Use of Bivalirudin for Chronic Total Occlusion Percutaneous Intervention: Insights From the PROGRESS-CTO Registry

Abstract

Background. There are limited data on the use of bivalirudin for chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Methods. We compared CTO-PCIs performed using bivalirudin vs unfractionated heparin in the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO; NCT02061436). The primary endpoint was net adverse cardiac events (NACE), defined as major adverse cardiac events (MACE) and vascular complications. Results. Between 2012 and 2022, a total of 73 of 9723 procedures (0.75%) were performed using bivalirudin. The J-CTO score (2.4 ± 1.2 vs 2.4 ± 1.3; P=.73) and the PROGRESS-CTO score (1.4 ± 0.9 vs 1.2 ± 1.0; P=.31) were similar in both groups, and the retrograde approach was used less often in the bivalirudin group (15% vs 30%; P<.01). Procedural success (89% vs 85%; P=.35), in-hospital NACE (1.4% vs 2.1%; P>.99), incidence of MACE (0% vs 0.76%; P=.64), and vascular access complications (1.4% vs 0.9%; P=.48) were not different between the 2 groups. On multivariable analysis, use of bivalirudin was not associated with an increased risk of NACE (odds ratio, 0.99; 95% confidence interval, 0.13-7.27). Conclusion. Bivalirudin is infrequently used during retrograde CTO-PCI. While the incidence of adverse events was similar with unfractionated heparin, larger studies are needed to assess the safety of bivalirudin.

J INVASIVE CARDIOL 2023;35(4):E179-E184. Epub 2023 February 15.

Key words: chronic total occlusion, percutaneous coronary intervention

Bivalirudin, a direct thrombin inhibitor, is an alternative anticoagulant to unfractionated heparin for percutaneous coronary intervention (PCI), especially in the context of heparin-induced thrombocytopenia (HIT).¹ It was shown to be an effective periprocedural anticoagulant for PCI of stable and unstable coronary artery disease in many randomized clinical trials.^2-9 It also appears to have a lower risk of bleeding complications when compared with unfractionated heparin, especially with femoral access.⁹ Despite its possible advantage in terms of bleeding risk reduction with femoral access, it is seldom used in the context of chronic total occlusion (CTO)-PCI, due to occasional need for anticoagulation reversal and unpublished reports of catheter thrombosis during CTO PCI.¹⁰ There are few small studies on the use of bivalidurin during CTO-PCI.^11-13 We examined the characteristics and outcomes of patients who underwent CTO-PCI with bivalirudin as compared with unfractionated heparin.

Methods

Study design and population. We conducted a cohort study of patients who underwent CTO-PCI with bivalirudin or heparin in the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO; NCT02061436). PROGRESS-CTO is an international prospective registry of CTO-PCI performed between 2012 and 2022 at experienced centers in the United States, Canada, Greece, Turkey, Egypt, Russia, and Lebanon. We analyzed the baseline and angiographic characteristics of the patients enrolled in the registry and compared the outcomes of bivalirudin and unfractionated heparin cases. The study was approved by the institutional review board of each site.

All patients who underwent a CTO-PCI and were enrolled in the PROGRESS-CTO registry were eligible for this study. The only exclusion criterion was the use of a left ventricular assist device (LVAD) for the procedure.

Endpoints and definitions. Definitions from the CTO Academic Research Consortium were used. CTO was defined as total occlusion with an estimated duration ≥3 months and a Thrombolysis in Myocardial Infarction (TIMI) grade 0 flow.¹⁴Technical success was defined as ≤30% residual stenosis of the target CTO lesion at procedure end with TIMI grade 2 or greater flow in all ≥2.5-mm branches.

Procedural success was defined as technical success in the absence of in-hospital major adverse cardiovascular event (MACE).¹⁴MACE was defined as the composite of death, myocardial infarction, stroke, urgent repeat revascularization, and tamponade requiring pericardiocentesis. Vascular access-site complications included small hematoma (<5 cm), large hematoma (≥5 cm), arteriovenous fistula, pseudoaneurysm, and acute arterial closure. Donor artery injury was defined as the composite of donor artery dissection and thrombosis.

The primary endpoint of this study was the occurrence of in-hospital NACE, defined as the composite of MACE and vascular access complications. Key secondary endpoints included MACE and vascular access complications.

Statistical analysis. Continuous variables are presented as mean ± standard deviation or as median with interquartile range (IQR) and were compared using the independent Student’s t test or the Mann-Whithney U test, as appropriate. Categorical variables are presented as numbers and percentages and were compared using the chi-square or Fisher’s exact test, as appropriate. Multivariable logistic regression was performed for the primary and secondary endpoints to adjust for confounding. We used a priori knowledge and statistical association of variables with the outcome, defined as a P-value <.10 on univariable analysis, to create the multivariable model. Statistical analyses were performed using Stata, version 17.0 (StataCorp).

