Publications by authors named "Dominick J Angiolillo"

495 Publications

Evidence and Recommendations for Uninterrupted Versus Interrupted Oral Anticoagulation in Patients Undergoing Percutaneous Coronary Intervention.

JACC Cardiovasc Interv 2021 Apr;14(7):764-767

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

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http://dx.doi.org/10.1016/j.jcin.2021.02.019DOI Listing
April 2021

Antithrombotic Management of Elderly Patients With Coronary Artery Disease.

JACC Cardiovasc Interv 2021 Apr;14(7):723-738

Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, USA. Electronic address:

Antithrombotic therapy represents the mainstay of treatment in patients with coronary artery disease (CAD), including elderly patients who are at increased risk for ischemic recurrences. However, the elderly population is also more vulnerable to bleeding complications. Numerous mechanisms, including abnormalities in the vasculature, thrombogenicity, comorbidities, and altered drug response, contribute to both increased thrombotic and bleeding risk. Age-related organ changes and drug-drug interactions secondary to polypharmacy lead to distinct pharmacokinetic and pharmacodynamic profiles of antithrombotic drugs. Overall these factors contribute to the risk-benefit profiles of antithrombotic therapies in elderly subjects and underscore the need for treatment regimens that can reduce bleeding while preserving efficacy. Given that the prevalence of CAD, as well as concomitant diseases with thromboembolic potential, such as atrial fibrillation, increases with age and that the elderly population is in continuous growth, understanding the safety and efficacy of different antithrombotic regimens is pivotal for patient-centered care. In the present overview the authors appraise the available data on the use of antithrombotic therapy in older patients with CAD to assist with the management of this high-risk population and define knowledge gaps that can set the basis for future research.
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http://dx.doi.org/10.1016/j.jcin.2021.01.040DOI Listing
April 2021

Letter by Angiolillo et al Regarding Article, "Cangrelor, Tirofiban, and Chewed or Standard Prasugrel Regimens in Patients With ST-Segment-Elevation Myocardial Infarction: Primary Results of the FABOLUS FASTER Trial".

Circulation 2021 Mar 29;143(13):e795-e796. Epub 2021 Mar 29.

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, NY (G.W.S.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050205DOI Listing
March 2021

Antithrombotic therapy in diabetes: which, when, and for how long?

Eur Heart J 2021 Mar 25. Epub 2021 Mar 25.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.

Cardiovascular disease remains the main cause of mortality in individuals with diabetes mellitus (DM) and also results in significant morbidity. Premature and more aggressive atherosclerotic disease, coupled with an enhanced thrombotic environment, contributes to the high vascular risk in individuals with DM. This prothrombotic milieu is due to increased platelet activity together with impaired fibrinolysis secondary to quantitative and qualitative changes in coagulation factors. However, management strategies to reduce thrombosis risk remain largely similar in individuals with and without DM. The current review covers the latest in the field of antithrombotic management in DM. The role of primary vascular prevention is discussed together with options for secondary prevention following an ischaemic event in different clinical scenarios including coronary, cerebrovascular, and peripheral artery diseases. Antiplatelet therapy combinations as well as combination of antiplatelet and anticoagulant agents are examined in both the acute phase and long term, including management of individuals with sinus rhythm and those with atrial fibrillation. The difficulties in tailoring therapy according to the variable atherothrombotic risk in different individuals are emphasized, in addition to the varying risk within an individual secondary to DM duration, presence of complications and predisposition to bleeding events. This review provides the reader with an up-to-date guide for antithrombotic management of individuals with DM and highlights gaps in knowledge that represent areas for future research, aiming to improve clinical outcome in this high-risk population.
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http://dx.doi.org/10.1093/eurheartj/ehab128DOI Listing
March 2021

Impact of renal function in high bleeding risk patients undergoing percutaneous coronary intervention: a patient-level stratified analysis from four post-approval studies.

J Thromb Thrombolysis 2021 Mar 11. Epub 2021 Mar 11.

The Zena and Michael A. Wiener Cardiovascular Institute, Center for Interventional Cardiovascular Research and Clinical Trials, Icahn School of Medicine At Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY, 10029, USA.

