Publications by authors named "Jean-Francois Tanguay"

157 Publications

Dual antiplatelet therapy (PEGASUS) vs. dual pathway (COMPASS): a head-to-head in vitro comparison.

Platelets 2021 Apr 15:1-6. Epub 2021 Apr 15.

Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is prescribed for 1-year after myocardial infarction. Two clinical strategies are considered at 1-year: continuation of DAPT or "Dual Pathway" (DP), using aspirin and rivaroxaban. No head-to-head comparative studies exist. In our study, 24 samples of donor blood were treated with clinically proven concentrations of 5 antithrombotic regimens: aspirin, ticagrelor, rivaroxaban, DAPT, and DP. Thrombosis was analyzed using the Total Thrombus Analysis System (T-TAS) to measure both antiplatelet and anticoagulant effects. Flow cytometry was performed to quantify platelet activation. DAPT was the most potent antiplatelet regimen, delaying thrombus onset ( < .0001) and reducing thrombogenicity ( < .0001), relative to control. DP did not delay thrombus formation relative to aspirin alone ( = .69). DP was the most potent anticoagulant regimen, delaying thrombus onset ( < .0001) and reducing thrombogenicity ( < .0001), relative to control. DP showed synergistic antithrombotic effects by delaying thrombus onset ( < .0001) and reducing thrombogenicity ( = .0003), relative to rivaroxaban alone. Flow cytometry showed only DAPT ( = .0023) reduced platelet activation. DP treatment demonstrated synergistic antithrombotic effects over rivaroxaban alone, but no additional antiplatelet synergism over aspirin alone.
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http://dx.doi.org/10.1080/09537104.2021.1904134DOI Listing
April 2021

The FDA and PLATO Investigators death lists: Call for a match.

Int J Clin Pract 2021 Mar 6:e14105. Epub 2021 Mar 6.

Bethany Beach, DE, USA.

Purpose: The FDA-issued PLATO trial dataset revealed that some primary death causes (PDCs) were inaccurately reported favouring ticagrelor. However, the PLATO Investigators operated the shorter death list of uncertain quality. We compared if PDC match when trial fatalities were reported to the FDA and by the PLATO Investigators.

Method: The FDA list contains precisely detailed 938 PLATO deaths, while shorter investigators dataset consists of 905 deaths. We matched four vascular (sudden, post-MI, heart failure and stroke), and three non-vascular (cancer, sepsis and suicide) PDC between death lists.

Results: There were more sudden deaths in the shorter list than in the FDA dataset (161 vs 138; P < .03) and post-AMI (373 vs 178; P < .001) but fewer heart failure deaths (73 vs 109; P = .02). Stroke numbers match well (39 vs 37; P = NS) with only two ticagrelor cases removed. Cancer matched well (32 vs 31; P = NS), and sepsis cases were identical (30 vs 30; P = NS). However, two extra clopidogrel suicides in the shorter list are impossible to comprehend.

Conclusions: The PLATO trial PDCs were mismatched between FDA and investigators sets. We are kindly asking the ticagrelor sponsor or/and concerned PLATO Investigators to clarify the PDC dataset match.
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http://dx.doi.org/10.1111/ijcp.14105DOI Listing
March 2021

Platelet Quiescence in Patients With Acute Coronary Syndrome Undergoing Coronary Artery Bypass Graft Surgery.

J Am Heart Assoc 2021 Feb 18;10(5):e016602. Epub 2021 Feb 18.

University of Ottawa Heart Institute Ottawa Ontario Canada.

Background The optimal antiplatelet strategy for patients with acute coronary syndromes who require coronary artery bypass surgery remains unclear. While a more potent antiplatelet regimen will predispose to perioperative bleeding, it is hypothesized that through "platelet quiescence," ischemic protection conferred by such therapy may provide a net clinical benefit. Methods and Results We compared patients undergoing coronary artery bypass surgery who were treated with a more potent antiplatelet inhibition strategy with those with a less potent inhibition through a meta-analysis. The primary outcome was all-cause mortality after bypass surgery. The analysis identified 4 studies in which the antiplatelet regimen was randomized and 6 studies that were nonrandomized. Combining all studies, there was an overall higher mortality with weaker strategies compared with more potent strategies (odds ratio, 1.38; 95% CI, 1.03-1.85; =0.03). Conclusions Our findings support the concept of platelet quiescence, in reducing mortality for patients with acute coronary syndrome requiring coronary artery bypass surgery. This suggests the routine up-front use of potent antiplatelet regimens in acute coronary syndrome, irrespective of likelihood of coronary artery bypass graft.
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http://dx.doi.org/10.1161/JAHA.120.016602DOI Listing
February 2021

Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A North American Perspective: 2021 Update.

Circulation 2021 Feb 8;143(6):583-596. Epub 2021 Feb 8.

Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA (D.L.B., C.P.C., D.P.F.).

A growing number of patients undergoing percutaneous coronary intervention (PCI) with stent implantation also have atrial fibrillation. This poses challenges for their optimal antithrombotic management because patients with atrial fibrillation undergoing PCI require oral anticoagulation for the prevention of cardiac thromboembolism and dual antiplatelet therapy for the prevention of coronary thrombotic complications. The combination of oral anticoagulation and dual antiplatelet therapy substantially increases the risk of bleeding. Over the last decade, a series of North American Consensus Statements on the Management of Antithrombotic Therapy in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention have been reported. Since the last update in 2018, several pivotal clinical trials in the field have been published. This document provides a focused updated of the 2018 recommendations. The group recommends that in patients with atrial fibrillation undergoing PCI, a non-vitamin K antagonist oral anticoagulant is the oral anticoagulation of choice. Dual antiplatelet therapy with aspirin and a P2Y inhibitor should be given to all patients during the peri-PCI period (during inpatient stay, until time of discharge, up to 1 week after PCI, at the discretion of the treating physician), after which the default strategy is to stop aspirin and continue treatment with a P2Y inhibitor, preferably clopidogrel, in combination with a non-vitamin K antagonist oral anticoagulant (ie, double therapy). In patients at increased thrombotic risk who have an acceptable risk of bleeding, it is reasonable to continue aspirin (ie, triple therapy) for up to 1 month. Double therapy should be given for 6 to 12 months with the actual duration depending on the ischemic and bleeding risk profile of the patient, after which patients should discontinue antiplatelet therapy and receive oral anticoagulation alone.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050438DOI Listing
February 2021

Antiplatelet therapy in patients with myocardial infarction without obstructive coronary artery disease.

