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Bivalirudin during Primary PCI in Acute Myocardial Infarction

Authors:
Gregg W Stone
Gregg W Stone
Gregg W Stone
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Bernhard Witzenbichler at HELIOS Kliniken
Bernhard Witzenbichler
Giulio Guagliumi
Giulio Guagliumi
Jan Zbigniew Peruga at Medical University of Łódź
Jan Zbigniew Peruga
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Abstract

Treatment with the direct thrombin inhibitor bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, results in similar suppression of ischemia while reducing hemorrhagic complications in patients with stable angina and non-ST-segment elevation acute coronary syndromes who are undergoing percutaneous coronary intervention (PCI). The safety and efficacy of bivalirudin in high-risk patients are unknown. We randomly assigned 3602 patients with ST-segment elevation myocardial infarction who presented within 12 hours after the onset of symptoms and who were undergoing primary PCI to treatment with heparin plus a glycoprotein IIb/IIIa inhibitor or to treatment with bivalirudin alone. The two primary end points of the study were major bleeding and combined adverse clinical events, defined as the combination of major bleeding or major adverse cardiovascular events, including death, reinfarction, target-vessel revascularization for ischemia, and stroke (hereinafter referred to as net adverse clinical events) within 30 days. Anticoagulation with bivalirudin alone, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in a reduced 30-day rate of net adverse clinical events (9.2% vs. 12.1%; relative risk, 0.76; 95% confidence interval [CI] 0.63 to 0.92; P=0.005), owing to a lower rate of major bleeding (4.9% vs. 8.3%; relative risk, 0.60; 95% CI, 0.46 to 0.77; P<0.001). There was an increased risk of acute stent thrombosis within 24 hours in the bivalirudin group, but no significant increase was present by 30 days. Treatment with bivalirudin alone, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in significantly lower 30-day rates of death from cardiac causes (1.8% vs. 2.9%; relative risk, 0.62; 95% CI, 0.40 to 0.95; P=0.03) and death from all causes (2.1% vs. 3.1%; relative risk, 0.66; 95% CI, 0.44 to 1.00; P=0.047). In patients with ST-segment elevation myocardial infarction who are undergoing primary PCI, anticoagulation with bivalirudin alone, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, results in significantly reduced 30-day rates of major bleeding and net adverse clinical events. (ClinicalTrials.gov number, NCT00433966 [ClinicalTrials.gov].).
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Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocar-
dial infarction. N Engl J Med 2008;358:2218-30.
Participating countries (with total enrollment), hospitals and principal investigators:
Argentina (total enrollment = 207): Fundación Favaloro, Capital Federal, Buenos Aires, Oscar
A Mendiz; Hospital Alemán, Buenos Aires, Jose Amadeo Alvarez; Hospital Britanico, Buenos
Aires, Jose Alvarez; Hospital Espanol de La Plata, La Plata, Buenos Aires, Diego David
Grinfeld; Hospital Gral. de Agudos Dr. Cosme Argerich, Capital Federal, Buenos Aires, Miguel
Angel Riccitelli; Hospital Italiano de Buenos Aires, Capital Federal, Buenos Aries, Daniel
Berrocal; Instituto Cardiovascular de Buenos Aires, Capital Federal, Buenos Aires, Jorge
Belardi; Instituto Cardiovascular de Rosario, Rosario, Santa Fe, Anibal Agustin Damonte;
Sanatorio Argentino de la Plata, La plata, Buenos Aires, Guillermo Cugat; Sanatorio Otamendi,
Buenos Aires, A. Rodriguez; Sanatorio Modelo Quilmes, Quilmes, Buenos Aires, Ernesto M.