Data on ischemic and bleeding outcomes after percutaneous coronary intervention (PCI) in high bleeding risk (HBR) patients with chronic kidney disease (CKD) are scarce. We aimed to evaluate the association between CKD and ischemic and bleeding outcomes in HBR patients who underwent PCI. Among 10,502 patients in the four post-approval registries evaluating patients undergoing PCI, 2,300 patients presented with at least one major or two minor ARC-HBR criteria. CKD was defined as eGFR < 60 mL/min/1.73 m. These HBR patients were divided into 3 groups: eGFR < 30 mL/min/1.73 m defined as severe CKD (N = 221), eGFR 30- < 60 mL/min/1.73 m defined as moderate CKD (N = 970), eGFR ≥ 60 mL/min/1.73 m defined as no CKD (N = 1,109). The primary endpoint was the composite of cardiac death, myocardial infarction, or stent thrombosis, and the safety endpoint was major bleeding up to 4-year follow-up. HBR patients with CKD were more often female and had higher rates of comorbidities compared to those without CKD. Reduced renal function was associated with higher rates of the primary endpoint (severe CKD vs. moderate CKD vs. no CKD: 30.2% vs. 12.5% vs. 9.1%, P < 0.01) as well as major bleeding (10.3% vs. 8.9% vs. 6.4%, P = 0.03). After adjustment, severe CKD and moderate CKD in HBR patients remained independent predictors for the primary endpoint (HR [95%CI] 2.84 [1.94-4.16], P < 0.01, 1.48 [1.10-2.00], P < 0.01) compared to those with no CKD. However, decreased renal function was no longer significantly associated with major bleeding after adjustment. In conclusions, in HBR patients undergoing PCI, CKD has an important impact on major ischemic events after PCI.
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http://dx.doi.org/10.1007/s11239-020-02321-2DOI Listing
March 2021

Aspirin for Primary Prevention of Cardiovascular Disease in the 21 Century: A Review of the Evidence.

Am J Cardiol 2021 04;144 Suppl 1:S15-S22

Division of Cardiology, A.O.U. "Policlinico-Vittorio Emanuele," University of Catania, Catania, Italy.

Aspirin (ASA) is the most commonly prescribed antiplatelet agent. Although the evidence for efficacy of aspirin for secondary prevention of ischemic events in patients with established cardiovascular disease is strong, its role in primary prevention has been subject of controversies over the past decades. In fact, historical trials have shown only modest benefit in terms of reduction of ischemic events, mostly myocardial infarction and to a lesser extent stroke, and only at the expense of an increased risk of bleeding. These observations have led to divergent recommendations from professional societies on the use of ASA for primary prevention of cardiovascular disease manifestations. However, recent results from three trials of primary prevention have shown either no benefit or modest benefit on combined ischemic end points, without any impact on hard cardiovascular events such as myocardial infarction or stroke, accompanied by an increased risk of bleeding. Overall, this translated into neutral net benefit or even harm with the use of aspirin in patients with no overt cardiovascular disease. These results have accordingly led to a downgrade in the current recommendations on the use of ASA for primary prevention. This article provides an overview on the current evidence on the use of aspirin for primary prevention of cardiovascular disease.
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http://dx.doi.org/10.1016/j.amjcard.2020.12.022DOI Listing
April 2021

Effects of D-allulose on glucose tolerance and insulin response to a standard oral sucrose load: results of a prospective, randomized, crossover study.

BMJ Open Diabetes Res Care 2021 Feb;9(1)

Department of Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA.

Introduction: Current dietary guidelines recommend limiting sugar intake for the prevention of diabetes mellitus (DM). Reduction in sugar intake may require sugar substitutes. Among these, D-allulose is a non-calorie rare monosaccharide with 70% sweetness of sucrose, which has shown anti-DM effects in Asian populations. However, there is limited data on the effects of D-allulose in other populations, including Westerners.

Research Design And Methods: This was a prospective, randomized, double-blind, placebo-controlled, crossover study conducted in 30 subjects without DM. Study participants were given a standard oral (50 g) sucrose load and randomized to placebo or escalating doses of D-allulose (2.5, 5.0, 7.5, 10.0 g). Subjects crossed-over to the alternate study treatment after 7-14 days of wash out. Plasma glucose and insulin levels were measured at five time points: before and at 30, 60, 90 and 120 min after ingestion.

Results: D-allulose was associated with a dose-dependent reduction of plasma glucose at 30 min compared with placebo. In particular, glucose was significantly lower with the 7.5 g (mean difference: 11; 95% CI 3 to 19; p=0.005) and 10 g (mean difference: 12; 95% CI 4 to 20; p=0.002) doses. Although glucose was not reduced at the other time points, there was a dose-dependent reduction in glucose excursion compared with placebo, which was significant with the 10 g dose (p=0.023). Accordingly, at 30 min D-allulose was associated with a trend towards lower insulin levels compared with placebo, which was significant with the 10 g dose (mean difference: 14; 95% CI 4 to 25; p=0.006). D-allulose did not reduce insulin at any other time point, but there was a significant dose-dependent reduction in insulin excursion compared with placebo (p=0.028), which was significant with the 10 g dose (p=0.002).

Conclusions: This is the largest study assessing the effects of D-allulose in Westerners demonstrating an early dose-dependent reduction in plasma glucose and insulin levels as well as decreased postprandial glucose and insulin excursion in subjects without DM. These pilot observations set the basis for large-scale investigations to support the anti-DM effects of D-allulose.

