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 3 Facilitated reperfusion with pre-hospital glycoprotein IIb/IIIa inhibition: Predictors of complete ST-segment resolution before primary PCI in the On-TIME 2 trial A.A.C.M. Heestermans, H. Suryapranata, J.M. ten Berg, A. Mosterd, A.T.M. Gosselink, W. Kochman, T. Dill, G. van Houwelingen, E. Kolkman, J.W. van Werkum, F. Zijlstra, C. Hamm, A.W.J. van t Hof Submitted

3 Chapter 3 Abstract Objective: To evaluated the incidence, predictors and outcome of complete ST-segment resolution (STR) during transportation after pre-treatment with dual or triple anti-platelet therapy in the Ongoing Tirofiban in Myocardial Infarction Evaluation (On-TIME) 2 trial. Methods: ST-segment elevation myocardial (STEMI) patients were randomized in the ambulance to pre-treatment with high dose tirofiban (HDT) or to a control pre-treatment (placebo or no HDT) on top of 600 mg clopidogrel, 500 mg aspirin and 5000 IU unfractionated heparin. Complete STR was defined as 70% STR on the ECG obtained before PCI as compared to the inclusion ECG. Results: Complete STR before PCI occurred in 16.8% and more frequently in the HDT group (19.0% vs. 14.6%; P =.05). Independent predictors for complete STR before PCI were younger age, fast diagnosis, longer pre-treatment time and randomization to HDT. Complete STR before PCI was associated with very low 30-day and 1-year mortality. Conclusions: Dual or triple anti-platelet pre-treatment in the ambulance results in complete STR before PCI in 17% of patients. Fast STEMI diagnosis, pre-hospital initiation of pre-treatment early after symptom onset and HDT independently predicted STR before PCI. Complete STR is associated with very favorable outcome. 50

4 Antiplatelet therapy in myocardial infarction Introduction In patients with ST-segment elevation myocardial infarction (STEMI) outcome is strongly influenced by the time from symptom onset to successful reperfusion therapy [1-3]. Primary percutaneous coronary intervention (PCI) combined with effective antiplatelet therapy including aspirin, clopidogrel and glycoprotein IIb/IIIa inhibitors is the preferred treatment [4-8]. Despite the evidence of improved clinical outcome with the use of glycoprotein IIb/IIIa inhibitors in primary PCI, the timing of administration is still debated [9,10]. Most often, glycoprotein 2b/3a inhibitors are initiated not earlier then at the PCI center, often shortly before or during PCI. However, than one misses the extra effect of the drug during transportation of the patient. Yet, it is appreciated that complete ST-segment resolution (STR), a well known marker of restored myocardial perfusion, might occur during transportation before primary PCI and this in particular has been associated with improved clinical outcomes [11-13]. In the present analysis of the Ongoing Tirofiban in Myocardial Infarction Evaluation (On-TIME) 2 trial we evaluated the incidence, characteristics and outcome of patients with complete STR before primary PCI. In addition, we evaluated whether early pre-hospital initiation of high dose tirofiban (HDT) increased the number of patients with complete STR before primary PCI. Methods Patient population The patient population of the On-TIME 2 trial [14] consisted of consecutive patients with STEMI who were candidates for primary PCI. In the run-in phase of the On-TIME 2 trial, two intervention centers in the Netherlands enrolled 414 patients in the ambulance to HDT or no HDT in an open-label randomized fashion. This open-label randomized phase was followed by a double-blind, placebo controlled phase which enrolled 984 patients in an international multicenter study [6]. Identical inclusion and exclusion criteria and concomitant treatment regimens were used in both phases of the On-TIME 2 trial [7]. Patients were randomly assigned to pre-hospital initiation of HDT (tirofiban (25 μg/kg bolus and 0.15 μg/kg/min maintenance infusion for 18 h) or no HDT in the ambulance in addition to 500 mg of aspirin (Aspegic ), 5000 IU unfractionated heparin administered intravenously, and a 600 mg loading dose of clopidogrel. For the present analyses data from the open-label randomized phase (414 patients) and the doubleblinded randomized phase [6] (984 patients) were combined to an active treatment group (randomization HDT) with 709 patients and a control group (randomization 51

