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Correspondence to David J. Moliterno, MD, Department of Cardiology, F-25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail molited{at}cesmtp.ccf.org
Methods and ResultsAt 273 hospitals in 20 countries, 2282
patients were randomly assigned to lamifiban (2x2 factorial design:
low-dose [1 µg/min] with and without heparin versus high-dose [5
µg/min] with and without heparin) or to standard therapy (placebo
and heparin). All patients received aspirin. The composite primary end
point of death or nonfatal myocardial infarction at 30 days occurred in
11.7% of those receiving standard therapy, 10.6% receiving low-dose
lamifiban, and 12.0% receiving high-dose lamifiban
(P=0.668). By 6 months, this composite was lowest for
those assigned to low-dose lamifiban (P=0.027) and
intermediate for those assigned to high-dose lamifiban
(P=0.450) compared with control (13.7%, 16.4%, and
17.9%, respectively). Compared with control, the combination of
high-dose lamifiban and heparin resulted in more intermediate or major
bleeding (12.1% versus 5.5%; P=0.002) and a similar
rate of ischemic events. Conversely, low-dose lamifiban and
heparin yielded similar bleeding rates as in the control group but
fewer ischemic events at 6 months (12.6% versus 17.9%;
P=0.025).
ConclusionsIn unstable angina and nonQ-wave infarction,
platelet IIb/IIIa antagonism with lamifiban reduces adverse
ischemic events at 6 months beyond that of aspirin and heparin
therapy. The role of conjunctive heparin remains uncertain but appears
more favorable with low-dose IIb/IIIa antagonism. Larger-scale study is
needed to more reliably estimate these effects.
Study Design
Systematic blinding of heparin administration and careful control of
anticoagulation was achieved by use of a bedside aPTT device that
produced encrypted results. Unblinded aPTT measurements were not
allowed. A Hemochron Jr microcoagulation instrument (International
Technidyne Corp) automatically assayed 15 µL of fresh whole blood and
generated a multidigit code corresponding to the aPTT in seconds.
Multiple codes were created for each aPTT value, and all values were
checksum protected (a specific mathematical formula using the encrypted
numbers and producing a known integer) to ensure that transcription
errors did not occur. Using the patient's study number and the coded
aPTT result, the healthcare provider telephoned a central computer
system, which deciphered the patient's aPTT and treatment assignment
and then directed heparin or heparin-placebo infusion adjustments. The
computer program titrated the heparin infusion according to a
standardized nomogram to keep the aPTT to a laboratory equivalent of 60
to 85 seconds. Heparin-placebo infusions were adjusted according to one
of several random patterns that were consistent with heparin
infusion adjustments. Bedside aPTT testing was performed 6 hours after
study drug initiation, then every 6 to 12 hours until the target
therapeutic range was reached. Thereafter, testing was performed at
least daily during study drug administration.
Invasive Cardiological Procedures
End Points
Data Management and Statistical Analysis
Time-to-event analyses were performed by Kaplan-Meier
estimates. Among patients who had no known event by 6 months, 73 had a
follow-up time <120 days. These patients were excluded from the
denominator of event rates under the assumption that their event
probabilities were similar to the other patients. The excluded patients
accounted for 4.1% of the control group and from 1.3% to 4.8% of
each of the four lamifiban groups. At 1 year, 154 patients were
excluded who were lost to follow-up before 300 days. Thus, follow-up
was completed on 96.8% and 93.3% of patients at 6 months and 1 year,
respectively. All patients with known follow-up times were included in
the time-to-event analyses.
Principal outcome data at 30 days and 6 months are provided in
Table 3
The event rates for both infarction and death diverged beyond 30 days
(Figures 4
The incidences of bleeding complications and stroke are
presented in Table 4
To assess the relative contribution of heparin to outcome, efficacy and
safety parameters were compared between the corresponding
lamifiban-dose groups subrandomized to heparin or heparin placebo. At
30 days, no clear distinctions in efficacy were observed (Table 3
Comparison With Other Trials
In both PARAGON and GUSTO-IIb (which tested hirudin against heparin),
the composite incidence of death or infarction increased roughly 50%
in the interval between 30-day and 6-month follow-up. Although both
trials demonstrated a modest early treatment benefit (9.4% and 8.5%
respective reductions in death and infarction compared with control),
patients receiving a glycoprotein IIb/IIIa
antagonist derived a steadily increasing benefit over time.
Late benefit has been observed among patients receiving IIb/IIIa
antagonists in some angioplasty
trials.11 19 A
meta-analysis20 of all large,
placebo-controlled trials of IIb/IIIa antagonists,
including 6-month follow-up data from >12 000 patients, showed a 22%
reduction in death and nonfatal infarction. Moreover, the Evaluation of
c7E3 in the Prevention of Ischemic Complications (EPIC)
investigators reported a 60% reduction in death at 3-year follow-up
among patients with unstable angina or evolving infarction who received
abciximab during angioplasty.19 Interestingly,
this benefit became most evident after the first year of follow-up.
Also consistent with other trials involving IIb/IIIa
antagonists is the infrequent occurrence of intracranial
hemorrhage. The rate of intracranial hemorrhage has
been reported to be <0.2% with IIb/IIIa inhibitor
use,21 which is as low as in the respective
placebo groups, and only one such event occurred in the present
study.
Role of Heparin With Glycoprotein IIb/IIIa
Inhibitors
Lack of Dose Response
This observation contrasts with some previous large studies of this
class of antithrombotic therapy by suggesting an upper limit of benefit
or potential "toxicity." Although the Canadian Lamifiban Study data
did suggest higher doses of lamifiban were potentially superior, our
findings differ, perhaps because of differences in study size, patient
baseline characteristics, or study drug administration. Compared with
that study, our patient population was substantially larger in number,
older, and required to have electrocardiographic evidence of
ischemia. Also in the current study, no downward adjustment in
lamifiban infusion was made for low patient body weight. These
differences may have resulted in even higher plasma levels than
expected. Theoretical explanations for the apparent "toxicity" of
high doses of lamifiban include intraplaque hemorrhage,
paradoxical platelet activation, or an interplay between excessive
bleeding and clinical outcomes.
Passivation
Study Limitations
Conclusions
Coordinating Center: Duke Clinical Research Institute,
Durham, NC. Clinicians: R. Califf, C. Granger, R.
Harrington, K. Newby. Administrators: S. Karnash, M.
Peek-Hackenson, J. Mabie, J. Melton, J. Snapp. Clinical Events
Committee: D. Brown, N. Dabolt, C. Granger, C. Greene, M.
McClanahan, G. Strand, B. Tardiff, M. Winchell. Coordinators and
assistants: M. Peek-Hackenson, J. Bolte, R. Evans, M. Poku, S.
Conder, K. Tinnin, W. Lloyd, G. Jackson. Statistics: K. Lee,
M. Bhapkar, W. Sense.
Executive Center: Cleveland Clinic
Cardiovascular Coordinating CenterE. Topol, D.
Moliterno, D. Passmore, L. Konczos.
Canadian Coordinating Center: University of Alberta,
Alberta, CanadaP. Armstrong, S. Caouette, S. Martin, W.
Sutherland.
European Coordinating Center: University of Leuven, Leuven,
BelgiumF. Van de Werf, A. Luyten, L. Tobback, K. Houbracken, R.
Brower, L. D'Hoore.
Australian Coordinating Center: National Health and Medical
Research Council Clinical Trials Center, University of Sydney, Sydney,
AustraliaJ. Simes, A. Keech, M. Kava.
Data and Safety Monitoring Committee: R. Frye, Chairman; M.
Cheitlin, D. DeMets, L. Fisher.
List of Institutions and Participants by Country (Number of
Patients)
Poland (238): Medical Academy of Gdansk, GdanskG.
Swiatecka; Institute of Cardiology, KrakowW.
Piwowarska; National Institute of Cardiology,
WarsawZ. Sadowski; Silesian Medical Academy, Katowxice-OchojelP.