Trial Registration Number: NCT02714413.
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http://dx.doi.org/10.1136/bmjdrc-2020-001939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919569PMC
February 2021

Ticagrelor Monotherapy Versus Dual-Antiplatelet Therapy After PCI: An Individual Patient-Level Meta-Analysis.

JACC Cardiovasc Interv 2021 Feb;14(4):444-456

Applied Health Research Centre of the Li Ka Shing Knowledge Institute, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Objectives: The aim of this study was to compare ticagrelor monotherapy with dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stents.

Background: The role of abbreviated DAPT followed by an oral P2Y inhibitor after PCI remains uncertain.

Methods: Two randomized trials, including 14,628 patients undergoing PCI, comparing ticagrelor monotherapy with standard DAPT on centrally adjudicated endpoints were identified, and individual patient data were analyzed using 1-step fixed-effect models. The protocol was registered in PROSPERO (CRD42019143120). The primary outcomes were the composite of Bleeding Academic Research Consortium type 3 or 5 bleeding tested for superiority and, if met, the composite of all-cause death, myocardial infarction, or stroke at 1 year, tested for noninferiority against a margin of 1.25 on a hazard ratio (HR) scale.

Results: Bleeding Academic Research Consortium type 3 or 5 bleeding occurred in fewer patients with ticagrelor than DAPT (0.9% vs. 1.7%, respectively; HR: 0.56; 95% confidence interval [CI]: 0.41 to 0.75; p < 0.001). The composite of all-cause death, myocardial infarction, or stroke occurred in 231 patients (3.2%) with ticagrelor and in 254 patients (3.5%) with DAPT (HR: 0.92; 95% CI: 0.76 to 1.10; p < 0.001 for noninferiority). Ticagrelor was associated with lower risk for all-cause (HR: 0.71; 95% CI: 0.52 to 0.96; p = 0.027) and cardiovascular (HR: 0.68; 95% CI: 0.47 to 0.99; p = 0.044) mortality. Rates of myocardial infarction (2.01% vs. 2.05%; p = 0.88), stent thrombosis (0.29% vs. 0.38%; p = 0.32), and stroke (0.47% vs. 0.36%; p = 0.30) were similar.

Conclusions: Ticagrelor monotherapy was associated with a lower risk for major bleeding compared with standard DAPT, without a concomitant increase in ischemic events.
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http://dx.doi.org/10.1016/j.jcin.2020.11.046DOI Listing
February 2021

Use of the VerifyNow point of care assay to assess the pharmacodynamic effects of loading and maintenance dose regimens of prasugrel and ticagrelor.

J Thromb Thrombolysis 2021 Feb 13. Epub 2021 Feb 13.

University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA.

Prasugrel and ticagrelor are potent oral platelet P2Y inhibitors and are recommended over clopidogrel in patients with acute coronary syndrome (ACS). Oral platelet P2Y inhibitors are characterized by varying degrees of pharmacodynamic response profiles as assessed by a variety of commercially available assays. Because of its ease of use, rapid turnaround times and ability to provide results specific to P2Y inhibitory effects, VerifyNow has emerged as one of the most commonly utilized platelet function assays. However, reference ranges with VerifyNow have been reported mainly for clopidogrel and there has not yet been any study specifically conducted to provide the expected on treatment reference ranges following administration of prasugrel and ticagrelor. This was a prospective single center investigation conducted in 120 patients with ACS who were treated with prasugrel or ticagrelor as per standard of care. Patients who underwent percutaneous coronary interventions (PCI) were treated with a loading dose of prasugrel (60 mg) or ticagrelor (180 mg), and patients who were on maintenance therapy were taking prasugrel (10 mg qd or 5 mg qd) or ticagrelor (90 mg bid). Platelet function testing was performed using the VerifyNow™ PRUTest™. The overall range of PRUTest values was lower than that observed in studies of patients treated with clopidogrel. The use of a maintenance dose regimen had a wider range of PRUTest values compared to the use of a loading dose for both prasugrel (1-179 vs. 2-128) and ticagrelor (1-196 vs. 1-177). The average PRUTest values in patients on prasugrel and ticagrelor maintenance dosing were 20% and 9% higher those observed in patients treated with a loading dose. PRUTest results following loading dose administration were very similar between drugs, but were 20% higher with prasugrel compared with ticagrelor during maintenance dosing. This study establishes expected PRUTest ranges for patients taking loading and maintenance doses of prasugrel and ticagrelor.Clinical Trial Registration http://www.clinicaltrials.gov Unique Identifier: NCT04492423, registered July 2020 retrospectively registered.
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http://dx.doi.org/10.1007/s11239-021-02386-7DOI Listing
February 2021

Predictors, Type, and Impact of Bleeding on the Net Clinical Benefit of Long-Term Ticagrelor in Stable Patients With Prior Myocardial Infarction.