Results

Baseline, angiographic, and procedural characteristics. Between 2012 and 2022, a total of 73 CTO-PCIs (0.75%) were performed with bivalirudin and 9650 were performed with unfractionated heparin. The baseline, angiographic, and procedural characteristics are summarized in Table 1. Most procedures with bivalirudin were performed between 2012 and 2016 (P<.001) (Figure 1). Reasons for the use of bivalirudin were not collected.

Most baseline characteristics were similar between the 2 groups, including age (66 ± 11 years vs 64 ± 10; P=.17), male sex (79% vs 81%; P=.94), and prior coronary artery bypass graft (22% vs 29%; P=.45). A lower proportion of patients in the bivalirudin group had a prior PCI (47% vs 62%; P<.01).

The angiographic characteristics were also comparable between the 2 groups, including the J-CTO score (2.4 ± 1.2 vs 2.4 ± 1.3; P=.73) and the PROGRESS-CTO score (1.4 ± 0.9 vs 1.2 ± 1.0; P=.31). The PROGRESS-CTO MACE score was lower in the bivalirudin group (2.0 ± 1.5 vs 2.5 ± 1.6; P<.01).

In the bivalirudin group, a higher proportion of patients underwent an ad hoc CTO-PCI (47% vs 9.0%; P<.001). An antegrade dissection and re-entry strategy (8.2% vs 21%; P<.01) and a retrograde approach (15% vs 30%; P<.01) were less frequently used in the bivalirudin group. The proportion of technical success was comparable in both groups (89% vs 86%; P=.50).

In-hospital outcomes. In-hospital outcomes are presented in Table 2. The incidence of the primary endpoint of in-hospital NACE was not different between the bivalidurin and unfractionated heparin groups (1.4% vs 2.1%; P>.99). There was no difference in in-hospital MACE (0% vs 0.76%; P=.64) and vascular access complications (1.4% vs 0.9%; P=.48). Procedural success (89% vs 85%; P=.35) and the risk of donor artery injury (0% vs 0.6%; P=.46) were also not different in the 2 groups.

Multivariable analysis. For the primary outcome of NACE, variables that were included in the multivariable model, in addition to bivalirudin use, were age, sex, peripheral artery disease, proximal cap type, proximal cap ambiguity, calcification, use of antegrade dissection and re-entry strategy, and a retrograde approach. After adjustment for potential confounders, the use of bivalirudin was not associated with an increased risk of NACE (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.13-7.27) (Figure 2 and Table 3).

For the secondary outcome of MACE, variables included in the multivariable model were age, sex, peripheral artery disease, proximal cap type, proximal cap ambiguity, use of antegrade dissection and re-entry strategy, and a retrograde approach. The adjusted OR for MACE was 1.20 (95% CI, 0.16-8.79) (Figure 3 and Table 3).

For the secondary outcome of vascular complications, variables that were included in the multivariable model were use of antegrade dissection and re-entry strategy and the retrograde approach, in addition to bivalirudin. There was no significant association between bivalirudin and the risk of vascular access complications (OR, 1.76; 95% CI, 0.24-12.82) (Figure 4 and Table 3).

Discussion

To the best of our knowledge, our study is the largest to date to examine use of bivalirudin for CTO-PCI. We found that use of bivalirudin was not associated with an increased risk of in-hospital NACE, MACE, or vascular access complications. The anatomic complexity of the bivalirudin cases was similar to those done with heparin, but bivalidurin was less often used with antegrade dissection and re-entry strategy or retrograde cases.

We found 3 studies that assessed the safety of bivalirudin for CTO-PCI, 2 of which were published in English.^11-13 Wang et al randomized 123 high-bleeding risk patients undergoing CTO-PCI (the retrograde approach was used in 30.1% of patients) to either bivalirudin or unfractionated heparin.¹¹ In-hospital (17.6% vs 20.0%; P=.82) and 6-month (1.5% vs 3.6%; P=.59) rates of MACE and bleeding were not different between both groups. Li et al randomized 84 patients undergoing CTO-PCI to either bivalirudin or unfractionated heparin.¹³ Among the 42 bivalirudin patients, 23.8% underwent retrograde crossing. The in-hospital (21.4% vs 14.3%; P=.39) and 12-month (0% vs 0%; P>.99) incidences of MACE were not different between the 2 groups. Bleeding was also comparable between the 2 groups (4.8% vs 9.5%; P=.68).