Heart 2021 Jan 27. Epub 2021 Jan 27.

Population Health Research Institute (PHRI), Hamilton, Ontario, Canada

Objective: Approximately 10% of patients with myocardial infarction (MI) have no obstructive coronary artery disease. The prognosis and role of intensified antiplatelet therapy in those patients were evaluated.

Methods: We analysed data from the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organisation to Assess Strategies in Ischaemic Symptoms trial randomising patients with ACS referred for early intervention to receive either double-dose (600 mg, day 1; 150 mg, days 2-7; then 75 mg/day) or standard-dose (300 mg, day 1; then 75 mg/day) clopidogrel. Outcomes in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) versus those with obstructive coronary artery disease (CAD) and their relation to standard-dose versus double-dose clopidogrel were evaluated. The primary outcome was cardiovascular (CV) death, MI or stroke at 30 days.

Results: We included 23 783 patients with MI and 1599 (6.7%) with MINOCA. Patients with MINOCA were younger, presented more frequently with non-ST-segment elevation MI and had fewer comorbidities. All-cause mortality (0.6% vs 2.3%, p=0.005), CV mortality (0.6% vs 2.2%, p=0.006), repeat MI (0.5% vs 2.3%, p=0.001) and major bleeding (0.6% vs 2.4%, p<0.0001) were lower among patients with MINOCA than among those with obstructive CAD. Among patients with MINOCA, 2.1% of patients in the double-dose clopidogrel group and 0.6% in the standard-dose group experienced a primary outcome (HR 3.57, 95% CI 1.31 to 9.76), whereas in those with obstructive CAD, rates were 4.3% and 4.7%, respectively (HR 0.91, 95% CI 0.80 to 1.03; p value for interaction=0.011).

Conclusions: Patients with MINOCA are at lower risk of recurrent CV events compared with patients with MI with obstructive CAD. Compared with a standard clopidogrel-based dual antiplatelet therapy (DAPT) regimen, an intensified dosing strategy appears to offer no additional benefit with a signal of possible harm. Further randomised trials evaluating the effects of potent DAPT in patients with MINOCA are warranted.

Trial Registration Number: NCT00335452.
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http://dx.doi.org/10.1136/heartjnl-2020-318045DOI Listing
January 2021

Verifying Death Reports in the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

Am J Ther 2020 Nov/Dec;27(6):e563-e572

Physician, Bethany Beach, DE.

Background: Excess vascular deaths in the PLATO trial comparing ticagrelor to clopidogrel have been repeatedly challenged by the Food and Drug Administration (FDA) reviewers and academia. Based on the Freedom of Information Act, BuzzFeed won a court order and shared with us the complete list of reported deaths for the ticagrelor FDA New Drug Application (NDA) 22-433. This dataset was matched against local patient-level records from PLATO sites monitored by the sponsor.

Study Question: Whether FDA death data in the PLATO trial matched the local site records.

Study Design: The NDA spreadsheet contains 938 precisely detailed PLATO deaths. We obtained and validated local evidence for 52 deaths among 861 PLATO patients from 14 enrolling sites in 8 countries and matched those with the official NDA dataset submitted to the FDA.

Measures And Outcomes: Existence, precise time, and primary cause of deaths in PLATO.

Results: Discrepant to the NDA document, sites confirmed 2 extra unreported deaths (Poland and Korea) and failed to confirm 4 deaths (Malaysia). Of the remaining 46 deaths, dates were reported correctly for 42 patients, earlier (2 clopidogrel), or later (2 ticagrelor) than the actual occurrence of death. In 12 clopidogrel patients, cause of death was changed to "vascular," whereas 6 NDA ticagrelor "nonvascular" or "unknown" deaths were site-reported as of "vascular" origin. Sudden death was incorrectly reported in 4 clopidogrel patients, but omitted in 4 ticagrelor patients directly affecting the primary efficacy PLATO endpoint.

Conclusions: Many deaths were inaccurately reported in PLATO favoring ticagrelor. The full extent of mortality misreporting is currently unclear, while especially worrisome is a mismatch in identifying primary death cause. Because all PLATO events are kept in the cloud electronic Medidata Rave capture system, securing the database content, examining the dataset changes or/and repeated entries, identifying potential interference origin, and assessing full magnitude of the problem are warranted.
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http://dx.doi.org/10.1097/MJT.0000000000001286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643806PMC
October 2020

The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodeling in experimental right heart disease.

Cardiovasc Res 2020 Aug 31. Epub 2020 Aug 31.

Montreal Heart Institute (MHI), Department of Medicine, Université de Montréal.

Aims: Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signaling and a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodeling in experimental RHD.

Methods And Results: Pulmonary hypertension (PH) and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting one day before MCT administration. Right-atrial (RA) conduction and gene-expression were analyzed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary-artery or right-ventricular remodeling. Nevertheless, in vivo transesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA-fibrosis but had no effect on RA-dilation. MCT increased RA-expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA-content of type-1 (proinflammatory) CD68-positive M1-macrophages without affecting type-2 (anti-inflammatory) M2-macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1-macrophages and increases in anti-inflammatory M2-macrophages versus MCT-only. MCT caused statistically-significant increases in protein-expression (Western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1 and CXCL2, and decreases in MMP2, versus control. RvD1-treatment suppressed all these MCT-induced protein-expression changes.

Conclusions: The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA-remodeling, while suppressing inflammatory changes and fibrotic/electrical remodeling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodeling by suppressing ongoing inflammatory signaling.

Translational Perspective: Mounting evidence suggests that chronic diseases are promoted by failure of inflammation to resolve. Here, we tested the effects of a molecule that promotes inflammation-resolution, Resolvin-D1, in a rat model of atrial arrhythmogenic remodeling caused by right-heart disease and marked by signs of persistent inflammatory signaling. Resolvin-D1 suppressed inflammatory signaling, shifted the balance of atrial macrophage-infiltration from proinflammatory M1-macrophages towards anti-inflammatory M2-macrophages and prevented atrial fibrosis. Disease-induced conduction-slowing was suppressed and atrial-fibrillation promotion was prevented. These findings support the potential value of a relatively non-toxic inflammation-resolving molecule in preventing the development of an arrhythmogenic substrate associated with chronic inflammatory signaling.
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http://dx.doi.org/10.1093/cvr/cvaa186DOI Listing
August 2020

Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial.