Torresani; Sanatorio Allende, Cordoba, Hugo F. Londero; Austria (total enrollment = 143): AKH
Wien, Vienna, Dietmar Glogar; Wilhelminen Hospital, Vienna, Kurt Huber; Hanusch-
Krankenhaus, Vienna, George Gaul; St. Johanns-Spital, Landesklinik fur Innere Medizin II und
Kardiologie, Salzburg, Johann Altenberger; Universitätsklinik für Innere Medizin II, Innsbruk,
Othmar Pachinger; Germany (total enrollment = 791): Asklepios Klinik Langer, Langen, Hans-
Georg Olbrich; Charité Campus Benjamin Franklin, Berlin, Bernhard Witzenbichler;
Charite/CVK, Berlin, Martin Moeckel; Charité Universitätsmedizin Campus Mitte, Berlin,
Wolfgang Rutsch; Heart Center Siegburg, Siegburg, Eberhard Grube;Herzzentrum Segeberger
Kliniken GmbH, Bad Segeberg, Gert Richardt; Klinik Innere Medizin I Friedrich-Schiller-
University Jena, Jena, Klaus Pethig; Klinikum Dachau d. Amperkliniken AG Kardiologie,
Dachau, Martin Desaga; Klinikum Darmstadt Medizinisch Klinik I, Darmstadt, Gerald Werner;
Klinikum Coburg, Coburg, Johannes Brachmann; Universitätsklinikum Heidelberg / Kardiologie,
Heidelberg, Helmut Kuecherer; University Hospital Aachen, Aachen, Rainer Hoffmann;
Universitätsklinikum Schleswig-Holstein, Lübeck, Franz Hartmann; University Hospital
Eppendorf Department of Cardiology, Hamburg, Stefan Willems; University of Ulm Head
Interventional Cardiology Leiter Forschungsgruppe Interventionelle, Ulm, Jochen Wöhrle;
Silesian Medical Academy, Munich, Adnan Kastrati; Israel (total enrollment = 526): Assaf
Harofe Medical Center Catheterization Laboratory, Cardiology Department, Zrifin, Ricardo
Krakover; Bnei Zion Medical Center, Haifa, Uri Rosenschein; Carmel Medical Center, Haifa,
Basil S. Lewis; Hadassah Hebrew University Medical Center-Jerusalem, Jerusalem, Morris
Mosseri; Rabin Medical Center-Belinson Campus, Ran Petach-Tikva Kornowski; Rambam
Medical Center-Department of Radiology, Haifa, Luis Gruberg; Shaare Zedek Medical Center-
Jerusalem, Jerusalem, Yaron Almagor; Sheba Medical Center-Tel-Hashomer Heart Institute,
Ramat-Gan, Victor Guetta; Sourasky Medical Center-Tel Aviv Head Dept of Cardiology, Tel
Aviv, Ariel Finkelstein; Wolfson Holon, Holon, Yoseph Rozenman; Italy (total enrollment = 219):
Ospedali Riuniti di Bergamo, Bergamo, Giulio Guagliumi; Ospedale San Raffaele Milano U.O di
Emodinamica e di Cardiologia Interventistic, Milan, Antonio Colombo; Netherlands (total
enrollment = 133): Catharina Hospital Dept. R&D, Eindhoven, Hans Bonnier; Hospital De
Weezenlanden, Zwolle, Harry Suryapranata; Medisch Centrum Rijnmond-Zuid, Rotterdam,
Peter Smits; Norway (total enrollment = 79): Haukeland University Hospital, Department of
Heart Disease, Bergen, Jan Erik Nordrehaug; Stavanger University Hospital, Rogaland, Dennis
Nilsen; Poland (total enrollment = 582): Institute of Cardiology - Haemodynamics Dept,
Warsawa, Witold Ruzyllo, Adam Witkowski; Jagiellonian University, Krakow, Dariusz Dudek;
Medical University of Gdask, Gdask, Andrzej Rynkiewicz; Silesian Center for Heart Disease,
Lodz, Jan Z Peruga; Silesian Medical Academy, Katowice, Andrzej Ochala; Szpital Jana Pawla
II - Dept. of Hemo and Angio, Krakow, Krzysztof Zmudka; Klinika Kardiologii Inwazyjnej CSK
MSWiA, Warsaw, Robert Gil; Spain (total enrollment = 6): Hospital General Universitario de
Alicante, Alicante, Pascual Bordes; United Kingdom (total enrollment = 102): John Radcliffe
Hospital, Oxford, Adrian Banning; Leeds Teaching Hospital NHS Trust, Leeds, Daniel
Blackman; Manchester Heart Center, Manchester, Magdi El-Omar; Royal Sussex County
Hospital, Brighton, East Sussex, Adam De Belder; Northern General Hospital, Sheffield, Ever
Grech; Wythenshawe Hospital, Manchester, Bernard Prendergast; United States (total
enrollment = 814): Alexian Brothers Medical Center, Elk Grove Village, IL, Sarah Johnson;
Anderson Area Medical Center, Anderson SC, Brent McLaurin; Bakersfield Memorial Hospital,
Bakersfield, CA, Tommy, Lee; Beth Israel Deaconess Medical; Cardiovascular Division, Boston,