J Am Heart Assoc 2021 Feb 9;10(4):e017008. Epub 2021 Feb 9.

University of ColoradoSchool of Medicine Aurora CO.

Background Ticagrelor reduces ischemic risk but increases bleeding in patients with prior myocardial infarction. Identification of patients at lower bleeding risk is important in selecting patients who are likely to derive more favorable outcomes versus risk from this strategy. Methods and Results PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) randomized 21 162 patients with prior myocardial infarction in a 1:1:1 fashion to ticagrelor 60 mg or 90 mg twice daily or placebo, with ticagrelor 60 mg approved for long-term use. TIMI major or minor bleeding was the primary end point for this analysis. Causes of bleeding were categorized by site and etiology, and independent predictors were identified. At 3 years, ticagrelor 60 mg increased the rate of TIMI major or minor bleeding by 2.0% versus placebo (1.4% placebo versus 3.4% ticagrelor). The bleeding excess was driven primarily by spontaneous gastrointestinal bleeds. A history of spontaneous bleeding requiring hospitalization and the presence of anemia were independent predictors of bleeding but not of ischemic risk. Patients with at least 1 risk predictor had 3-fold higher rates of bleeding with ticagrelor 60 mg versus those who had neither (absolute risk increase, 4.4% versus 1.5%; =0.01). Patients with neither predictor had a more favorable benefit profile with ticagrelor 60 mg versus placebo including lower mortality (hazard ratio, 0.79; 95% CI, 0.65-0.96; interaction = 0.03). Conclusions In patients with prior myocardial infarction, bleeding with ticagrelor 60 mg twice daily is predominantly spontaneous gastrointestinal. A history of spontaneous bleeding requiring hospitalization or the presence of anemia identifies patients at higher risk of bleeding, and the absence of either identifies patients likely to have a more favorable net benefit with ticagrelor. Registration URL https://www.clinicaltrials.gov/. Unique identifier: NCT01225562.
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http://dx.doi.org/10.1161/JAHA.120.017008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955333PMC
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

Canakinumab for secondary prevention of coronary artery disease.

Future Cardiol 2021 Feb 3. Epub 2021 Feb 3.

Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL 32209, USA.

Cardiovascular disease manifestations (CVD) are the world's leading cause of death, and their impact on morbidity requires effective prevention strategies of recurrent adverse events. For decades, inflammation has been proposed as a key promoter for atherosclerosis and its complications. However, studies on the use of drugs to target the excess inflammation in CVD are limited. In 2017, the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial confirmed the key role of inflammation on atherosclerotic disease. Canakinumab is a monoclonal antibody that blocks an inflammatory pathway mediated by IL-1β. The results of the CANTOS trial opened a new era of investigating new therapeutics targeting inflammation for CVD secondary prevention. This review presents the canakinumab's pharmacology, current clinical development status and regulatory perspectives.
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http://dx.doi.org/10.2217/fca-2020-0211DOI Listing
February 2021

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

TH Open 2020 Oct 23;4(4):e437-e445. Epub 2020 Dec 23.

University of Florida College of Medicine, Jacksonville, Florida, United States.

 The aim of the study is to describe the real-world use of the P2Y 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).  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.  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.  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.
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http://dx.doi.org/10.1055/s-0040-1721504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758156PMC
October 2020

Effect of Prehospital Crushed Prasugrel Tablets in Patients With ST-Segment-Elevation Myocardial Infarction Planned for Primary Percutaneous Coronary Intervention: The Randomized COMPARE CRUSH Trial.

Circulation 2020 Dec 14;142(24):2316-2328. Epub 2020 Oct 14.

Maasstad Hospital, Rotterdam, The Netherlands (G.J.V., V.P., P.C.S.).

Background: Early treatment with a potent oral platelet P2Y inhibitor is recommended in patients presenting with ST-segment-elevation myocardial infarction scheduled to undergo primary percutaneous coronary intervention (pPCI). The impact on coronary reperfusion of crushed P2Y inhibitor tablets, which lead to more prompt and potent platelet inhibition, is unknown.

Methods: We conducted a randomized controlled, multicenter trial in the Netherlands, enrolling patients with ST-segment-elevation myocardial infarction scheduled to undergo pPCI. Patients were randomly allocated to receive in the ambulance, before transfer, a 60-mg loading dose of prasugrel either as crushed or integral tablets. The independent primary end points were thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at initial coronary angiography, and complete (≥70%) ST-segment resolution 1 hour after pPCI. The safety end points were TIMI major and Bleeding Academic Research Consortium ≥3 bleedings. Secondary end points included platelet reactivity and ischemic outcomes.