5 Chapter 3 placebo or no HDT) with 689 patients [7]. The study inclusion criteria for patients were age years, symptoms of STEMI more than 30 minutes but less then 24 hours, and ST-segment elevation >1 mv in 2 adjacent electrocardiogram (ECG) leads. Full exclusion criteria have been published previously [14]. Key exclusion criteria included known severe renal dysfunction, therapy resistant cardiogenic shock, or an increased risk for bleeding. Before primary PCI additional unfractionated heparin was administered only in cases where the activated clotting time was less then 200 seconds. Informed consent was obtained in the ambulance or referring hospital. All local ethical committees involved approved the study protocol of the On-TIME 2 trial for both the open-label and double-blinded phase. ST-segment analysis ST-segment analysis was performed on ECGs recorded at several time points. First, prehospital at the time of inclusion by the ambulance employees. Second, in the cathlab before angiography and thirdly, one hour after primary PCI. An independent core lab (Diagram BV, Zwolle, Netherlands) analyzed all ECGs as previously described [15]. Briefly, the sum of ST-segment deviation in all 12 leads was measured 20 ms after the end of the QRS complex with a caliper. ST segment-deviation was calculated on the single ECG obtained pre-hospital, at the catheterization lab before angiography and after primary PCI. In patients with available paired ST-segment analysis we defined STR before angiography as complete ( 70%), partial (between 30% and 70%), and no resolution (<30%) as described previously [15,16]. Assessment of angiographic and clinical outcome Detailed data on angiographic and procedural characteristics of the primary PCI were collected. An independent core lab (Diagram BV, Zwolle, Netherlands) analyzed all angiograms. Thrombolysis in myocardial infarction (TIMI) epicardial flow and myocardial blush grade (MBG) were assessed as described previously [17]. Intra coronary thrombus was defined as the presence of a intraluminal non calcified central filling defect or lucency surrounded by contrast material seen in multiple projections. Enzymatic myocardial infarction (MI) size was estimated by peak creatinine kinase (CK) in IU/L in the first 48 hours after the acute event. Detailed information on major adverse cardiac events such as death, recurrent MI, urgent target vessel revascularization and TIMI major bleeding was collected through outpatient clinic visits, telephone interviews, hospital records, attending physicians or interviews with relatives. A blinded, independent clinical endpoint committee adjudicated all clinical endpoints apart from death. 52

6 Antiplatelet therapy in myocardial infarction Statistical analysis All statistical analyses were performed with SPSS for Windows (Rel Chicago: SPSS Inc.). Univariate analyses of predictors for complete STR before primary PCI were conducted with the chi-square test or Fisher s exact test for categorical variables, the chi-square for trend for ordinal variables, and the Mann-Whitney U test for continuous variables. Multivariate analyses of predictors for complete STR before primary PCI were done using logistic regression models. Statistical analyses were performed on the combined data from the On-TIME 2 trial double blind and open label phases. Baseline characteristics and outcome of the open-label phase and doubleblinded phase were analyzed for similarity before combining the data. All p-values were two-sided with significance level P <.05. Results Information of STR before angiography was available in 1121 patients (80.2%) and these patients form the basis of this report. Complete STR before PCI was present in 188 patients (16.8%). Baseline characteristics of patients with complete versus incomplete STR before PCI are described in Table 1. The extent of ST deviation at baseline, upon diagnosis in the ambulance, was not different between the 2 groups. Patients with complete ST resolution were younger, were more often active smokers, had a shorter duration of symptoms upon diagnosis and had a longer time from study drug administration to angiography (pre-treatment time). After multivariate analyses, younger age, shorter time to diagnosis, longer duration of pre-treatment and randomization to HDT were independently associated with complete STR before PCI (Table 2). Angiographic findings and outcome Patients with complete STR before PCI less often had visible thrombus (33.1% vs. 63.5%, P <.001) and more often had TIMI 3 flow of the infarct related vessel at initial angiography (50.8% vs. 14.4%, P <.001). In patients with complete STR at initial angiography operators used shorter stents, (22.5 ± 11.8 mm vs ± 11.6 mm, P =.007, and more often stented without pre-dilatation, 48.6% vs. 34.9%, P =.002. After PCI, MBG 3 was more often present in patients with complete STR before angiography (58.8% vs. 40.3%, P <.001) (Table 3). 53