JAMA 2020 08;324(8):761-771

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.

Importance: After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown.

Objective: To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 LOF carriers after PCI.

Design, Setting, And Participants: Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019.

Interventions: Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping. CYP2C19 LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months.

Main Outcomes And Measures: The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with CYP2C19 LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50.

Results: Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with CYP2C19 LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903 CYP2C19 LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02]; P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51]; P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07]; P = .16).

Conclusions And Relevance: Among CYP2C19 LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months.

Trial Registration: ClinicalTrials.gov Identifier: NCT01742117.
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http://dx.doi.org/10.1001/jama.2020.12443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448831PMC
August 2020

Drug-Coated Stents Versus Bare-Metal Stents in Academic Research Consortium-Defined High Bleeding Risk Patients.

EuroIntervention 2020 Aug 25. Epub 2020 Aug 25.

Duke Clinical Research Institute, Durham, NC, USA.

Aims: To model the safety and effectiveness of drug-coated stents (DCS) vs. bare-metal stents (BMS) in high bleeding risk (HBR) patients according to the Academic Research Criteria (ARC) criteria.

Methods And Results: Participants from the LEADERS FREE (LF) and LEADERS FREE (LFII) studies were pooled into one dataset. Participants were treated with 30 days of DAPT. The primary safety (composite of cardiac death, myocardial infarction, or stent thrombosis) and effectiveness (target-lesion revascularization) endpoints were compared between DCS and BMS in the subgroup of patients satisfying the ARC-HBR definition using propensity-score modelling. From the 3,635 participants included in the combined LF & LFII dataset, 2,898 (79.7%) satisfied the ARC-HBR criteria (DCS: 1,923; BMS: 975). The primary safety endpoint occurred in 184 (9.8%) and in 132 (13.8%) participants in the DCS and BMS groups, respectively (adjusted HR: 0.72; 95% CI: 0.57-0.91; p=0.006). The risk of the primary effectiveness endpoint was also significantly lower with DCS (6.2%) vs. BMS (8.8%) (adjusted HR: 0.70; 95% CI: 0.52-0.94; p=0.016). Safety and effectiveness of DCS vs. BMS were consistent according to ARC-HBR status (p interaction = 0.206 and 0.260, respectively).

Conclusions: DCS are safer and more effective than BMS in an ARC-defined HBR population.
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http://dx.doi.org/10.4244/EIJ-D-20-00749DOI Listing
August 2020

Immediate vs Delayed Stenting in ST-Elevation Myocardial Infarction: Rationale and Design of the International PRIMACY Bayesian Randomized Controlled Trial.

Can J Cardiol 2020 11 25;36(11):1805-1814. Epub 2020 Jan 25.

Hospital of Annecy, Centre Hospitalier Annecy Genevois, Annecy, France.

Background: Primary percutaneous coronary intervention is used to restore blood flow in the infarct-related coronary artery, followed by immediate stenting to prevent reocclusion. Stents implanted in thrombus-laden arteries cause distal embolization, which paradoxically impairs myocardial reperfusion and ventricular function. Whether a strategy of delayed stenting improves outcomes in patients with acute ST-elevation myocardial infarction (STEMI) is uncertain.

Methods: The Primary Reperfusion Secondary Stenting (PRIMACY) is a Bayesian prospective, randomized, open-label, blinded end point trial in which delayed vs immediate stenting in patients with STEMI were compared for prevention of cardiovascular death, nonfatal myocardial infarction, heart failure, or unplanned target vessel revascularization at 9 months. All participants were immediately reperfused, but those assigned to the delayed arm underwent stenting after an interval of 24 to 48 hours. This interval was bridged with antithrombin therapy to reduce thrombus burden. In the principal Bayesian hierarchical random effects analysis, data from exchangeable trials will be combined into a study prior and updated with PRIMACY into a posterior probability of efficacy.

Results: A total of 305 participants were randomized across 15 centres in France and Canada between April 2014 and September 2017. At baseline, the median age of participants was 59 years, 81% were male, and 3% had a history of percutaneous coronary intervention. Results from PRIMACY will be updated from the patient-level data of 1568 participants enrolled in the Deferred Stent Trial in STEMI (DEFER; United Kingdom), Minimalist Immediate Mechanical Intervention (MIMI; France), Danish Trial in Acute Myocardial Infarction-3 (DANAMI-3; Denmark), and Impact of Immediate Stent Implantation Versus Deferred Stent Implantation on Infarct Size and Microvascular Perfusion in Patients With ST Segment-Elevation Myocardial Infarction (INNOVATION, South Korea) trials.

Conclusions: We expect to clarify whether delayed stenting can safely reduce the occurrence of adverse cardiovascular end points compared with immediate stenting in patients with STEMI.
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http://dx.doi.org/10.1016/j.cjca.2020.01.019DOI Listing
November 2020

A Critical Comparison of Canadian and International Guidelines Recommendations for Antiplatelet Therapy in Coronary Artery Disease.

Can J Cardiol 2020 08 16;36(8):1298-1307. Epub 2019 Dec 16.

Montreal Heart Institute, Department of Medicine, Université de Montréal, Montréal, Québec, Canada. Electronic address:

Antiplatelet therapy for patients with coronary artery disease has evolved dramatically over the last decade. P2Y12 inhibitors offering more potent and consistent platelet inhibition than clopidogrel are now widely available, dual antiplatelet therapy (DAPT) duration can be tailored to individual ischemic and bleeding risks, and strategies to personalize antiplatelet therapy have been developed when concomitant oral anticoagulation (OAC) is indicated. Scientific societies from Canada, the United States, and Europe have all published updated recommendations addressing antiplatelet therapy in the recent years. The purpose of this review is to put the Canadian guidelines into perspective vis-à-vis international recommendations by highlighting similarities and critically analyzing differences. We focus on 3 major topics relevant for clinical practice: DAPT duration following drug-eluting stent implantation, DAPT following percutaneous coronary intervention in patients with concomitant indications for OAC, and DAPT management for noncardiac surgery following drug-eluting stent implantation. Although guidelines broadly agree on the majority of recommendations, the justifications for major differences were contrasted in the manuscript. Unanswered questions remain, including the place of aspirin in secondary prevention of coronary artery disease in the contemporary era, aspirin-free strategies early after percutaneous coronary intervention, and the safe minimal duration of DAPT with newer generation stents.
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http://dx.doi.org/10.1016/j.cjca.2019.12.013DOI Listing
August 2020

Meta-analysis Comparing Outcomes of Type 2 Myocardial Infarction and Type 1 Myocardial Infarction With a Focus on Dual Antiplatelet Therapy.

