Abstract: Objective. We compared the angiographic and clinical outcomes of heparin and bivalirudin in patients who underwent orbital atherectomy for severely calcified coronary lesions. Background. Severely calcified coronary lesions are associated with increased ischemic complications. Orbital atherectomy modifies calcified plaque, thereby facilitating stent delivery and stent expansion. The ideal antithrombotic agent during orbital atherectomy is unknown. Previous studies reported that bivalirudin was associated with lower bleeding rates compared with heparin plus glycoprotein IIb/IIa inhibitors during percutaneous coronary intervention. Methods. This retrospective multicenter analysis included 458 consecutive real-world patients with severely calcified coronary arteries who underwent orbital atherectomy. Patients were stratified based on the antithrombotic agent that was used. The primary safety endpoint was the 30-day rate of major adverse cardiac and cerebrovascular events, defined as death, myocardial infarction, target-vessel revascularization, and stroke. Results. Heparin was used in 356/458 cases (77.2%) and bivalirudin was used in 102/458 cases (22.8%). The primary endpoint was similar in the heparin and bivalirudin groups (2% vs 3%; P=.55), as were the 30-day rates of death (1% vs 2%; P=.51), myocardial infarction (1% vs 1%; P=.90), target-vessel revascularization (0% vs 0%; P>.99), and stroke (0% vs 0%; P=.59). Angiographic complication, stent thrombosis, and major bleeding complication rates were similarly low in both groups. Conclusion. Both heparin and bivalirudin were safe and effective antithrombotic agents for patients who underwent orbital atherectomy. A randomized trial is needed to determine the antithrombotic agent of choice for orbital atherectomy.
J INVASIVE CARDIOL 2017;29(11):397-400.
Key words: orbital atherectomy, calcification, percutaneous coronary intervention, coronary artery disease, heparin, bivalirudin
Unfractionated heparin and bivalirudin are the most commonly used antithrombotic agents for percutaneous coronary intervention (PCI). Although bivalirudin has a more favorable pharmacokinetic profile and beneficial reduction in platelet reactivity compared to heparin, controversy still surrounds the ideal antithrombotic agent for PCI.1-3
Coronary artery calcification increases the procedural complexity of PCI and is associated with high ischemic complication rates.4 Plaque modification with orbital atherectomy facilitates stent delivery and expansion.5 The ORBIT II trial demonstrated the safety and efficacy of orbital atherectomy in coronary artery calcification prior to stenting for up to 3 years.6,7 Similar results were observed in a multicenter registry.8
The choice of antithrombotic agent used during orbital atherectomy is particularly important given the increased risk of coronary perforation and ischemic events due to distal embolization and slow flow. No study has compared the use of heparin against the use of bivalirudin during orbital atherectomy. In this study, we retrospectively assessed the outcomes of patients with severe coronary artery calcification who underwent orbital atherectomy with either heparin or bivalirudin.
This analysis included 458 consecutive patients with severe coronary artery calcification who underwent orbital atherectomy between October 2013 and December 2015 at three centers (UCLA Medical Center, Los Angeles, California; St. Francis Hospital, Roslyn, New York; and Northwell Health, Manhasset, New York). Severe coronary artery calcification was defined as the presence of radiopacities on fluoroscopy involving the vessel wall. The Institutional Review Board at each site approved the review of the data.
The coronary orbital atherectomy device (Cardiovascular Systems, Inc. [CSI]) is advanced over a specialized 0.014˝ guidewire (ViperWire; CSI). The ViperSlide lubricant (CSI) is infused through the drive shaft to reduce the friction during device advancement. The mechanism of action of orbital atherectomy is differential sanding, in which the centrifugal force from a 30 micron, diamond-coated, eccentrically mounted crown laterally expands and ablates coronary artery calcification, facilitating stent delivery and expansion.
It was at the discretion of the operator to insert a temporary pacemaker and a hemodynamic support device. After the initial pass with low speed (80,000 rpm), subsequent high-speed atherectomy (120,000 rpm) was performed at the operator’s discretion, with each pass executed for ≤20 sec. The operator had full discretion to predilate the lesion and perform intravascular imaging following atherectomy.