Tadeusz; University School of Medicine BydgoszczE. Nartowics;
University Medical School, WarsawT. Kraska; Siaska Akademia Medyczna,
KatowiceL. Giec; Emergency Medical Service, WarsawA. Dyduszynski;
National Institute of Cardiology, WarszawaJ.
Stepinska; Instytut Medycyny Morskiek, GdyniaJ. Gorski;
Pomeranian Medical Academy, SzczecinK.-J. Zdzislawa;
Szpital Miejski, GdyniaE. Czestochowska; Jagiellonian
University College, CracowJ. Kazimierz; University of Medical
Sciences, PoznanM. Wierzchowiecki; University School of
Medical Science, PoznanA. Cieslinski; Postgraduate Medical School,
WarsawL. Ceremuzynski; Specjalistyczny Szpital Zespol, WroclawK.
Loboz-Grudzien; Medical University, LodzM. Krzeminska-Pakula; County
Hospital, WroclawW. Krzysztof; Silesian Medical Academy, ZabrzeJ.
Wodniecki.
France (213): Hopital Central, NancyPr Aliot: Center
Hospitalier Marechal Jo, PerpignanDr Bonot: Hopital Dupuytren,
LimogesDr Cassat; Hopital de Lorient, LorientDr Cazaux; C.H.
IntercommunalDr Chestier; Hopital St. Antoine, ParisDr Cohen;
Hopital Beaujon, ClichyDr Cohen Solal; Center Hospitalier Du Mans, Le
MansDr Fagart; Hopital Victor Dupouy, ArgenteuilDr Fruchaud;
Hopital Rene Dubos, PontoiseF. Funck; Hopital Get R. Laennec,
NantesDr Godin; Hopital Arnaud de Villeneuve, MontpellierG. Raoux;
Hopital Notre Dame de Bon Secours, MetzDr Khalife; Hopital Civil,
StrasbourgProf Mossard; Center Hospitalier Intercommunal,
MontfermeilDr Nallet; Hopital Andre Mignot, Le ChesnayDr Normand;
Center Hospitalier Schaffnes, LensDr Pecheux; Hopital Gilles de
Corbeil, Corbeil EssonnesDr Pezzano; Hopital Sud, AmiensDr Quiret;
Hopital de Font Pre, ToulonDr Sans; Hopital Antoine Beclere,
ClamartDr Michel Slama; Hopital de Feugrais, ElboeufDr Toussaint;
Center Hospitalier de Long Jum, LongjumeauT. Thanh; Tenon Hospital,
ParisA. Vahanian; Center Hospitalier, LagnyDr Vedel; Center
Hospitalier, NeversB. Vitoux.
Finland (184): Kuopio University Hospital, KuopioM.
Halinen; Jorvi Hospital, EspooV. Naukkarinen; Pohjois-Karjala Central
Hospital, JoensuuJ. Nurminen; Kymenlaakso Central Hospital,
KotkaEero Koskela; Keski-Suomi Central Hospital,
JyväskyälJ. Melin; Satakunta Central Hospital, PoriH.
Koskivirta; Vaasa Central Hospital, VaasaH. Kivelä; Kuusankoski
District Hospital, SairaalamäkiM. Rynen; Oulo University
Central Hospital, OuloA.K. Niemi.
Belgium (171): O.L.V. Middelares, DeurneDr Gillebert;
Kliniek St. Maria, HalleDr Croonenberghs; A.Z. St.-Elizabeth,
ZottegemB. Dirk; St. Norbertusziekenhuis, DuffelDr
Van Walleghem; Ziekenhuis de Pelikaan, TemseDr Koentges; Kliniek
Zusters Van Barmhartig, RonseDr Vermeersch; Imeldaziekenhuis,
BonheidenDr Verstreken; Heilig Hart Ziekenhuis, NeerpeltDr Van
Dorpe; A.Z. St. Elizabeth, AntwerpenDr Van Schuylenbergh; A.Z.
Heilige Familie, ReetDr Caenepeel; A.Z. St. Jozef, MalleDr
Claessens; Kliniek Andre Dumont, GenkW. Van Mieghem; St.
Jozefkliniek, OostendeDr Stroobandt; Ziekenhuis Oost Limburg,
GenkDr Eerdekens; Hopital de Braine L Alleud, Braine L AlleudDr
Lignian; St. Niklaaskliniek, KortrijkDr Dejaegher; Hopital de
Jolimont, Haine-St-PaulDr de Meester; St. Elizabethziekenhuis,
HerentalsDr de Scheper; Heilig Hartziekenhuis, MolDr Elsschot;
Algemeen Ziekenhuis St. Dimpna, GeelDr Schurmans; St. Elisabeth
Ziekenhuis, TurnhoutDr Thoeng; O.L.V.-Ziekenhuis, OudenaardeDr
Emmerechts; Stadskliniek, Sint-NiklaasDr Thiels; Kliniek St.
Augustinus, VeurneDr Popeye; Universitaire Ziekenhuizen Leuven,
LeuvenF. Van de Werf; Cliniques Saint-Luc, BrusselsJ. Col;
Sint-Janskliniek, BrusselsDr Goethals.
Italy (152): S. Maria Delle Croci Hospital, RavennaF.
Ottani; Galliera Hospital, GenovaC. Vecchio; Hospital Maggiore di
Lodi, Maggiore di LodiM. Orlandi; Ospedale Civile, PiacenzaA.
Capucci; S. Anna Hospital, ComoA. Politi; Hospital of Merate,
MerateF. Mauri; Ospedale Civile, Rho (Milano)G. Rovelli; IRCCS
Policlinico San Matteo, PaviaC. Montemartini; Nicholas Green
Hospital, RomaS. Vajola; Ospedale Ca Granda Niguarda, MilanoA.
Pezzano; Ospedale "Le Molinette," TorinoA. Brusca; Ospedale Ca
Granda Niguarda, MilanoC. de Vita; Ospedale Bellaria,
BolognaG. Pinelli; Policlinico S. Orsola, BolognaA. Branzi; General
Hospital, TrevisoS. Paolo; General Hospital, BrindisiG. Ignone;
Azienda Sopedaliera Careggi, Florence G. Berni; M. Bufalini
Hospital, CesenaF. Tartagni; General Hospital, NovaraC.
Cernigliaro; G.B. Morgagni Hospital, ForliF. Rusticali; Caserta
General Hospital, CasertaG. Corsini; Ospedale "I Sacco,"
MilanoA. Polese.
Canada (147): Sunnybrook Hospital, Toronto,
OntarioChristopher Morgan, Kaye Freskiw; Prince George Regional
Hospital, Prince George, British ColumbiaDon Macritchie, Rita
Sweeney; University of Alberta Hospitals, Edmonton, AlbertaWayne
Tymchak, Cheryl Kee; Victoria Hospital, London, OntarioKeith Finnie,
Shirley McCreery; Campbell Hospital, Campbell River, British
ColumbiaJohn Heath, Mia Thompson; Northern Lights Hospital, Fort
McMurray, AlbertaMichel Suave, Beth Szlachetka; Pasqua Hospital,
Regina, SaskatchewanVernon Gebhardt, Jennifer Taylor; Lake of the
Woods District Hospital, Kenora, OntarioWilliam Cameron,
Claire Noseworthy; Ridge Meadows Hospital, Maple Ridge,
British ColumbiaFrancis Ervin, Sue Leclair; Royal Alexandra
Hospital, Edmonton, AlbertaWilliam Hui, Linda Kvill; St. Michael's
Hospital, Toronto, OntarioAnatoly Langer; Grace General
Hospital, Winnipeg, ManitobaJ. McDowell, Ruth Ziemski; L'Hopital
Maisonneuve Rosemont, Montreal, QuebecDenis Gossard, Odette
Magnon; Hopital du St-Sacrement, Montreal, QuebecGuy Tremblay;
Grey Nun's Hospital, Edmonton, AlbertaManohara Senaratne, Marlene
Goeres; Camp Hill Medical Center, Halifax, Nova ScotiaShauna Curley;
Misericordia Hospital, Edmonton, AlbertaPaul Greenwood, Anne Prosser;
Saskatoon City Hospital, Saskatoon City, SaskatchewanJ. Lopez,
Patricia Kuny.
