Antiplatelet therapy in myocardial infarction and coronary stent thrombosis Heestermans, Antonius Adrianus Cornelius Maria

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1 University of Groningen Antiplatelet therapy in myocardial infarction and coronary stent thrombosis Heestermans, Antonius Adrianus Cornelius Maria IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2010 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Heestermans, A. A. C. M. (2010). Antiplatelet therapy in myocardial infarction and coronary stent thrombosis Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 2 Pre-hospital initiation of Tirofiban in patients with ST elevation Myocardial Infarction undergoing Primary Angioplasty: the On-TIME 2 Trial A.W.J. van t Hof, J.M. ten Berg, A.A.C.M. Heestermans, T. Dill, R.C. Funck, J.W. van Werkum, J-H.E. Dambrink, H. Suryapranata, G. van Houwelingen, J.P. Ottervanger, P. Stella, E. Giannitsis, C. Hamm Lancet. 2008;372:537-46

3 Chapter 2 Abstract Summary: The magnitude and timing of optimal antiplatelet therapy is important in patients with acute ST elevation myocardial infarction (STEMI). We investigated whether the results of primary coronary angioplasty (PCI) can further be improved by the early administration of the glycoprotein 2b/3a blocker tirofiban at first medical contact in the ambulance or referral center. Methods: STEMI patients were randomized to either high bolus dose (HBD) tirofiban or placebo on top of aspirin, heparin and 600 mg clopidogrel. The primary end point was the extent of residual ST segment deviation 1 hour after PCI. Key secondary end point was the combined incidence of death, re-infarction, urgent target vessel revascularization or blinded bailout use of tirofiban at 30 days. The On-TIME 2 trial was registered with ISRCTN number Findings: From June 2006 until November 2007, 984 patients were randomized; 95% in the ambulance, at a median of 76 minutes after symptom onset. Residual ST deviation before PCI (10.9 ± 9.2 mm versus 12.1 ± 9.4 mm, p=0.028) and 1 hour after PCI (3.6 ± 4.6 mm versus 4.8 ± 6.3 mm, p=0.003) was significantly lower in patients pre-treated with HBD tirofiban. Also the key secondary end point was significantly reduced in tirofiban pre-treated patients (26.0% versus 32.9%, p=0.020). No significant difference in bleeding was present. Interpretation: Routine pre-hospital initiation of HBD tirofiban, on top of high dose clopidogrel, improved ST segment resolution and clinical outcome after PCI. The results emphasize that further platelet aggregation inhibition besides high dose clopidogrel is mandated in patients with STEMI undergoing PCI. 30

4 Antiplatelet therapy in myocardial infarction Background Early and complete restoration of blood flow in the infarct-related vessel (IRV) after acute myocardial infarction (MI) is associated with improved survival and clinical outcomes [1-3]. Both short- and long-term outcomes are better after primary percutaneous coronary angioplasty (PCI) than after fibrinolytic therapy for acute MI [4-6]. The benefits of PCI have mainly been attributed to accelerated and improved myocardial reperfusion [3]. Platelet activation and aggregation play a crucial role in the cascade of events leading to MI, as well as in the thrombotic complications that can accompany PCI. Insufficient inhibition of platelet aggregation at the time of PCI correlates with increased likelihood of major cardiovascular adverse events after PCI [7]. Antiplatelet therapy, therefore, is an important component of medical therapy for patients with acute MI. Triple antiplatelet treatment, including aspirin, a thienopyridine, and a glycoprotein 2b/3a blocker, is recommended for high-risk patients with non-st segment elevation acute coronary syndromes [8]. Although many studies have reported beneficial results of routine treatment with a glycoprotein 2b/3a blocker shortly before PCI [9,10], the additional value of early pre-hospital 2b/3a blockade on top of dual antiplatelet therapy including high dose clopidogrel in patients with acute MI has not been established. Similarly, the most effective timing of administration of antiplatelet and anti-thrombotic drugs in this setting remains subject of clinical investigation [11,12]. Patients and Methods The Ongoing Tirofiban in Myocardial Evaluation (On-TIME) 2 trial was a prospective, multicenter, placebo controlled, randomized, clinical trial. The rationale and design of the study has been described previously [13]. In brief: the study population consisted of patients with STEMI who were candidates to undergo primary PCI. Eligible patients were men and women years of age with symptoms of acute MI of >30 minutes but <24 hours and ST-segment elevation of >1 mv in 2 adjacent electrocardiogram (ECG) leads. Exclusion criteria were known severe renal dysfunction (glomerular filtration rate <30 ml/min or serum creatinine >200 mmol/l [>2.5 mg/dl]); therapy resistant cardiogenic shock (systolic blood pressure 80mmHg for >30 minutes), persistent severe hypertension (systolic pressure >180mmHg and/or diastolic pressure >110mmHg) or a contraindication to anticoagulation or increased risk of bleeding. Also patients with a left bundle branch block, pregnant women or women who were breast-feeding and patients with a life expectancy of <1 year were not eligible for the study. 31