The choice of antithrombotic therapy (unfractionated heparin or bivalirudin) and P2Y12 inhibitor were left to the discretion of the operator. Glycoprotein IIb/IIIa inhibitors were only used as a bailout strategy. The operator was also given discretion concerning the dose of heparin administered, the target activated clotting time, and the timing of P2Y12 inhibitor treatment. Dual-antiplatelet therapy was continued for a least 1 month after bare-metal stent implantation and for 12 months after drug-eluting stent implantation.
The primary endpoint was 30-day major adverse cardiac and cerebrovascular event (MACCE), defined as the composite of death, myocardial infarction, target-vessel revascularization, and stroke. Myocardial infarction was deﬁned as recurrent ischemic symptoms with new ST-segment elevation or re-elevation of cardiac biomarkers to at least twice the upper limit of normal. Target-vessel revascularization was defined as a repeat revascularization of the target vessel. Stent thrombosis was defined based on the Academic Research Consortium definition.9 Major bleeding was defined as intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss resulting in a decrease in hemoglobin of more than 3 g/dL; any decrease in hemoglobin of more than 4 g/dL; or transfusion of 2 or more units of packed red cells or whole blood.3 Patient data were collected from medical records, and adverse clinical events were recorded into a dedicated PCI database.
Statistical analysis. Descriptive statistics are expressed as median with interquartile ranges (IQR) for continuous variables and frequencies (percentages) for categorical variables. Statistical analysis was performed with Stata Statistical Software, version 14.
Heparin was used in 356/458 cases (77.2%) and bivalirudin was used in 102/458 cases (22.8%) (Table 1). The heparin group had a higher percentage of transfemoral intervention (73% vs 38%; P<.001), volume of contrast used (194 mL [IQR, 140-250 mL] vs 148 mL [IQR, 99-200 mL]; P<.001), and more frequent use of intravascular imaging (36% vs 10%; P<.001) (Table 2). Use of glycoprotein IIb/IIIa inhibitors was low in both groups (3% vs 5%; P=.24).
Angiographic complications were low in the heparin and bivalirudin groups (perforation [1% vs 1%; P=.64], dissection [1% vs 2%; P=.81], and no reflow [1% vs 0%; P=.35]) (Table 3).
The heparin and bivalirudin groups had low rates of 30-day MACCE (2% vs 3%; P=.55), mortality (1% vs 2%; P=.51), myocardial infarction (1% vs 1%; P=.90), target-vessel revascularization (0% vs 0%; P>.99), and stroke (0% vs 0%; P=.59) (Table 4). Stent thrombosis rates were similar in both groups as well (1% vs 1%; P=.90). The major bleeding rates were low in both groups (1% vs 0%; P=.82).
In the first study to assess the safety and efficacy of antithrombotic agents used during orbital atherectomy in patients with severely calcified coronary lesions, the main finding was that ischemic and bleeding complications were similarly low in the heparin and bivalirudin groups.
The ORBIT II trial reported high procedural and angiographic success rates as well as low target-vessel revascularization rates at 3 years, but did not report on which antithrombotic agents were used.6,7 Excellent success rates with orbital atherectomy were also revealed in our multicenter registry, which included high-risk patients who were excluded from the ORBIT II trial, such as those with recent myocardial infarction, chronic kidney disease, severe left ventricular systolic dysfunction (ejection fraction ≤25%), and unprotected left main disease.8 Like other atherectomy techniques, orbital atherectomy can induce thermal injury and activate platelets, increasing vascular complications risks and propagating thrombus formation.10,11 Thus, proper selection of the antithrombotic agent during orbital atherectomy becomes crucial given the increased risk of ischemic events.
Heparin is an indirect thrombin inhibitor, which has unfavorable characteristics including activating platelets and binding to plasma proteins and cells.12 The non-specific binding of heparin results in a non-linear dose response that exhibits interpatient variability. Platelet factor 4, a chemokine released from alpha granules upon platelet activation, inactivates heparin. The production of antibodies in response to the platelet factor 4-heparin complex can lead to heparin-induced thrombocytopenia. Advantages of heparin are its low cost (approximately $5 compared with bivalirudin, which costs approximately $450) and the ability to reverse its antithrombotic effect with protamine if a complication like a coronary perforation or vascular access bleeding occurs.
