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Anti-thrombotic therapy - news from ESC Congress 2006 / World Congress of Cardiology 2006

An article from the e-journal of the ESC Council for Cardiology Practice

  • EXTRACT-TIMI involving 20,479 subjects showed that enoxaparin is a good option after thrombolysis up to and during a subsequent PCI.
  • TROICA, involving 1,050 patients did not support the routine use of thrombolysis in refractory CA
  • The WAVE study involving 2,100 subjects concluded that the combined therapy offered no beneficial effect (and a higher bleeding risk) in patients with peripheral atherosclerotic disease.
  • OASIS-5 and -6 combined data, involving more than 20,000 patients, showed that fondaparinux is superior to UFH/enoxaparin in reducing death/MI/stroke across the whole spectrum of patients with ACS and is associated with less major bleeding.
  •  Interesting abstracts will also be reviewed in this article.

I - EXTRACT-TIMI 25 Trial PCI cohort (CM Gibson, hot line)

The investigators studied whether enoxaparin is superior to unfractionated heparin (UFH) as adjunctive therapy for fibrinolytic therapy. The study was carried out among ST-elevation myocardial infarction (STEMI) patients, who subsequently underwent percutaneous coronary intervention (PCI). 

A total of 20,479 subjects for whom fibrinolysis was planned were randomised to
- a strategy of enoxaparin throughout the index hospitalisation or
- weight-based UFH for 48 hours in a double-blind manner, with blinded study drug to continue if PCI was performed before day 8 or hospital discharge.

In this pre-specified study, the primary efficacy end point of death or nonfatal recurrent myocardial infarction through 30 days was compared for enoxaparin vs UFH among patients who underwent PCI (n=4,676). 

Results: Fewer patients underwent PCI following the administration of enoxaparin vs UFH through 30 days (22.8% vs 24.2%, p=0.027).




UFH (%) 


  RR (95% CI)  




Death 2.9 3.0 0.98 (0.71-1.37) NS
MI  8.2 11.3 0.73 (0.61-0.87) <0.001
Stroke  0.3 0.9 0.30 (0.12-0.75) 0.006
Major Bleed   1.4 1.6 0.87 (0.55-1.39) NS
Death/MI 10.7 13.8  0.77 (0.66-0.90)   <0.001
Death/MI/Major Bleed   11.5 14.8 0.78 (0.67-0.90) <0.001
Death/MI/Stroke/Major Bleed  11.5 15.2 0.75 (0.65-0.87) <0.001

As shown above, enoxaparin administration for the duration of the index hospitalisation was associated with a reduced 30 day risk of the composite of death, recurrent MI, and stroke compared to UFH administered for 48 hours. These advantages of enoxaparin were observed without an increase in the risk of major bleeding, consistent with a significant net clinical benefit in favor of enoxaparin. These favorable outcomes were also evident in the cohort of patients who underwent PCI while on blinded study drug. Enoxaparin is a good option after thrombolysis up to and during a subsequent PCI.

II - Thrombolysis in Cardiac Arrest (TROICA) Trial (BW Bottinger, hot line)

Out-of-hospital cardiac arrest (CA) comprises a cascade of events with no specific treatment beyond cardio-pulmonary resuscitation (CPR), but with mortality as high as 95%. Up to 70% of CA patients have underlying acute myocardial infarction or pulmonary embolism. Both conditions are potentially responsive to fibrinolytic therapy, as demonstrated in small trials/observational studies.

This was the rationale for the TROICA trial. 1,050 patients suffering from witnessed out-of-hospital arrest of presumed cardiac origin were randomly assigned to tenecteplase (TNK) or placebo, plus standard therapy for CA.

The ITT analysis showed that the addition of TNK to standard CPR did not increase the 30-day survival rate (18.2% vs. 20.2%, NS) nor the hospital admission rate (59.0% vs. 59.5%, NS). The symptomatic intracranial haemorrhage (1% vs. 0%) and major bleeding (8.9% versus 7.4%) rates were not significantly different between groups.

Possible explanations for these unexpected results: inappropriate timing of TNK administration (too early/too late); negative interactions (e.g., vasopressors, pH, etc.); and lack of adjunctive antithrombotic therapy. The study does not support the routine use of thrombolysis in refractory CA.

III - Warfarin Antiplatelet Vascular Event (WAVE) study (S Anand, hot line)

Patients with peripheral atherosclerotic disease from 80 centers in 7 countries were randomised to receive either
- antiplatelet therapy only (n=1,081) or
- antiplatelet therapy combined with oral anticoagulants (n=1,080).

Patients with peripheral atherosclerotic disease are at increased risk of late cardiovascular events and the combined strategy has been shown to be effective in patients with CVD. The aspirin dose varied between 81 and 325 mg. The oral anticoagulant therapy was of moderate intensity aiming at an INR 2-3.

Results after 42 months follow-up showed that 12.2% of patients with combined therapy suffered cardiovascular death, infarction or stroke compared to 13.3% of patients receiving aspirin only (P=0.49). In addition, 4% of the patients with combined therapy experienced life-threatening bleeds compared to 1.2% in the aspirin only group (P<0.001). It was concluded that the combined therapy offered no beneficial effect (and a higher bleeding risk) in patients with peripheral atherosclerotic disease.