5 Chapter 2 Written informed consent was obtained by either the physician or intensive care nurse in the ambulance or referring hospital. The study protocol was approved by all local ethics committees involved. Patients were randomly assigned to pre-hospital treatment with tirofiban (25 µg/kg bolus and 0.15 µg/kg/min maintenance infusion for 18 hours) or placebo (bolus plus infusion) by using blinded sealed kits with study medication. Kits were distributed among the ambulance services or referring centers in blocks of 4 (2 containing active medication and 2 placebo). The study flow chart is shown in Figure 1. In the ambulance or referring centre, all patients also received a bolus of unfractionated heparin (5000 IU) intravenously together with aspirin 500 mg (Aspegic ) intravenously and a 600 mg loading dose of clopidogrel orally. Before PCI, additional unfractionated heparin was only administered if the activated clotting time was less than 200 seconds. Coronary angiography and PCI were performed according to each institution s guidelines and standards. Before, during or after PCI, bail-out tirofiban could be administered for the following indications: decrement in TIMI flow grade (TIMI flow grades of 0 2 or slow reflow), dissection with decreased flow, distal embolization, side branch closure, abrupt closure of the culprit vessel, clinical instability, and prolonged ischemia. Bailout tirofiban was also administered as the high bolus dose (25 µg/kg bolus). Blinded bail-out bolus vials were included in the medication kit in order to maintain blinding of the initial treatment assignment and to match with the content of the primary infusion. When a bail-out bolus vial was given, the study infusion was replaced by open-label tirofiban maintenance infusion. The primary efficacy endpoint was the extent of residual ST-segment deviation at 1 hour after PCI, as previously described [14]. In brief, the sum of ST-segment deviation in all 12 leads was measured 20 ms after the end of the QRS complex with a caliper. Both residual ST segment deviation on the single post PCI ECG as well as ST segment deviation resolution from paired ECG s were calculated. Patients were divided into 4 groups of residual ST segment deviation (0 mm = normalised ST segment no residual ST-segment deviation; 1-3 mm = residual ST-segment deviation between 1 and 3 mm; 4-6 mm = residual ST-segment deviation between 4 and 6 mm; >6 mm = residual ST-segment deviation more than 6 mm) and into 3 groups of ST segment deviation resolution (complete (>70% resolution), partial (>30% but <70% resolution) and no resolution (<30% resolution), as described previously [14,15]. The key secondary endpoint was the composite of death, recurrent MI, urgent target vessel revascularization (TVR) or blinded bail-out use of tirofiban at 30 days. Other secondary endpoints were Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow of the infarct related vessel (IRV) at initial angiography as well as distal embolisation after PCI. All electrocardiograms and angiograms were analysed by an independent core lab (Diagram BV, Zwolle, the Netherlands). 32