CJC Open 2020 May 24;2(3):118-128. Epub 2020 Feb 24.

Division of Cardiology, McGill Health University Center, McGill University, Montreal, Quebec, Canada.

Background: There are important knowledge gaps in type 2 myocardial infarction (T2MI). Our primary objective was to compare the outcomes of patients with T2MI with those of patients with type 1 myocardial infarction (T1MI). Our secondary objective was to determine whether randomized controlled trials (RCTs) evaluating dual antiplatelets (DAPTs) have explicitly included patients with T2MI.

Methods: We performed a meta-analysis comparing outcomes of patients with T2MI with patients with T1MI and a separate systematic review to evaluate the inclusion of T2MI in RCTs evaluating DAPT. There were 19 cohorts enrolling 48,829 patients (40,604 with T1MI and 5361 with T2MI) and 51 RCTs enrolling 188,132 patients with acute coronary syndrome.

Results: Patients with T2MI had approximately 2-fold increases in unadjusted odds of long-term mortality compared with patients with T1MI (odds ratio, 2.47; 95% confidence interval, 2.06-2.96; 0.0001) and a 45% increase in adjusted odds of long-term mortality (odds ratio, 1.45; 95% confidence interval, 1.25-1.69; 0.0001, respectively). There was no published evaluation of efficacy, effectiveness, and safety of DAPT in patients with T2MI.

Conclusion: Patients with T2MI are at increased risk of adjusted all-cause long-term mortality compared with patients with T1MI. The role of DAPT remains unclear in T2MI.
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http://dx.doi.org/10.1016/j.cjco.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242509PMC
May 2020

Global Approach to High Bleeding Risk Patients With Polymer-Free Drug-Coated Coronary Stents: The LF II Study.

Circ Cardiovasc Interv 2020 04 13;13(4):e008603. Epub 2020 Apr 13.

Columbia University Medical Center/New York-Presbyterian Hospital (M.B.L.).

Background: High bleeding risk (HBR) patients undergoing percutaneous coronary intervention have been widely excluded from randomized device registration trials. The LF study (LEADERS FREE) reported superior outcomes of HBR patients receiving 30-day dual antiplatelet therapy after percutaneous coronary intervention with a polymer-free drug-coated stent (DCS). LFII was designed to assess the reproducibility and generalizability of the benefits of DCS observed in LF to inform the US Food and Drug Administration in a device registration decision.

Methods: LFII was a single-arm study using HBR inclusion/exclusion criteria and 30-day dual antiplatelet therapy after percutaneous coronary intervention with DCS, identical to LF. The 365-day rates of the primary effectiveness (clinically indicated target lesion revascularization) and safety (composite cardiac death and myocardial infarction) end points were reported using a propensity-stratified analysis compared with the LF bare metal stent arm patients as controls.

Results: A total of 1203 LFII patients were enrolled with an average 1.7 HBR criteria per patient, including 60.7% >75 years of age, 34.1% on anticoagulants, and 14.7% with renal failure. Propensity-adjusted 365-day clinically indicated target lesion revascularization was significantly lower with DCS (7.2% versus 9.2%; hazard ratio, 0.72 [95% CI, 0.52-0.98]; =0.0338 for superiority), as was the primary safety (cardiac death and myocardial infarction) composite (9.3% versus 12.4%; hazard ratio, 0.72 [95% CI, 0.55-0.94]; =0.0150 for superiority). Stent thrombosis rates were 2.0% DCS and 2.2% bare metal stent. Major bleeding at 1 year occurred in 7.2% DCS patients and 7.2% bare metal stent.

Conclusions: LFII reproduces the results of the DCS arm of LF in an independent, predominantly North American cohort of HBR patients.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008603DOI Listing
April 2020

Ticagrelor with or without Aspirin after PCI.

N Engl J Med 2020 03;382(11):1076

Montreal Heart Institute, Montreal, QC, Canada

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http://dx.doi.org/10.1056/NEJMc1917041DOI Listing
March 2020

Targeted Temperature Management After Cardiac Arrest: The Montreal Heart Institute Experience.

CJC Open 2019 Sep 22;1(5):238-244. Epub 2019 Aug 22.

Department of Medicine, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada.

Background: Targeted temperature management (TTM) has been associated with an improvement in neurological function and survival in patients with cardiac arrest (CA) and an initially shockable rhythm. We report the Montreal Heart Institute (MHI) experience using TTM to evaluate mortality and neurological outcome in patients remaining in coma after CA, regardless of the initial rhythm.

Methods: We performed a retrospective review of all patients receiving TTM at the MHI between 2008 and 2015. Primary outcome was a composite of mortality and poor neurological outcome at hospital discharge. We also evaluated the long-term outcomes of those who initially survived to hospital discharge.

Results: A total of 147 patients (120 men, mean age 59.5 ± 12.5 years) underwent TTM at the MHI during the study period. Overall survival to hospital discharge with good neurological outcome was 45.6%. Shockable rhythm was associated with a better outcome (mortality odds ratio, 0.212; 95% confidence interval, 0.068-0.664;  = 0.008). Of the 11 initial survivors with a poor neurological status (Cerebral Performance Category ≥ 3), 4 died rapidly (within 1 month of hospital discharge), but 6 (54.5%) markedly improved their neurological status to Cerebral Performance Category 1. Long-term survival (mean follow-up of 38 ± 26 months) for those alive at hospital discharge (n = 76 patients) was 81.9%.

Conclusion: Our retrospective analysis of CA survivors treated with TTM at MHI showed good survival, similar to the published results from the landmark randomized controlled trials, despite enrolling patients with nonshockable rhythms. A significant proportion of survivors with poor neurological outcome at discharge improved at follow-up.
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http://dx.doi.org/10.1016/j.cjco.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063633PMC
September 2019

Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes.

Eur Heart J 2020 09;41(33):3132-3140

Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA.

Aims: To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS).

Methods And Results: In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4-11%).

Conclusions: Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.
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http://dx.doi.org/10.1093/eurheartj/ehz807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556746PMC
September 2020

Head-to-Head Comparison of Consensus-Recommended Platelet Function Tests to Assess P2Y Inhibition-Insights for Multi-Center Trials.