Results: A total of 727 patients were assigned to either crushed or integral tablets of prasugrel loading dose. The median time from study treatment to wire-crossing during pPCI was 57 (47-70) minutes. The primary end point TIMI 3 flow in the infarct-related artery before pPCI occurred in 31.0% in the crushed group versus 32.7% in the integral group (odds ratio, 0.92 [95% CI, 0.65-1.30], =0.64). Complete ST-segment resolution 1 hour after pPCI was present in 59.9% in the crushed group versus 57.3% in the integral group (odds ratio, 1.11 [95% CI, 0.78-1.58], =0.55). Platelet reactivity at the beginning of pPCI, measured as P2Y reactivity unit, differed significantly between groups (crushed, 192 [132-245] versus integral, 227 [184-254], ≤0.01). TIMI major and Bleeding Academic Research Consortium ≥3 bleeding occurred in 0% in the crushed group versus 0.8% in the integral group, and in 0.3% in the crushed group versus 1.1% in the integral group, respectively. There were no differences observed between groups regarding ischemic events at 30 days.

Conclusions: Prehospital administration of crushed prasugrel tablets does not improve TIMI 3 flow in the infarct-related artery before pPCI or complete ST-segment resolution 1 h after pPCI in patients presenting with ST-segment-elevation myocardial infarction scheduled for pPCI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03296540.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051532DOI Listing
December 2020

When Less Becomes More: Insights on the Pharmacodynamic Effects of Aspirin Withdrawal in Patients With Potent Platelet P2Y Inhibition Induced by Ticagrelor.

J Am Heart Assoc 2020 12 11;9(24):e019432. Epub 2020 Dec 11.

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

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http://dx.doi.org/10.1161/JAHA.120.019432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955356PMC
December 2020

Lipid Management in Patients Presenting With Acute Coronary Syndromes: A Review.

J Am Heart Assoc 2020 12 8;9(24):e018897. Epub 2020 Dec 8.

The Zena and Michael A. Wiener Cardiovascular Institute Icahn School of Medicine at Mount Sinai New York NY.

Despite many improvements in its prevention and management, acute coronary syndrome (ACS) remains a major cause of morbidity and mortality in the developed world. Lipid management is an important part of secondary prevention after ACS, but many patients currently remain undertreated and do not attain guideline-recommended levels of low-density lipoprotein cholesterol reduction. This review details the current state of evidence on lipid management in patients presenting with ACS, provides directions for identification of patients who may benefit from early escalation of lipid-lowering therapy, and discusses novel lipid-lowering medication that is currently under investigation in clinical trials. Moreover, a treatment algorithm aimed at attaining guideline-recommended low-density lipoprotein cholesterol levels is proposed. Despite important advances in the initial treatment and secondary prevention of ACS, ≈20% of ACS survivors experience a subsequent ischemic cardiovascular event within 24 months, and 5-year mortality ranges from 19% to 22%. Knowledge of the current state of evidence-based lipid management after ACS is of paramount importance to improve outcomes after ACS.
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http://dx.doi.org/10.1161/JAHA.120.018897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955383PMC
December 2020

Antiplatelet strategies in acute coronary syndromes: design and methodology of an international collaborative network meta-analysis of randomized controlled trials.

Minerva Cardioangiol 2020 Dec 1. Epub 2020 Dec 1.

Clinical Trials Center, Cardiovascular Research Foundation, New York, NY, USA -

Introduction: The optimal choice of oral P2Y12 receptor inhibitors has the potential to significantly influence outcomes. We seek to compare the safety and efficacy of the three most commonly used oral P2Y12 receptor inhibitors (clopidogrel, prasugrel, and ticagrelor) in acute coronary syndromes (ACS) via a comprehensive systematic review and network meta-analysis.

Evidence Acquisition: We will perform a comprehensive search for randomized clinical trials which compared cardiovascular and hemorrhagic outcomes after use of at least two of the distinct oral P2Y12 receptor inhibitors (i.e. clopidogrel, prasugrel, and ticagrelor). In addition, key inclusion criteria will be trial size of at least 100 patients and at least 1 month of follow-up time. Several pre-specified subgroups will be explored, including Asian patients, patients presenting with ST-elevation myocardial infarction, patients of advanced age, and others.

Evidence Synthesis: Exploratory frequentist pairwise meta-analyses will be based primarily on a random-effects method, relying on relative risks (RR) for short-term endpoints and incidence rate ratios (IRR) for long-term endpoints. Inferential frequentist network meta-analysis will be based primarily on a random-effects method, relying on RR and IRR as specified above. Results will be reported as point summary of effect, 95% CI, and p-values for effect, and graphically represented using forest plots.