MA, Duane S Pinto; Bethesda North Hospital, Montgomery, OH, Joe Choo; Brotman Medical
Center, Culver City, CA, Ronald Karlsberg; Cannon Cardiac & Vascular Research Ctr. of
Northern Michigan, Petoskey, MI, Louis A. Cannon; Cardiovascular Medicine Associates,
Middleburg Heights, OH, Trilok Sharma; Christiana Care Health Services, Newark, DE, James
Ritter; Columbia University, New York, NY, Leroy Rabbani; Deaconess Medical Center,
Spokane, WA, Pierre P. Leimgruber; Doctors Hospital at Renaissance, Edinburg, TX, Ofsman
Quintana; Doylestown Hospital, Doylestown, PA, Joseph McGarvey, Jr; El Paso Heart Clinic, El
Paso, TX, Oscar Aguilar; Emory University School of Medicine Emory Crawford, Atlanta, GA,
Henry Liberman; Geisinger Medical Center, Danville, PA, Jim Blankenship; Good Samaritan
Hospital, Cincinnati, OH, Ali Razavi; Harrisburg Hospital/Pinnacle Health, Harrisburg, PA,
Rajesh Dave; Heart Care Midwest/St. Francis Medical Center, Peoria, IL, John Rashid; Heart
Care Research Foundation, Merrionette Park, IL, Joseph F. Stella; Innovis Health, South Fargo,
ND, Edmund Finkinski; Jersey Shore University Medical Center, Neptune, NJ, Matthew Bach;
LeBauer CV Research Foundation/Moses Cone Hospital, Greensboro, NC, Bruce Brodie; Maine
Medical Center, Portland, ME, Mirle A. Kellett, Jr.;McAllen Heart Hospital, McAllen, TX, Ofsman
Quintana; MedStar Research Institute, Cardiovascular Research, Washington, D.C. Ron
Waksman; Mid Carolina Cardiology/Presbyterian Hospital, Charlotte, NC, Robert Iwaoka; Mid
Ohio Heart Clinic, Inc., Mansfield, OH, Gregory M. Eaton; Northwest Indiana Cardiovascular
Physicians, Valparaiso, IN, Keith Atassi; NYU Medical Center, New York, NY, Michael Attubato;
Oklahoma Heart Institute, Tulsa, OK, Raj Chandwaney; Providence Heart and Vascular
Institute, Portland, OR, Bradley Evans; Providence Memorial Hospital , El Paso, TX, Oscar
Aguilar; Research Associates of Jackson, Jackson, TN, Henry Lui; Scottdale Healthcare –
Osborn, Scottsdale, AZ, David Rizik; Scottsdale Healthcare-Shea, Scottsdale, AZ, David Rizik;
Sentara Virginia Beach General Hospital, Virginia Beach, VA, John Griffin; Somerset Medical
Center, Bridgewater, NJ, Jason O. Hall; South Carolina Heart Center, Columbia, SC, Michael C.
Foster; Sparks Regional Medical Center, Fort Smith, AR, Jorge A. Hernandez; St. James
Hospital & Health Centers Chicago Heights, Chicago Heights, IL, Noel Camba; St. John
Hospital, Detroit, MI, Thomas LaLonde; St. Josephs Regional Medical Center, Paterson, NJ,
Mahesh, Bikkina; St. Luke's Hospital MAHI, Kansas City, MO, Barry Rutherford; Suncoast
Cardiovascular Research, Saint Petersburg, FL, Vibhuti Singh; Tennessee Cardiovascular
Research Institute, Nashville, TN, John McPherson; The Cardiovascular Specialists/Cape Cod
Hospital, Hyannis, MA, Richard B. Zelman; The Care Group Hospital: The Heart Center of
Indiana Clinical Laboratory / St. Vincent's Hospital, Indianapolis, Indiana, James B. Hermiller;
The Charlton Memorial Hospital, Fall River, MA, Kenneth S. Korr; The Heart
Center/Cardiovascular Associates, P.C., Kingsport, TN, Christopher Metzger; The Miriam
Hospital, Providence, RI, Paul Gordon; The Valley Hospital, Ridgewood, NJ, Cary Hirsch; The
Western Pennsylvania Hospital, Pittsburgh, PA, Venkatraman Srinivasan; Valley Baptist
Medical Center, Brownsville, TX, Kalim Habet; Washington Adventist Hospital, Takoma Park,
MD, Mark A. Turco; Watson Clinic Center for Research Inc., Lakeland, FL, Douglas Ebersole;
William Beaumont Hospital, Royal Oak, MI, Cindy L. Grines.
... Thrombolytic therapy should only be considered in patients in whom PCI cannot be performed within 2 hours of admission. A delay in opening the blocked artery can cause signi cant myocardial damage and increase the patient's mortality rate (7,8). A risk assessment in these patients is necessary to select the correct treatment and therefore to perform the correct procedure (9,10). ...
