoms, and who on the basis of thrombotic bleeding or restenosis risk criteria, qualified as uncertain candidates for DES, to receive ZES or BMS. DAPT duration was on the basis of patient characteristics, rather than stent characteristics, and allowed for a personalized 1-month dual antiplatelet regimen. The primary endpoint was the risk of 1-year major adverse cardiovascular events (MACE), which included death, myocardial infarction (MI), or target vessel revascularization (TVR). RESULTS: Median DAPT duration was 32 days (interquartile range [IQR]: 30 to 180 days) and did not differ between the groups. In the ZES group, 140 patients (17.5%) reached the primary endpoint, compared with 178 patients (22.1%) in the BMS group (hazard ratio: 0.76; 95% confidence interval: 0.61 to 0.95; p = 0.011) as a result of lower MI (2.9% vs. 8.1%; p < 0.001) and TVR rates (5.9% vs.10.7%; p = 0.001) in the ZES group. Definite or probable stent thrombosis was also significantly reduced in ZES recipients (2.0% vs. 4.1%; p = 0.019). CONCLUSIONS: Compared with BMS, DES implantation using a stent with a biocompatible polymer and fast drug-eluting characteristics, combined with an abbreviated, tailored DAPT regimen, resulted in a lower risk of 1-year MACE in uncertain candidates for DES implantation. (Zotarolimus-eluting Endeavor Sprint Stent in Uncertain DES Candidates [ZEUS] Study; NCT01385319).

Randomized comparison of Zotarolimus-Eluting Endeavor Sprint versus bare-metal stent implantation in uncertain drug-eluting stent candidates: rationale, design, and characterization of the patient population for the Zotarolimus-eluting Endeavor Sprint stent in uncertain DES candidates study.

BACKGROUND: The use of drug-eluting stent (DES) instead of bare-metal stent (BMS) in patients at high stent thrombosis or bleeding risk as well as in those at low restenosis risk (ie, uncertain DES candidates) remains a matter of debate. Zotarolimus-Eluting Endeavor Sprint stent (E-ZES) (Santa Rosa, CA) is a hydrophilic polymer-based second-generation device with unique drug fast-release profile, which may allow for a shorter dual antiplatelet therapy (DAPT) duration without safety concerns. HYPOTHESIS: The primary objective is to assess whether E-ZES implantation followed by a shorter than currently recommended course of DAPT will decrease the incidence of 12-month major adverse cardiovascular events as compared with BMS in undefined DES recipients. Actual duration of DAPT regimen will be dictated by patients' characteristics and not by stent type and, as such, can be as short as 30 days after intervention in both stent groups. STUDY DESIGN: The ZEUS study is an open-label randomized clinical trial conducted at 20 clinical sites in Italy, Switzerland, Portugal, and Hungary. With 1,600 individuals, this study will have 85% power to detect a 33% difference in the primary end point consisting of the composite of death, nonfatal myocardial infarction, or target vessel revascularization. SUMMARY: The ZEUS trial aims to assess whether the use of E-ZES, followed by a DAPT duration regimen based on patients' characteristics and not by stent type, is superior to conventional BMS implantation in undefined DES recipients who qualify for the presence of high thrombosis, bleeding, or low restenosis risk criteria.

Three-year follow-up of the MULTIcentre evaluation of Single high-dose Bolus TiRofiban versus Abciximab with Sirolimus-eluting STEnt or Bare-Metal Stent in Acute Myocardial Infarction StudY (MULTISTRATEGY).

BACKGROUND: The Multicentre Evaluation of Single high-dose Bolus TiRofiban versus Abciximab with Sirolimus-eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study [MULTISTRATEGY]) randomised 745 patients with ST-elevation myocardial infarction to receive high-dose bolus (HDB) tirofiban or abciximab infusion and sirolimus-eluting (SES) or uncoated-stent (BMS) implantation. Tirofiban was non-inferior to abciximab in terms of ST-segment resolution after intervention, whereas 8 month-major adverse cardiac events occurred in 14.5% in the BMS and 7.8% in the SES groups (P = 0.0039), reflecting a reduction of reintervention rates (10.2% vs. 3.2%). A three-year follow-up was performed to extend previous short- to mid-term findings. METHODS AND RESULTS: Complete data at 3 years was available for 736 patients (99%). All-cause mortality was 6.7% in the tirofiban and 7.8% in the abciximab (P = 0.56) and 7.5% in the BMS vs 7.0 in the SES groups, P = 0.79. The composite of all-cause death or MI was identical at 12.9% in tirofiban and abciximab groups, P = 0.99 and it occurred in 13.2% in the BMS vs. 12.6% in the SES groups (P = 0.83). The need for reintervention remained more than twice as common with BMS (13.7%; versus 6.2%, P = 0.0006). The cumulative rate of stent thrombosis (ST) did not differ. This is inspite of a higher very late definite, probable or possible ST thrombosis rate in the SES group. CONCLUSIONS: The 3-year follow-up of MULTISTRATEGY demonstrated comparable outcomes with HDB Tirofiban or abciximab and a sustained efficacy of SES to reduce reintervention with no difference in death, repeat MI or ST.

Sex-specific benefits of sirolimus-eluting stent on long-term outcomes in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: insights from the Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study trial.

OBJECTIVES: We assessed the relation between female sex and sirolimus-eluting stent (SES) use on long-term outcomes in acute myocardial infarction. BACKGROUND: There are no data on sex-specific differences in long-term benefit of SES use compared with bare-metal stent (BMS) use among patients undergoing primary percutaneous coronary interventions. METHODS: We performed a post hoc analysis of the MULTISTRATEGY trial. Hazard ratios (HRs) of events with 95% CI for sex and stent type were computed using Cox proportional regression with adjustment for confounders. RESULTS: A total of 744 patients, 64 years old (55-73 years old), 179 (24.1%) women, were enrolled. After a follow-up of 1,080 days, SES use was associated with a significant reduction of major adverse cardiovascular events, that is, the composite of all-cause death, reinfarction, or clinically driven target vessel revascularization (TVR) (13.9% vs 23.6%, adjusted HR 0.62, 95% CI 0.41-0.94, P = .026) and of TVR (6.1% vs 15.1%, adjusted HR 0.35, 95% CI 0.19-0.63, P < .001) in men. Conversely, SES use was not associated to a better outcome among women (major adverse cardiovascular events 21.9% in SES vs 18.2% in the BMS group, adjusted HR 1.27, 95% CI 0.53-3.02, P = .59; TVR 6.6% vs 9.1%, adjusted HR 0.62, 95% CI 0.17-2.21, P = .46). CONCLUSIONS: In this analysis, the clinical benefit of SES use, over BMS, at 3-year follow-up was restricted to men and was not observed among women.