6 Antiplatelet therapy in myocardial infarction A blinded independent clinical endpoint committee (CEC) adjudicated all clinical endpoints except death. Death was defined as all-cause mortality. Recurrent MI was defined as a new increase of creatine kinase MB (CK-MB) 3 times the upper limit of normal, present in two separate blood samples accompanied by chest pain and/or ECG changes. Early recurrent MI was defined as a decrease in creatine kinase MB of at least 50% of the upper limit of normal from a prior peak level to a valley followed by a new increase with a value above the sum of the preceding valley and three times the upper limit of normal. Urgent TVR during the hospitalization period was defined as a new episode of ischemic signs or symptoms at rest with documentation of a new ST-segment shift 0.05 mv (0.5 mm) on a 12-lead ECG that necessitated an unplanned coronary intervention or coronary artery bypass grafting. The safety endpoints of interest included the rates of hemorrhage, transfusions, stroke, thrombocytopenia, and serious adverse events. An independent Data Safety Monitoring Committee (DSMC) was responsible for identifying safety issues and making any recommendation regarding modification or termination of the study to the Executive Committee. Bleeding was assessed by use of the TIMI criteria [16]. Major bleeding was defined as clinical overt signs of hemorrhage associated with a drop in hemoglobin by >5 g/dl (or, when hemoglobin assessment is not available, a decrease in hematocrit of >15%). For patients undergoing coronary artery bypass graft (CABG) surgery, the rate of surgical re-exploration for bleeding and the postoperative volume of blood loss were also evaluated. Follow-up information was derived from outpatient clinic visits or via contact by telephone at 30 days. Statistical Analysis Sample size calculation was based upon the assumption that residual ST-segment deviation of >3 mm at 1 hour after PCI is present in 50% of unselected infarct patients who have not received GP 2b/3a blocker treatment in addition to aspirin, heparin, and clopidogrel [14]. Treatment with the high bolus dose of tirofiban was assumed to decrease the incidence of residual ST deviation of >3 mm by 20%, from 50% to 40%. On the basis of these assumptions, with 80% power and an alpha of 0.05, 814 (2x407) patients were needed to show superiority of tirofiban pre-treatment. To account for incomplete or uninterpretable ECG data and false positive ECG diagnoses for approximately 15% of patients, 958 patients should be randomized. All analyses were performed according to the intention-to-treat principle. The primary and key secondary efficacy variable was analyzed using the χ 2 test or Fischer exact test. In addition the χ 2 test for trend was used to analyze the percentages of patients in each of the four prespecified groups of residual ST-segment deviation and in each of 33

7 Chapter 2 the three groups of ST segment resolution, TIMI flow or Myocardial Blush Grade. All p values were 2 sided. Time-to-event analysis was performed to describe survival free from MACE from the date when the patient was admitted to the hospital with SPSS for Windows, version 15. Survival was represented by Kaplan-Meier curves. Role of funding sources The trial was an investigator initiated trial, designed by the principal investigator (Dr. van t Hof) and the executive committee. The study was partly funded by an unrestricted grant from Merck & Co., Inc., Whitehouse Station, NJ, USA. Other than supplying financial support and the study medication, the funding company was not involved with study processes, including site selection and management, data collection, and analysis. Results From June 2006 until November 2007, 984 patients were randomised at 24 participating centers in 3 countries (the Netherlands, Germany and Belgium). A flow chart of the study is depicted in Figure 1. Four hundred and ninety-one patients were randomised to tirofiban and 493 patients to placebo. Baseline clinical and angiographic characteristics of the patients were not significantly different between the groups (Table 1). Ninety-five percent of patients were included and randomised after pre-hospital infarct diagnosis in the ambulance at a median of 76 minutes after the onset of symptoms. The median transportation distance to the nearest PCI center was 25 km (range km) and the median time from start of antithrombotic pre-treatment (heparin/aspirin/clopidogrel) and study medication until angiography was 55 minutes (interquartile range min). Sixty patients (6.1%) had a false positive infarct diagnosis and were evenly distributed between the groups. 34

8 Antiplatelet therapy in myocardial infarction 984 pa!ents randomized (all included in ITT analysis) 491 assigned to pretreatment with Tiro ban 493 assigned to pretreatment with placebo 482 underwent angiogram 488 underwent angiogram 26 had no CAD 14 CABG indicated 46 treated conserva!vely 422 underwent PCI 439 underwent PCI 22 had no CAD 13 CABG indicated 36 treated conserva!vely 451 could be assessed for primary end point 455 could be assessed for primary end point 14 refused wri"en or withdrew consent 4 lost to FUP 473 had clinical follow-up 477 had clinical follow-up 13 refused wri"en or withdrew consent 3 lost to follow-up Figure 1: Study flow chart showing group assignment and follow-up of patients Upon arrival at the PCI center, a second ECG was made before angiography at a median of 31 minutes after the initiation of study medication. The total amount of residual ST segment deviation was significantly lower in patients pre-treated with tirofiban (10.9 ± 9.2 mm versus 12.1 ± 9.4 mm, p=0.028). Also ST segment resolution was improved before angiography in tirofiban pre-treated patients (Table 2). Acute angiography was performed in 970/984 (98.6%) patients. Four patients died before angiography could be performed and 10 patients did not undergo angiography because of a clear false positive diagnosis on arrival at the hospital. Angiographic characteristics are shown in Table 1. At initial angiography, a completely occluded infarct related vessel (TIMI 0 or 1 flow) was present in 42.0 % in the tirofiban group versus 50.2 % in the placebo group (p=0.01). However, no significant difference in initial TIMI 3 flow of the infarct related artery was present between the groups (21.7 % versus 19.5 % for tirofiban and placebo group respectively (p=0.43). PCI was performed in 861 patients (87.8%). Blinded bail-out tirofiban was administered in 19.9 % and 28.5 % of patients in the tirofiban and placebo group respectively (p=0.002). Distal embolisation was present in 4.5% of tirofiban pretreated patients versus 7.8% in the placebo group (p=0.074). Distal embolisation or no reflow, defined as TIMI 0/1 flow after PCI, occurred less often after pre-treatment with tirofiban (Table 1). 35

