Abstract: Aims. The aim of this subanalysis was to assess the net clinical effect of prehospital administration of tirofiban in ST-elevation myocardial infarction (STEMI) patients with high risk of bleeding. Methods. This is a retrospective subanalysis of the On-TIME 2 trial, a multicenter, controlled randomized trial of the effects of high bolus-dose tirofiban given in the ambulance in STEMI patients. Tirofiban was given on top of aspirin, heparin, and clopidogrel. According to CRUSADE, patients with a moderate to very high baseline risk of bleeding were defined as high risk and patients with a very low or low baseline bleeding risk were defined as low risk. Primary endpoint was net adverse clinical events (NACE) at 30 days (defined as the combined incidence of death, recurrent myocardial infarction, urgent target vessel revascularization, stroke, or non-coronary artery bypass graft [CABG]-related major bleeding). Results. Of 1309 patients, a high bleeding risk was present in 291 patients (22.2%). In these high-risk bleeding patients, tirofiban significantly improved after percutaneous coronary intervention (PCI) ST-segment resolution. Administration of tirofiban in high-risk bleeding patients showed no difference in 30-day major adverse cardiac events (MACE) (9.4% vs 13.0%; P=.330; relative risk [RR], 0.72; 95% confidence interval [CI], 0.37-1.39). However, pretreatment with tirofiban was associated with a nonsignificant increase in non-CABG related bleeding (8.6% vs 3.6%; P=.082; RR, 2.38; 95% CI, 0.90-6.39). The net clinical effect (30-day NACE) of tirofiban in this group was balanced (11.5% vs 15.2%; P=.365; RR, 0.76; 95% CI, 0.41-1.38). Conclusion. Prehospital use of tirofiban in STEMI patients with high risk of bleeding improves post-PCI ST-segment resolution, but increases nonsignificantly the risk of non-CABG related bleeding. The net result is a balanced effect on 30-day NACE. Additional studies should clarify how use of bleeding risk scores should modify medical (antiplatelet) therapy.
J INVASIVE CARDIOL 2012;24:84–89
Key words: high-dose tirofiban, glycoprotein IIb/IIIa inhibitors, CRUSADE bleeding score, bleeding, STEMI, primary PCI
Prehospital initiation of high bolus dose (HBD) tirofiban in addition to aspirin, heparin, and high-dose clopidogrel improves clinical outcome,1,2 and is associated with a low risk of bleeding.3 However, bleeding is currently the most common noncardiac complication in patients treated for ST-elevation myocardial infarction (STEMI), and has emerged as an independent predictor for subsequent mortality in patients with acute coronary syndromes (ACS).4-9 Therefore, in patients with a high risk of bleeding, the benefits of tirofiban may be counterbalanced by bleeding complications, resulting in less benefit or even an increased risk of mortality after administration of tirofiban.
It is currently unknown whether prehospital HBD tirofiban in high-risk bleeding patients is beneficial. The aim of this study was to assess the net clinical benefit of early initiation of HBD tirofiban in STEMI patients with high risk of bleeding, using data of the On-TIME 2 trial.
Study design. This study concerns a retrospective pooled subanalysis of the On-TIME 2 trial (n = 984) and its open-label run-in phase (n = 414). The On-TIME 2 trial was a prospective, multicenter, placebo-controlled, randomized clinical trial investigating the effect of prehospital administration of HBD tirofiban on top of aspirin, clopidogrel, and heparin in STEMI patients treated with primary PCI. The On-TIME 2 trial is registered (#ISRCTN06195297). Rationale, design, primary results, and 1-year results of the study have been described previously.1,2,10
Procedures. Patients were randomly assigned to prehospital treatment with HBD tirofiban (25 μg/kg bolus and 0.15 μg/kg/min maintenance infusion for 18 hours) or no HBD tirofiban (‘phase 1’) or placebo (bolus plus infusion) by blinded sealed kits with study drug (‘phase 2’). In the ambulance or referring center, all patients also received a bolus of 5000 IU of unfractionated heparin (UFH) intravenously together with aspirin 500 mg intravenously and a 600 mg loading dose of clopidogrel orally. Before PCI, additional UFH (2500 IU) was only given if the activated clotting time (ACT) was less than 200 seconds. Coronary angiography and PCI were done according to each institution’s guidelines and standards.
Measurements (endpoints, definitions). The primary efficacy endpoint of this retrospective pooled analysis was to assess the net clinical benefit of early initiation of HBD tirofiban in STEMI patients with a high bleeding risk. Net clinical benefit was defined as net adverse clinical events (NACE, defined as the combined incidence of death, recurrent myocardial infarction, urgent target vessel revascularization, stroke, or non-CABG related major bleeding) at 30 days.
