Vienna, Austria, 3 September 2007: We have demonstrated that patients who have an acute myocardial infarction and are admitted to a hospital which has no possibility to perform direct angioplasty, benefit from being transferred immediately after having received thrombolytics to a hospital where angioplasty (percutaneous coronary intervention, PCI, often including stent implantation) can be immediately performed.

Patients who are transferred and receive angioplasty immediately after thrombolytics are much more likely (4.1% vs. 11.1% at 30 days, p<0.001) to be free from adverse events such as death, a new myocardial infarction, a new acute episode of chest pain and ECG changes requiring urgent angioplasty (refractory ischaemia). This advantage was present despite the fact that all the patients (36% of the entire conservative group) randomized to the group of more conservative treatment (no immediate transfer) were also promptly referred during the first hours post treatment if there was no evidence in their ECG/clinical status that the lytic drugs had open the occluded artery.

Clinical implications: When a patient cannot receive direct angioplasty, which unfortunately still includes the majority of the patients with acute myocardial infarction in most European countries, the current practice in most hospitals in Europe is to administer lytics and to wait, watching the effect of the drug on ECG and patient's symptoms. It appears that this practice is wrong and all patients should be transferred immediately for angioplasty after thrombolysis is started. The reason why this does not happen, despite the fact that an ESC Guideline advises the practice, is because there was evidence from recent trials, namely ASSENT-4, reported in Lancet 2006; 367:569-68, that lytics immediately before PCI can be deleterious and increase the risk of adverse events, especially bleedings but also death and need for new emergency angioplasty.

We had an opposite result and we believe the reason is the type of lytic treatment used -- not just a thrombolytic drug, but a cocktail of a powerful intravenous anti-platelet agent called abciximab, and a reduced dose of a fibrin specific lytic drug called reteplase. This combination is very powerful and rapid in its action, with a synergistic effect demonstrated in previous trials and in in-vitro models, and achieved restoration of flow in the occluded artery in 85% of cases by the time patients reached the hospital where angioplasty was performed. Its main advantage is, however, the ability to inactivate platelets during the subsequent angioplasty, the opposite of the result observed when only lytics are given which tend to activate platelets instead.

The study: The trial was conducted in 3 European countries (Italy, Poland and France), involved various networks of community hospitals referring to a larger hospital with a 24 hour service 7 day a week for direct PCI of acute myocardial infarction. Patients were randomized with telephone allocation at the time of admission with all adverse events blindly reviewed by an independent Committee for adjudication and all ECG and angiograms analysed by an independent Core Laboratory unaware of the treatment received. The study was sponsored by a scientific society, the Italian Society of Invasive Cardiology -GISE) and was designed and conducted by independent investigators, with data entry and analysis performed blind to the randomization code by the Clinical Trial Unit of the Royal Brompton Hospital in London.

The interval between administration of the thrombolytic drug and angioplasty was greater than 120 minutes in more than half of the patients (median 136 minutes) which means they were not candidate for primary angioplasty under the current guidelines which require an interval of less than 90 minutes between first qualified medical contact and direct angioplasty. The current fear to give thrombolytics before angioplasty is challenged by the low incidence of bleeding observed in this trial (0.8% intracranial haemorrhages and 2.9% bleedings requiring 1 or more transfusions, with no difference between patients transferred for immediate angioplasty and patients who remained in the hospital of initial admission ).

In our view, the lower rate of bleeding complications was due to the inclusion of patients at low risk of bleeding (young, ie < 75 years old and well screened for contraindications to thrombolytics). We excluded older patients or patients with high bleeding risk from this trial because we believed in those cases it was more reasonable a less aggressive pharmacological strategy (for instance using only abciximab) or primary angioplasty. We believe the results will also lead to a more liberal use of a strategy of facilitated angioplasty (ie the use of lytics before angioplasty) when there is no certainty that the angioplasty can be swiftly performed within 90 minutes.

