The established antithrombotic agents are effective but they have limitations which have provided opportunities for the development of new antithrombotic compounds. Of these new agents, the antithrombin III-independent thrombin inhibitors and the platelet GPllb/llla receptor antagonists are the most advanced in their development. Other new antithrombotic agents include the antithrombin III-independent factor Xa inhibitors, activated protein C, soluble thrombomodulin and tissue factor pathway inhibitor. Of the GPIIb/IIIa antagonists, the humanized 7E3 antibody and integrin have been evaluated in phase III studies. The 7E3 antibody was effective in preventing both short-term and longer-term complications of coronary angioplasty. The antithrombin III-independent thrombin inhibitors hirudin and hirulog have also been evaluated in phase III studies. The studies with hirudin as an adjuvant to coronary thrombolysis had to be terminated and restarted at lower dosages because of an unacceptable incidence at intracranial hemorrhage and the study with hirulog produced equivocal results.
MaraganoreJ MBourdonPJablonskiJ. Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin. Biochemistry1990; 29: 7095–101.
2.
KikumotoRTamaoYTesukaT. Selective inhibition of thrombin by (2R,4R)-4-methyl-1 [N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl) sulfonyl]-L-arginyl)]-2-piperidinecarboxylic acid. Biochemistry1984; 23: 85–90.
3.
GoldH KTorresF WGarabedianH D. Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. J Am Coll Cardiol1993; 21: 1039–47.
4.
KettnerCShawE. D-Phe-Pro-ArgCh2Cl. A selective affinity label for thrombin. Thromb Res1979; 14: 969–73.
5.
KettnerCMersingerLKnabbR. The selective inhibition of thrombin by peptides of boroarginine. J Biol Chem1990; 265: 18289–97.
6.
BagdyDBarabasESzaboG. In vivo anticoagulant and antiplatelet effect of D-Phe-Pro-Arg-H and D-MePhe-Pro-Arg-H. Thromb Haemost1992; 67: 357–65.
7.
NeeperM PWaxmanLSmithD E. Characterization of recombinant tick anticoagulant peptide. J Biol Chem1990; 265: 17746–52.
8.
HansonS RParetiF IRuggeriZ M. Effects of monoclonal antibodies against the platelet glycoprotein IIb/IIIa complex on thrombosis and hemostasis in the baboon. J Clin Invest1988; 82: 149–58.
9.
TuszynskiGGasicTGasicG. Isolation and characterization of antistasin. J Biol Chem1987; 262: 9718–23.
10.
GruberAHarkerL AHansonS R. Antithrombotic effects of combining activated protein C and urokinase in nonhuman primates. Circulation1991; 84: 2454–64.
11.
HansonS RKellyA BGruberA. Antithrombotic efficacy and hemostatic safety of activated protein C in vivo. Adv Appl Biotechnol1990; 11: 187–96.
12.
HaskelE JTorrS RDayK C. Prevention of arterial reocclusion after thrombolysis with recombinant lipoprotein-associated coagulation inhibitor. Circulation1991; 84: 821–27.
13.
CollerB S. Platelets and thrombolytic therapy. N Engl J Med1990; 322: 33–42.
14.
CollerB SFoltsJ DScudderL E. Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model. Blood1986; 69: 783–86.
15.
CookJ JHuangT FRucinskiB. Inhibition of platelet hemostatic plug formation by trigramin, a novel RGD-peptide. Am J Physiol1989; 256: H1038–43.
16.
HaskelE JAdamsS PFeigenL P. Prevention of reoccluding platelet-rich thrombi in canine femoral arteries with a novel peptide antagonist of platelet glycoprotein IIb/IIIa receptors. Circulation1989; 80: 1775–82.
17.
YasudaTGoldH KFallonJ T. Monoclonal antibody against the platelet glycoprotein after reperfusion with recombinant tissue-type plasminogen activator in dogs. J Clin Invest1988; 81: 1284–91.
18.
YasudaTGoldH KLeinbachR C. Kistrin, a polypeptide platelet GPIIb/IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activator in a canine preparation. Circulation1991; 83: 1038–47.
19.
KleinmanN SOhmanMCaliffR M. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab following thrombolytic therapy: Results of the TAMI 8 pilot study. J Am Coll Cardiol1993; 22: 318–19.
20.