United States (134): Cardiovascular
Associates, Birmingham, AlaW. Harrison, L. Maske; Loma Linda
University Medical Center Cardiology, Loma Linda,
CalifP. Ribeiro, V. Bishop; Alameda Hospital, Alameda, CalifS.
Raskin, J. Carr; Sharp Memorial Hospital, San Diego, CalifM.
Bushbinder, Diane Koester; UC Davis Medical Center, Sacramento,
CalifGary Gershony, Beverly Atherton-Pierce;
Cardio-Pulmonary Associates, Plantation, FlaOwen Peller,
Patricia Schofel; Tampa General Hospital, Tampa, FlaJames Smith,
Cindi Sullivan; University Hospital, Augusta, GaA. Bleakley Chandler,
Marcia Edwards; St. Joseph's Hospital, Savannah, GaPhilip Gainey,
Sandra Arsenaul; Straub Cardiology, Honolulu,
HawaiiRoger White, Susan Van Ham; St. Therese Medical Center,
Waukegan, IllTien Cheng, Catherine Monroe; Community Hospital East,
Indianapolis, IndRichard Hahn, David Quinn; River Cities
Cardiology, Jeffersonville, IndDolph Denny, Traci
McCartney; Androscoggin Cardiology Associates, Auburn,
MaineRobert Weiss, Diane Thornton- Chandler; Duke University
Medical Center, Durham, NCRobert Harrington, Cathy Martz;
Dartmouth-Hitchcock Medical Center, Lebanon, NHNathaniel Niles, Susan
Kennedy; New Mexico Heart Institute, Albuquerque, NMJerome Goss,
Susan Goebel; Albany Medical Center, Albany, NYRobert Millar, Kay
Zolezzi; Buffalo Heart Group, Buffalo, NYZaki Masud, Teresa Giambra;
St. Francis Hospital, Roslyn, NYAlan Guerci, Carolyn
Christie-Gulotta; Bronx Lebanon Hospital, Bronx,
NYNarendra Bhalodkar, Amada Valeria; Cleveland Clinic Foundation,
Cleveland, OhioDavid Moliterno, Nadine Juran;
Cardiovascular Research, Cleveland, OhioArvindkumar
Shah, Cindy Edel; Harvey Center for Cardiovascular
Research, Tulsa, OklaWayne Leimbach, Jolene Durham; Hershey Medical
Center, Hershey, PaMark Kozak, Helen Zimmerman; Westmoreland Regional
Hospital, Greensburg, PaPeter DiBattiste, Deborah Poskus; Heart
Center, Salt Lake City, UtahJoe Perry, Wendy Schvaneveldt; Lynchburg
General Hospital, Lynchburg, VaThomas Nygaard, Joyce White;
Vermont Cardiac Investigations, Montpelier, VtGregory MacDonald,
Sharon Segel; Veteran's Administration Medical Center, Seattle,
WashKenneth Lehmann, Mimi Platt; Waukesha Memorial Hospital,
Waukesha, WiscSanjay Singh, Jean Sesing; Ohio Valley Medical Center,
Wheeling, WVWilliam Noble, Dawn Baltich Noble.
New Zealand (122): North Shore HospitalH. Hart, H.
Brannigan; Wairau HospitalD. Durham, R. Currie; Memorial HospitalR.
Luke, D. Schmid; Napier HospitalG. Lewis, M. Bent; Rotorua
HospitalB. Bruns, M. Liley, A. Morley; Tauranga HospitalH. Patel,
V. Watts; Wellington HospitalP. Leslie, K. Saunders; Christchurch
HospitalH. Iikram, T. Lawson; Hutt HospitalS. Mann, J. Dewar;
Waikato HospitalD. Friedlander, L. Low; Nelson HospitalA. Hamer, J.
Tomlinson; Timaru HospitalD. Jardine, P. Carstensen; Dunedin
HospitalG. Wilkins, M. Blok; Ashburton HospitalM. Audeau, A. Smart;
Taranaki Base HospitalG. Chia, S. Megee; Green Lane Hospital,
AucklandH. White, L. Bush.
The Netherlands (107): Hospital Canisius-Wilhelmina,
NijmegenD. Hertzberger; Hospital de Honte, TerneuzenR.
Ciampricotti; Beatrix Hospital, GorinchemP. Van Rossum; Oosterschelde
Hospital, GoesRoeters Van Lennep; de Baronie Hospital,
BredaStrikwerda; Catharina Hospital, EindhovenH. Bonnier;
University Hospital Nijmegen, NijmegenF. Verheugt; Sint Lucas
Ziekenhuis, AmsterdamB. Lutterman; Antonius Hospital, SneekA.
Gomen; Scheper Hospital, EmmenJ. Engbers; Martini Hospital,
GroningenP. Bernink; St. Jans Gasthuis Weert, WeertJ.
Chin; Ziekenhuis Gelderse Vallei, BennekomT. Van Loenhout; St. Anna
Hospital, Geldrop; P. Polak; Diakonessenhuis, EindhovenL. Wely.
Argentina (103): Hospital Frances, Buenos AiresDr Nordaby;
Hospital Leonidas Lucero, Bahia BlancaDr Marcos; Instituto de
Cardiologia de Tucuha, S. Miguel de TucumanDr Castellanos; Hospital
Italiano, La PiataO. Perrino; Sanatorio Rivadavia, San Miguel de
TucumaE.G. Hasbani; Sanatoria Allenda, CordobaJ.O. Bono; Hospital
Luis C. Lagomaggiore, MendozaA.J. Gambarte; Hospital Italiano
Garibaldi, RosarioJ.L. Ramos; Instituto
Cardiovascular Rosario, RosarioG. Zapata; Instituto
de Cardiologia J.F Cabral, CorrientesJ. Garcia; Sanatorio Agote, Cap
FederalC. Pellegrini; Hospital Fernandez, Capital FederalS.
Simon; Sanatorio Delta, Rosario-Sta. FeGuillermo Covelli;
Icycc-Fundacion Favaloro, Capital FederalA. Barbagelata;
Sanatorio Anchorena, Capital FederalDr Mele; Hospital de Clinicas
"J. De San.", CapitalE.A. Sampo.
Iceland (74): National University Hospital, ReykjavikA.
Kristinsson; Borgarspitalinn City Hospital, ReykjavikG. Oddson;
FSA-Hospital, AkureyriJ.T. Sverrisson.
Israel (68): Shaare Zedek Medical Center, JerusalemProf
Tzivoni; Bnei Zion Medical Center, HaifaDr Abinader; Nahariya
Hospital, NahariyaProf Roguin; Barzilai Medical Center, AshkelonDr
Reisin; Kaplan Hospital, RehovotProf Caspi; Rivka Ziv Hospital,
SafedDr Marmor; Carmel Medical CenterS. Chen; Rabin Medical Center
(Hasharon), Petach TikkaProf Zahavi; Beilinson Hospital,
Petach-TikraProf Sclarovski.
Denmark (65): Rigshospitalet, KobenhavnP. Grande; Gentofte
Hospital, HellerupE. Kassis; Aarhus Amtssygehus, AarhusK. Thygesen;
Hvidovre Hospital, HvidovreJ.F. Hansen; Nesived Hospital,
NaestvaedH. Madsen; Oresund, HelsingorE. Agner; R.A.S. Koge,
KogeS.L. Rasmussen; Svendborg Hospital, SvendborgT. Pindborg;
Frederiksberg Hospital, FrederiksbergP. Hildebrandt; Horsholm
Hospital, HorsholmH.V. Nielsen.
Germany (62): Stadt Krankenhaus, SolingenD. Kikis;
Krankenhaus Post Am Rhein, KolnV. Hossmann; Stadt Krankenhaus,
GuterslohH. Ditter; Stadt Krankenhaus Heilbronn, HeilbronnI. Cyron;
Krankenhaus D. Landkreises, PeineO.A. Beck; Klinikum Erfurt,
ErfurtI. Assmann; Krankenhaus Dresden-Friedrich, DresdenK.E.