9 Chapter 2 Table 1 Baseline and Angiographic Characteristics Placebo (n=493) Tirofiban (n=491) P-value Baseline characteristics Age (years) 62.0 ± ± Male gender 370/493 (75.1%) 376/491 (76.6%) BMI (kg, ± SD ) 26.7 ± ± Current smoker 240/488 (49.2%) 219/488 (44.9%) Anterior infarct location 185/441 (42.0%) 182/426 (42.7%) Diabetes 54/493 (11.0%) 59/490 (12.0%) Hypertension 170/493 (34.5%) 166/491 (33.8%) Hypercholesterolemia 124/492 (25.2%) 140/490 (28.6%) Family history 192/487 (39.4%) 184/483 (38.1%) Previous MI 37/492 (7.5%) 46/489 (9.4%) Previous PCI 37/493 (7.5%) 50/491 (10.2%) Previous CABG 9/493 (1.8%) 8/491 (1.6%) Previous CVA 11/493 (2.2%) 6/490 (1.2%) Inclusion in ambulance 472/493 (95.7%) 464/491 (94.5%) Killip class > 1 65/485 (13.4%) 54/480 (11.3%) Systolic BP (mm Hg, ± SD) ± ± Diastolic BP (mm Hg ± SD) 77.0 ± ± Heart rate (beats/min ± SD) 75.3 ± ± Cumulative ST deviation diagnostic ECG 14.3 ± ± (mm ± SD) False positive diagnosis 29/493 (5.9%) 31/491 (6.3%) Ischemic Time (minutes, median, Q1-Q3) 167 ( ) 165 ( ) Time SO-diagnosis (minutes, median, Q1-79 (45-156) 72 (44-141) Q3) Time study medication-angio (minutes, 55 (43-70) 55.5 (43-70) median, Q1-Q3) Angiographic characteristics Angiography performed 488/493 (99.0%) 482/491 (98.2%) Three vessel disease 85/488 (17.4%) 84/482 (17.4%) IRV LAD 185/457 (40.5%) 193/450 (42.9%) RCX 53/457 (11.6%) 51/450 (11.3%) RCA 213/457 (46.6%) 202/450 (44.9%) Graft 4/457 (0.9%) 3/450 (0.7%) Left main 2/457 (0.4%) 1/450 (0.2%) TIMI flow at initial angiography TIMI 0/1 229/456 (50.2%) 186/443 (42.0%) TIMI 2 138/456 (30.3%) 161/443 (36.3%) TIMI 3 89/456 (19.5%) 96/443 (21.7%) ACT value (seconds ± SD) 180 ± ± Extra UFH (2.500 IU) 353/485 (72.8%) 345/477 (72.3%) PCI performed 439/493 (89.0%) 422/488 (86.5%)