LidonR MTherouxPBonanR. A pilot early angiographic patency study using a direct thrombin inhibitor as adjunctive therapy to streptokinase in acute myocardial infarction. Circulation1994; 89: 1567–72.
21.
CannonC PMcCabeC HHenryT D. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial. Am J Coll Cardiol1994; 23: 993–1003.
22.
LeeL VMcCabeC HAntmanE MFor the TIMI 6 Investigators. Initial experience with hirudin and streptokinase in acute myocardial infarction: Results of the TIMI 6 trial. J Am Coll Cardiol1994; (special issue): 344A (abstract).
23.
NeuhausK LNiedererWWagnerJ. HIT (Hirudin for the Improvement of Thrombolysis): Results of a dose escalation study. Circulation1993; 88 (No. 4, Part 2): 292 (abstract).
24.
NeuhausK LVon EssenRTebbeU. Safety observations from the pilot phase of the randomized r-hirudin for improvement of thrombolysis (HIT-III) study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärtze (ALKK). Circulation1994; 90: 1638–42.
25.
Global Use of Strategies to Open Coronary Arteries (GUSTO) IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation1994; 90: 1631–37.
26.
Antmann EM for the TIMI 9A Investigators. Hirudin in acute myocardial infarction. Safety report from the thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9A trial. Circulation1994; 90: 1624–30.
27.
EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med1994; 330: 956–61.
28.
TopolE JCaliffR MWeismanH F. Randomized trial of coronary intervention with antibody against platelet Ilb/IIIa integrin for reduction of clinical restenosis: Results at six months. Lancet1994; 343: 881–86.
29.
TchengJ EEllisS GKleimanN S. Outcome of patients treated with the GPIIb/IIIa inhibitor integrelin during coronary angioplasty: Results of the IMPACT study. Circulation1993; 88 (suppl II): 1–595.
30.
TopolE JBonanRJewittD. Use of a direct antithrombin, hirulog, in place of heparin during coronary angioplasty. Circulation1993; 87: 1622–29.
31.
Van den BosA ADeckersJ WHeyndrickxG R. Safety and efficacy of recombinant hirudin (CGP 39 393) versus heparin in patients with stable angina undergoing coronary angioplasty. Circulation1993; 88: 2058–66.
32.
BittiJ AStronyJBinkerJ A. Treatment with bivalirudin (Hiralog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med1995; 333: 764–69.
33.
SerruysP WHerrmanJ PSimonR. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. Helvetica Investigators. N Engl J Med1995; 333: 757–63.
34.
AmbroseJ AWintersS LStemA. Angiographic morphology and the pathogeneis of unstable angina pectoris. J Am Coll Cardiol1985; 5: 609–16.
35.
ShermanC TLitvackFGrundfestW. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med1986; 315: 913–19.
36.
HoggP JJacksonC M. Fibrin monomer protects thrombin from inactivation by heparin–antithrombin III: Implications for heparin efficacy. Proc Natl Acad Sci USA1989; 86: 3619–23.
37.
WeitzJ IHudobaMMasselD. Clot-bound thrombin is protected from inhibition by heparin–antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest1990; 86: 385–91.
SimoonsM Lde BoerJan MBrandM. Randomized trial of a IIb/IIa platelet receptor blocker in refractory unstable angina. Circulation1994; 89: 596–603.
40.
SchulmanS PGoldschmidt-ClermontP JNavettaF IIntegrelin in unstable angina: A double-blind randomized trial. Circulation1993; 88: 1–608 (abstact).
41.
TopolE JFusterVHarringtonR A. Recombinant hirudin for unstable angina pectoris: A multicenter, randomized angiographic trial. Circulation1994; 89: 1557–66.
42.
SharmaG V R KLapsleyD EVitaJ A. Safety and efficacy of hirulog in patients with unstable angina. Circulation1992; 86 (suppl I): 1–386 (abstract).
43.
LidonRTherouxPJuneauM. Initial experience with a direct antithrombin, hirulog, in unstable angina: Anticoagulant, antithrombotic and clinical effects. Circulation1993; 88: 1495–501.
44.
FuchsJMcCabeC HAntmanE MFor the TIMI 7 Investigators. Hirulog in the treatment of unstable angina: Results of the TIMI 7 trial. Am J Coll Cardiol1994; 23: 56a (abstract).