7 Chapter 3 Table 1 Baseline and angiographic characteristics of the patients Variable 54 Incomplete STsegment resolution before angio (n=933) Complete ST-segment resolution before angio (n=188) P value Baseline characteristics Age, year, median (25th, 75th percentile) 62 (53.7, 71.6) 57 (51.1, 65.8) <.001 Men, % Diabetes mellitus, % Hypertension, % Current smoking, % Hyperlipidemia, % Anterior infarct location, % Family history of CVD, % Prior MI, % Prior PCI, % Prior CABG, % Prior stroke, % Body mass index, kg/m 2, (25th, 75th 26.5 (24.3, 28.7) 26.1 (24.2, 28.4).24 percentile) Cumulative ST-segment deviation at.25 diagnosis, mm, mean ± SD 14.2 ± ± 10.9 Time from onset of symptoms to diagnosis, min (25th, 75th percentile) 81 (47,154) 57 (37,116) <.001 Time from start study medication to angiography, min (25th, 75th percentile) 55 (45, 70) 61 (48.3, 83.8).001 Transportation time, min (25th, 75th 35 (20, 49.5) 37 (20, 51.25).378 percentile) Door-to-balloon time, min (25th, 75th percentile) 37 (26, 52) 40 (27, 70).015 Ischemic time, min (25th, 75th percentile) (131, 246) (120, 219).15 Angiographic characteristics Multi-vessel disease, % Infarct-related vessel Left anterior descending coronary artery, % Right coronary artery, % Left circumflex artery, % Saphenous-vein graft, % Left main coronary artery, % Coronary flow infarct related artery before PCI TIMI 0-1 flow, % TIMI 2-3 flow, % <.001 Intracoronary thrombus, % <.001 Procedural characteristics Thrombus aspiration, % Coronary stenting, % TIMI 3 flow after PCI, % MBG 3 after PCI, % <.001 Distal embolization, %

8 Antiplatelet therapy in myocardial infarction Table 2 Independent predictors of complete ST-segment resolution before angiography Variable Odds ratio P value (95% confidence interval) Randomization Tirofiban 1.39 ( ).05 Current smoking 1.29 ( ).13 Male sex 1.27 ( ).23 Time from start study medication to angiography per 15 minutes 1.09 ( ).003 Time from onset of symptoms to diagnosis per 15 minutes 0.97 ( ).004 Age per 10 year increase 0.82 ( ).01 The extent of residual ST-segment deviation one-hour post PCI was significantly lower in those with complete STR at initial angiography (4.8 ± 6.1 mm vs. 1.4 ± 2.8 mm, P <.001). Fig. 1 shows the percentage of patients in each group of residual ST deviation. Enzymatic infarct size (Peak CK (650 ± 851 IU/L vs ± 1816 IU/L, P <.0001)), 30-day mortality (0.5% vs. 2.8%, P =.07) and 1-year mortality (1.1% vs. 5.0%, P =.019) were lower in patients with complete STR during transportation (Table 3). We found no difference in the incidence of TIMI major or minor bleeding between patients with complete STR and incomplete STR before PCI (2.2% vs. 3.6%, P =.34 and 4.4% vs. 4.8%, P =.802 for 30-day TIMI major en minor bleeds respectively). More important we found no difference in TIMI major or minor bleeds between HDT treatment and the controls (Fig. 2) > 6 mm residual ST devia!on Pa!ents (%) mm residual ST devia!on 1-3 mm residual ST devia!on normalized n p-value Incomplete Complete ST Resolu!on ST Resolu!on < Fig. 1. Cumulative ST-segment deviation post PCI 55