J Clin Med 2020 Jan 24;9(2). Epub 2020 Jan 24.

Montreal Heart Institute Research Center, Montréal, QC H1T 1C8, Canada.

The vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation level is a highly specific method to assess P2Y12 receptor inhibition. Traditionally, VASP phosphorylation is analyzed by flow cytometry, which is laborious and restricted to specialized laboratories. Recently, a simple ELISA kit has been commercialized. The primary objective of this study was to compare the performance of VASP assessment by ELISA and flow cytometry in relation to functional platelet aggregation testing by Multiplate whole-blood aggregometry. Blood from 24 healthy volunteers was incubated with increasing concentration of a P2Y12 receptor inhibitor (AR-C 66096). Platelet function testing was carried out simultaneously by Multiplate aggregometry and by VASP assessment through ELISA and flow cytometry. As expected, increasing concentrations of the P2Y12 receptor inhibitor induced a proportional inhibition of platelet aggregation and P2Y12 receptor activation across the modalities. Platelet reactivity index values of both ELISA- and flow cytometry-based VASP assessment methods correlated strongly ( = 0.87, < 0.0001) and showed minimal bias (1.05%). Correlation with Multiplate was slightly higher for the flow cytometry-based VASP assay ( = 0.79, < 0.0001) than for the ELISA-based assay ( = 0.69, < 0.0001). Intraclass correlation (ICC) was moderate for all the assays tested (ICC between 0.62 and 0.84). However, categorization into low, optimal, or high platelet reactivity based on these assays was strongly concordant (κ between 0.86 and 0.92). In conclusion, the consensus-recommended assays with their standardized cut-offs should not be used interchangeably in multi-center clinical studies but, rather, they should be standardized throughout sites.
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http://dx.doi.org/10.3390/jcm9020332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073745PMC
January 2020

Timing of Staged Nonculprit Artery Revascularization in Patients With ST-Segment Elevation Myocardial Infarction: COMPLETE Trial.

J Am Coll Cardiol 2019 12;74(22):2713-2723

Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. Electronic address:

Background: The COMPLETE (Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI) trial demonstrated that staged nonculprit lesion percutaneous coronary intervention (PCI) reduced major cardiovascular (CV) events in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (CAD).

Objectives: The purpose of this study was to determine the effect of nonculprit-lesion PCI timing on major CV outcomes and also the time course of the benefit of complete revascularization.

Methods: Following culprit-lesion PCI, 4,041 patients with STEMI and multivessel CAD were randomized to staged nonculprit-lesion PCI or culprit-lesion only PCI. Randomization was stratified according to investigator-planned timing of nonculprit-lesion PCI: during or after the index hospitalization. The first coprimary outcome was the composite of CV death or myocardial infarction (MI). In pre-specified analyses, hazard ratios (HRs) were calculated for each time stratum. Landmark analyses of the entire population were performed within 45 days and after 45 days.

Results: For nonculprit-lesion PCI planned during the index hospitalization (actual time: median 1 day), CV death or MI was reduced with complete revascularization compared with culprit-lesion only PCI (HR: 0.77; 95% confidence interval [CI]: 0.59 to 1.00). For nonculprit lesion PCI planned to occur after hospital discharge (actual time: median 23 days), CV death or MI was also reduced with complete revascularization (HR: 0.69; 95% CI: 0.49 to 0.97; interaction p = 0.62). Landmark analyses demonstrated an HR of 0.86 (95% CI: 0.59 to 1.24) during the first 45 days and 0.69 (95% CI: 0.54 to 0.89) from 45 days to the end of follow-up for intended nonculprit lesion PCI versus culprit lesion only PCI.

Conclusions: Among STEMI patients with multivessel disease, the benefit of complete revascularization over culprit-lesion only PCI was consistent irrespective of the investigator-determined timing of nonculprit-lesion intervention. The benefit of complete revascularization on hard clinical outcomes emerged mainly over the long term.
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http://dx.doi.org/10.1016/j.jacc.2019.09.051DOI Listing
December 2019

Interruption of Dual Antiplatelet Therapy Within Six Months After Coronary Stents (from the Dual Antiplatelet Therapy Study).

Am J Cardiol 2019 12 26;124(12):1813-1820. Epub 2019 Sep 26.

Baim Institute for Clinical Research, Boston, Massachusetts; Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

The risk of major adverse cardiac and cerebrovascular events (MACCE) in subjects who interrupt temporarily or permanently thienopyridine therapy in the first 6 months after percutaneous coronary intervention (PCI) remains uncertain. In the dual antiplatelet therapy (DAPT) study subjects were enrolled within 72 hours of PCI and treated with aspirin and a thienopyridine for 12 months before being randomized to continued thienopyridine versus placebo. This analysis focuses on the 12-month period before randomization. Thienopyridine interruptions of greater than 24 hours, occurring in the first 6 months after PCI were evaluated. The incidence of MACCE and moderate or severe bleeding occurring within 12 months after PCI were compared between subjects with and without interruptions. Among 23,002 subjects, the incidence of interruption of thienopyridine was 5.1% (n = 1,173). Compared with subjects who adhered to treatment, subjects with an interruption had a higher incidence of MACCE (6.1% vs 4.3%, p = 0.005), death (2.2% vs 1.4%, p = 0.02), myocardial infarction (3.8% vs 2.7%, p = 0.03), and bleeding (3.1% vs 2.2%, p = 0.04) at 12 months. After adjusting for baseline characteristics, interruptions were associated with MACCE (adjusted odds ratio 1.3, 95% confidence interval 1.0, 1.7, p = 0.04) and had a borderline association with subsequent bleeding (adjusted odds ratio 1.4, 95% confidence interval 1.0, 2.0, p = 0.05). In conclusion, interruption of thienopyridine in the first 6 months after PCI occurs not infrequently and is associated with an increased risk of MACCE and subsequent bleeding between the time of interruption and 12 months after PCI.
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http://dx.doi.org/10.1016/j.amjcard.2019.09.006DOI Listing
December 2019

Right Atrial Mechanisms of Atrial Fibrillation in a Rat Model of Right Heart Disease.

J Am Coll Cardiol 2019 09;74(10):1332-1347

Montreal Heart Institute (MHI), Department of Medicine, Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; IHU Liryc and Fondation Bordeaux Université, Bordeaux, France; Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany. Electronic address:

Background: Conditions affecting the right heart, including diseases of the lungs and pulmonary circulation, promote atrial fibrillation (AF), but the mechanisms are poorly understood.

