Original Contribution

Periprocedural Bivalirudin Versus Unfractionated Heparin During Percutaneous Coronary Intervention Following Fibrinolysis for ST-Segment Elevation Myocardial Infarction

Mohammed K. Rashid, MD1;  Kuljit Singh, MD, PhD2;  Jordan Bernick, MSc3;  George A. Wells, PhD3;  Benjamin Hibbert, MD3;  Juan Russo, MD3;  Derek Y. So, MD3;  Michel R. Le May, MD3;  on behalf of the CAPITAL PCI Group

Mohammed K. Rashid, MD1;  Kuljit Singh, MD, PhD2;  Jordan Bernick, MSc3;  George A. Wells, PhD3;  Benjamin Hibbert, MD3;  Juan Russo, MD3;  Derek Y. So, MD3;  Michel R. Le May, MD3;  on behalf of the CAPITAL PCI Group

Abstract: Background. A pharmacoinvasive strategy for ST-segment elevation myocardial infarction (STEMI) management combines the use of fibrinolysis with the routine transfer to coronary angiography, with percutaneous coronary intervention (PCI) if needed. This method reduces the risk of major adverse cardiovascular event (MACE) compared with fibrinolysis alone; however, it is associated with higher bleeding risk. We sought to assess the bivalirudin compared with unfractionated heparin (UFH) used during PCI as part of a pharmacoinvasive strategy. Methods. We identified consecutive patients referred to the University of Ottawa Heart Institute between April 2009 and May 2011 as part of a pharmacoinvasive strategy for STEMI. The primary efficacy outcome was MACE, defined as a composite of death, reinfarction, or stroke during index hospitalization. The primary safety outcome was TIMI bleeding. Results. We identified 200 patients meeting inclusion criteria: 123 patients (61.5%) in the bivalirudin group and 77 patients (37.5%) in the UFH group. Median fibrinolysis to balloon time was 324 minutes in the bivalirudin group and 226 minutes in the UFH group (P<.001). Initial TIMI grade 3 flow was higher in the bivalirudin group vs the UFH group, but there was no difference in the rates post PCI. MACE rates were 4.9% vs 7.8% (P=.40) and TIMI bleeding rates were 7.3% vs 11.7% (P=.29) in patients treated with bivalirudin vs UFH, respectively. Conclusion. The periprocedural use of bivalirudin vs UFH was associated with similar rates of MACE and bleeding. Given the expense of bivalirudin and lack of demonstrable clinical superiority, UFH remains the first-line periprocedural anticoagulant in a pharmacoinvasive strategy. 

J INVASIVE CARDIOL 2019;31(12):E387-E391.

Key words: acute myocardial infarction, PCI post fibrinolysis, periprocedural anticoagulation


A pharmacoinvasive strategy has been proposed for patients presenting with ST-segment elevation myocardial infarction (STEMI) who are outside the recommended door-to-balloon time for primary percutaneous coronary intervention (PCI).1-6 In this strategy, patients receive fibrinolysis and then undergo routine early transfer for coronary angiography, and PCI if needed.1-6 This approach, compared with fibrinolysis alone, has been found to reduce the risk of major adverse cardiovascular event (MACE).3-6 However, such an approach could be associated with a higher risk of bleeding.4 Bleeding complications in the context of acute coronary syndromes have been shown to lead to higher risk of morbidity and mortality. 7-9 Therefore, efforts have been made to identify strategies to reduce the bleeding risk in these patients.10 One such method is the periprocedural use of bivalirudin, a direct thrombin inhibitor, instead of unfractionated heparin (UFH), as an adjuvant antithrombotic therapy during PCI. Compared with UFH, the use of bivalirudin has been found to lead to similar MACE rates and lower major bleeding  rates at 30 days in STEMI patients treated with a primary PCI strategy.11,12 We investigated the use of bivalirudin during PCI in STEMI patients treated with a pharmacoinvasive strategy.