10 Antiplatelet therapy in myocardial infarction PCI immediately after angiography 437/439 (99.5%) 418/422 (99.1%) Stent placement 392/437 (89.7%) 378/418 (90.4%) Drug eluting stent 85/392 (21.7%) 97/378 (25.7%) Bare metal stent 310/392 (79.1%) 286/378 (75.7%) Additional devices 103/488 (21.1%) 84/482 (17.4%) Rescue trombosuction 75/488 (15.4%) 58/482 (12.0%) IABP 26/488 (5.3%) 19/482 (3.9%) Temporary pacemaker 2/488 (0.4%) 6/482 (1.2%) Other 5/488 (1.0%) 8/482 (1.7%) TIMI flow post PCI TIMI 0/1 17/436 (3.9%) 11/419 (2.6%) TIMI 2 15/436 (3.4%) 31/419 (7.4%) TIMI 3 404/436 (92.7%) 377/419 (90.0%) Distal embolization post PCI 28/360 (7.8%) 15/333 (4.5%) Timi flow 0/1 or distal embolization post PCI 45/436 (10.3%) 26/419 (6.2%) Myocardial Blush Grade post PCI MBG 0/1 86/411 (20.9%) 101/394 (25.6%) MBG 2 143/411 (34.8%) 121/394 (30.7%) MBG 3 182/411 (44.3%) 172/394 (43.7%) BMI= Body Mass Index, MI = Myocardial Infarction, PCI = Percutaneous Myocardial Infarction, CABG = Coronary Artery Bypass Grafting, CVA = Cerebrovascular Attack, BP = Blood Pressure, SO = Symptom Oet IRV = Infarct Related Vessel, LAD = Left Anterior Descending artery, RCX = Ramus Circumflex artery, RCA = Right Coronary Artery, TIMI = Thrombolysis In Myocardial Infarction, ACT = Activated Clotting Time, UFH = Unfractionated Heparin, IABP = Intra Aortic Balloon Pump, MBG = Myocardial Blush Grade No difference in final TIMI 3 flow was present between the groups. An interpretable ECG minutes post Angio or PCI was present in 906 patients (92.1%). The percentage of patients with more than 3 mm residual ST deviation, was 38.1 % in the tirofiban group versus 45.1 % in the placebo group, (primary end point, p=0.035, Table 2). Further analysis showed a significant trend towards less residual ST deviation in each of the 4 pre-specified subgroups for the patients pre-treated with tirofiban and a significant better ST segment resolution after comparison with the ECG made at diagnosis (Table 2, Figure 2). Figure 3 shows the Risk Ratios and 95% confidence intervals for the incidence of the primary end point in each of the pre-specified subgroups of patients. Thirty day follow-up was complete for 950/984 patients (96.5%). Twenty-seven patients refused written informed consent after having given oral informed consent in the ambulance and 7 patients were lost to follow-up. All clinical and safety associated parameters are described in Table 3. The combined incidence of death, recurrent MI, urgent TVR or blinded bail-out use of tirofiban was 26.0 % in the patients pre-treated with tirofiban as compared to 32.9 % in the placebo arm (p=0.020), with especially a strong reduction in the need for bail-out study medication. The extent of residual ST 37

11 Chapter 2 deviation one hour after PCI (5.5 ± 7.2 mm for bail-out versus 3.7 ± 4.8 mm for no bailout, p=0.005) and the rate of major adverse cardiac events (MACE: 12.2% (29/237) for bail-out versus 5.6% (40/709) for no bail-out, p=0.001) were significantly related to the need for bail-out study medication. Kaplan Meier survival free from the key secondary end point is depicted in Figure 4. Total mortality was 2.3% in tirofiban pre-treated patients as compared to 4.0% in patients allocated to placebo or no tirofiban (p=0.144). The incidence of major bleeding was not significantly different between the two groups. Table 2: ECG parameters at baseline, upon arrival at PCI center and after Angio/PCI Placebo (n=493 ) Tirofiban (n=491 ) P value Cum. ST deviation Diagnostic ECG (Ambu, mm ± SD) 14.3 ± 9.1 (n=475) 14.5 ± 9.1 (n=470) Cum ST deviation pre Angio (PCI center, mm ± SD) 12.1 ± 9.4 (n=409) 10.9 ± 9.2 (n=380) ST resolution Diagnosis pre Angio Complete ST resolution 61/396 (15.4%) 76/367 (20.7%) Partial resolution 74/396 (18.7%) 72/367 (19.6%) No resolution 261/396 (65.9%) 219/367 (59.7%) Cum ST deviation 1 hr post Angio/PCI (mm ± SD) 4.8 ± 6.3 (n=455) 3.6 ± 4.6 (n=451) Residual ST deviation > 3 mm 1 hr post Angio/ PCI 205/455 (45.1%) 172/451 (38.1%) Residual ST deviation 1 hr post Angio/PCI Normalized ST segment 132/455(29.0%) 160/451 (35.5%) 1 3 mm residual ST deviation 118/455 (25.9%) 119/451 (26.4%) 4-6 mm residual ST deviation 92/455 (20.2%) 85/451 (18.8%) >6 mm residual ST deviation 113/455 (24.8%) 87/451 (19.3%) ST resolution Diagnosis 1 hr post Angio/PCI Complete ST resolution 264/440 (60.0%) 286/436 (65.6%) Partial resolution 104/440 (23.6%) 100/436 (22.9%) No resolution 72/440 (16.4%) 50/436 (11.5%) Cum = Cumulated, PCI = Percutaneous Coronary Intervention 38