Bivalirudin is a direct thrombin inhibitor that has more predictable pharmacokinetics, does not require a binding cofactor, does not activate platelets, and does not provoke heparin-induced thrombocytopenia, making it an attractive anticoagulant.1-3 Bivalirudin does not have a reversal agent.
Studies previously reported that the use of bivalirudin during PCI reduced bleeding complications without loss of efficacy in ischemic endpoints when compared to heparin with glycoprotein IIb/IIIa inhibitors.2,3 However, these studies did not include patients who underwent orbital atherectomy.
In a subanalysis of the ROTAXUS trial, patients who underwent rotational atherectomy with bivalirudin had a lower periprocedural myocardial infarction rate compared to heparin (15.7% vs 38.7%; P=.01) and a trend toward lower major access-site bleeding rate (2.9% vs 10.2%; P=.09).13 The higher bleeding rate in the ROTAXUS trial compared to our multicenter registry may be explained by the fact that all patients underwent rotational atherectomy transfemorally and more than one-half underwent the procedure with a 7 Fr guiding catheter. Early trials originally suggested bivalirudin was non-inferior to heparin in efficacy with potentially lower bleeding risks. The HORIZONS-AMI trial reported a lower bleeding rate with bivalirudin compared to heparin with glycoprotein IIb/IIIa inhibitors (4.9% vs 8.3%; P<.001),14 but a higher acute stent thrombosis rate with bivalirudin. The EUROMAX, BRIGHT, and ACUITY trials also showed lower major bleeding risk and improved net adverse clinical events in bivalirudin vs heparin patients.15-17 However, many of these trials used high heparin doses with unequal use of adjunctive glycoprotein IIb/IIIa inhibitors. The HEAT-PPCI trial, with similar rates of glycoprotein IIb/IIIa inhibitor use in the heparin and bivalirudin arms, reported no significant differences in major bleeding (3.1 vs 3.5%, respectively), but a higher stent thrombosis rate with bivalirudin.1 These findings were further supported by the MATRIX trial, which found similar efficacy with both heparin and bivalirudin and reported no differences in primary endpoints of major adverse cardiac events (10.9% vs 10.3%; P=.44).18
Study limitations. This was a retrospective analysis with a limited follow-up duration. Although the number of patients was relatively small, this study represents the largest number of patients who underwent orbital atherectomy to date. Routine assessment with cardiac biomarkers was not performed after PCI. Therefore, differences in periprocedural myocardial infarction between the two groups are unknown. Differences in baseline patient and procedural characteristics could have affected clinical outcomes between the heparin and bivalirudin groups. The activated clotting times were not recorded.
In the first study to assess the safety and efficacy of different anticoagulation strategies used during orbital atherectomy in patients with severely calcified coronary lesions, both heparin and bivalirudin were associated with low ischemic and bleeding complications.
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2. Mehran R, Lansky AJ, Witzenbichler B, et al; HORIZONS-AMI Trial Investigators. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet. 2009;374:1149-1159.
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8. Lee MS, Shlofmitz E, Kaplan B, Alexandru D, Meraj P, Shlofmitz R. Real-world multicenter registry of patients with severe coronary artery calcifications undergoing orbital atherectomy. J Interv Cardiol. 2016;29:357-362.
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18. Valgimigli M, Frigoli E, Leonardi S, et al; MATRIX Investigators. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med. 2015;373:997-1009.
From 1UCLA Medical Center, Los Angeles, California; 2Northwell Health, Manhasset, New York; and ³St. Francis Hospital — The Heart Center, Roslyn, New York.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lee and Dr E. Shlofmitz report personal fees from CSI. Dr R. Shlofmitz reports non-financial consultant support from CSI and Abbott Vascular. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted March 26, 2017, provisional acceptance given April 4, 2017, final version accepted April 20, 2017.
Address for correspondence: Michael S. Lee, MD, Associate Professor of Medicine, 100 Medical Plaza, Suite 630, Los Angeles, CA 90095. Email: email@example.com