Conclusions: An international collaborative network meta-analysis has begun to comprehensively analyze the safety and efficacy of prasugrel, ticagrelor and clopidogrel, each on a background of aspirin, for management of patients with ACS. It is our hope that the rigor and breadth of the undertaking described herein will provide novel insights that will inform optimal patient care for patients with ACS treated conservatively, or undergoing revascularization.
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http://dx.doi.org/10.23736/S0026-4725.20.05353-0DOI Listing
December 2020

Antithrombotic Therapy for Atherosclerotic Cardiovascular Disease Risk Mitigation in Patients With Coronary Artery Disease and Diabetes Mellitus.

Circulation 2020 Dec 30;142(22):2172-2188. Epub 2020 Nov 30.

Division of Cardiology, University of Florida College of Medicine, Jacksonville (D.J.A.).

Patients with diabetes mellitus (DM) are characterized by enhanced thrombotic risk attributed to multiple mechanisms including hyperreactive platelets, hypercoagulable status, and endothelial dysfunction. As such, they are more prone to atherosclerotic cardiovascular events than patients without DM, both before and after coronary artery disease (CAD) is established. In patients with DM without established CAD, primary prevention with aspirin is not routinely advocated because of its increased risk of major bleeding that largely offsets its ischemic benefit. In patients with DM with established CAD, secondary prevention with antiplatelet drugs is an asset of pharmacological strategies aimed at reducing the risk of atherosclerotic cardiovascular events and their adverse prognostic consequences. Such antithrombotic strategies include single antiplatelet therapy (eg, with aspirin or a P2Y inhibitor), dual antiplatelet therapy (eg, aspirin combined with a P2Y inhibitor), and dual-pathway inhibition (eg, aspirin combined with the vascular dose of the direct oral anticoagulant rivaroxaban) for patients with chronic ischemic heart disease, acute coronary syndromes, and those undergoing percutaneous coronary intervention. Because of their increased risk of thrombotic complications, patients with DM commonly achieve enhanced absolute benefit from more potent antithrombotic approaches compared with those without DM, which most often occurs at the expense of increased bleeding. Nevertheless, studies have shown that when excluding individuals at high risk for bleeding, the net clinical benefit favors the use of intensified long-term antithrombotic therapy in patients with DM and CAD. Several studies are ongoing to establish the role of novel antithrombotic strategies and drug formulations in maximizing the net benefit of antithrombotic therapy for patients with DM. The scope of this review article is to provide an overview of current and evolving antithrombotic strategies for primary and secondary prevention of atherosclerotic cardiovascular events in patients with CAD and DM.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045465DOI Listing
December 2020

Bridging the gap: Current and future insights for improving suboptimal platelet inhibition in STEMI.

Int J Cardiol 2021 Apr 23;328:40-45. Epub 2020 Nov 23.

Department of Cardiology, Isala, Zwolle, the Netherlands; Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands; Department of Cardiology, Zuyderland Medical Centre, Heerlen, the Netherlands.

Antiplatelet therapy is one of the cornerstones in the acute treatment of patients with ST-elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI). However, hemodynamic changes and delayed intestinal absorption of P2Y inhibitors leads to a delay in the onset of antiplatelet effects resulting in a gap of platelet inhibition. Several strategies have been proposed to bridge this gap, such as pre-hospital administration of antiplatelet therapy, higher loading doses of P2Y inhibitors, crushing or chewing tablets, subcutaneous or intravenous administration of platelet inhibitors, or use of pain relievers alternative to opioids that do not delay intestinal absorption of oral platelet inhibitors. These strategies may improve platelet inhibition with the goal of optimizing clinical outcomes in the acute phase of STEMI. In this review we present current and future insights for bridging the gap in platelet inhibition in STEMI patients undergoing primary PCI.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.042DOI Listing
April 2021

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

Trials 2020 Nov 24;21(1):966. Epub 2020 Nov 24.

Division of Cardiology, Azienda Sanitaria Ospedaliera Ordine Mauriziano, Torino, Italy.

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.
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http://dx.doi.org/10.1186/s13063-020-04859-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686679PMC
November 2020

Coronavirus Disease 2019-Associated Thrombosis and Coagulopathy: Review of the Pathophysiological Characteristics and Implications for Antithrombotic Management.

J Am Heart Assoc 2021 02 24;10(3):e019650. Epub 2020 Nov 24.

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

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2, which has posed a significant threat to global health. Although the infection is frequently asymptomatic or associated with mild symptoms, in a small proportion of patients it can produce an intense inflammatory and prothrombotic state that can lead to acute respiratory distress syndrome, multiple organ failure, and death. Angiotensin-converting enzyme 2, highly expressed in the respiratory system, has been identified as a functional receptor for severe acute respiratory syndrome coronavirus-2. Notably, angiotensin-converting enzyme 2 is also expressed in the cardiovascular system, and there are multiple cardiovascular implications of COVID-19. Cardiovascular risk factors and cardiovascular disease have been associated with severe manifestations and poor prognosis in patients with COVID-19. More important, patients with COVID-19 may have thrombotic and coagulation abnormalities, promoting a hypercoagulable state and resulting in an increased rate of thrombotic and thromboembolic events. This review will describe the pathophysiological characteristics of the cardiovascular involvement following infection by severe acute respiratory syndrome coronavirus-2, with a focus on thrombotic and thromboembolic manifestations and implications for antithrombotic management.
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http://dx.doi.org/10.1161/JAHA.120.019650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955431PMC
February 2021

Ticagrelor or Prasugrel in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes.