12 Antiplatelet therapy in myocardial infarction A Residual ST segment deviation Pa!ents (%) > 6 mm 4-6 mm 1-3 mm normalized n=906 Tiro ban Placebo B ST segment elevation resolution Pa!ents (%) no par!al complete n=876 Tiro ban Placebo Figure 2: Myocardial reperfusion data on electrocardiography, according to treatment group. The percentages of patients are shown according to the degree of residual ST segment deviation (Panel A) or ST segment resolution (Panel B) on the electrocardiogram between 30 and 90 minutes post Angio/PCI. PCI denotes percutaneous coronary intervention. 39

13 Chapter 2 Table 3: Clinical outcome and Safety Placebo (n=477) Tirofiban (n=473) P-value Clinical outcome Death/re-MI/urgent TVR or thrombotic bail-out 157/477 (32.9%) 123/473 (26.0%) Death/re-MI or urgent TVR 39/477 (8.2%) 33/473 (7.0%) Death 19/477 (4.0%) 11/473 (2.3%) Recurrent MI 14/477 (2.9%) 13/473 (2.7%) Urgent TVR 20/477 (4.2%) 18/473 (3.8%) Urgent PCI 19/477 (4.0%) 11/473 (2.3%) Urgent CABG 1/477 (0.2%) 7/473 (1.5%) Thrombotic bail-out 140/492 (28.5%) 97/488 (19.9%) TIMI flow grade 0-2 or 45/492 (9.1%) 29/488 (5.9%) slow reflow Dissection 6/492 (1.2%) 5/488 (1.0%) Distal embolisation 58/492 (11.8%) 44/488 (9.0%) Side branch closure 4/492 (0.8%) 3/488 (0.6%) Abrupt closure of 11/492 (2.2%) 1/488 (0.2%) Culprit vessel Clinical instability 15/492 (3.0%) 13/488 (2.7%) Prolonged ischemia 4/492 (0.8%) 4/488 (0.8%) Safety Major bleeding 14/477 (2.9%) 19/473 (4.0%) Major CABG related 7/477 (1.5%) 10/473 (2.1%) Major non-cabg related 7/477 (1.5%) 9/473 (1.9%) Minor bleeding 21/477 (4.4%) 29/473 (6.1%) Minor CABG related 8/477 (1.7%) 7/473 (1.5%) Minor non-cabg related 13/477 (2.7%) 22/473 (4.7%) Stroke within 30 days 7/477 (1.5%) 1/473 (0.2%) Trombocytopenia (in-hospital) 9/492 (1.8%) 10/489 (2.0%) Net Clinical Outcome * 56/477 (11.7%) 44/473 (9.3%) MI = Myocardial Infarction, TVR = Target Vessel Revascularization, PCI = Percutaneous Myocardial Infarction, CABG = Coronary Artery Bypass Grafting, TIMI = Thrombolysis In Myocardial Infarction, CABG = Coronary Artery Bypass Surgery * the combined incidence of death, re-mi, urgent TVR, stroke or major bleeding. 40

14 Antiplatelet therapy in myocardial infarction Tiro ban Placebo rimary endpoint Residual ST > 3 mm (1 hour) no. / total no. 95% con dence interval p-value All pa!ents 172/ / ( ) Sex female 30/107 47/ ( ) male 142/ / ( ) Age <= 61.3 yr 84/228 99/ ( ) > 61.3 yr 88/ / ( ) Diabetes no 150/ / ( ) yes 22/53 30/ ( ) Loca!on anterior MI 98/ / ( ) non-anterior MI 54/231 78/ ( ) Killip > 1 no 145/ / ( ) yes 25/49 29/ ( ) TIMI ow grade before PCI / / ( ) /91 18/ ( ) Time start study medica!on to balloon in a!on or angio <= 55 min 98/ / ( ) > 55 min 72/221 93/ ( ) Time symptom onset to diagnosis <= 76 min 81/234 89/ ( ) > 76 min 86/ / ( ) Tiro ban be"er Placebo be"er markerwidth indicates number of events Figure 3: Risk Ratios for the primary end point, according to prespecified clinical or angiographic subgroups. Data are reported for the patients who had clinical electrocardiographic data at baseline. MI denotes myocardial infarction, HR heart rate and TIMI Thrombolysis In Myocardial Infarction. 41