Thirty-day major or minor bleeding (non-CABG related) was assessed and adjudicated using the thrombolysis in myocardial infarction (TIMI) scale.11 Because of the low incidence of major and minor bleeding, both bleeding definitions were combined. Major bleeding was defined as either intracranial bleeding or overt bleeding with a decrease in hemoglobin ≥5 g/dL (≥3.1 mmol/L) or a decrease in hematocrit ≥15% within 30 days after admission. Minor bleeding was defined as identified bleeding with decrease in hemoglobin ≥3 g/dL (≥1.9 mmol/L), or >10% decrease in hematocrit. If a bleeding site was not identified, a >4 g/dL (≥2.4 mmol/L) decrease in the hemoglobin concentration or >12% decrease in hematocrit within 30 days after admission would be the criteria. Another secondary endpoint was the composite of major adverse cardiac events (MACE, defined as the combined incidence of death, recurrent myocardial infarction, or urgent target vessel revascularization) at 30 days.
Renal clearance of creatinine was calculated with the Cockcroft-Gault formula.12 The definition of prior vascular disease (prior stroke and/or peripheral artery disease) was adapted from the CRUSADE registry. The definitions of death, recurrent MI, early recurrent MI, and urgent target vessel revascularization have been described previously.1 A blinded, independent clinical endpoint committee adjudicated all clinical endpoints except for death. Follow-up information was derived from outpatient clinic visits or via contact by telephone at 30 days and 1 year.
CRUSADE bleeding score. The CRUSADE bleeding score13 was developed by assigning a weighted integer to each independent predictor on the basis of its coefficient in the final model. The 8 predictors of in-hospital major bleeding were: baseline hematocrit, estimated creatinine clearance, baseline heart rate, baseline systolic blood pressure, female sex, signs of congestive heart failure on presentation, prior vascular disease, and diabetes mellitus. This score was found to perform consistently across the postadmission treatment subgroups (eg, invasive care, use of antiplatelet and/or anticoagulants) in patients with NSTEMI. A point score for each patient was calculated by summing the weighted integers (range, 1 to 100 points) and the bleeding score was divided into quintiles: very low risk ( 20), low risk (21 to 30), moderate risk (31 to 40), high risk (41 to 50), and very high risk (>50).
According to CRUSADE, patients with a moderate to very high baseline risk of bleeding in this sub-analysis were defined as high risk and patients with a very low or low risk baseline bleeding risk were defined as low risk.
Statistical analysis. Statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS Inc.) version 15.0.1. All analyses were done according to the intention-to-treat principle. All P-values were two-sided. For all analyses, statistical significance was assumed when the two-tailed probability value was <.05. Continuous data were expressed as means ± standard deviations and categorical data as percentages, unless otherwise denoted. Differences between continuous data were performed by student’s t test or Mann Whitney U test and the chi-square or Fisher’s exact test was used as appropriate for dichotomous data.
In 1309 patients (93.6%), all 8 CRUSADE variables could be assessed and a high bleeding risk was present in 291 patients (22.2%; Figure 1). The distribution of the CRUSADE bleeding risk quartiles are depicted in Figure 2. Of the 1309 patients, complete 30-day follow-up was observed in 1261 patients (96.3%).
Comparison between low-risk and high-risk bleeding patients. The baseline and angiographic characteristics between high-risk bleeding patients and low-risk bleeding patients were, as expected, different (Table 1). High-risk bleeding patients were older, more often male, had more often a previous history of diabetes mellitus, hypertension, and renal insufficiency. Furthermore, high-risk bleeding patients had more often a TIMI risk score >3 and a Killip class >1 on admission as compared to low-risk bleeding patients. Randomization to tirofiban was not significantly different in both groups.
High-risk bleeding patients had significantly more often triple-vessel disease and use of an intra-aortic balloon pump (IABP) as compared to low-risk bleeding patients. Furthermore, high-risk bleeding patients had more often an overdosage of UFH (82.5% vs 51.5%; P<.001) and a higher mean activated clotting time (ACT) (189 ± 68 vs 177 ± 60; P=.015) as compared to low-risk bleeding patients, whereas treatment with additional UFH at the cath lab did not differ between groups.
As expected, high-risk bleeding patients had a significantly higher rate of non-CABG related bleeding as compared to low risk patients (6.1% vs 2.9%; P=.009; RR, 2.16; 95% CI, 1.2-3.9). However, in contrast to low-risk bleeding patients, the localization of bleeding in these high-risk patients was mostly access-site related (53.0% vs 32.1%; Table 2).
These ‘vulnerable’ high-risk bleeding patients had a significantly higher rate of 30-day all cause mortality (7.2% vs 0.6%; P<.001; RR, 12.2; 95% CI, 5.2-29.3) and 30-day MACE (11.2% vs 4.3%; P<.001; RR, 2.6; 95% CI, 1.7-4.1) as compared with low-risk bleeding patients.