J Am Coll Cardiol 2020 11;76(21):2436-2446

Deutsches Herzzentrum München, Cardiology, and Technische Universität München, Munich, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.

Background: Current guidelines recommend intensified platelet inhibition by prasugrel or ticagrelor in patients with unstable angina (UA) or non-ST-segment elevation (NSTE) myocardial infarction (MI).

Objectives: This study sought to investigate the benefits and risks of ticagrelor as compared with prasugrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and planned invasive management.

Methods: This post hoc analysis combines the pre-specified subgroups of UA and NSTEMI of the randomized ISAR-REACT 5 trial. It included 1,179 patients assigned to ticagrelor and 1,186 assigned to prasugrel. Ticagrelor was started immediately after randomization and prasugrel after coronary angiography. The primary endpoint was a composite of death, MI, or stroke during 1-year follow-up, and the safety endpoint was Bleeding Academic Research Consortium class 3-5.

Results: The primary endpoint was reached in 101 (8.7%) patients in the ticagrelor and in 73 (6.3%) patients in the prasugrel group (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.04 to 1.90). The HR for all-cause death was 1.43 (95% CI: 0.93 to 2.21) and that for MI 1.43 (95% CI: 0.94 to 2.19). The safety endpoint occurred in 49 (5.2%) patients in the ticagrelor and in 41 (4.7%) patients in the prasugrel group (HR: 1.09; 95% CI: 0.72 to 1.65). Landmark analysis revealed persistence of the efficacy advantage with prasugrel after the first month.

Conclusions: In patients with NSTE-ACS, we found that prasugrel was superior to ticagrelor in reducing the combined 1-year risk of death, MI, and stroke without increasing the risk of bleeding. Due to the post hoc nature of the analysis, these findings need confirmation by further studies. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome; NCT01944800).
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http://dx.doi.org/10.1016/j.jacc.2020.09.584DOI Listing
November 2020

Safety and efficacy of P2Y inhibitor monotherapy in patients undergoing percutaneous coronary interventions.

Expert Opin Drug Saf 2021 Jan 30;20(1):9-21. Epub 2020 Nov 30.

Division of Cardiology, University of Florida College of Medicine , Jacksonville, Florida, United States.

: Antiplatelet therapy represents a key strategy for the prevention of thrombotic complications in patients with both acute and chronic coronary syndromes, particularly those undergoing percutaneous coronary intervention (PCI). Nevertheless, dual antiplatelet therapy (DAPT) is associated with a bleeding risk proportionate to its duration. Ever growing appreciation of the prognostic implications associated with bleeding and the development of safer stent platforms over the past years have led to a number of novel antiplatelet treatment strategies being tested among patients undergoing PCI. : P2Y inhibitor monotherapy after ashort course DAPT has emerged as ableeding reduction strategy to mitigate such risk while still preventing thrombotic complications. In this review we describe the latest evidence regarding the safety and efficacy of P2Y inhibitor monotherapy in patients undergoing PCI in different clinical settings. : P2Y inhibitor monotherapy after a brief period of DAPT has emerged as an effective approach to reduce the risk of bleeding without any tradeoff in efficacy (i.e., thrombotic complications). This strategy has shown consistent findings in a number of different clinical settings of patients undergoing PCI. Nevertheless, unanswered questions on the ideal patient and the precise P2Y monotherapy regimen warrant further investigation.
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http://dx.doi.org/10.1080/14740338.2021.1850691DOI Listing
January 2021

The East Asian Paradox: An Updated Position Statement on the Challenges to the Current Antithrombotic Strategy in Patients with Cardiovascular Disease.

Thromb Haemost 2021 Apr 10;121(4):422-432. Epub 2020 Nov 10.

Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, South Korea.

East Asian patients have reduced anti-ischemic benefits and increased bleeding risk during antithrombotic therapies compared with Caucasian patients. As potent P2Y receptor inhibitors (e.g., ticagrelor and prasugrel) and direct oral anticoagulants are commonly used in current daily practice, the unique risk-benefit trade-off in East Asians has been a topic of emerging interest. In this article, we propose updated evidence and future directions of antithrombotic treatment in East Asian patients.
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http://dx.doi.org/10.1055/s-0040-1718729DOI Listing
April 2021

Ticagrelor or Prasugrel in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Circulation 2020 Dec 29;142(24):2329-2337. Epub 2020 Oct 29.