The results are of particular interest for patients living in rural areas or in the mountains, with an expected delay greater than 90 minutes to reach a centre able to perform angioplasty. Interestingly, even in the best models of angioplasty network (for instance in the recently reported experience of the Minnesota -AMC Minneapolis acute myocardial infarction network, using medically equipped helicopters for patient transferred in >70% of cases) almost half of the patients reached the Cath Lab of the receiving hospital in more than 120 minutes, suggesting that facilitated angioplasty has great potential applications.

IMPORTANT NOTE: This study will be presented immediately after a larger trial of almost 2,000 patients called FINESSE, with a PI from the Cleveland Clinic, Dr Stephen Ellis. The results of this second trial in AMI will be complementary to the CARESS results because FINESSE compares direct (primary) angioplasty with facilitated angioplasty using only abciximab or using the same combination of drugs we used in this trial. I expect the combined presentation of these 2 trials, with ours clearly positive and reaching unquestionable statistical significance with a favourable effects on all the endpoints (death, re-AMI and refractory ischaemia) will represent one of the highlights of this year's ESC congress.

REFERENCES
Collet J, Montalescot G, Lesty C, Weisel JW. A structural and dynamic investigation of the facilitating effect of glycoprotein IIb/IIIa inhibitors in dissolving platelet-rich clots. Circ Res 2002; 90: 428-32

Herrman HC, Moliterno DJ, Ohman EM, et al. Strategies for Patency Enhancement in the Emergency Department (SPEED) Group. Trial of Abciximab with and without low-dose Reteplase for acute myocardial infarction. Circulation 2000;101:2788-2794.

Antman EM, Giugliano RP, Gibson CM, et al. for the TIMI 14 Investigators. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. Circulation 1999;99:2720-32

Savonitto S, Armstrong PW, Lincoff, et al. Risk of intracranial haemorrhage with combined fibrinolytic glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction. Dichotomous response as a function of age in the GUSTO V trial. Eur Heart J 2003; 20: 1807-14

Dudek D, Zmudka K, Kaluzag L, et al. Facilitated percutaneous coronary intervention in patients with acute myocardial infarction transferred from remote hospitals. Am J Cardiol 2003; 91: 227-9

Di Mario C, Dudek D, Bolognese L, et al. ClinicalTrials.gov Protocol registration number 00220571
Van der Werf F on behalf of the "Assessment of Safety and Efficacy of a New Treatment strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) Investigators. Primary vs tenecteplase facilitated percutaneous coronary intervention in patients with ST segment elevation acute myocardial infarction. The ASSENT 4 PCI randomised trial. Lancet 2006;367:569-78

Kastrati A, Mehilli J, Schlotterbeck K, Dotzer F, Dirschinger J, Schmitt C, Nekolla SG, Seyfarth M, Martinoff S, Markwardt C, Clermont G, Gerbig HW, Leiss J, Schwaiger M, Schomig A; Bavarian Reperfusion Alternatives Evaluation (BRAVE) Study Investigators.Early administration of reteplase plus abciximab vs abciximab alone in patients with acute myocardial infarction referred for percutaneous coronary intervention: a randomized controlled trial. JAMA. 2004;29:947-54.

Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C, Underwood SR, Vahanian A, Verheugt FW, Wijns W. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2003;24(1):28-66.

Notes to editors:
Liberal grants from pharmacological (Eli Lilly) and device Companies (Biotronik AG) were used to cover the costs of running the trial with no interference allowed in the study interpretation and report. The study was approved by the Ethics Committees of all participating hospitals, with informed consent obtained in all cases.

The European Society of Cardiology (ESC)
The ESC represents nearly 53,000 cardiology professionals across Europe and the Mediterranean. Its mission is to reduce the burden of cardiovascular disease in Europe.

The ESC achieves this through a variety of scientific and educational activities including the coordination of: clinical practice guidelines, education courses and initiatives, pan-European surveys on specific disease areas and the ESC Annual Congress, the largest medical meeting in Europe. The ESC also works closely with the European Commission and WHO to improve health policy in the EU.

The ESC comprises 3 Councils, 5 Associations, 19 Working Groups, 50 National Cardiac Societies and an ESC Fellowship Community (Fellow, FESC; Nurse Fellow, NFESC). For more information on ESC Initiatives, Congresses and Constituent Bodies see www.escardio.org.

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