Altmann; Ketteler Krankenhaus, OffenbachH.-P. Nast; Krankenhaus Am
Sud, StralsundG. Muller-Esch; Krankenhaus Moabit, BerlinK.P.
Schusen; Universitatsklinikum Charite, BerlinW. Rutsch; Krankenhaus
Altstadt Magdeburg, MagdeburgW. Kettner; Universitatsklinikum,
NürnbergDr Bachmann; Klinikum Der Univers GiessenH.
Tillmanns; Allgemeines Krankenhaus, ViersenF.-R. Althoff; Rheinische
Friedrich-Wilhelms, BonnB. Luderitz; Klinikum Der
Philipps-University, MarburgB. Maisch; Drk-Krankenhaus Kopenick,
BerlinH.-F. Vohringer; Krankenhaus Zehlendorf, BerlinC. Von
Wissmann; Stadtisches Krankenhaus Am Urb, BerlinDr Dissmann; Fu
Virchow-Klinikum, BerlinD. Barckow; Kreiskrankenhaus, LubbenF.
Schwerffeger; Stadt Krankenhaus Neukolln, BerlinJ. Wagner;
Saarbrucker Winterbergkliniken, SaarbruckenK. Zwirner;
Universitatsklinikum Karl Gust, DresdenG.W. Daniel;
Universitatsklinikum Ulm, UlmM. Kochs; Krankenhaus Merheim, KolnR.
Griebenow; Zentralklinikum, AugsburgH.-D. Bolte.
South Africa (46): St. Augustine S Hospital, DurbanR.E.
Matisonn; Wentworth Hospital, DurbanProf A.S. Milha; Baragwanath
Hospital, JohannesburgA.R. Essop; Glynwood Hospital, BenoniR.M.
Jardine; J.G. Strijdom Hospital, JohannesburgM.K. Gebka; Millpark
Hospital, JohannesburgG.A. Cassel; H.F. Verwoerd Hospital,
JohannesburgProf D.P. Myburgh; Pretoria Heart Hospital, PretoriaF.
Snyders; Unitas Hospital, PretoriaJ.M. Bennett; Greenacres Hospital,
Port ElizabethS. Spilkin; Panorama Clinic, Parow, Cape TownT.
Mabin.
Portugal (42): Hospital de Santa Cruz, CarnaxideR.
Seabra-Gomes; Hospital Distrital do Barreiro, BarreiroV.C.
D'Almeida; Hospital Santo Espirito de Ang, AcoresJ. Coelho Gil;
Hospital Distrital de Aveiro, AveiroN. Pinheiro; Hospitas San
Francisco Xavier, LisboaL. Santos; Hospitais da Universidade, Coimbra
CodexL. Providencia; Hospital da Senmora Oliveira, GuimaraesJ.
Almeida; Hospital Pulido Valente, LisboaA. Ramos; Hospital de S.
Joao, PortoJ.C. dos Santos; Hospital de S. Bernardo, SetubalL.
Ines; Hospital Distrital de Santarem, SantaremG.F. Da Silva; Hospital
de Sta Marta, LisbonR. Ferreira; Hospital Distrital de Faro,
FaroJ.G. Leiria; Hospital Garcia de Orta, AlmadaM. Carrageta;
Centro Hospitalar de Coimbra, CoimbraA. Gonsalves; Hospital Sta
Maria, LisbonC. Ribeiro.
Sweden (37): Sahlgrenska Sjukhuset, GoteborgH.
Emanuelsson; Molndalssjukhus, MolndalM. Risenfors; Norra Alvsborgs
Lanssjukhus, TrollhattanL. Sandstedt; Centralsjukhuset,
KarlstadC. Abjorn; Regionsjukhuset, OrebroK. Christensen.
United Kingdom (16): Oldchurch Hospital, Romford EssexJ.
Stephens; Victoria Infirmary, GlasgowR. Northcote; Derbyshire Royal
Infirmary, DerbyM. Millar-Craig; Derby City Hospital, DerbyA. Mc
Cance; Daunton and Somerset Hospital, Taunton SomersetD. Maciver;
Halton General Hospital, Runcorn, CheshireE. Rosen.
Brazil (1): Instituto Danta Pazzanese, Sao PauloR.
Rui Fernando; Instituto Molestias Cardiovasculares, Sao I. Rio
Preto-SpJ. Nicolau; Hospital Sao Paulo, Cep Sao PauloD.
Carvalho.
Received November 17, 1997;
revision received February 3, 1998;
accepted February 9, 1998.
2.
Falk E, Shah P, Fuster V. Coronary plaque
disruption. Circulation. 1995;92:657671.
3.
Willard JE, Lange RA, Hillis LD. The use of aspirin in
ischemic heart disease. N Engl J Med. 1992;327:175181.[Medline]
[Order article via Infotrieve]
4.
Cairns JA, Gent M, Singer J, Finnie KJ, Frogatt GM,
Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers MG, Sackett DL,
Sealey BJ, Tanser PH. Aspirin, sulfinpyrazone, or both in unstable
angina. N Engl J Med. 1985;313:13691375.[Abstract]
5.
Cohen M, Adams PC, Parry G, Xiong J, Chamberlain D,
Wieczorek I, Fox KAA, Chesebro JH, Strain J, Keller C, Kelly A,
Lancaster G, Ali J, Kronmal R, Fuster V, and the Antithrombotic Therapy
in Acute Coronary Syndromes Research Group. Combination
antithrombotic therapy in unstable rest angina and nonQ-wave
infarction in nonprior aspirin users: primary end points
analysis from the ATACS trial. Circulation. 1994;89:8188.
6.
Holdright D, Patel D, Cunningham D, Thomas R,
Hubbard W, Hendry G, Sutton G, Fox K. Comparison of the effect of
heparin and aspirin versus aspirin alone on transient myocardial
ischemia and in-hospital prognosis in patients with unstable
angina. J Am Coll Cardiol. 1994;24:3945.[Abstract]
7.
The RISC Group. Risk of myocardial infarction and
death during treatment with low dose aspirin and
intravenous heparin in men with unstable coronary
artery disease. Lancet. 1990;336:827830.[Medline]
[Order article via Infotrieve]
8.
Théroux P, Ouimet H, McCans J, Latour J, Joly P,
Levy G, Pelletier E, Juneau M, Stasiak J, de Guise P, Pelletier GB,
Rinzler D, Waters DD. Aspirin, heparin, or both to treat acute unstable
angina. N Engl J Med. 1988;319:11051111.[Abstract]
9.
Antiplatelet Trialists' Collaboration.
Collaborative overview of randomised trials of antiplatelet
therapy, I: prevention of death, myocardial infarction, and stroke by
prolonged antiplatelet therapy in various categories of patients.
BMJ. 1994;308:81106.
10.
Oler A, Whooley MA, Oler J, Grady D. Adding heparin to
aspirin reduces the incidence of myocardial infarction and death in
patients with unstable angina: a meta-analysis.
JAMA. 1996;2276:811815.
11.
The EPIC Investigators. Use of a monoclonal antibody
directed against the glycoprotein IIb/IIIa receptor in
high-risk coronary angioplasty. N Engl J
Med. 1994;330:956961.
12.
The EPILOG Investigators. Platelet
glycoprotein IIb/IIIa receptor blockade and low-dose
heparin during percutaneous coronary
revascularization. N Engl J
Med. 1997;336:16891696.
13.
Théroux P, Kouz S, Roy L, Knudtson M, Diodati J,
Marquis J-F, Nasmith J, Fung A, Boudreault J-R, Delage F, Dupuis R,
Kells C, Bokslag M, Steiner B, Rapold H, on Behalf of the
Investigators. Platelet membrane receptor glycoprotein
IIb/IIIa antagonism in unstable angina: The Canadian Lamifiban
Study. Circulation. 1996;94:899905.
14.