Objectives: This study sought to determine whether right heart disease promotes atrial arrhythmogenesis in a rat model of pulmonary hypertension (PH) and, if so, to define the underlying mechanisms.

Methods: PH was induced in male Wistar rats with a single intraperitoneal injection of 60 mg/kg of monocrotaline, and rats were studied 21 days later when right heart disease was well developed. AF vulnerability was assessed in vivo and in situ, and mechanisms were defined by optical mapping, histochemistry, and biochemistry.

Results: Monocrotaline-treated rats developed increased right ventricular pressure and mass, along with right atrial (RA) enlargement. AF/flutter was inducible in 32 of 32 PH rats (100%) in vivo and 11 of 12 (92%) in situ, versus 2 of 32 (6%) and 2 of 12 (17%), respectively, in control rats (p < 0.001 vs. PH for each). PH rats had significant RA (16.1 ± 0.5% of cross-sectional area, vs. 3.0 ± 0.6% in control) and left atrial (LA: 11.8 ± 0.5% vs. 5.4 ± 0.8% control) fibrosis. Multiple extracellular matrix proteins, including collagen 1 and 3, fibronectin, and matrix metalloproteinases 2 and 9, were up-regulated in PH rat RA. Optical mapping revealed significant rate-dependent RA conduction slowing and rotor activity, including stable rotors in 4 of 11 PH rats, whereas no significant conduction slowing or rotor activity occurred in the LA of monocrotaline-treated rats. Transcriptomic analysis revealed differentially enriched genes related to hypertrophy, inflammation, and fibrosis in RA of monocrotaline-treated rats versus control. Biochemical results in PH rats were compared with those of AF-prone rats with atrial remodeling in the context of left ventricular dysfunction due to myocardial infarction: myocardial infarction rat LA shared molecular motifs with PH rat RA.

Conclusions: Right heart disease produces a substrate for AF maintenance due to RA re-entrant activity, with an underlying substrate prominently involving RA fibrosis and conduction abnormalities.
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http://dx.doi.org/10.1016/j.jacc.2019.06.066DOI Listing
September 2019

Isolating and expanding endothelial progenitor cells from peripheral blood on peptide-functionalized polystyrene surfaces.

Biotechnol Bioeng 2019 10 21;116(10):2598-2609. Epub 2019 Jul 21.

Department of Chemical Engineering, McGill University, Montréal, Quebec, Canada.

The expansion of human peripheral blood endothelial progenitor cells to obtain therapeutically relevant endothelial colony-forming cells (ECFCs) has been commonly performed on xeno-derived extracellular matrix proteins. For cellular therapy applications, xeno-free culture conditions are desirable to improve product safety and reduce process variability. We have previously described a novel fluorophore-tagged RGD peptide (RGD-TAMRA) that enhanced the adhesion of mature endothelial cells in vitro. To investigate whether this peptide can replace animal-derived extracellular matrix proteins in the isolation and expansion of ECFCs, peripheral blood mononuclear cells from 22 healthy adult donors were seeded on RGD-TAMRA-modified polystyrene culture surfaces. Endothelial colony formation was significantly enhanced on RGD-TAMRA-modified surfaces compared to the unmodified control. No phenotypic differences were detected between ECFCs obtained on RGD-TAMRA compared to ECFCs obtained on rat-tail collagen-coated surfaces. Compared with collagen-coated surfaces and unmodified surfaces, RGD-TAMRA surfaces promoted ECFC adhesion, cell spreading, and clonal expansion. This study presents a platform that allows for a comprehensive in vitro evaluation of peptide-based biofunctionalization as a promising avenue for ex vivo ECFC expansion.
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http://dx.doi.org/10.1002/bit.27107DOI Listing
October 2019

A web-based tailored nursing intervention (TAVIE en m@rche) aimed at increasing walking after an acute coronary syndrome: Multicentre randomized trial.

J Adv Nurs 2019 Nov 7;75(11):2727-2741. Epub 2019 Aug 7.

Montreal Health Innovations Coordinating Center, Montréal, Quebec, Canada.

Aim: Evaluate a web-based tailored nursing intervention, TAVIE en m@rche, on increasing daily steps after an acute coronary syndrome.

Design: Parallel two-group multicentre randomized trial.

Methods: An experimental group receiving TAVIE en m@rche, was compared to  a control group receiving hyperlinks to public websites. Acute coronary syndrome patients who were insufficiently active were recruited from three coronary care units. Daily steps at 12 weeks were the primary outcome. Secondary outcomes included self-reported walking and moderate to vigorous physical activity (MVPA). Exploratory outcomes were angina frequency, emergency department visits, hospitalizations and secondary prevention programme attendance.

Results: Primary data were analysed for 39 participants. No significant effects were found. At 12 weeks 275.9 more daily steps and 1,464.3 more energy expenditure in MVPA were found in the experimental group relative to the control. No effects were found for angina frequency, emergency department visits, hospitalizations and secondary prevention programme attendance.

Conclusion: The lack of effect on our primary result may be explained by the intervention goal that was mismatched to the needs of our mostly sufficiently active sample at randomization, resulting in no meaningful change in daily steps. Although the non-significantly greater increase in self-reported MVPA may represent gains in health among the participants that accessed TAVIE en m@rche, this result should be interpreted with caution.

Impact: From 40%-60% of acute coronary syndrome patients self-report insufficient levels of physical activity. No effect was found on the primary outcome of daily steps. Although not significant, a greater increase in MVPA was found at 12 weeks. The primary outcome can be explained by most of the sample having attained the physical activity recommendation at randomization. Caution in interpreting the non-significant increase in MVPA is warranted due to attrition bias and statistical uncertainty. Future directions may consider the timing of randomization in relation to meeting the needs of insufficiently active acute coronary syndrome patients.
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http://dx.doi.org/10.1111/jan.14119DOI Listing
November 2019

Interval From Initiation of Prasugrel to Coronary Angiography in Patients With Non-ST-Segment Elevation Myocardial Infarction.

J Am Coll Cardiol 2019 03;73(8):906-914

Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland.

Background: In the ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial, the prasugrel pre-treatment strategy versus placebo was associated with excess bleeding complications and no improved ischemic outcome in non-ST-segment elevation myocardial infarction (MI). Whether patients with the longest pre-treatment duration had an ischemic benefit is unknown.