The Effect of Urea Nitrogen/Creatinin Ratio Level on in Hospital Mortality and One Year Mortality of Patients with ST Segment elevation Myocardial Infarction undergone thrombolytic therapy
Preprint
Full-text available
  • Nov 2023
Introduction & Objective: Considering the increasing prevalence of ST-elevation myocardial infarction (STE-MI) and its health care costs and clinical consequences, as well as the fact that kidney problems are among the most common cases in these patients, treatment system and the evaluation of its functional improvement will be considered, Therefore, in the present study, we intend to investigate the effect of blood urea nitrogen to creatinin ratio (BUN/Cr) on in-hospital mortality (IHM) and one-year mortality of patients diagnosed with STEMI undergoing thrombolytic treatment. Materials and Methods: This descriptive cross-sectional descriptive study was conducted in in Shahid Madani, University of Medical Science, Tabriz, Iran in 2021. A list of patients diagnosed with STEMI and received thrombolytic treatments in 2017- 2019 were compiled. The file was included in the study and analyzed taking into account the inclusion and exclusion criteria. A checklist was used to collect the data. Data were analyzed using SPSS-15 software and descriptive and inferential statistics. Results: The results of the present study showed that blood BUN/Cr tolevel had no association with IHM and one-year mortality of STEMI patients who underwent thrombolytic treatment. There was also no association between the BUN/Cr ratio and in-hospital complications such as heart failure (HF) and cardiogenic shock (CS). Conclusion: we found that BUN/Cr ratio is not a reliable prognostic factor for mortality and hospital complications in STEMI patients.
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Differential Use of Glycoprotein IIb/IIIa Inhibitors with Bivalirudin in Patients with STEMI Undergoing PCI: A Systematic Review and Meta-Analysis
Article
  • Apr 2024
  • AM J CARDIOVASC DRUG
The efficacy and safety of bivalirudin when used concurrently with glycoprotein IIb/IIIa inhibitors (GPI) is uncertain. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) and to explore the impact of differential use (greater and balanced) of GPI. Online databases were queried from inception to March 2023 to identify eight randomized controlled trials (n = 22,483) for inclusion. The primary outcomes included all-cause mortality, major bleeding, major adverse cardiovascular events (MACE), and net adverse clinical events (NACE). Secondary efficacy endpoints included cardiac death, reinfarction, stent thrombosis (ST), and stroke. Data were pooled using a random-effects model to derive risk ratios (RRs) and 95% confidence intervals (CIs). When compared to heparin, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.83; 95% CI 0.72–0.97; P = 0.02), major bleeding (RR 0.73; 95% CI 0.57–0.93; P = 0.01), cardiac death (RR 0.79; 95% CI 0.66–0.94; P = 0.01), and NACE (RR 0.80; 95% CI 0.72–0.89; P < 0.0001). However, while the bivalirudin arm showed an increased likelihood of ST in the greater GPI subgroup (RR 1.70; 95% CI 1.13–2.56; P = 0.01), it was associated with a decreased likelihood of ST in the balanced GPI subgroup (RR 0.40; 95% CI 0.24–0.65; P = 0.0003). Overall, our findings suggest that bivalirudin may be a more efficacious intervention than heparin for reducing certain adverse events in patients with STEMI undergoing primary PCI.
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Ticagrelor vs. Clopidogrel When Co-administered With Bivalirudin in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention
Article
Full-text available
  • Mar 2024
Background The optimal perioperative antithrombotic strategy for patients with acute coronary syndrome (ACS) during percutaneous coronary intervention (PCI) remains controversial. Objectives To determine the safety and effectiveness of bivalirudin plus ticagrelor vs bivalirudin plus clopidogrel in patients with ACS undergoing PCI in the real world. Methods Between March 2016 and March 2019, 7234 patients with ACS who had undergone PCI, received bivalirudin periprocedurally, and were prescribed ticagrelor or clopidogrel were enrolled in a single-center, all-comer, modern, retrospective cohort study. Incidence rates of 12-month ischemia (cardiac death, myocardial infarction, or stroke), all-cause death, Bleeding Academic Research Consortium (BARC) type 2,3,5 bleeding, and BARC type 3,5 bleeding were compared between different groups. Results In total, 4960 patients received bivalirudin plus clopidogrel and 2274 patients received bivalirudin plus ticagrelor. Compared with bivalirudin plus clopidogrel, bivalirudin plus ticagrelor was associated with lower ischemic events (1.74% vs 2.84%; relative risk, 0.61; 95% CI, 0.41-0.91; P = .02) and stroke (0.05% vs 1.01%, P < .001) within 12 months after PCI without excessive risk of bleeding (BARC type 2,3,5 bleeding: 4.49% vs 3.76%, P = .22; BARC type 3,5 bleeding: 2.84% vs 2.02%, P = .08). The beneficial effects of bivalirudin plus ticagrelor were consistent among subgroups. Conclusion As an initial treatment strategy, bivalirudin plus ticagrelor could reduce the 12-month risk of ischemic events compared with bivalirudin plus clopidogrel significantly without increasing the bleeding risk in ACS patients undergoing PCI.