Topol E, Califf R, Van de Werf F, Simoons M, Hampton J,
Lee K, White H, Simes J, Armstrong P, for the Virtual Coordinating
Center for Global Collaborative Cardiovascular Research
(VIGOUR) Group. Perspectives on large-scale
cardiovascular clinical trials for the new millennium.
Circulation. 1997;95:10721082.
15.
The Global Use of Strategies to Open Occluded
Coronary Arteries (GUSTO) IIa Investigators. Randomized trial
of intravenous heparin versus recombinant hirudin for acute
coronary syndromes. Circulation. 1994;90:16311637.
16.
The Global Use of Strategies to Open Occluded
Coronary Arteries (GUSTO) IIb Investigators. A comparison of
recombinant hirudin with heparin for the treatment of acute
coronary syndromes. N Engl J Med. 1996;335:775782.
17.
The TIMI IIIB Investigators. Effects of tissue-type
plasminogen activator and a comparison of early
invasive and conservative strategies in unstable angina and nonQ-wave
myocardial infarction: results of the TIMI IIIB trial.
Circulation. 1994;89:15451556.
18.
Théroux P. The Platelet Receptor Inhibition
for Ischemic Syndrome Management in Patients Limited by
Unstable Signs and Symptoms (PRISM-PLUS) study. Presented at
the American College of Cardiology (ACC) 46th Annual
Scientific Session; March 18, 1997; Anaheim, Calif.
19.
Topol E, Ferguson J, Weisman H, Tcheng J, Ellis S,
Kleiman N, Ivanhoe R, Wang A, Miller D, Anderson K, Califf R, on behalf
of the EPIC Investigators. Long-term protection from myocardial
ischemic events in a randomized trial of brief integrin
ß3 blockade with percutaneous
intervention. JAMA. 1997;278:479484.
20.
Moliterno D, Topol E. Meta-analysis of
platelet GP IIb/IIIa antagonist randomized clinical
trials: consistent, durable, salutary effects.
Circulation. 1997;96(suppl I):I-475. Abstract.
21.
Lefkovits J, Horigan M. Is the risk of
intracerebral hemorrhage greater with direct
thrombin inhibitors than with platelet GP IIb/IIIa
antagonists? A meta-analysis of recent clinical
trials. Circulation. 1995;92(suppl I):I-80. Abstract.
22.
Lincoff A, Califf R, Anderson K, Weisman H, Aguirre F,
Kleiman N, Harrington R, Topol E, for the EPIC Investigators. Evidence
for prevention of death and myocardial infarction with platelet
membrane glycoprotein IIb/IIIa receptor blockade by
abciximab (c7E3 Fab) among patients with unstable angina undergoing
percutaneous coronary
revascularization. J Am Coll
Cardiol. 1997;30:149156.[Abstract]
23.
Willerson JT, Golino P, Eidt J, Campbell WB, Buja LM.
Specific platelet mediators and unstable coronary artery
lesions: experimental evidence and potential clinical implications.
Circulation. 1989;80:198205.
24.
Schwartz RS, Holmes D Jr, Topol EJ. The
restenosis paradigm revisited: an alternative proposal for
cellular mechanisms. J Am Coll Cardiol. 1992;20:12841293.[Abstract]
25.
Kong T, Davidson C, Meyers S, Tauke J, Parker M, Bonow
R. Prognostic implication of creatine kinase elevation following
elective coronary artery interventions. JAMA. 1997;277:461466.
26.
Abdelmeguid A, Ellis S, Sapp S, Whitlow P, Topol E.
Defining the appropriate threshold of creatine kinase elevation after
percutaneous coronary interventions. Am
Heart J. 1996;131:10971105.[Medline]
[Order article via Infotrieve]
27.
Abdelmeguid A, Topol E, Whitlow P, Sapp S, Ellis S.
Significance of mild transient release of creatine kinase MB fraction
after percutaneous interventions.
Circulation. 1996;94:15281536.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
International, Randomized, Controlled Trial of Lamifiban (a Platelet Glycoprotein IIb/IIIa Inhibitor), Heparin, or Both in Unstable Angina
![]()
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
BackgroundUnstable angina and
nonQ-wave myocardial infarction involve coronary
arterial plaque rupture, platelet activation, and
thrombus formation. This study tested the benefit of different doses of
lamifiban (a platelet IIb/IIIa antagonist) alone and in
combination with heparin in patients with these conditions to select
the most promising lamifiban regimen for subsequent
evaluation.
Key Words: angina myocardial infarction platelet aggregation inhibitors heparin
![]()
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Acute
coronary syndromes are characterized by coronary
arterial plaque rupture, platelet activation, and
thrombus formation.1 2 Aspirin and heparin have
been used as the therapeutic mainstay for acute coronary
syndromes, acting as an antiplatelet and an antithrombin,
respectively. Although the ability of aspirin to reduce recurrent
ischemic events in acute coronary syndromes is
consistent,3 4 5 6 7 8 9 the benefit of adding
heparin to aspirin therapy remains less
certain.6 7 10 More potent platelet
inhibitors, the glycoprotein IIb/IIIa
antagonists, have been proved effective in reducing
ischemic events associated with coronary
angioplasty.11 12 This benefit is beyond that
provided by aspirin and has persisted while reducing concomitant
heparin.12 Lamifiban is a small-molecule member
of the new class of IIb/IIIa inhibitors developed for
intravenous administration. In a pilot trial of 365
patients with unstable angina and nonQ-wave myocardial infarction,
lamifiban at varying doses yielded encouraging
results.13 Because adverse ischemic
events were reduced and only a minority of patients received
concomitant heparin, we designed the current trial to test two doses of
lamifiban with and without heparin. Our objective was to assess the
benefit and safety of IIb/IIIa inhibition and to select the best
regimen for further evaluation compared with heparin to determine an
optimal treatment strategy in patients with unstable angina and
nonQ-wave myocardial infarction.14
![]()
Methods
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Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Patient Population
Patients enrolled into study had chest discomfort within the
previous 12 hours associated with transient or persistent ST-segment
depression (
0.5 mm) or T-wave inversion or transient (30
minutes) ST-segment elevation (
0.5 mm). Patients were excluded
if they were receiving oral anticoagulants and had an international
normalized ratio >1.5x control, if they were receiving
intravenous heparin and had an activated partial
thromboplastin time (aPTT) >85 seconds (not due to recent bolus), or
if they had received thrombolytic therapy within 24
hours. Patients were also excluded for active, significant bleeding;
contraindication to aspirin or heparin; systolic blood pressure
180 mm Hg or diastolic blood pressure
100
mm Hg despite treatment; serum creatinine level >2.0
mg/dL (177 µmol/L); platelet count
<100 000/mm3; cerebrovascular accident within
the past year; any history of hemorrhagic stroke, tumor, or
intracranial aneurysm; angioplasty within the previous week; or
gastrointestinal bleeding, major surgery, or trauma within 1 month.
Women of childbearing potential were excluded unless the pregnancy test
was negative. For safety reasons, patients were discontinued from study
after enrollment if the creatinine was found to be
2.0
mg/dL, the platelet count decreased by one third and was
<100 000/mm3, or important bleeding occurred.
All enrolled patients gave informed consent, and the study protocol was
approved by each participating hospital's institutional review
board.
As previously described,14 the objective
of this trial was to assess treatment strategies of
glycoprotein IIb/IIIa inhibition, with the optimal strategy
to be further tested against standard therapy. Therefore, a partial
factorial design was implemented with patients randomized to low-dose
versus high-dose lamifiban and to heparin or no heparin therapy. The
fifth group for which randomization was possible was the control group,
who received lamifiban placebo and heparin (Figure 1
). Thus, each patient received
lamifiban, unfractionated heparin, or both in addition to aspirin. The
study was double-blinded such that all patients received lamifiban or
lamifiban placebo and heparin or heparin placebo. The protocol required
study drug administration for a minimum of 3 days and a maximum of 5
days unless the patient underwent percutaneous
coronary intervention on day 5, in which case they were to
receive study drug for an additional 12 to 24 hours after the
procedure. Study drug was not discontinued for coronary
angiography or intervention, but heparin or heparin placebo was
discontinued 4 hours in advance to protect study blinding. All patients
received aspirin at enrollment (160 mg recommended) and daily
thereafter (80 to 325 mg). Porcine heparin of a single lot was used,
and matching heparin-placebo vials were supplied by the same
manufacturer (Elkins-Sinn Inc). Patients assigned to low-dose lamifiban
(Hoffman-La Roche) received a 300-µg bolus followed by an infusion of
1.0 µg/min; those assigned to high-dose lamifiban received a 750-µg
bolus followed by an infusion of 5.0 µg/min. All patients assigned to
standard therapy (control group) received heparin, whereas by factorial
design, heparin therapy was randomized among those receiving lamifiban.
