Combining glycoprotein blockers with fibrinolysis: a bold stroke?

Freek W.A. Verheugt*

Department of Cardiology, University Medical Center St Radboud, Nijmegen, The Netherlands

* Correspondence to: Freek W. A. Verheugt, MD, FESC, FACC, Professor of Cardiology, Heartcenter, 540 Department of Cardiology, P.0. Box 9101, University Medical Center St Radboud, Nijmegen, The Netherlands. Tel.: +31-24-3614220; Fax: +31-24-3540537
E-mail address: f.verheugt{at}cardio.umcn.nl

Received 19 August 2003; accepted 21 August 2003

See doi:10.1016/j.ehj.2003.07.004for the article to which this editorial refers

For the future treatment of ST-elevation myocardial infarction, fibrinolytic therapy will be the most widely used therapy, because of its simplicity, worldwide availability and relatively low cost. In comparison to primary angioplasty, which will continuously be hampered by its limited availability and inherent time delay, fibrinolytic therapy has two major drawbacks: partial efficacy and a small, but significant risk of major life-threatening bleeding. Several modifications in fibrinolytic drug design have optimized simplicity and efficacy in that 90min patency of about 60% can be achieved withthe bolus agents tenecteplase and reteplase. Butlife-threatening bleeding, especially intracranial bleeding, remains a serious problem.



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Fig. 1 Meta-analysis of the incidence of severe extracranial bleeding in the published acute ST elevation infarction trials comparing full dose fibrinolysis to reduced dose fibrinolysis combined with glycoprotein IIb/IIIa receptor antagonists (test for heterogeneity=ns). Shown are odds ratios and 95% confidence intervals.

 
To increase efficacy and decrease bleeding much effort has been put in modification of adjunctive therapy to fibrinolysis. By replacing unfractionated heparin with low molecular weight heparin efficacy of modern lysis seems to be increased,1but cerebral bleeding remains the major problem.2Lowering the dose of the lytic has only a limited effect on efficacy, but may decrease bleeding. By combining dose-lowering with enhancing antiplatelet therapy using stronger agents than aspirin alone the idea came up to study the combination of reduced dose lytic with full dose glycoprotein IIb/IIIa antagonists in comparison to full dose lytic alone. The first angiographic dosing trials were promising,3,4but the results of the clinical megatrials GUSTO-V5and ASSENT-3 were disappointing with regard to efficacy in that 30 day6and 1-year mortality7were not reduced in comparison to lytic alone. Even more disappointing, when all the published trials on combo-therapy are analysed,3–5,7–10were both the significant increase in major bleeding(Fig. 1) and the absence of a decrease in cerebral haemorrhage (Fig. 2).



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Fig. 2 Meta-analysis of the incidence of cerebral haemorrhage in the published acute ST elevation infarction trials comparing full dose fibrinolysis to reduced dose fibrinolysis combined with glycoprotein IIb/IIIa receptor antagonists (test for heterogeneity=ns). Shown are odds ratios and 95% confidence intervals.

 
The most disturbing point in the lack of safety in the trials on combo therapy is that reducing the dose of the lytic does not reduce bleeding, whereas the use of glycoprotein IIB/IIIA blockers in the absence of lytic therapy seems to be rather safe.11

In the current issue the interesting paper by Savonitto et al.12provides some insight into this paradox. In the large GUSTO-V trial, in which overall cerebral haemorrhage was not decreased by the half dose of a lytic plus abciximab, it was shown that younger patients had significant less cerebral bleeding with half dose lytic plus abciximab than full dose lytic, and that it was the other way around in the elderly. That the risk of lytic induced cerebral bleeding is significantly increased with age, is not new. But that this risk follows the exact line of age is an important new finding, that, of course, can only be derived from the large number of patients in the GUSTO-V megatrial. In fact, experience with the IIb/IIIa blocker abciximab in patients over the age of 75 was rather scarce before the megatrials GUSTO-IV, GUSTO-V and ASSENT-3. Abciximab had almost exclusively been used in trials with percutaneous intervention and high age was a common exclusion criterion in these studies. It was a courageous step to include the elderly in the abciximab megatrials, but, quite frankly, it ended at the same time the role of the agent for routine use in acute coronary syndrome with or without ST elevation.

Should we now administer half dose lytic plus abciximab to all patients younger than 55? The study published today is well performed, but is a post-hoc analysis. Although well controlled for confounding factors, it is not more than an observation, which learns us more about the relationship of age with drug-induced cerebral bleeding than about new therapeutic strategies in subsets of patients. For that purpose a prospective randomized study exclusively in younger patients is required. It is unlikely that such a trial will ever be initiated.

References

  1. ASSENT-3. Efficacy and safety of tenecteplase with enoxaparin, abciximab or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet. 2001;358:605–613.[CrossRef][Medline]
  2. Wallentin L, Goldstein P, Armstrong PW et al. Efficacy and safety of tenecteplase in combination with the low-molecular weight heparin enoxaparin, or unfractionated heparin in the pre-hospital setting: the ASSENT-3 PLUS randomized trial in acute myocardial infarction. Circulation. 2003;108:135–142.[Abstract/Free Full Text]
  3. Antman EM, Giugliano RP, Gibson CM et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction-14 (TIMI-14) trial. Circulation. 1999;99:2720–2732.[Abstract/Free Full Text]
  4. SPEED. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation. 2000;101:2788–2794.[Abstract/Free Full Text]
  5. GUSTO-V. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition. Lancet. 2001;357:1905–1914.[CrossRef][Medline]
  6. Verheugt FWA. GUSTO-V, the bottom line in fibrinolytic reperfusion therapy. Lancet. 2001;357:1899–1900.[CrossRef][Medline]
  7. Lincoff AM, Califf RM, Van de Werf F et al. Mortality at 1 year with combination platelet glycoprotein IIb/IIIa inhibition and reduced-dose fibrinolytic therapy vs conventional fibrinolytic therapy for acute myocardial infarction: GUSTO-V randomized trial. JAMA. 2002;288:2130–2135.[Abstract/Free Full Text]
  8. Antman EM, Louwerenburg HW, Baars HF et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: the ENTIRE-TIMI 23 trial. Circulation. 2002;105:1642–1649.[Abstract/Free Full Text]
  9. Brener SJ, Zeymer U, Adgey AAJ et al. Eptifibatide and low-dose tissue plasminogen activator in acute myocardial infarction: The INTRO-AMI trial. J Am Coll Cardiol. 2002;39:377–386.[Medline]
  10. Gugliano RP, Roe MT, Harrington RA et al. Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction: results of the integrelin and tenecteplase in acute myocardial infarction (INTEGRITI) phase II angiographic trial. J Am Coll Cardiol. 2003;41:1251–1260.[CrossRef][Medline]
  11. Boersma E, Harrington A, Moliterno DJ et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet. 2002;359:189–198.[CrossRef][Medline]
  12. Savonitto S, Armstrong PW, Lincoff AM. Risk of intracranial hemorrhage with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction: dichotomous response as a function. Eur Heart J. 2003;24:1807–1814.[Abstract/Free Full Text]

Related articles in EHJ:

Risk of intracranial haemorrhage with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction: Dichotomous response as a function of age in the GUSTO V trial
S. Savonitto, P.W. Armstrong, A.M. Lincoff, G. Jia, C.A. Sila, J. Booth, P. Terrosu, C. Cavallini, H.D. White, D. Ardissino, R.M. Califf, E.J. Topol, and for the GUSTO V Investigators
EHJ 2003 24: 1807-1814. [Abstract] [Full Text]  




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