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Postprocedural Anticoagulation After Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction: A Multicenter, Randomized, Double-Blind Trial
Article
  • Feb 2024
  • CIRCULATION
BACKGROUND Postprocedural anticoagulation (PPA) is frequently administered after primary percutaneous coronary intervention in ST-segment–elevation myocardial infarction, although no conclusive data support this practice. METHODS The RIGHT trial (Comparison of Anticoagulation Prolongation vs no Anticoagulation in STEMI Patients After Primary PCI) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled, superiority trial conducted at 53 centers in China. Patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention were randomly assigned by center to receive low-dose PPA or matching placebo for at least 48 hours. Before trial initiation, each center selected 1 of 3 PPA regimens (40 mg of enoxaparin once daily subcutaneously; 10 U·kg·h of unfractionated heparin intravenously, adjusted to maintain activated clotting time between 150 and 220 seconds; or 0.2 mg·kg·h of bivalirudin intravenously). The primary efficacy objective was to demonstrate superiority of PPA to reduce the primary efficacy end point of all-cause death, nonfatal myocardial infarction, nonfatal stroke, stent thrombosis (definite), or urgent revascularization (any vessel) within 30 days. The key secondary objective was to evaluate the effect of each specific anticoagulation regimen (enoxaparin, unfractionated heparin, or bivalirudin) on the primary efficacy end point. The primary safety end point was Bleeding Academic Research Consortium 3 to 5 bleeding at 30 days. RESULTS Between January 10, 2019, and September 18, 2021, a total of 2989 patients were randomized. The primary efficacy end point occurred in 37 patients (2.5%) in both the PPA and placebo groups (hazard ratio, 1.00 [95% CI, 0.63 to 1.57]). The incidence of Bleeding Academic Research Consortium 3 or 5 bleeding did not differ between the PPA and placebo groups (8 [0.5%] vs 11 [0.7%] patients; hazard ratio, 0.74 [95% CI, 0.30 to 1.83]). CONCLUSIONS Routine PPA after primary percutaneous coronary intervention was safe but did not reduce 30-day ischemic events. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03664180.
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An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting: STOPDAPT-3 Randomized Trial
Article
  • Nov 2023
BACKGROUND Bleeding rates on dual antiplatelet therapy (DAPT) within 1 month after percutaneous coronary intervention (PCI) remain high in clinical practice, particularly in patients with acute coronary syndrome or high bleeding risk. Aspirin-free strategy might result in lower bleeding early after PCI without increasing cardiovascular events, but its efficacy and safety have not yet been proven in randomized trials. METHODS We randomly assigned 6002 patients with acute coronary syndrome or high bleeding risk just before PCI either to prasugrel (3.75 mg/day) monotherapy or to DAPT with aspirin (81–100 mg/day) and prasugrel (3.75 mg/day) after loading of 20 mg of prasugrel in both groups. The coprimary end points were major bleeding (Bleeding Academic Research Consortium 3 or 5) for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) for noninferiority with a relative 50% margin. RESULTS The full analysis set population consisted of 5966 patients (no-aspirin group, 2984 patients; DAPT group, 2982 patients; age, 71.6±11.7 years; men, 76.6%; acute coronary syndrome, 75.0%). Within 7 days before randomization, aspirin alone, aspirin with P2Y12 inhibitor, oral anticoagulants, and intravenous heparin infusion were given in 21.3%, 6.4%, 8.9%, and 24.5%, respectively. Adherence to the protocol-specified antiplatelet therapy was 88% in both groups at 1 month. At 1 month, the no-aspirin group was not superior to the DAPT group for the coprimary bleeding end point (4.47% and 4.71%; hazard ratio, 0.95 [95% CI, 0.75–1.20]; P superiority =0.66). The no-aspirin group was noninferior to the DAPT group for the coprimary cardiovascular end point (4.12% and 3.69%; hazard ratio, 1.12 [95% CI, 0.87–1.45]; P non inferiority =0.01). There was no difference in net adverse clinical outcomes and each component of coprimary cardiovascular end point. There was an excess of any unplanned coronary revascularization (1.05% and 0.57%; hazard ratio, 1.83 [95%CI, 1.01–3.30]) and subacute definite or probable stent thrombosis (0.58% and 0.17%; hazard ratio, 3.40 [95% CI, 1.26–9.23]) in the no-aspirin group compared with the DAPT group. CONCLUSIONS The aspirin-free strategy using low-dose prasugrel compared with the DAPT strategy failed to attest superiority for major bleeding within 1 month after PCI but was noninferior for cardiovascular events within 1 month after PCI. However, the aspirin-free strategy was associated with a signal suggesting an excess of coronary events. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04609111.