German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Germany (I.B., D.S., K.L.L., H.B.S., M.J., H.S., S.S., A.K.).

Background: Data on the comparative efficacy and safety of ticagrelor versus prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention are limited. We assessed the efficacy and safety of ticagrelor versus prasugrel in a head-to-head comparison in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Methods: In this prespecified subgroup analysis, we included 1653 patients with ST-segment-elevation myocardial infarction randomized to receive ticagrelor or prasugrel in the setting of the ISAR REACT-5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5). The primary end point was the incidence of death, myocardial infarction, or stroke at 1 year after randomization. The secondary end point was the incidence of bleeding defined as BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 1 year after randomization.

Results: The primary end point occurred in 83 patients (10.1%) in the ticagrelor group and in 64 patients (7.9%) in the prasugrel group (hazard ratio, 1.31 [95% CI, 0.95-1.82]; =0.10). One-year incidence of all-cause death (4.9% versus 4.7%; =0.83), stroke (1.3% versus 1.0%; =0.46), and definite stent thrombosis (1.8% versus 1.0%; =0.15) did not differ significantly in patients assigned to ticagrelor or prasugrel. One-year incidence of myocardial infarction (5.3% versus 2.8%; hazard ratio, 1.95 [95% CI, 1.18-3.23]; =0.010) was higher with ticagrelor than with prasugrel. BARC type 3 to 5 bleeding occurred in 46 patients (6.1%) in the ticagrelor group and in 39 patients (5.1%) in the prasugrel group (hazard ratio, 1.22 [95% CI, 0.80-1.87]; =0.36).

Conclusions: In patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, there was no significant difference in the primary end point between prasugrel and ticagrelor. Ticagrelor was associated with a significant increase in the risk for recurrent myocardial infarction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01944800.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050244DOI Listing
December 2020

Ticagrelor monotherapy in patients with concomitant diabetes mellitus and chronic kidney disease: a post hoc analysis of the GLOBAL LEADERS trial.

Cardiovasc Diabetol 2020 10 16;19(1):179. Epub 2020 Oct 16.

Department of Cardiology, National University of Ireland Galway, Galway, Ireland.

Background: Patients with both diabetes mellitus (DM) and chronic kidney disease (CKD) are a subpopulation characterized by ultrahigh ischemic and bleeding risk after percutaneous coronary intervention. There are limited data on the impact of ticagrelor monotherapy among these patients.

Methods: In this post hoc analysis of the GLOBAL-LEADERS trial, the treatment effects of the experimental (one-month dual-antiplatelet therapy [DAPT] followed by 23-month ticagrelor monotherapy) versus the reference regimen (12-month DAPT followed by 12-month aspirin alone) were analyzed according to DM/CKD status. The primary endpoint was a composite endpoint of all-cause death or new Q-wave myocardial infarction at 2-years. The patient-oriented composite endpoint (POCE) was defined as the composite of all-cause death, any stroke, site-reported MI and any revascularization, whereas net adverse clinical events (NACE) combined POCE with BARC type 3 or 5 bleeding events.

Results: At 2 years, the DM + /CKD + patients had significantly higher incidences of the primary endpoint (9.5% versus 3.1%, adjusted HR 2.16; 95% CI [1.66-2.80], p < 0.001), BARC type 3 or 5 bleeding events, stroke, site-reported myocardial infraction, all revascularization, POCE, and NACE, compared with the DM-/CKD- patients. Among the DM + /CKD + patients, after adjustment, there were no significant differences in the primary endpoints between the experimental and reference regimen; however, the experimental regimen was associated with lower rates of POCE (20.6% versus 25.9%, HR 0.74; 95% CI [0.55-0.99], p = 0.043, p = 0.155) and NACE (22.7% versus 28.3%, HR 0.75; 95% CI [0.56-0.99], p = 0.044, p = 0.310), which was mainly driven by a lower rate of all revascularization, as compared with the reference regimen. The landmark analysis showed that while the experimental and reference regimen had similar rates of all the clinical endpoints during the first year, the experimental regimen was associated with significantly lower rates of POCE (5.8% versus 11.0%, HR 0.49; 95% CI [0.29-0.82], p = 0.007, p = 0.040) and NACE (5.8% versus 11.2%, HR 0.48; 95% CI [0.29-0.82], p = 0.007, p = 0.013) in the second year.

Conclusion: Among patients with both DM and CKD, ticagrelor monotherapy was not associated with lower rates of all-cause death or new Q-wave, or major bleeding complications; however, it was associated with lower rates of POCE and NACE. These findings should be interpreted as hypothesis-generating.

Clinical Trial Registration: ClinicalTrials.gov (NCT01813435).
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http://dx.doi.org/10.1186/s12933-020-01153-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568378PMC
October 2020