Methods

Study population. The University of Ottawa Heart Institute’s regional STEMI program covers a population of approximately 1.2 million. The program provides primary PCI to patients presenting within a 90 km radius of the cardiac care center and a pharmacoinvasive strategy to patients presenting outside the 90 km radius. In this post hoc subgroup analysis of a previously published study,3 we identified all consecutive patients referred to our center between April 2009 and May 2011 as part of a pharmacoinvasive strategy for STEMI. Patients were included in this study if they had an onset of myocardial ischemic symptoms of <12 hours and ST-segment elevation of ≥1 mm in 2 contiguous leads on a 12-lead electrocardiogram. We excluded patients who did not undergo PCI within 24 hours of receiving fibrinolytic therapy or required therapeutic hypothermia. 

All patients received 160 mg of chewable aspirin, 600 mg of oral clopidogrel (or 300 mg if ≤75 years old), 60 U/kg (maximum dose of 4000 U) of intravenous bolus of UFH, and weight-adjusted intravenous bolus of tenecteplase. Included patients were stratified based on the anticoagulant used during PCI (either bivalirudin or UFH). The use of these agents during PCI was at the discretion of the individual interventional cardiologist.

Definitions and outcomes. The primary efficacy outcome (MACE) was defined as the composite of death, reinfarction, or stroke during index hospitalization. The primary safety outcome was Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding. The secondary outcome was net adverse cardiovascular event (NACE) rate, defined as the composite of MACE and TIMI bleeding. Individual outcomes were also analyzed. A stroke was defined as any new neurological deficits lasting for >24 hours with evidence of ischemia or hemorrhage on computed tomography or magnetic resonance imaging. A reinfarction was defined as the recurrence of cardiac ischemic symptoms happening at rest and lasting for >30 minutes in combination with re-elevation of ST-segment on electrocardiogram, elevation of cardiac enzymes to 2x the upper limit of normal, or angiographic evidence of reocclusion of the culprit artery. Bleeding was defined based on the TIMI criteria.14 The study was approved by the institutional review board at the University of Ottawa Heart Institute.

Statistical analysis. All categorical variables are described as proportions and compared using Chi-square test or Fisher’s exact test, as appropriate. All normally distributed continuous variables are described as mean ± standard deviation and compared using the Student’s t-test. Time intervals are described as median with interquartile range (IQR) and compared using the Wilcoxon test. A multivariable logistic regression was performed for NACE, including baseline characteristics with P<.10. Subgroup analyses were performed to analyze MACE and NACE outcomes based on access site and time from fibrinolysis to balloon. A 2-sided P-value of <.05 was considered significant. All statistical analyses were performed using SAS software, version 9.3 (SAS Institute).

Results

Patient characteristics. Between April 2009 and May 2011, we identified 200 consecutive patients who were referred to the cardiac care center as part of a pharmacoinvasive strategy for STEMI and underwent PCI within 24 hours of receiving fibrinolytic therapy. Among these patients, a total of 123 (61.5%) received bivalirudin and 77 (37.5%) received UFH during PCI. The baseline patient characteristics are shown in Table 1. The two groups were largely similar at baseline. The mean age was 60.7 ± 11.8 years in the bivalirudin group and 60.6 ± 11.1 years in the UFH group. Approximately 25% of the bivalirudin group and 22% of the UFH group were women. Anterior myocardial infarction occurred in 35.0% of the bivalirudin group and 36.4% of the UFH group (P=.84). Patients in the bivalirudin group had a trend toward a lower Killip class (P=.05). The time between fibrinolysis and balloon inflation was longer in the bivalirudin group vs the UFH group (324 minutes vs 226 minutes, respectively; P<.001).

Procedural characteristics and adjunctive medical therapy. Procedural characteristics and adjunctive medical therapy are shown in Table 2. PCI was performed in all patients. Stent insertion was performed in 98.4% of the bivalirudin group and 98.7% of the UFH group (P=.85). The rate of femoral access for PCI was similar between the bivalirudin and UFH groups (45.9% vs 44.7%, respectively; P=.97). Likewise, the rate of glycoprotein IIb/IIIa inhibitor use was similar between the two groups. Initial TIMI flow grade 3 was observed in 63.4% of the bivalirudin group vs 40.3% of the UFH group (P<.01). After the procedure, the rate of TIMI flow grade 3 was comparable between the bivalirudin and UFH groups (97.6% vs 96.1%, respectively; P=.56). The use of adjunctive therapy on discharge from hospital was similar between the two groups.