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Bivalirudin and Provisional Glycoprotein IIb/IIIa Blockade Compared With Heparin and Planned Glycoprotein IIb/IIIa Blockade During Percutaneous Coronary InterventionREPLACE-2 Randomized Trial
Article
Full-text available
  • Feb 2003
Context The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary percutaneous coronary intervention (PCI).Objective To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned Gp IIb/IIIa blockade with regard to protection from periprocedural ischemic and hemorrhagic complications.Design, Setting, and Participants The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)–2 trial, a randomized, double-blind, active-controlled trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002.Interventions Patients were randomly assigned to receive intravenous bivalirudin (0.75-mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition (n = 2999), or heparin (65-U/kg bolus) with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3011). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI.Main Outcome Measures The primary composite end point was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding; the secondary composite end point was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization.Results Provisional Gp IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group vs 10.0% of patients in the heparin-plus-Gp IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, 0.77-1.09; P = .32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin vs 7.1% of patients in the heparin-plus-Gp IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval 0.90-1.32; P = .40). Prespecified statistical criteria for noninferiority to heparin plus Gp IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs 4.1%; P<.001).Conclusions Bivalirudin with provisional Gp IIb/IIIa blockade is statistically not inferior to heparin plus planned Gp IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding. Figures in this Article Unfractionated heparin has been the standard of adjunctive antithrombin therapy during percutaneous coronary intervention (PCI) for more than 25 years. Yet heparin is subject to important intrinsic limitations, including unpredictable pharmacokinetics, inhibition by plasma proteins, and the potential to activate platelets.1- 4 Considerable reductions in periprocedural complications have been achieved with administration of glycoprotein IIb/IIIa (Gp IIb/IIIa) antagonists in addition to heparin.5 These potent platelet inhibitors are not used universally, however, in part because of concerns about cost and increased bleeding risk. The direct thrombin inhibitor bivalirudin was approved for clinical use in December 2000 as an alternative to heparin for patients with unstable angina during PCI, based primarily on the results of a randomized trial conducted between 1993 and 1994. In that study of 4312 patients, ischemic events were decreased by 22% and hemorrhagic complications by 62% with bivalirudin compared with heparin.6- 7 The relevance of these data to current interventional practice is unknown, given that coronary artery stents, Gp IIb/IIIa inhibitors, low-dose heparin regimens, and thienopyridines were not used at the time of that trial. Two smaller more contemporary pilot studies did suggest, however, that by replacing heparin with bivalirudin during PCI, adjunctive Gp IIb/IIIa blockade might be used selectively rather than for all patients.8- 9 If validated, such an approach might offer potential advantages with regard to cost, hemorrhagic risk, and procedural simplicity. Our current randomized trial was therefore performed to determine if bivalirudin, with Gp IIb/IIIa inhibitors used in a provisional fashion if necessary during the procedure, could provide protection from ischemic and bleeding complications of PCI comparable with the current efficacy standard of low-dose heparin plus routine Gp IIb/IIIa blockade.
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Controlling The False Discovery Rate - A Practical And Powerful Approach To Multiple Testing
Article
Full-text available
  • Nov 1995
The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses – the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferroni-type procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.