IV - OASIS-5 and -6 combined (SR Mehta, hot line)

The OASIS-5  (N=20,000) and OASIS-6 (N=12,000) randomized trials demonstrated reductions in all-cause mortality and bleeding with fondaparinux compared with standard care in patients with unstable angina/NSTEMI and STEMI, respectively. When combining the data from these two mega-trials,  Mehta and coworkers showed that  fondaparinux is superior to UFH/enoxaparin in reducing death/MI/stroke across the whole spectrum of patients with ACS, and is associated with markedly lower rates of major bleeding than UFH/enoxaparin.

V - Interesting Abstracts

  • New data from the OASIS-5 study revealed that the 50% decrease in early bleeding with fondaparinux compared to enoxaparin was consistent regardless of the use of UFH, and that this lower risk of bleeding was associated with reduced long-term mortality (1)
  • Analysis of the combined data from the OASIS-5 and -6 trials showed that low baseline haemoglobin levels were related to a poor outcome and risk of bleeding, which was significantly lower with fondaparinux than with enoxaparin/UFH/placebo (2). Also, in STEMI patients undergoing primary PCI anaemia at presentation was associated with a bad outcome (3).
  • Register studies suggested that clopidogrel therapy is beneficial in the treatment of STEMI and in NSTEMI/STEMI (4,5). A maintenance dose of 150 mg daily of clopidogrel was shown to inhibit ADP-induced platelet aggregation more efficiently than the usual dose of 75 mg daily in a randomized study on patients undergoing PCI (6). The PRACTICE study revealed no effect of eptifibatide in patients with NSTEMI treated with aspirin, clopidogrel and invasive therapy (7).
  • German register data from diabetics with STEMI showed a 50 % reduction in hospital mortality with primary PCI as compared to thrombolysis (8). In the recently published EMERALD and the RESCUE Trial, neither distal protection nor thrombectomy improved outcome during primary PCI. Accordingly, a meta-analysis showed no benefit of thrombectomy and distal protection (9). However, in the VAMPIRE study thrombus aspiration prior to primary PCI improved myocardial microcirculation evaluated by myocardial blush rate (10). In patients with late reperfusion (>12 hours) thrombus aspiration was associated with an improvement in post-procedural TIMI-3 flow (10) and, furthermore, in the DEAR-MI study thrombus aspiration led to better myocardial reperfusion (11).

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.


1. C.B. Granger, L. Wallentin, A. Avezum. Fondaparinux results in less bleeding than enoxaparin, irrespective of heparin use, for patients with acute coronary syndromes. Eur Heart J 2006; 27: abstract 2736

2. J.-P. Bassand, A. Budaj, L. Wallentin. Relationship of baseline hemoglobin levels with short term outcome in acute coronary syndromes. Insights from the OASIS 5 and 6 trials. Eur Heart J 2006; 27: abstract 1035

3.  K. Ando, Y. Soga, S. Shirai et al. The impact of anemia on in-hospital and long-term outcomes in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Eur Heart J 2006; 27: abstract 1428

4. U. Zeymer, O. Koeth, T. Bauer. Effect of clopidogrel on inhospital events in patients with acute ST elevation myocardial infarction treated with and without early reperfusion therapy.  Eur Heart J 2006; 27: abstract 5036.

5. JC Stauffer, D Rado vanovic, P Urban et al.Clopidogrel: what is the impact of such treatment on MACE rate and mortality in acute coronary syndromes? Eur Heart J 2006; 27: abstract 5037

6. N.V.B. Von Beckerath, A.K. Kastrati, A.W. Wieczorek, G.P.M. Pogatsa-Murray, D.S. Sibbing, A.S. Schoemig. A double-blind randomized comparison between two different clopidogrel maintenance doses after percutaneous coronary intervention (ISAR-CHOICE 2 Trial). Eur Heart J 2006; 27: abstract 5039

7. E. Durand, C. Hamm, C.M. Macaya et al. A randomized controlled trial of eptifibatide in patients presenting non-ST segment elevation acute myocardial infarction treated with an invasive strategy. Eur Heart J 2006; 27: abstract 2737.

8. A.K. Gitt, H. Wienbergen, U. Zeumer, T. Heer, F. Towae, M.G. Gottwik. Relative 50%-reduction of hospital mortality by primary PCI ad compared to thrombolysis for STEMI in the high risk polulation of diabetics in clinical practice - results of the ACOS registry. Eur Heart J 2006; 27: abstract 190.

9. H. Salazar, M. Masotti, R. Ruiz-Salmeron et al. Role of thrombectomy and distal protection devices in acute myocardial infarction. Is their routine use of clinical benefit: A meta-analysis. Eur Heart J 2006; 27: abstract 4604.

10. T. Isshiki, K. Kozuma, M. Sakurada et al. Thrombus aspiration prior to coronary intervention improves myocardial microcirculation in patients with ST elevation acute myocardial infarction, the VAMPIRE study.  Eur Heart J 2006; 27: abstract 1022.

11. P. Colombo, P.S.O. Silva Orrego, R.B. Bigi, D.G. Gregori. Thrombus aspiration improves myocardial reperfusion in acute myocardial infarction: the DEAR-MI (Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction) study. Eur Heart J 2006; 27: abstract 4608.


Vol5 N°09

Notes to editor

Dr. S. D. Kristensen,
Aarhus, Denmark
Past-chairman of the ESC WG Thrombosis

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.