Clinical outcomes. Clinical outcomes are shown in Table 3. The primary efficacy outcome occurred at a rate of 4.9% in the bivalirudin group and 7.8% in the UFH group (P=.40). Among the bivalirudin group, four patients died, one patient had a reinfarction, and 3 patients had a stroke. Among the UFH group, three patients died, one patient had a reinfarction, and 2 patients had a stroke. TIMI bleeding was also similar between the two groups (7.3% in the bivalirudin group vs 11.7% in the UFH group; P=.29). 

Table 4 shows subgroup analyses for MACE and NACE stratified by access site and time from fibrinolysis to balloon inflation. Results of the subgroup analyses were consistent with the primary analysis. Using a multivariable logistical analysis (Table 5), there was no difference between the two groups with regard to NACE; however, we found that baseline Killip class 4 and initial TIMI flow grade 3 were significant predictors of NACE in the logistical model.

Discussion

In this study, we assessed the periprocedural use of bivalirudin and compared it with unfractionated heparin as an adjunct antithrombotic therapy during PCI in STEMI patients treated with a pharmacoinvasive strategy. We found that the bleeding rates and the composite rates of death, reinfarction, or stroke were similar between the two groups. 

The use of bivalirudin in STEMI patients treated with a primary PCI strategy has been well studied through randomized controlled trials (RCTs). In a recent meta-analysis by Shah et al,11 the authors evaluated data from HORIZONS-AMI,12 EUROMAX,13 HEAT-PPCI,14 BRIGHT-STEMI,15 BRAVE-4,16 and MATRIX-STEMI,17 for a total of 14,095 patients. They found that compared with UFH (and with or without glycoprotein IIb/IIIa inhibitors), bivalirudin was associated with similar MACE rate (relative risk, 1.02; P=.80) and lower risk of major bleeding at 30 days (relative risk, 0.63; P=.01). However, this reduction appears to be influenced by the co-administration of P2Y12 inhibitors along with bivalirudin, the use of radial access, and avoiding the use of glycoprotein IIb/IIIa inhibitors along with UFH.11 In the VALIDATE-SWEDEHEART trial, which included 6006 patients, Erlinge et al found that there was no difference between bivalirudin and UFH in the composite rate of death, myocardial infarction, or major bleeding (12.3% vs 12.8%, respectively; P=.54) at 180 days in patients treated with PCI for myocardial infarction.18

Literature review. Literature on the use of bivalirudin in STEMI patients treated initially with fibrinolytic therapy is scarce. In the Hirulog and Early Reperfusion for Occlusion (HERO)-1 trial, White et al found that bivalirudin was associated with superior early patency and there was no increase in the rate of major bleeding compared with UFH in patients treated with a fibrinolytic therapy for an acute myocardial infarction.19 In HERO-2, bivalirudin was not found to reduce the rate of mortality at 30 days; however, it reduced the rate of adjudicated reinfarction within 96 hours.20 Sardi et al evaluated 104 patients treated with a pharmacoinvasive strategy and reported major bleeding rates of 6.4% in the bivalirudin group and 12.3% in the UFH group (P=.51).21 While the NACE rates were 6.4% in the bivalirudin group and 21.1% in the UFH group (P=.03), there was no difference in the rates of TIMI major bleeding, all-cause mortality, and ischemic stroke.21 The liberal use of intraprocedural glycoprotein IIb/IIIa inhibitors in the UFH group (31.6% vs 0.0% in the bivalirudin group) may have contributed to higher rates of major bleeding in the UFH group. In fact, current guidelines advise caution regarding the use of glycoprotein IIb/IIIa inhibitors along with fibrinolysis due to the increase risk of bleeding.1

Mallidi et al compared the use of bivalirudin vs UFH, with or without glycoprotein IIb/IIIa inhibitors, during urgent PCI following fibrinolysis.22 The authors reported no difference in the MACE rates between bivalirudin (1.2%), UFH with glycoprotein IIb/IIIa inhibitors (4.4%), and UFH alone (2.7%; P=.11); however, major bleeding complications were lower in the bivalirudin group (0.3% vs 7.6% in the UFH with glycoprotein IIb/IIIa inhibitor group vs 2.3% in the UFH along group; P<.001).22 After adjustment, there was no difference in MACE between the three groups; however, the odds of NACE were significantly lower in the bivalirudin group.22 Of note, the event rates were relatively low in contrast to those reported in RCTs, suggesting that sicker patients may have been excluded.13-18 Furthermore, there was no report on fibrinolysis to balloon time, a key variable in the understanding of the interaction between the pharmacological agents used during the procedures. 