15 Chapter p-value = event free survival (%) Tiro ban Placebo no. at risk days Tiro ban Placebo Figure 4: Kaplan Meier event free survival showing survival free from death, recurrent myocardial infarction, urgent target vessel revascularization or blinded bail-out use of study medication. Discussion This study shows that in patients with STEMI, routine pre-hospital initiation of a glycoprotein 2b/3a blocker on top of aspirin, heparin and high dose clopidogrel, improves ST segment resolution before and after PCI. This was associated with a better outcome free from adverse angiographic or clinical events at 30 day follow-up without a significant increase in major bleeding. The routine administration of glycoprotein 2b/3a blockers in patients with STEMI is a class IIa indication according to the 2003/04 guidelines of the American and European Societies of Cardiology [17,18]. However, large registry studies show that in real world daily practice glycoprotein 2b/3a blockers are given in only 25-30% of patients with STEMI, often for bail-out situations [19,20]. Therefore the placebo arm in our study, with provisional use of (HBD) tirofiban in 29% of patients, is a good representation of routine daily practice and is not undertreated. This study shows that further optimalisation of 42

16 Antiplatelet therapy in myocardial infarction platelet aggregation inhibition by using a glycoprotein 2b/3a blocker early before PCI is beneficial. The 2b/3a blocker should not be restricted to those with complications after PCI, even in a setting where high dose clopidogrel is given well in advance of PCI. Previous studies showed that the maximal antiplatelet effect of 600 mg clopidogrel is achieved only after two to four hours and is less effective in patients with STEMI [21,22]. In our study the high bolus dose (25 microgram/kg) of tirofiban was used. Previous studies showed that the 10 microgram/kg bolus dosage did not achieve sufficient platelet aggregation inhibition early after administration [23]. Recent studies indicate that the high bolus dose of tirofiban results in optimal platelet aggregation in a large percentage of patients very early after PCI [24,25]. Recently it was shown that the aspirate which was obtained using thrombosuction before angioplasty in acute STEMI patients, contained platelet rich thrombi in the large majority of patients, emphasizing the importance of early initiation of effective anti-platelet treatment in these patients [26]. Much of the efficacy of tirofiban in this study might be related to the short time-frame between the onset of symptoms of acute myocardial infarction and the administration of study medication. Table 1 shows that the median time from the onset of symptoms until the initiation of study drug was only 76 minutes. Recently, the results of the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) and the Bavarian Reperfusion AlternatiVes Evaluation (BRAVE) 3 Study were published and presented respectively. In FINESSE, no benefit of early versus late administration of abciximab was found [27]. In the BRAVE 3 study, abciximab did not reduce infarct size in patients already pre-treated with 600 mg of clopidogrel [28]. However, in both studies Abciximab was initiated relatively late after the onset of symptoms (> 200 minutes). The Abciximab before Direct Angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up (ADMIRAL) study already showed that most of the benefit was found in those patients who received the 2b/3a blocker in the ambulance well in advance of arrival at the PCI center [29]. Subgroup analysis in our study also shows that the largest effect is seen when patients received tirofiban shortly after the onset of symptoms (Figure 3). It is well known that pre-hospital diagnosis and immediate triage to the nearest PCI center reduces time to treatment and improves outcome [30,31]. In our study patients were diagnosed and triaged in the ambulance by either a physician or a dedicated well trained paramedic. Diagnosis was correct in 94% of patients using computerized ECG algorhythms only, without the need for transmission of the ECG to the hospital. This pre-hospital infarct diagnosis and triage in the ambulance enables the early initiation of anti-thrombotic and antiplatelet pre-treatment well in advance of arrival at the PCI center and early after the start of symptoms. Furthermore, PCI was performed within 90 minutes after infarct diagnosis in the majority of patients and total ischemic time was 166 minutes, also near the goal of 120 minutes, according to the latest 43