9 Chapter 3 Table 3 ST resolution, enzymatic infarct size, clinical outcome and safety Variable Incomplete ST-segment resolution before PCI (n=933) Complete ST-segment resolution before PCI (n=188) P value Electrocardiographic outcome Residual ST deviation 1 hr after PCI 0 mm, % mm, % mm, % >6 mm, % <.001 Complete ST resolution, % <.001 Residual ST deviation > 3mm, % <.001 Enzymatic infarct size Peak CK, median (25th, 75th percentile) 1520 (643, 2909) 321 (155, 778) <.001 Troponin T at 24 hrs, median (25th, 75th percentile) 2.94 (1.33, 4.96) 0.55 (0.17, 1.76) <.001 Troponin T at 72 hrs, median (25th, 75th 2.19 (1.05, 3.35) 0.54 (1.13, 1.33) <.001 percentile) Clinical outcome Clinical outcome at 30-days Death, % Re MI, % Urgent TVR, % MACE, % Clinical outcome at 1-year Total death, % Cardiac death, % Safety end points at 30-days TIMI bleeding, % TIMI minor bleeding, % TIMI major bleeding, % CABG related bleeding, % Stroke, %

10 Antiplatelet therapy in myocardial infarction Pa!ents (%) 5.0 minor bleeding major bleeding Controls High Dose Tiro ban n total p-values (minor), (major), (total) Fig. 2. TIMI major and minor bleeding according to randomization Effect of high dose tirofiban on ST resolution before PCI The incidence of complete STR before PCI was 19.0% (105/553) in the HDT group vs. 14.6% (83/568) in the control group (P =.05). HDT as compared to the controls was most effective in patients with a short time to diagnosis ( 75 min) and in patients with a longer duration of pre-treatment (> 55 min) (24.6% vs. 17.0%, P =.03 and 23.7% vs. 16.4%, P =.03, respectively), whereas the difference between HDT and controls was not significant in patients with a longer time to diagnosis (> 75 min) or a shorter time of pre-treatment ( 55 min) (21.1% vs. 12.5%, P =.9 and 13.6% vs. 12.5%, P =.72) (Fig. 3). 57

11 Chapter 3 30 Controls High Dose Tiro ban Pa!ents with Complete ST-Resolu!on (%) n Total Cohort Time Symptom Onset- Diagnosis # Time Symptom Onset- Diagnosis > Time Study Medica!on- Angio # Time Study Medica!on- Angio > 55 p-value Fig. 3. The effect of pre-hospital high dose tirofiban on complete ST-segment resolution before angiography Discussion This study showed that pre-hospital infarct diagnosis in the ambulance, with concomitant initiation of potent antithrombotic and antiplatelet drugs, is associated with a high rate of complete reperfusion before PCI. Complete reperfusion before PCI is more likely to occur in younger patients and in patients with a short duration of symptoms. Also a longer time of drug pre-treatment during transportation or while awaiting preparation of the cathlab was associated with improved ST resolution before PCI. Patients with complete STR before PCI had improved rates of myocardial reperfusion as reflected by improved myocardial blush and ST resolution after PCI, had significantly smaller infarct size and a much better short and long term clinical outcome. The On-TIME 2 trial evaluated whether triple anti-platelet pre-treatment including a glycoprotein 2b/3a blocker may further improve outcome as compared to dual antiplatelet therapy with aspirin and a high loading dose of clopidogrel (600 mg). This subanalysis found that a combination of unfractionated heparin, aspirin, clopidogrel and HDT resulted in complete myocardial reperfusion before PCI in almost 1 in every 5 patients treated. This was particularly evident in patients who received HDT shortly after 58