In our study, we included consecutive patients managed with a pharmacoinvasive approach, all of whom underwent PCI within 24 hours of receiving fibrinolysis. This may explain why our event rates appear to be higher than in the study reported by Mallidi et al.22 We found no difference in efficacy or safety between bivalirudin and UFH used during PCI following fibrinolytic therapy. The strength of our study stems from the use of real-world data in the context of a regional STEMI system in which standardized protocols have been applied. Our results add to the limited body of knowledge surrounding the use of bivalirudin during PCI in a pharmacoinvasive strategy. Our findings are also congruent with the results of large randomized trials, such as MATRIX-STEMI17 and SWEDEHEART,18 comparing bivalirudin and UFH in the context of acute coronary syndromes. 

Study limitations. Our study is limited by the fact that it is an observational, retrospective study of registry data and not an RCT. Confounding variables could have affected our results. We performed a multivariable logistic regression to control for possible confounding variables. Furthermore, the current study is under-powered to fully examine bleeding outcomes. 

Conclusion

This study demonstrates that composite rates of death, reinfarction, or stroke, as well as rates of bleeding, are similar when comparing the use of bivalirudin with the use of UFH during PCI as part of a pharmacoinvasive strategy. Given the expense of bivalirudin and lack of demonstrable clinical superiority, UFH remains the first-line periprocedural anticoagulant in a pharmacoinvasive strategy. 

Acknowledgment. The authors would like to thank Melissa Blondeau and Christina Osborne for their assistance with data collection. 

References

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12. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358:2218-2230. 

13. Zeymer U, van’t Hof A, Adgey J, et al. Bivalirudin is superior to heparins alone with bailout GP IIb/IIIa inhibitors in patients with ST-segment elevation myocardial infarction transported emergently for primary percutaneous coronary intervention: a pre-specified analysis from the EUROMAX trial. Eur Heart J. 2014;35:2460-2467. 

14. Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014;384:1849-1858. 

15. Han Y, Guo J, Zheng Y, et al. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA. 2015;313:1336-1346. 

16. Schulz S, Richardt G, Laugwitz KL, et al. Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2014;35:2285-2294. 

17. Valgimigli M, Frigoli E, Leonardi S, et al. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med. 2015;373:997-1009.

18. Erlinge D, Omerovic E, Fröbert O, et al. Bivalirudin versus heparin monotherapy in myocardial infarction. N Engl J Med. 2017;377:1132-1142. 

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21. Sardi GL, Lindsay J, Waksman R. Safety of bivalirudin in percutaneous coronary intervention following thrombolytic therapy. Catheter Cardiovasc Interv. 2013;82:614-620. 

22. Mallidi JR, Robinson P, Visintainer PF, Lotfi AS, Mulvey S, Giugliano GR. Comparison of antithrombotic agents during urgent percutaneous coronary intervention following thrombolytic therapy: a retrospective cohort study. Catheter Cardiovasc Interv. 2017;90:898-904.


From the 1Internal Medicine Residency Program, McMaster University, Hamilton, Ontario, Canada; 2Department of Cardiology, Gold Coast University Hospital, Griffith University, Gold Coast, Australia; and 3University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Funding: This study was supported by The University of Ottawa Heart Institute Regional STEMI Program.  

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted June 15, 2019, provisional acceptance given June 24, 2019, final version accepted July 8, 2019.

Address for correspondence: Michel R. Le May, MD, University of Ottawa Heart Institute, 40 Ruskin street, Ottawa, Ontario K1Y 4W7, Canada. Email: mlemay@ottawaheart.ca

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