17 Chapter 2 STEMI guideline of the American Heart Association and American College of Cardiology [3]. Surprisingly pre treatment with tirofiban improved ST segment resolution after PCI without a significant improvement of final TIMI flow or myocardial blush. This discrepancy between electrocardiographic and angiographic assessment of myocardial reperfusion has been described previously. In the first publication on myocardial blush it is shown that only 65% of patients with blush grade 3 have complete ST segment resolution [33]. Poli et al shows that 19% of patients have residual ST segment elevation despite normal myocardial blush, a group at intermediate risk of adverse events [34]. Presumably, both parameters reflect myocardial reperfusion differently. However, each of them have shown independent prognostic value [35,36]. It is probably the reduction in PCI complications together with the clear trend towards better initial TIMI flow and less distal embolization or no reflow which are responsible for the better ST segment resolution 1 hour after PCI. Our study demonstrates that (HBD) tirofiban improved ST segment elevation resolution already during ambulance transport, before PCI. After PCI, the difference in ST segment resolution between the groups further increased. The latter finding is new as compared to studies on facilitated PCI. The ASsessment of the Safety and Efficacy of a New Treatment strategy with percutaneous coronary intervention (ASSENT) 4 study showed a benefit in ST segment resolution before PCI, but this totally disappeared after PCI and even resulted in a worse outcome in patients pre-treated with full dose Tenecteplase (TNK) [37]. Only few strategies have been able to improve ST segment resolution after PCI: routine thrombosuction of intracoronary thrombus or debris [26], but also earlier reperfusion has been shown to be a major determinant of final ST segment elevation resolution [38]. Both these strategies again demonstrated a clear relationship between ST resolution and mortality. The better ST resolution might also be the reason for the trend towards better survival in our study. Whether this results in a mortality benefit at longer term follow-up will have to be awaited. Clinical outcome will be monitored until one year after randomisation. Triple antiplatelet therapy, with high dose tirofiban on top of high dose clopidogrel (600 mg) and aspirin pre-treatment was not associated with an increased risk of major bleeding. This might be related to a very careful heparin dosing protocol with routine ACT measurements at the catheterization laboratory. Extra heparin (2.500 IU) was only given when ACT was below 200 seconds. A closure device (Angioseal ) was used in 70% of patients. Furthermore, post PCI low molecular weight heparin was discouraged except for patients with large anterior MI. With the results of the recently published Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, one might argue that the unfractionated heparin and glycoprotein 2b/3a blocker is better replaced by 44

18 Antiplatelet therapy in myocardial infarction bivalirudin in order to reduce bleeding [39]. However, in HORIZONS, the high rate of major bleeding in the 2b/3a arm of the study might partly be due to a less strict heparin protocol (heparin given both before (76%) and during procedure (99%), target ACT around 250 seconds). In addition the glycoprotein blocker was given relatively late after symptom onset (> 2 hrs) thereby losing the opportunity for improvement of ST resolution. Therefore a trial comparing the 2 drugs when administered in the ambulance shortly after symptom onset might be needed before switching to bivalirudin in patients undergoing primary PCI for STEMI. The trial was not powered on a difference in clinical outcome between the groups. However, a clear trend towards a better clinical outcome was present, with lower overall mortality and less urgent repeat PCI. One may have doubt about the clinical significance of the need for bail-out study medication. The strong relationship however between MACE and the need for bail-out therapy supports the trend towards better clinical outcome for early tirofiban treatment. Before the start of the On-TIME 2 trial, 2 participating centers in the Netherlands randomised 414 patients in the ambulance to HBD tirofiban or no tirofiban (open label) using the same in- and exclusion criteria and concomitant teatment. By pooling the data of these 414 open label study patients with the 984 patients included in the double blind study (N=1398), the rate of MACE was significantly reduced by early prehospital initiation of HBD tirofiban (5.8% versus 8.6%, p=0.043) with a stong trend towards reduced mortality (2.2% versus 4.1%, p=0.051) without an increased risk of major bleeding (3.4% versus 2.9%, p=0.581, unpublished data). Although combining the results from 2 studies with different design (open label versus double blind) has statistical limitations, it further support the main study findings. A limitation of the trial is that the study results may not apply for patients in cardiogenic shock, renal insufficiency or the very elderly population (>85 years). In addition the study does not answer the question whether initiation of the 2b/3a blocker other than in the ambulance or at a referral center is beneficial. Although many studies showed a beneficial effect of routine 2b/3a blocker initiation pre-pci in the catheterisation laboratory, the results of the BRAVE study suggest less benefit of initiation in the catheterisation laboratory when patients have been pre-treated with high dose clopidogrel [28]. In conclusion, routine pre-hospital administration of the high bolus dose of tirofiban on top of aspirin, high dose clopidogrel and unfractionated heparin improves ST resolution and clinical outcome after PCI for acute ST elevation MI. This effect was seen without an increased risk of major bleeding. The results emphasize that performing primary angioplasty without further intensifying platelet aggregation inhibition before PCI results in supoptimal results, even with upstream high dose clopidogrel. 45

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