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A Randomized Comparison of Antiplatelet and Anticoagulant Therapy After the Placement of Coronary-Artery Stents
Article
Full-text available
  • May 1996
The clinical benefit of coronary-artery stenting performed in conjunction with coronary angioplasty is limited by the risk of thrombotic occlusion of the stent as well as hemorrhagic and vascular complications of intensive anticoagulation. We compared antiplatelet therapy with conventional anticoagulant therapy with respect to clinical outcomes 30 days after coronary-artery stenting. After successful placement of Palmaz-Schatz coronary-artery stents, 257 patients were randomly assigned to receive antiplatelet therapy (ticlopidine plus aspirin) and 260 to receive anticoagulant therapy (intravenous heparin, phenprocoumon, and aspirin). The primary cardiac end point was a composite measure reflecting death from cardiac causes or the occurrence of myocardial infarction, aortocoronary bypass surgery, or repeat angioplasty. The primary noncardiac end point comprised death from noncardiac causes, cerebrovascular accident, severe hemorrhage, and peripheral vascular events. Of the patients assigned to antiplatelet therapy, 1.6 percent reached a primary cardiac end point, as did 6.2 percent of those assigned to anticoagulant therapy (relative risk, 0.25; 95 percent confidence interval, 0.06 to 0.77). With antiplatelet therapy, there was an 82 percent lower risk of myocardial infarction than in the anticoagulant-therapy group, and a 78 percent lower need for repeat interventions. Occlusion of the stented vessel occurred in 0.8 percent of the antiplatelet-therapy group and in 5.4 percent of the anticoagulant-therapy group (relative risk, 0.14; 95 percent confidence interval, 0.02 to 0.62). A primary noncardiac end point was reached by 1.2 percent of the antiplatelet-therapy group and 12.3 percent of the anticoagulant-therapy group (relative risk, 0.09; 95 percent confidence interval, 0.02 to 0.31). Hemorrhagic complications occurred only in the anticoagulant-therapy group (in 6.5 percent). An 87 percent reduction in the risk of peripheral vascular events was observed with antiplatelet therapy. As compared with conventional anticoagulant therapy, combined antiplatelet therapy after the placement of coronary-artery stents reduces the incidence of both cardiac events and hemorrhagic and vascular complications.
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Platelet Glycoprotein IIb/IIIa Inhibition with Coronary Stenting for Acute Myocardial Infarction
Article
Full-text available
  • Jul 2001
When administered in conjunction with primary coronary stenting for the treatment of acute myocardial infarction, a platelet glycoprotein IIb/IIIa inhibitor may provide additional clinical benefit, but data on this combination therapy are limited. We randomly assigned 300 patients with acute myocardial infarction in a double-blind fashion either to abciximab plus stenting (149 patients) or placebo plus stenting (151 patients) before they underwent coronary angiography. Clinical outcomes were evaluated 30 days and 6 months after the procedure. The angiographic patency of the infarct-related vessel and the left ventricular ejection fraction were evaluated at 24 hours and 6 months. At 30 days, the primary end point--a composite of death, reinfarction, or urgent revascularization of the target vessel--had occurred in 6.0 percent of the patients in the abciximab group, as compared with 14.6 percent of those in the placebo group (P=0.01); at 6 months, the corresponding figures were 7.4 percent and 15.9 percent (P=0.02). The better clinical outcomes in the abciximab group were related to the greater frequency of grade 3 coronary flow (according to the classification of the Thrombolysis in Myocardial Infarction trial) in this group than in the placebo group before the procedure (16.8 percent vs. 5.4 percent, P=0.01), immediately afterward (95.1 percent vs. 86.7 percent, P=0.04), and six months afterward (94.3 percent vs. 82.8 percent, P=0.04). One major bleeding event occurred in the abciximab group (0.7 percent); none occurred in the placebo group. As compared with placebo, early administration of abciximab in patients with acute myocardial infarction improves coronary patency before stenting, the success rate of the stenting procedure, the rate of coronary patency at six months, left ventricular function, and clinical outcomes.
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Comparison of Angioplasty with Stenting, with or without Abciximab, in Acute Myocardial Infarction
Article
Full-text available
  • Apr 2002
  • NEW ENGL J MED
As compared with thrombolytic therapy, primary percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction reduces the rates of death, reinfarction, and stroke, but recurrent ischemia, restenosis, and reocclusion of the infarct-related artery remain problematic. When used in combination with PTCA, coronary stenting and platelet glycoprotein IIb/IIIa inhibitors may further improve outcomes. Using a 2-by-2 factorial design, we randomly assigned 2082 patients with acute myocardial infarction to undergo PTCA alone (518 patients), PTCA plus abciximab therapy (528), stenting alone with the MultiLink stent (512), or stenting plus abciximab therapy (524). Normal flow was restored in the target vessel in 94.5 to 96.9 percent of patients and did not vary according to the reperfusion strategy. At six months, the primary end point - a composite of death, reinfarction, disabling stroke, and ischemia-driven revascularization of the target vessel - had occurred in 20.0 percent of patients after PTCA, 16.5 percent after PTCA plus abciximab, 11.5 percent after stenting, and 10.2 percent after stenting plus abciximab (P<0.001). There were no significant differences among the groups in the rates of death, stroke, or reinfarction; the difference in the incidence of the primary end point was due entirely to differences in the rates of target-vessel revascularization (ranging from 15.7 percent after PTCA to 5.2 percent after stenting plus abciximab, P<0.001). The rate of angiographically established restenosis was 40.8 percent after PTCA and 22.2 percent after stenting (P<0.001), and the respective rates of reocclusion of the infarcted-related artery were 11.3 percent and 5.7 percent (P=0.01), both independent of abciximab use. At experienced centers, stent implantation (with or without abciximab therapy) should be considered the routine reperfusion strategy.