Objectives: This pre-specified analysis of the ACCOAST trial aimed to assess the effect of pre-treatment duration with prasugrel (time from randomization to angiography) on outcomes.

Methods: Within the 4,033 patients randomized in the ACCOAST trial, pre-treatment duration was available in 4,001 patients (99.2%). The population of the trial was divided into quartiles of pre-treatment duration (0.1 to 2.5 h, 2.5 to 3.9 h, 3.9 to 13.6 h, and >13.6 h) with an evaluation of the primary efficacy endpoint of cardiovascular death, MI, stroke, urgent revascularization or glycoprotein IIb/IIIa inhibitor bailout use. Secondary efficacy outcomes including cardiovascular death, MI, or stroke; all-cause death; stent thrombosis and safety outcomes (all coronary artery bypass graft [CABG] or non-CABG TIMI [Thrombolysis In Myocardial Infarction] major bleeding) were also evaluated at 7 days.

Results: The primary efficacy outcome of cardiovascular death, MI, stroke, urgent revascularization or glycoprotein IIb/IIIa inhibitor bailout use did not differ between the quartiles of pre-treatment duration in the trial population (p = 0.17 for interaction). None of the secondary efficacy outcomes were found to be dependent on pre-treatment duration. The safety outcome of all CABG or non-CABG TIMI major bleeding did not differ between the quartiles of pre-treatment duration (p = 0.37 for interaction).

Conclusions: In non-ST-segment elevation MI patients, the excess risk of bleeding and the absence of ischemic benefit were consistent across the quartiles of increasing duration of prasugrel pre-treatment. (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction [ACCOAST]; NCT01015287).
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http://dx.doi.org/10.1016/j.jacc.2018.11.055DOI Listing
March 2019

2019 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Guidelines on the Acute Management of ST-Elevation Myocardial Infarction: Focused Update on Regionalization and Reperfusion.

Can J Cardiol 2019 02;35(2):107-132

Southlake Regional Health Centre, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Rapid reperfusion of the infarct-related artery is the cornerstone of therapy for the management of acute ST-elevation myocardial infarction (STEMI). Canada's geography presents unique challenges for timely delivery of reperfusion therapy for STEMI patients. The Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology STEMI guideline was developed to provide advice regarding the optimal acute management of STEMI patients irrespective of where they are initially identified: in the field, at a non-percutaneous coronary intervention-capable centre or at a percutaneous coronary intervention-capable centre. We had also planned to evaluate and incorporate sex and gender considerations in the development of our recommendations. Unfortunately, inadequate enrollment of women in randomized trials, lack of publication of main outcomes stratified according to sex, and lack of inclusion of gender as a study variable in the available literature limited the feasibility of such an approach. The Grading Recommendations, Assessment, Development, and Evaluation system was used to develop specific evidence-based recommendations for the early identification of STEMI patients, practical aspects of patient transport, regional reperfusion decision-making, adjunctive prehospital interventions (oxygen, opioids, antiplatelet therapy), and procedural aspects of mechanical reperfusion (access site, thrombectomy, antithrombotic therapy, extent of revascularization). Emphasis is placed on integrating these recommendations as part of an organized regional network of STEMI care and the development of appropriate reperfusion and transportation pathways for any given region. It is anticipated that these guidelines will serve as a practical template to develop systems of care capable of providing optimal treatment for a wide range of STEMI patients.
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http://dx.doi.org/10.1016/j.cjca.2018.11.031DOI Listing
February 2019

Management of Patients with Asymptomatic and Symptomatic Carotid Artery Disease: Update on Anti-Thrombotic Therapy.

Thromb Haemost 2019 Apr 31;119(4):576-585. Epub 2019 Jan 31.

I Clinica Medica, Atherothrombosis Centre, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

The most common causes of ischaemic stroke are represented by carotid artery atherosclerotic disease (CAAD) and atrial fibrillation. While oral anticoagulants substantially reduce the incidence of thromboembolic stroke (< 1%/year), the rate of ischaemic stroke and other cardiovascular disease events in patients with CAAD remains high, ranging from 8.4 to 18.1 events per 100 patient-years. Similar to any other atherosclerotic disease, anti-thrombotic therapies are proposed for CAAD to reduce stroke and other cardiovascular events. The 2017 European Society of Cardiology (ESC)/European Society for Vascular Surgery (ESVS) guidelines recommend for patients with asymptomatic CAAD ≥60% the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily at the exception of patient at very high bleeding risk. For patients with symptomatic CAAD ≥50%, the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily is recommended. New perspectives for anti-thrombotic therapy for the treatment of patients with CAAD come from the novel dual pathway strategy combining a low-dose anticoagulant (i.e. rivaroxaban) and aspirin that may help reduce long-term ischaemic complications in patients with CAAD. This review summarizes current evidence and recommendations for the anti-thrombotic management of patients with symptomatic or asymptomatic CAAD or those undergoing carotid revascularization.
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http://dx.doi.org/10.1055/s-0039-1678527DOI Listing
April 2019

Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A North American Perspective-2018 Update.

Circulation 2018 07;138(5):527-536

Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA (D.L.B., C.P.C., L.M., D.P.F.).

The optimal antithrombotic treatment regimen for patients with atrial fibrillation undergoing percutaneous coronary intervention with stent implantation represents a challenge in clinical practice. In 2016, an updated opinion of selected experts from the United States and Canada on the treatment of patients with atrial fibrillation undergoing percutaneous coronary intervention was reported. After the 2016 North American consensus statement on the management of antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention, results of pivotal clinical trials assessing the type of oral anticoagulant agent and the duration of antiplatelet treatment have been published. On the basis of these results, this focused update on the antithrombotic management of patients with atrial fibrillation undergoing percutaneous coronary intervention recommends that a non-vitamin K antagonist oral anticoagulant be preferred over a vitamin K antagonist as the oral anticoagulant of choice. Moreover, a double-therapy regimen (oral anticoagulant plus single antiplatelet therapy with a P2Y inhibitor) by the time of hospital discharge should be considered for most patients, whereas extending the use of aspirin beyond hospital discharge (ie, triple therapy) should be considered only for selected patients at high ischemic/thrombotic and low bleeding risks and for a limited period of time. The present document provides a focused updated on the rationale for the new expert consensus-derived recommendations on the antithrombotic management of patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034722DOI Listing
July 2018

Long-Term Survival Following Multivessel Revascularization in Patients With Diabetes: The FREEDOM Follow-On Study.