For patients who weighed
80 kg, the heparin dose was 5000 U as bolus
and 1000 U/h as initial infusion. Patients who weighed <80 kg were
given a weight-adjusted heparin bolus (60 U/kg) and initial infusion
(12 U · kg-1 ·
h-1).

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Figure 1. Flow diagram summarizing the study protocol,
partial factorial design, and number of patients randomized.
Coronary angiography and
revascularization were not to be performed during
the first 48 hours unless clinically necessitated by
hemodynamic instability or recurrent ischemia.
In patients undergoing coronary angiography or
percutaneous coronary intervention, the heparin
or heparin-placebo infusion was to be stopped 4 hours before the
procedure. During coronary
revascularization, open-label heparin was used at
the direction of the attending physician. Lamifiban and
lamifiban-placebo infusions were given at a constant rate throughout
study and were not interrupted for coronary angiography or
percutaneous intervention.
The primary end point was a composite of all-cause mortality and
nonfatal myocardial infarction (or reinfarction) in the first 30 days
of follow-up. Secondary end points included death, myocardial
(re)infarction, disabling stroke, major bleeding, and intermediate
bleeding (red blood cell transfusion or >5 g of hemoglobin drop
without hemodynamic compromise) at 30 days; death and
myocardial infarction at 6 months; and death at 1-year follow-up. A
Clinical Events Committee, which consisted of practicing cardiologists,
was blinded to treatment assignment and adjudicated all clinical
primary and main secondary end point events according to published
predefined criteria.15 16 On the basis of
clinical outcome data from a corresponding phase II
study13 and event rates from previous similar
trials,13 15 16 a sample size of 2250 patients
was considered adequate to select the successive regimen. A
statistically significant treatment effect was not expected for a
particular lamifiban dose because a 50% reduction in events would be
needed for
=0.05 and ß
0.90 at 30 days.
Data were collected on all randomized patients, and these were
included in the statistical analysis according to the
intention-to-treat principle. In addition to reviewing source documents
for all end-point events, 10% of all patient records were
systematically reviewed, and all participating centers were visited by
a study monitor. Continuous variables were descriptively summarized
by use of medians with 25th and 75th percentiles. Discrete
variables were summarized in terms of frequencies and percentages.
Simple descriptive statistics of efficacy and safety measures were used
to compare treatments to select the best regimen for further clinical
trial evaluation. Comparisons among groups for the primary and
secondary end points were made by use of
2 and
log-rank tests. P values were two-sided, with
0.05 being
considered significant.
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Results
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Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Between August 11, 1995, and May 29, 1996, there were 2282
patients enrolled at 273 hospitals in 20 countries (see Appendix
).
Baseline characteristics of the entire cohort separated by treatment
assignment are presented in Table 1
. No differences in baseline
characteristics were noted among the groups. Overall, study drug was
given to 98.4% of the treatment group and 99.1% of the control group.
The median duration of study drug administration was 72 hours for all
groups. Drug was terminated early in 13% of the control group and in
19% of the lamifiban-treated patients, most commonly for bleeding or
planned surgical revascularization. Plasma
lamifiban concentrations were measured in 810 patients, and the median
levels for those receiving 1-µg/min and 5-µg/min infusions were
15.0 and 69.7 ng/mL, respectively (P<0.001). Study drug
administration, as well as concomitant medications and in-hospital
cardiac procedures, is detailed in Table 2
.
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Table 1. Baseline Characteristics of the Study Groups
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Table 2. Medications Given and Procedures Performed During
Hospitalization According to Treatment Group
. No difference in the composite
of death or nonfatal myocardial infarction was noted between the
control group and any lamifiban group at 30 days. In contrast, at
6-month follow-up, a substantial treatment effect was present:
compared with the control group, three of the four lamifiban-treated
groups had a numerically lower composite event rate (Figure 2
). Specifically, death or nonfatal
myocardial infarction at 6 months was lowered 23% by low-dose
lamifiban with or without heparin (odds ratio, 0.73; 95% CI, 0.55 to
0.97) and 8% by high-dose lamifiban with or without heparin (odds
ratio, 0.90; 95% CI, 0.69 to 1.18) compared with control (Figure 3
). The fourth group, patients receiving
high-dose lamifiban with heparin, had 30-day and 6-month outcomes
similar to those of the control group. In both of these groups
12%
and 18% of patients had reached the primary end point at 30 days and 6
months, respectively. All remaining lamifiban-treated groups had
continued reduction in events compared with the control group over the
first 180 days (Figure 2
) (odds ratio, 0.75; 95% CI, 0.58 to
0.97).
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Table 3. Incidence of Efficacy End Points at 30 Days and 6
Months

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Figure 2. Kaplan-Meier estimates of the probability of death
or nonfatal myocardial (re)infarction (MI) during 6-month follow-up
separated according to treatment assignment. At 30 days, all groups had
similar outcomes, whereas at 6 months the group receiving low-dose
lamifiban with heparin had the fewest end-point events compared with
control (P=0.025). Pts indicates patients; Hep,
heparin.

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Figure 3. Kaplan-Meier estimates of the probability of death
or nonfatal myocardial (re)infarction (MI) during 6-month follow-up
with lamifiban patients (Pts) grouped by low-dose and high-dose.
Compared with 17.9% of the control group having an end-point event,
13.7% of all low-dose lamifiban (P=0.027) and 16.4% of
all high-dose lamifiban (P=0.450) patients had an
event.
and 5
) although neither individual end point
was statistically different between treatment and control. The relative
increase in myocardial (re)infarction between 30 and 180 days was 35%
for the control group, 15% for the low-dose lamifiban groups, and 18%
for the high-dose lamifiban groups. Likewise, the relative increase in
deaths during this time was 128% for the control group, 73% for the
low-dose lamifiban groups, and 89% for the high-dose lamifiban groups.
At 1 year, all-cause mortality was 8.7%, 7.3%, and 8.9%,
respectively (P=0.320; Figure 5
).

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Figure 4. Kaplan-Meier estimates of the probability of
myocardial (re)infarction (MI) during 6-month follow-up with control
compared with lamifiban patients (Pts) grouped by low-dose and
high-dose. Nonfatal infarctions occurred in 14.3%, 10.8%, and 12.9%,
respectively (P=0.115).

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Figure 5. Kaplan-Meier estimates of the probability of death
during 1-year follow-up with control compared with lamifiban patients
(Pts) grouped by low-dose and high-dose. All-cause mortality was 8.7%,
7.3%, and 8.9%, respectively (P=0.320).
. There were
more bleeding-related events among those receiving high-dose lamifiban.
The combination of major and intermediate bleeding occurred in 5.5% of
control patients, 6% of low-dose lamifiban patients, and 10.7% of
high-dose lamifiban patients (P=0.002). This pattern was
also observed after analysis of bleeding events not related to
invasive procedures. One intracranial hemorrhage occurred
during study in the high-dose lamifiban group without heparin.