12 Antiplatelet therapy in myocardial infarction the onset of symptoms and in patients with longer time-intervals between the start of HDT and angiography. These results show that glycoprotein IIb/IIIa blockers exert their beneficial effect already during transportation of the patient to the cathlab and not only during PCI. This extra beneficial effect is lost when the drug is given only during or even after primary PCI. This is probably the reason why results from recent meta-analyses showed a benefit of early administration as compared with late administration of the drug [9,10]. The FINESSE study however, did not show a benefit from early start of Abciximab [18]. However, this is probably due to the fact that Abciximab was given relatively late after symptom onset. Our sub-analysis shows that HDT has most efficacy when it was given very shortly after the onset of symptoms. The incidence of complete STR upon arrival at the cathlab was 14.6% in patients who received aspirin, heparin and high dose clopidogrel only. This percentage is not higher than the 14.9% as mentioned in a study of Bainey and coworkers who gave only heparin and aspirin during transportation [11]. Despite reports of improved initial patency with clopidogrel pre-treatment in STEMI [19] we expect this effect to be limited in the present study. Platelet activation in the setting of STEMI is substantially increased and the level of achieved inhibition of platelet aggregation from a high clopidogrel loading dose in the short time interval between loading dose and primary PCI (+/- 70 min) in the present study is probably insufficient to provide an optimal PCI result [20]. This is in line with a previous study which demonstrated a restricted effect of a 600 mg loading dose of clopidogrel in STEMI patients. A significantly reduced gastrointestinal absorption of clopidogrel in STEMI patients was found, resulting in a significantly lower and delayed magnitude of platelet inhibition as compared to healthy volunteers [21]. This suggests that in patients with STEMI, pharmacologic agents should preferably be given intravenously instead of by mouth. Of equal importance is the fact that pre-hospital administering of HDT is safe and feasible and not associated with an increase in 30-day TIMI major or minor bleeds. We detected several independent predictors of complete STR during transportation: younger age, decreasing time from symptom onset to diagnosis, longer duration of pharmacological pre-treatment and pre-hospital initiation of HDT by the ambulance employees. The association of shorter time from symptom onset to diagnosis and increased incidence of complete STR before PCI in our study is not unexpected and in line with previous reports [22,23]. Patients with complete STR before PCI more often had an open infarct related vessel at initial angiography. These findings agree with the findings of Zijlstra et al who demonstrated that pre-hospital administration of aspirin and heparin resulted in a higher initial patency of the infarct related vessel in patients with acute myocardial infarction [24]. However, not all patients with TIMI 3 flow also have complete STR. A recent study [11] showed that complete STR before PCI was a stronger predictor of outcome than 59

13 Chapter 3 spontaneous or induced coronary patency before PCI. This is probably explained by the fact that myocardial reperfusion often remains impaired despite complete epicardial reperfusion (TIMI 3 flow). In the present analyses earlier initiation and longer pre-treatment time were independent predictors of complete STR. This emphasizes that potent antiplatelet and antithrombotic treatment should be started at the most early possible point in time. One should not wait until arrival of the patient in the cathlab [6,7,9,10]. This seems to be in line with the effectivity of thrombolytic agents which also have the best effect shortly after the onset of symptoms (the so called golden hour )[25]. The success rate of primary PCI was higher in patients with complete STR at the time of arrival in the cathlab (more often MBG grade 3). Enzymatic infarct size was significantly lower and there was a lower mortality at 30-day and 1-year follow-up. This is in accordance with previous studies showing the very favorable outcome of patients with complete normalization of ST-segment elevation before PCI [11,13]. Limitations There are several aspects of this analysis that merit careful consideration. First, data from the two phases of the On-TIME 2 trial with different design (open label and double blind) were combined. However, both study phases had identical in- and exclusion criteria and baseline characteristics and outcome were not statistically different [7]. The effect of Tirofiban on ST recovery before PCI was seen in each study phase. Second, paired ECGs at diagnosis and before angiography were available in 80.2% of patients. However, baseline characteristics of patients without paired ECGs were similar except for Killip classification. Third, this analysis was a post-hoc analysis and therefore should be viewed as hypothesis generating and partly explicatory for the positive results of pre-hospital initiation of HDT in STEMI patients on STR one hour post PCI and mortality in the main On-TIME 2 study [6]. Conclusions Dual or triple anti-platelet pre-treatment in the ambulance results in complete STR before primary PCI in 17% of patients. Fast STEMI diagnosis, early pre-hospital initiation of drug pre-treatment and high dose tirofiban therapy are predictive of complete reperfusion before primary PCI. Complete ST resolution before PCI is associated with a high PCI success rate, small infarct size and very favorable clinical outcome. This effect is missed when potent anti-thrombotic and anti-platelet drugs, including glycoprotein IIb/IIIa blockers are given only after arrival in the catheterization lab. 60

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