Effect of tirofiban in both bleeding risk groups on angiographic and clinical outcomes. Table 3 shows the angiographic and clinical outcomes. Early initiation of tirofiban in the high-risk bleeding group significantly decreases ST deviation >3 mm 1 hour post PCI (43.3% vs 58.9%; P=.015; RR, 0.74; 95% CI, 0.57-0.94), whereas no significant difference was found in ST-segment deviation in the low-risk bleeding group. There was no significant difference in initial TIMI 3 flow, final TIMI 3 flow, and myocardial blush grade (MBG) between the study medication groups in the high-risk bleeding group, whereas in the low-risk bleeding group final TIMI 3 flow was less often established in patients with tirofiban pretreatment.
Pretreatment with tirofiban in high-risk bleeding patients had no significant impact on 30-day NACE (11.5% vs 15.2%; P=.365; RR, 0.76; 95% CI, 0.41-1.38). However, tirofiban significantly reduced the rate of 30-day NACE in low-risk bleeding patients (Table 4). Although prehospital administration of tirofiban in high-risk bleeding patients reduced 30-day mortality with 50%, it had no significant impact on 30-day all-cause mortality (5.0% vs 10.1%; P=.108; RR, 0.50; 95% CI, 0.21-1.16) or on 1-year all-cause mortality (9.4% vs 13.2%; P=.309; RR, 0.71; 95% CI, 0.36-1.37). However, in low-risk bleeding patients, early treatment with tirofiban significantly reduced 30-day and 1-year mortality (Table 4). There were no significant differences in 30-day MACE in patients treated with tirofiban compared to no tirofiban in either bleeding risk group. In contrast to low-risk bleeding patients, high-risk bleeding patients who were treated with tirofiban showed a strong trend toward a higher incidence of non-CABG related bleeding as compared to those without tirofiban pretreatment (8.6% vs 3.6%; P=.082; RR, 2.38; 95% CI, 0.90-6.39).
Our results show that prehospital tirofiban for primary PCI in patients with a high risk of bleeding: (1) improves post-PCI ST-segment resolution; (2) shows no difference in 30-day MACE; and (3) is associated with a nonsignificant increase of non-CABG related bleeding, mostly access-site related. The net result is a balanced effect on 30-day MACE.
The On-TIME 2 trial recently demonstrated that the glycoprotein IIb/IIIa inhibitor (GPI) tirofiban, when given in the ambulance, resulted in an improvement of ST-segment resolution (primary endpoint) as a marker for myocardial perfusion and an improved clinical outcome in patients with STEMI undergoing primary PCI.1,2 Consistent with these findings, several other trials showed a greater benefit for patients who received early GPI treatment after the onset of symptoms.14-17 However, not all studies have demonstrated such clinical benefits from (early) GPI use.18-21
Impact of antiplatelet and antithrombotic agents in patients with high risk of bleeding. Bleeding is an independent determinant of both short- and long-term mortality.3-7,22 Potential explanations for the high mortality after bleeding include a hemodynamic disturbance caused by the bleeding, premature cessation of antiplatelet therapy, and liberal use of blood transfusion.5,7,8,23-26 Therefore, in patients with high risk of bleeding, the potential benefits of GPIs may be less clear and use of these agents may be even harmful in these patients. In our study, patients at high risk of bleeding did have benefit from tirofiban as shown by an improved ST deviation post PCI, at the cost of a (nonsignificant) increase in bleeding. Effect on clinical outcome was a nonsignificant reduction in 30-day (and 1-year) all-cause mortality after tirofiban. Explanation for this trend toward improved clinical outcome may be that bleeding occurred mostly at the access site (Table 2), which has in general a good prognosis.27,28 Since there are no differences in urgent TVR in re-MI, we don’t think that these determinants influenced mortality differences.
Because groups were randomized and had comparable baseline variables, we do not expect differences in noncardiac mortality. Therefore, pretreatment with high-dose tirofiban may be considered in high-risk bleeding patients. However, the net clinical benefit of tirofiban can be further improved in this group. Possibly, a radial approach in these high-risk bleeding patients will decrease bleeding, with more pronounced benefits of tirofiban. However, there is a need for further research to support this approach. Furthermore, excess dosing of (post-PCI) heparin may contribute to the increased incidence of bleeding, particularly in the high-risk bleeding group.29 Improved heparin dosing may also increase net clinical effect of tirofiban in these patients.
HORIZONS-AMI demonstrated that bivalirudin alone as compared to UFH and GPI in STEMI patients improved clinical outcome and reduced bleeding.20 However, in this study, bleeding in the UFH/GPI group was very high. Additional studies should clarify how use of these bleeding risk scores should modify medical (antiplatelet) therapy.