View this table:
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Table 4. Incidence of Bleeding Complications
). At
6 months, the combination of heparin and lamifiban produced opposing
results. Specifically, the lowest rates of death and infarction were
observed among patients receiving low-dose lamifiban with heparin,
whereas the highest event rates were among those receiving high-dose
lamifiban with heparin (Table 3
; Figure 2
). Compared with the
respective group without heparin, 14% fewer ischemic events
occurred in the low-dose lamifibanwith-heparin group, whereas 22%
more events occurred in the high-dose lamifibanwith-heparin group,
although neither difference reached statistical significance. Patients
receiving heparin in combination with lamifiban had an increased
incidence of intermediate bleeding. For those receiving heparin,
lamifiban, or the combination, the incidence of red blood cell
transfusion was 4.4%, 5.7%, and 7.5%, respectively (Table 4
;
P=0.034).
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Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
This is the first large study to test platelet
glycoprotein IIb/IIIa inhibition in patients with unstable
angina and nonQ-wave myocardial infarction. At 6-month follow-up, a
distinct treatment benefit was observed with lamifiban for the
composite end point of death and nonfatal myocardial infarction.
Compared with standard therapy, low-dose lamifiban resulted in a 23%
lower event rate (P=0.027), and high-dose lamifiban resulted
in a nonsignificant 8% reduction in events. Interestingly, at
early (30-day) follow-up (the primary end-point assessment of the
study), no treatment difference had reached statistical significance.
Low-dose lamifiban combined with heparin had the greatest composite
event rate reduction at both 30 days (12%) and 6 months (30%)
relative to standard therapy. This group also had the greatest
reduction (20%) in all-cause mortality at 1 year compared with
control. The study was not adequately powered to draw clear conclusions
regarding the benefit of heparin coadministration.
The baseline characteristics of the current study population are
similar to those of other recent unstable angina
studies.16 17 Nevertheless, the 11.7% occurrence
of death and nonfatal myocardial infarction at 30 days for the standard
therapy group is higher than the 8.7% reported in the GUSTO IIb trial,
the largest unstable angina data set available.16
The 30-day ischemic composite is more similar to the 11.9%
observed in the control group of the PRISM-PLUS
study,18 a trial of high-risk patients, 45% of
whom had an infarction at enrollment. Thirty-six percent of patients in
PARAGON had an infarction at enrollment.
Oler et al10 performed a
meta-analysis of six small, unstable angina studies that
randomized patients to aspirin (a relatively weak antiplatelet
agent) or a combination of aspirin and heparin, because no study alone
showed a clear benefit with the combination. The pooled data from 1353
patients suggested a benefit from heparin addition, but this was of
marginal statistical significance (relative risk, 0.67; 95% CI, 0.44
to 1.02; P=0.06). In the present study, heparin
administration and adjustment was fully blinded with the use of a
bedside automated system, encrypted values, and centralized computers
according to a predefined nomogram. Overall, heparin provided no
consistent benefit when combined with lamifiban. This may
reflect the fact that the 30-day and 6-month composite ischemic
event rates were numerically highest among those receiving heparin with
high-dose lamifiban and lowest for those receiving heparin with
low-dose lamifiban. At 6 months, the incidence of death or nonfatal
infarction among patients receiving low-dose lamifiban plus heparin was
30% lower (P=0.025) than with heparin alone and 14% lower
(P=0.411) than with low-dose lamifiban alone. Likewise,
bleeding events were increased among those receiving heparin with
high-dose lamifiban but not with low-dose lamifiban. In the current
trial, as well as in previous glycoprotein IIb/IIIa
angioplasty studies, bleeding and adverse events were linked to the
combination of potent platelet inhibition and heparin. Compared
with control, the composite of intermediate and major bleeding rates
was more than doubled with high-dose lamifiban plus heparin (5.5%
versus 12.1%; P=0.002). Grouping patients as receiving
heparin, lamifiban, or both resulted in a composite rate of
intermediate and major bleeding of 5.9%, 7.8%, and 10.5%,
respectively (P=0.014).
Our data are consistent with those of the Canadian
Lamifiban Study,13 a 365-patient dose-exploring
study with parallel assignment to one of four doses of lamifiban or
placebo for unstable angina or nonQ-wave infarction. In that study,
the dose of lamifiban correlated well with the extent of inhibition of
ex vivo platelet aggregation, although no clear dose-related
correlation to clinical benefit was shown, in part due to the small
sample size. The ADP-induced platelet aggregation was inhibited
60% by a 1-µg/min infusion, and this group of patients had the
lowest 30-day ischemic event rate. The two high doses studied
(4 and 5 µg/min) completely inhibited ADP-induced platelet
aggregation and when combined provided a lower 30-day event rate than
placebo or the combined lower doses of lamifiban (1 and 2 µg/min). In
the present study, despite clearly higher plasma levels in the
high-dose groups, this did not provide benefit but rather an overall
neutral effect on ischemic outcome and a negative effect
regarding bleeding. As displayed in Figure 3
, the incidence of death
and infarction for the high-dose groups was consistently above
that for the low-dose groups.
Perhaps the most noteworthy feature of our findings is the
significant reduction of late ischemic events in the low-dose
lamifiban group, which was only marginally evident at 30 days. Compared
with the control group, among whom the composite of death and nonfatal
myocardial infarction increased 54% between 30 and 180 days, there was
a 33% increase for all lamifiban-treated patients and only a 22%
increase for those assigned to low-dose lamifiban with heparin. This
benefit was observed in addition to the known ischemic event
reduction provided by aspirin therapy. The term "passivation" has
been used to describe the action of glycoprotein IIb/IIIa
inhibitors in which the early and potent inhibition of
platelet function renders the disrupted coronary
arterial surface incapable of supporting platelet
deposition. Heightened platelet activity associated with acute
coronary syndromes is known to be associated with abrupt
closure after angioplasty, coronary reocclusion after
thrombolysis, and hyperplasia after vessel wall
injury.22 23 24 Passivation may include limiting
production of platelet-derived vasoconstrictors in the
short term and growth factors in the long term. Importantly, by
preventing platelet deposition and microaggregate formation, the
arterial surface may heal more favorably, thus reducing the
likelihood of (re)infarction.20 Several
observational studies have shown that even small enzymatic infarctions
during angioplasty are associated with a worse late
survival,25 26 27 and IIb/IIIa
inhibitors used during percutaneous
revascularization have been shown to concomitantly
reduce periprocedural creatine kinase and late
mortality.20
Although this is the largest reported study to date with long-term
follow-up testing the use of IIb/IIIa inhibitors in
unstable angina and nonQ-wave myocardial infarction, the sample size
of this study limits our ability to draw definitive conclusions. The
current study was designed to identify an optimal treatment strategy of
lamifiban and heparin to be further studied against standard therapy.
We observed low-dose lamifiban alone to be superior to heparin alone at
6-month follow-up; however, we cannot be certain, given the current
sample size, whether the addition of heparin to a low dose of lamifiban
will offer further benefit.
NonST-segment elevation acute coronary syndromes
continue to be associated with a high incidence of death and
(re)infarction in the months after the index event. During this
follow-up period, studies of thrombin inhibitors in these
patients have shown only a modest benefit when added to
aspirin.10 16 In contrast, our data suggest that
potent platelet inhibition with glycoprotein IIb/IIIa
antagonism can provide substantial and durable benefit. A more precise
evaluation of the effect of low-dose lamifiban in conjunction with
heparin will be assessed in a dedicated placebo-controlled trial.
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Appendix 1
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Steering Committee: E. Topol (Study Chairman), United
States; R. Califf (Director, Duke Clinical Research Institute), United
States; F. Van de Werf (Director, Intermediate Coordinating Center),
Belgium; R. Diaz, Argentina; E. Paolasso, Argentina; P. Aylward,
Australia; J. Simes, Australia; J. Col, Belgium; L. Piegas, Brazil; P.
Armstrong, Canada; A. Langer, Canada; P. Grande, Denmark; D. DeBono,
England; J. Heikkilä, Finland; A. Vahanian, France; K.
Neuhaus, Germany; W. Rutsch, Germany; P. Toutouzas, Greece; A.
Kristinsson, Iceland; D. Tzivoni, Israel; D. Ardissino, Italy; H.
White, New Zealand; R. Seabra-Gomes, Portugal; A. Betriu, Spain; A.