J Am Coll Cardiol 2019 02 11;73(6):629-638. Epub 2018 Nov 11.

Zena and Michael Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain. Electronic address:

Background: The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that for patients with diabetes mellitus (DM) and multivessel coronary disease (MVD), coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention with drug-eluting stents (PCI-DES) in reducing the rate of major adverse cardiovascular and cerebrovascular events after a median follow-up of 3.8 years. It is not known, however, whether CABG confers a survival benefit after an extended follow-up period.

Objectives: The purpose of this study was to evaluate the long-term survival of DM patients with MVD undergoing coronary revascularization in the FREEDOM trial.

Methods: The FREEDOM trial randomized 1,900 patients with DM and MVD to undergo either PCI with sirolimus-eluting or paclitaxel-eluting stents or CABG on a background of optimal medical therapy. After completion of the trial, enrolling centers and patients were invited to participate in the FREEDOM Follow-On study. Survival was evaluated using Kaplan-Meier analysis, and Cox proportional hazards models were used for subgroup and multivariate analyses.

Results: A total of 25 centers (of 140 original centers) agreed to participate in the FREEDOM Follow-On study and contributed a total of 943 patients (49.6% of the original cohort) with a median follow-up of 7.5 years (range 0 to 13.2 years). Of the 1,900 patients, there were 314 deaths during the entire follow-up period (204 deaths in the original trial and 110 deaths in the FREEDOM Follow-On). The all-cause mortality rate was significantly higher in the PCI-DES group than in the CABG group (24.3% [159 deaths] vs. 18.3% [112 deaths]; hazard ratio: 1.36; 95% confidence interval: 1.07 to 1.74; p = 0.01). Of the 943 patients with extended follow-up, the all-cause mortality rate was 23.7% (99 deaths) in the PCI-DES group and 18.7% (72 deaths) in the CABG group (hazard ratio: 1.32; 95% confidence interval: 0.97 to 1.78; p = 0.076).

Conclusions: In patients with DM and MVD, coronary revascularization with CABG leads to lower all-cause mortality than with PCI-DES in long-term follow-up. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450).
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http://dx.doi.org/10.1016/j.jacc.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839829PMC
February 2019

Clinical outcomes of bioresorbable vascular scaffold to treat all-comer patients. Are patients with acute coronary syndrome better candidates for bioresorbable vascular scaffold?

Cardiovasc Revasc Med 2019 03 4;20(3):228-234. Epub 2018 Jul 4.

Interventional Cardiology, Department of Medicine, Montreal Heart Institute, Université de Montréal, Montréal, QC, Canada. Electronic address:

Background: Scaffold thromboses (ST) and adverse events and have been associated with bioresorbable vascular scaffolds (BVS) at long-term, but their mechanism remains unclear. We sought to evaluate patient and lesion characteristics associated with mid- to long-term outcomes in patients treated with BVS.

Methods: This is an observational single-center, single-arm, retrospective study evaluating the performance of BVS in an all-comer population, including complex lesions (chronic total occlusions, long lesions), small vessels, and acute coronary syndromes (ACS).

Results: From May 2013 to June 2015, we included 482 patients (580 lesions) that were treated with BVS implantation including 71.2% treated for ACS in the present analysis. Mean follow-up period was 816.2 ± 242.6 days. The primary endpoint was device oriented cardiac events (DOCE), defined as a composite of target-lesion revascularization (TLR), ST, target vessel myocardial infarction (TVMI) and cardiac death. Using Kaplan-Meier methods, the DOCE and ST rates at 36 months were 9.4% and 2.3%, respectively. No ST occurred between 2 and 3 years and ST occurred after 3 years, in one patient. Using multivariate analysis, ACS was the only significant predictor of lower rates of DOCE (p = 0.04, HR: 0.47, 95% CI: 0.23-0.96).

Conclusions: In this large all-comers real-world cohort, lesions treated with BVS had non-negligible rates of DOCE and ST, in line with previous published randomized trials. The occurrence of very late event was very low after 24 months. ACS patients had lower rates of DOCE.
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http://dx.doi.org/10.1016/j.carrev.2018.06.022DOI Listing
March 2019

Simplifying the assessment of coronary artery stenosis by enhancing instantaneous wave free ratio.

Cardiovasc Diagn Ther 2018 Apr;8(2):156-163

Department of Cardiology, Montréal Heart Institute, Université de Montréal, Montréal, Canada.

Background: Instantaneous wave free ratio (iFR) does not require adenosine, but has a relatively wide intermediate range where functional assessment remains inconclusive. In this pilot study, we sought to enhance iFR through with the use of intracoronary (IC) saline (iFRs) and contrast media (iFRc) and determine whether these techniques correlated well with fractional flow reserve (FFR).

Methods: Patients with coronary artery stenosis (CAS) associated with an iFR in the intermediate zone (≥0.86 and ≤0.93) were prospectively assessed with resting distal coronary pressure/aorta pressure (Pd/Pa), iFR, iFRs, iFRc and FFR.

Results: A total of 40 coronary lesions were studied (40 patients). Pearson correlation coefficients for FFR and iFR, FFR and iFRs, FFR and iFRc were respectively: 0.57 (P=0.0002), 0.80 (P<0.0001) and 0.77 (P<0.0001). Receiver-operating characteristic (ROC) curve analysis showed similar area under the curve (AUC) of iFRs and iFR [0.90 (95% CI: 0.76-1) 0.89 (95% CI: 0.79-0.99), P=0.89]. Youden's index established cut-off values of ≤0.90 for iFR (sensitivity =91%, specificity =74%) and ≤0.78 for iFRs (sensitivity =73%, specificity =100%). In contrast, the AUC of iFRc was superior to the AUC of iFR [0.99 (95% CI: 0.98-1), P=0.049]. iFRc showed excellent accuracy and established cut-off values of ≤0.81 in predicting an FFR value of ≤0.80 (sensitivity =100%, specificity =93%).

Conclusions: When iFR is in the intermediate zone, functional assessment of CAS by iFR is enhanced with the use of contrast media but not saline. This pilot study could be hypothesis generating for further study to enhance iFR specificity and sensibility.
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http://dx.doi.org/10.21037/cdt.2017.12.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951993PMC
April 2018