Bleeding risk score. Baseline prediction of bleeding risk can complement ischemic risk prediction, and optimize medical or invasive strategies for ACS. The CRUSADE bleeding risk score has been generally validated and found to be useful in another cohort of NSTEMI patients.30 However, recently, another bleeding risk score has been developed to predict 30-day non-CABG related major bleeding in ACS patients.31 Because of the novel finding of a higher white blood count predicting major bleeding in this risk score, which first deserves further investigation, and absence of Killip class in this risk score, which is a strong independent predictor of bleeding, we only used the CRUSADE bleeding risk score for predicting bleeding risk.
Study limitations. Several limitations of the present analysis should be considered. First of all, 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 inclusion and exclusion criteria and there was no difference in baseline characteristics between the two phases of the study. The included STEMI patients in On-TIME 2 were obviously not low-risk patients, because 29.4% of the patients (Table 1) were identified as high ischemic risk according to the TIMI risk score.32 Although the data were collected prospectively, this was a post hoc analysis with a relatively small sample size, and the study was not powered to demonstrate benefits of tirofiban in our subgroups. Furthermore, primary PCI was performed in all patients by the femoral approach. Finally, the CRUSADE bleeding risk score was developed for and validated in NSTEMI patients to predict in-hospital major bleeding, whereas we used it for STEMI patients to determine whether patients had a low or high bleeding risk.
Prehospital use of tirofiban in STEMI in patients with high risk of bleeding improves post-PCI ST-segment resolution and has no impact on 30-day MACE, but increases nonsignificantly the risk of non-CABG related bleeding. The net result is a balanced effect on 30-day NACE. Additional studies should clarify how use of bleeding risk scores should modify medical (antiplatelet) therapy.
Acknowledgment. We thank Vera Derks for excellent editorial assistance.
- Van ’t Hof AWJ, Ten Berg JM, Heestermans AA, et al. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomised controlled trial. Lancet. 2008;372(9638):537-546.
- Ten Berg JM, van ’t Hof AWJ, Dill T, et al; Ongoing Tirofiban In Myocardial infarction Evaluation (On-TIME) 2 study group. Effect of early, pre-hospital initiation of high-bolus dose tirofiban in patients with ST-segment elevation myocardial infarction on short and long-term clinical outcome. J Am Coll Cardiol. 2010;55(22):2446-2455.
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- Kinnaird TD, Satbile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol. 2003;92(8):930-935.
- Rao SV, O’Grady K, Pieper KS, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol. 2005;96(9):1200-1206.
- Eikelboom JW, Metha SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114(8):774-782.
- Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 trial. Am J Cardiol. 2007;100(9):1364-1369.
- Manoukian SV, Feit F, Mehran R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY trial. J Am Coll Cardiol. 2007;49(12):1362-1368.
- Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol. 2008;51(7):690-697.
- Van ’t Hof AWJ, Hamm C, Rasoul S, et al, on behalf of the On-TIME 2 investigators. Ongoing tirofiban in myocardial infarction evaluation (On-TIME) 2 trial: rationale and study design. EuroIntervention. 2007;3(3):371-380.
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- Cockgroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41.
- Subherwal S, Bach RG, Chen Ay, et al. Baseline risk of major bleeding in non-ST elevation myocardial infarction. Circulation. 2009;119(14):1873-1882.
- Goto S, Tamura N, Ishida H. Ability of anti-glycoprotein IIb/IIIa agents to dissolve platelet thrombi formed on a collagen surface under blood flow conditions. J Am Coll Cardiol. 2004;44(2):316-323.
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- Ortolani P, Marzocchi A, Marrozzini C, et al. Long-term effectiveness of early administration of glycoprotein IIb/IIIa agents to real-world patients undergoing primary percutaneous coronary interventions: results of a registry study in an ST-elevation myocardial infarction network. Eur Heart J. 2009;30(1):33-43.
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From 1Isala klinieken, Department of Cardiology, Zwolle, The Netherlands, 2St. Antonius Ziekenhuis, Department of Cardiology, Nieuwegein, The Netherlands, 3Medisch Spectrum Twente, Department of Cardiology, Enschede, The Netherlands, 4Universitair Medisch Centrum Utrecht, Department of Cardiology, Utrecht, The Netherlands, and 5Kerckhoff-Klinik, Department of Cardiology, Bad Nauheim, Germany.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. van ’t Hof holds a research grant from Merck. Dr. Hamm holds an unrestricted grant for the ONTIME-2.
Manuscript submitted June 16, 2011, provisional acceptance given July 19, 2011, final version accepted December 1, 2011.
Address for correspondence: Arnoud W.J. van ’t Hof, MD, PhD, FESC, Isala klinieken, Department of Cardiology, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands. Email: email@example.com