Our study included 73 CTO-PCIs performed with bivalirudin. The in-hospital event rate was much lower in our study (below 1%) compared with the aforementioned studies (around 20%). Differences in definitions could explain part of it, but similar to other studies, we did not find increased risk of NACE, MACE, or vascular complications with bivalirudin. The higher PROGRESS-CTO Complications score in the heparin group could bias the results in favor of bivalirudin, but the absence of any MACE in the bivalirudin group is reassuring.

When performing CTO-PCI, target activated clotting time (ACT) is usually >300 seconds for antegrade procedures and >350 seconds for retrograde procedures. Like other studies, ACT levels achieved with bivalirudin were comparable with those achieved with heparin.^11,13 However, while ACT levels have been shown to correlate with periprocedural ischemic events with heparin, ACT levels with bivalirudin do not seem to be a reliable predictor of ischemic events.^15,16 Whether or not this is true for CTO-PCI is uncertain since stagnant equipment and flow disturbances may increase the risk of thrombosis.

The inherent higher risk of complications with CTO-PCI compels operators to use the safest strategy at each step of the procedure. One of the most dreaded and common complications of CTO-PCI is coronary perforation, which can lead to tamponade.¹⁷ Depending on the situation, many times reversal of heparin with protamine will be done after the coronary equipment is removed. The lack of a reversal agent with bivalirudin is a major limitation. On the other hand, thrombotic complications during CTO-PCI have also pushed the CTO community to avoid bivalirudin.¹⁰ Although our study did not find any signal of increased risk of catheter thrombosis or donor artery injury with bivalirudin, the small number of patients who underwent antegrade dissection and re-entry strategy or retrograde intervention precludes strong conclusions regarding its safety in these cases.

Study limitations. Our study has limitations. First, the use of bivalirudin may have been more likely in patients with perceived lower ischemic risk profile. However, baseline and angiographic characteristics were similar in the bivalirudin and unfractionated heparin groups. Second, the follow-up of the PROGRESS-CTO registry is limited to in-hospital outcomes, and the adverse events were not independently adjudicated. Third, only 11 of 73 bivalirudin-treated patients in our study underwent a retrograde approach. While none of these procedures was complicated by donor artery injury or thrombosis, the sample size was small.

Conclusion

Heparin should remain the first choice of anticoagulant when performing CTO-PCI. When heparin use is not possible, bivalirudin represents a safe alternative, especially when an antegrade-only approach is likely. Further research is needed to confirm the safety of bivalirudin for retrograde CTO-PCI.

Affiliations and Disclosures

From the ¹Division of Cardiology, Emory University, Atlanta, Georgia; ²Center for Coronary Artery Disease, Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, Minneapolis, Minnesota; ³Division of Cardiology, Tristar Centennial Medical Center, Nashville, Tennessee; ⁴Division of Cardiovascular Medicine, University of California, San Diego, School of Medicine, San Diego, California; ⁵Division of Cardiology, University Hospitals, Case Western Reserve University, Cleveland, Ohio; ⁶Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, ⁷Edith and Benson Ford Heart and Vascular Institute, Henry Ford Hospital, Henry Ford Health System, Wayne State University, Detroit, Michigan; ⁸Division of Cardiology, Biruni University School of Medicine, Istanbul, Turkey; ⁹Division of Cardiology, Memorial Bahcelievler Hospital, Istanbul, Turkey; ¹⁰Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio; and the ¹¹Division of Cardiology, Meshalkin Novosibirsk Research Institute, Novosibirsk, Russia.

Disclosures: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr M. Patel has received consulting honoraria from Abbott, Medtronic, Terumo, Cardiovascular Systems, Inc. Dr Alaswad is a consultant and speaker for Boston Scientific, Abbott Cardiovascular, Teleflex, and CSI. Dr Gorgulu has received proctoring and consultation fees from Boston Scientific. Dr Khatri has received proctoring and speaking honoraria from Boston Scientific, Medtronic, Terumo, Abbott, Asahi Intecc, and Shockwave. Dr Rinfret reports being a consultant for Boston Scientific, Medtronic, and Teleflex. Dr Brilakis reports consulting/speaker honoraria from Abbott Vascular, American Heart Association (associate editor, Circulation), Amgen, Asahi Intecc, Biotronik, Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), ControlRad, CSI, Elsevier, GE Healthcare, IMDS, InfraRedx, Medicure, Medtronic, Opsens, Siemens, and Teleflex; research support from Boston Scientific, GE Healthcare; owner, Hippocrates LLC; shareholder in MHI Ventures, Cleerly Health, and Stallion Medical. Dr Jaber has received consultation fees and educational funds from Medtronic and Inari Medical. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted December 22, 2022.

Address for correspondence: Wissam A. Jaber, MD, Emory University Hospital, 1364 Clifton Road NE, Suite F-607, Atlanta, GA 30322. Email: wissam.jaber@emory.edu

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