Dalby, South Africa; H. Emanuelsson, Sweden; M. Pfisterer, Switzerland;
F. Verheugt, The Netherlands; Z. Sadowski, Poland; E. Bates, United
States; W. Gibler, United States; J. Gore, United States; C. Granger,
United States; A. Guerci, United States; R. Harrington, United States;
J. Hochman, United States; D. Holmes, United States; N. Kleiman, United
States; D. Moliterno, United States; D. Morris, United States; E.
Ohman, United States; W. Weaver, United States.
Australia (300): Woden Valley Hospital, Australian
Capital TerritoryIan Jeffery, Pearl Taverner; Prince of Wales
Hospital, New South WalesWarren Walsh, Cheryl Friend; John Hunter
Hospital, New South WalesJim Leitch, Karen Cox; Concord Repatriation
General Hospital, New South WalesBenjamin Freedman, Maureen Gaynor;
St Vincent's Hospital, New South WalesTerry Campbell, Seval D'Arcy;
Illawarra Regional Hospital, New South WalesDwain Owensby, Trish
Davidson; St George & Community Health Service, New South WalesDavid
Ramsey, Trish Davidson; Bowral & District Hospital, New South
WalesWilliam Quinn, Marose Verzosa; Canterbury Hospital, New
South WalesRanji Wikramanayake, Geoffrey Manners; Coffs Harbour
Hospital, New South WalesJon Waites, Pauline Cahill; Central Coast
Regional Hospital, New South WalesJohn Woods, Alison Kearney; The
Nepean Hospital, New South WalesDrew Fitzpatrick, Denise
Schoevers; The Royal Melbourne Hospital, VictoriaDavid Hunt, Michele
Sallaberger; Alfred Healthcare Group, VictoriaJack Federman, Heather
Briggs; The Geelong Hospital, VictoriaAlan Appelbe, Monica Miller;
Western Hospital, VictoriaRobert Newman, Catherine Peeler; Box
Hill Hospital, VictoriaJeffrey Lefkovits, Louise Roberts; Dandenong
Hospital, VictoriaJohn Counsell, Marianne Martin; Mildura Base
Hospital, VictoriaAlan Soward, Jeff Breeding; Austin Hospital/Austin
Campus, VictoriaAnew Tonkin, Louise Brown; Royal Brisbane Hospital,
QueenslandDavid Cross, Loretta Fitzpatrick; Princess Alexana
Hospital, QueenslandPaul Garrahy, Cindy Hall; Rockhampton Base
Hospital, QueenslandChelliah Gnanaharan, Catherine Armstrong;
Redcliffe Hospital, QueenslandPat Carroll, Maree Duroux; Cairns Base
Hospital, QueenslandChin Lim, Beverly Cooke; Nambour General
Hospital, QueenslandSteve Coverdale, Lyn Joy; The Prince Charles
Hospital, QueenslandJHN Bett, Donalee O'Brien; Gold Coast Hospital,
QueenslandGregory Aroney, Pam Hicks; Flinders Medical Center, South
AustraliaPhilip Aylward, Leny Arnolder; Queen Elizabeth Hospital,
South AustraliaJohn Horowitz, Sue Lesley, Simon Stewart; Sir Charles
Gairdner Hospital, Western AustraliaPeter Thompson, Pam Bradshaw;
Fremantle Hospital, Western AustraliaRandall Henicks, Jan Garrett;
Launceston General Hospital, TasmaniaBhuwan Singh, Monica
Decampo.
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Acknowledgments
This study was supported by Hoffman La-Roche (Basel,
Switzerland).
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Footnotes
1 The investigators and sites participating in the Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON) trial are listed in the Appendix
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References
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
1.
Davies MJ, Thomas AC. Plaque fissuring: the
cause of acute myocardial infarction, sudden ischaemic death, and
crescendo angina. Br Heart J. 1985;53:363373.
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
![]() |
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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A. T. Nurden, C. Poujol, C. Durrieu-Jais, and P. Nurden Platelet Glycoprotein IIb/IIIa Inhibitors : Basic and Clinical Aspects Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 2835 - 2840. [Full Text] [PDF] |
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P. J. Zed, J. E. Tisdale, and S. Borzak Low-Molecular-Weight Heparins in the Management of Acute Coronary Syndromes Arch Intern Med, September 13, 1999; 159(16): 1849 - 1857. [Abstract] [Full Text] [PDF] |
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P. Aukrust, F. Muller, T. Ueland, T. Berget, E. Aaser, A. Brunsvig, N. O. Solum, K. Forfang, S. S. Froland, and L. Gullestad Enhanced Levels of Soluble and Membrane-Bound CD40 Ligand in Patients With Unstable Angina : Possible Reflection of T Lymphocyte and Platelet Involvement in the Pathogenesis of Acute Coronary Syndromes Circulation, August 10, 1999; 100(6): 614 - 620. [Abstract] [Full Text] [PDF] |
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L. F. M. van den Merkhof, F. Zijlstra, H. Olsson, L. Grip, G. Veen, F. W. H. M. Bar, M. J. B. M. van den Brand, M. L. Simoons, and F. W. A. Verheugt Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty: Results of the glycoprotein receptor antagonist patency evaluation (GRAPE) pilot study J. Am. Coll. Cardiol., May 1, 1999; 33(6): 1528 - 1532. [Abstract] [Full Text] [PDF] |
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D. A. Vorchheimer, J. J. Badimon, and V. Fuster Platelet Glycoprotein IIb/IIIa Receptor Antagonists in Cardiovascular Disease JAMA, April 21, 1999; 281(15): 1407 - 1414. [Abstract] [Full Text] [PDF] |
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D. F. Kong, R. M. Califf, D. P. Miller, D. J. Moliterno, H. D. White, R. A. Harrington, J. E. Tcheng, A. M. Lincoff, V. Hasselblad, and E. J. Topol Clinical Outcomes of Therapeutic Agents That Block the Platelet Glycoprotein IIb/IIIa Integrin in Ischemic Heart Disease Circulation, December 22, 1998; 98(25): 2829 - 2835. [Abstract] [Full Text] [PDF] |
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M. Madan, S. D. Berkowitz, and J. E. Tcheng Glycoprotein IIb/IIIa Integrin Blockade Circulation, December 8, 1998; 98(23): 2629 - 2635. [Full Text] [PDF] |
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The Paradigm Investigators Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifiban: results of the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) Trial J. Am. Coll. Cardiol., December 1, 1998; 32(7): 2003 - 2010. [Abstract] [Full Text] [PDF] |
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E. J. Topol and P. W. Serruys Frontiers in Interventional Cardiology Circulation, October 27, 1998; 98(17): 1802 - 1820. [Full Text] [PDF] |
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M. Liron, P. Theroux, H. D. White, The PRISM Study Investigators, J. H. Chesebro, and J. J. Badimon Tirofiban in Unstable Coronary Disease N. Engl. J. Med., October 15, 1998; 339(16): 1163 - 1165. [Full Text] |
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Platelet Inhibitor Shows Promise in Unstable Angina Journal Watch Emergency Medicine, October 1, 1998; 1998(1001): 9 - 9. [Full Text] |
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The PURSUIT Trial Investigators Inhibition of Platelet Glycoprotein IIb/IIIa with Eptifibatide in Patients with Acute Coronary Syndromes N. Engl. J. Med., August 13, 1998; 339(7): 436 - 443. [Abstract] [Full Text] [PDF] |
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Lamifiban and Heparin in Unstable Angina: The PARAGON Trial Journal Watch Cardiology, July 24, 1998; 1998(724): 4 - 4. [Full Text] |
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V. Rukshin, P. K. Shah, B. Cercek, A. Finkelstein, V. Tsang, and S. Kaul Comparative Antithrombotic Effects of Magnesium Sulfate and the Platelet Glycoprotein IIb/IIIa Inhibitors Tirofiban and Eptifibatide in a Canine Model of Stent Thrombosis Circulation, April 23, 2002; 105(16): 1970 - 1975. [Abstract] [Full Text] [PDF] |
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