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Impact of Major Bleeding on 30-Day Mortality and Clinical Outcomes in Patients With Acute Coronary Syndromes. An Analysis From the ACUITY Trial
Article
  • Mar 2007
The purpose of this study was to determine the predictors of major bleeding and the impact of major bleeding on outcomes, including mortality, in acute coronary syndromes (ACS). Whether major bleeding independently predicts mortality in patients with ACS undergoing an early invasive strategy is undefined. Patients (n = 13,819) with moderate- and high-risk ACS were randomized to heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition (GPI), bivalirudin plus GPI, or bivalirudin monotherapy (plus provisional GPI). Logistic regression was used to determine predictors of 30-day major bleeding and mortality. Major bleeding rates in patients treated with heparin plus GPI were higher versus bivalirudin monotherapy (5.7% vs. 3.0%, p < 0.001) and similar versus bivalirudin plus GPI (5.7% vs. 5.3%, p = 0.38). Independent predictors of major bleeding were advanced age, female gender, diabetes, hypertension, renal insufficiency, anemia, no prior percutaneous coronary intervention, cardiac biomarker elevation, ST-segment deviation >/=1 mm, and treatment with heparin plus GPI versus bivalirudin monotherapy. Patients with major bleeding had higher 30-day rates of mortality (7.3% vs. 1.2%, p < 0.0001), composite ischemia (23.1% vs. 6.8%, p < 0.0001), and stent thrombosis (3.4% vs. 0.6%, p < 0.0001) versus those without major bleeding. Major bleeding was an independent predictor of 30-day mortality (odds ratio 7.55, 95% confidence interval 4.68 to 12.18, p < 0.0001). Major bleeding is a powerful independent predictor of 30-day mortality in patients with ACS managed invasively. Several factors independently predict major bleeding, including treatment with heparin plus GPI compared with bivalirudin monotherapy. Knowledge of these findings might be useful to reduce bleeding risk and improve outcomes in ACS.
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Clinical correlates and course of thrombocytopenia during percutaneous coronary intervention in the era of abciximab platelet glycoprotein IIb/IIIa blockade
Article
  • Jul 2000
  • AM HEART J
Thrombocytopenia is infrequently associated with abciximab therapy but may contribute to hemorrhagic risk. Factors associated with development of thrombocytopenia, the role of weight-adjustment in concomitant heparin administration, and clinical outcomes in patients with thrombocytopenia are not well defined. Pooled data from 3 placebo-controlled, randomized trials (EPIC, EPILOG, and EPISTENT) of abciximab therapy during percutaneous coronary intervention identified 178 patients (2. 4% of 7290 patients) in whom thrombocytopenia (platelet count <100 x 10(9)/L) developed after enrollment. Multivariate regression analysis identified age (>65 years; P <.001), weight (<90 kg; P =. 023), baseline platelet count (<200 x 10(9)/L; P <.001), abciximab therapy (P =.002), and enrollment into the EPIC trial (P <.001) to be associated with development of thrombocytopenia. Major and minor nonsurgical hemorrhage and transfusion were more frequent (all P <. 001) in thrombocytopenic patients. Although the primary composite clinical end point of these trials (death, myocardial infarction, or urgent revascularization to 30 days) was observed with similar frequency in patients with (11.2%) and those without (7.9%; P =.114) thrombocytopenia, 30-day mortality rate was higher in thrombocytopenic patients (8.4% vs 0.6%, respectively; P <.001). This excess mortality rate persisted after excluding patients in whom thrombocytopenia was first noted after the performance of coronary bypass surgery (4.8% vs 0.6%; P <.001). Among patients in whom thrombocytopenia developed during these trials, those who received prophylactic abciximab had fewer primary end point events (7.1% vs 23.1%; P =.056) and had a lower 30-day mortality rate (3.5% vs 15.4%; P =.048) than patients with thrombocytopenia who had received prophylactic placebo. Thrombocytopenia associated with abciximab therapy for percutaneous coronary intervention was more frequent in older, lighter-weight patients, those with lower baseline platelet counts, and in those patients who were enrolled into the EPIC trial. Both bleeding and transfusion events occur more frequently in patients with thrombocytopenia. Patients in whom thrombocytopenia developed during these trials had increased mortality rates to 30 days not attributable to the performance of coronary bypass surgery. Among patients with thrombocytopenia, those who received prophylactic abciximab had better clinical outcomes including survival than those who did not.
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