Use of Low-Dose Heparin with Bivalirudin for Ad-hoc Transradial Coronary Interventions: Experience from a Single Center

ABSTRACT: Background. The majority of coronary angioplasty is done via the femoral artery, with vascular complications being a major adverse event. Bivalirudin has been shown to reduce bleeding complication and improve outcomes. The use of bivalirudin in radial interventions has largely been limited due to the routine use of heparin for the diagnostic procedure. In current practice there is a concern with using the traditional 5,000 Units of heparin during radial sheath insertion and administration of bivalirudin when proceeding to percutaneous coronary intervention (PCI). We describe outcome analysis of the use of low-dose heparin (2,500 Units) with bivalirudin in patients who underwent PCI comparing the adverse outcomes related to bleeding and radial artery occlusion. Methods. The study was an institutional review board-approved retrospective analysis of patients who underwent coronary intervention using the radial approach and the use of bivalirudin over 9-month period. Patients on heparin/low-molecular-weight heparin (LMWH), acute myocardial infarction or allergy to bivalirudin were excluded from the study. Results. We evaluated 155 patients in the radial and 100 patients in the femoral group. The mean age of the population was 63 ± 11 years (males 68%, weight 88 ± 18 kg) and 66 ± 12 years (males 56%, weight 82 ± 16 kg) in the radial and femoral groups, respectively. Ninety-two percent of the radial and 98% of the femoral cases were elective. The vessels intervened upon were similar in the two groups (left main: 0.65% vs. 2%, left anterior descending artery: 39% vs. 38%, diagonal: 3.8% vs.7%, left circumflex: 16% vs. 21%, obtuse marginal: 7 vs. 11%, right coronary artery: 30% vs. 31%, grafts: 1% vs. 5%, in the radial and femoral groups, respectively; p > 0.05). The mean activated clotting time at the end of infusion was 376 ± 47 seconds in the radial and 331 ± 18 seconds in the femoral group. There was only 1 case of documented radial artery occlusion that resolved with 2 weeks of LMWH. Six patients in the radial group and 5 in the femoral group reported minor bruising. There were no reported events related to any major bleeding or transfusions. Conclusions. Bivalirudin in combination with low-dose heparin (2,500 Units) is safe to use in patients undergoing radial angioplasty with similar event rates to the femoral approach. J INVASIVE CARDIOL 2011;23:101–104 ————————————————————

Cardiac catheterization techniques have undergone a revolutionary change in the last two decades. A tremendous effort has been made to improve angioplasty techniques and equipment. While we have been successfully intervening on lesions with good short- and long-term results, the access site and periprocedural complications remain issues in improving patient outcomes.¹ Femoral access is the traditional method to perform cardiac catheterization, but it has its inherent complications related to patient discomfort, access-site bleeding, difficulty in maintaining hemostasis and the patient’s inability to ambulate immediately. Many of these limitations are overcome by using the radial approach for percutaneous coronary intervention (PCI).^2,3 In all major percutaneous coronary intervention (PCI) trials including ESPIRIT, GUSTO and REPLACE, the majority of bleeding events were related to the access site. In the meta-analysis by Jolly et al, radial access was found to reduce the rate of major bleeding by 73%, with success rates similar to those seen with the femoral approach.⁴ Lucien Campeau first described use of the radial approach for cardiac catheterization with a relatively low complication rate.^5,6 Since then, there have been significant advances in improving the equipment used for radial PCI. Despite this, only 1.3% of PCIs are performed via the radial approach in the United States.⁷ In their analysis from the National Cardiovascular Data Registry, Rao et al concluded that transradial PCI results in a significantly lower risk of bleeding and vascular complications without sacrificing procedural success or the use of more contrast.⁷

Bleeding complications are an inherent risk with the use of anticoagulants in PCI and have a negative impact on hospital stay and mortality.^8,9 Newer, shorter half-life pharmacological agents have been introduced and have thus far shown promising results to reduce access and non-access site bleeding complications. Unfractionated heparin (UFH) has been the traditional anticoagulant of choice, but its use is weighed by its limitations due to unpredictable pharmacokinetics and efficacy. Bivalirudin has offered a promising alternative to UFH. As demonstrated in the REPLACE-2 trial, bivalirudin with provisional glycoprotein (GP) IIb/IIIa reduces the risk of bleeding compared to UFH and GP IIb/IIIa (2.4% vs. 4.1%; p 10

The utility of bivalirudin goes beyond just the access-site complications, with 47% of bleeding complications being non-access-site-related. This, coupled with the reduction in event rates, makes it a desirable anticoagulant in PCI. We hypothesize that bivalirudin can be used in patients undergoing angiography with a radial access site. However, what is not so clear is how to transition from the use of heparin to bivalirudin in patients undergoing radial PCI for ad-hoc interventions, as radial artery occlusion is a real concern in obtaining radial access. Traditionally, 5,000 Units are injected for diagnostic cardiac catheterization to limit the risk of radial artery occlusion, which can occur in up to 5% of patients. Thus, patients undergoing ad-hoc transradial interventions traditionally need UFH during diagnostic catheterization, but it is unclear how the transition to bivalirudin should be undertaken if a subsequent intervention is performed.

The purpose of this study was to demonstrate a single-center experience of the use of lower-dose UFH (2,500 Units) during diagnostic angiography with standard-dose bivalirudin during PCI, with the aim to establish a standard protocol for using bivalirudin with UFH in patients undergoing ad-hoc transradial PCI.

Methods

Study population. This study was a retrospective observational study involving patients who underwent ad-hoc cardiac catheterization with coronary intervention via the radial route from June 2008 to December 2009. The study was approved by the institutional review board at the North Shore Long Island Jewish Health System. Exclusion criteria. Subjects were excluded if they had an active bleeding event in the last 2 weeks, allergy to bivalirudin or its components, if they had received thrombolytic therapy within 6 hours of the scheduled procedure, concurrent warfarin administration, heparin allergy, or had a previous history of heparin-induced thrombocytopenia and acute ST-elevation myocardial infarction (MI). If the patients required an intra-aortic balloon pump or there was an inadvertent procedural complication like vessel dissection or major side-branch closure, then they were excluded from the study. Study protocol. Radial artery access was obtained using a standard procedure and 6 French sheath (Prelude^® Sheath System, Merit Medical Systems, Inc., South Jordan, Utah) and catheter system was used in all cases as per the local practice. The operators had at least 5 years and over 500 cases of experience in transradial cardiac catheterization. All patients received aspirin 325 mg orally and clopidogrel 300 mg or 600 mg orally before or immediately after the procedure. Patients in the radial group received 2,500 Units of UFH through the sheath after sheath insertion for the diagnostic procedure. Patients in the femoral group did not receive UFH for the diagnostic procedure. Upon determination of the need for coronary intervention, bivalirudin 0.75 mg/kg bolus and then 1.75 mg/kg/hr infusion were administered for the duration of the case. GP IIb/IIIa inhibitors were used for high-risk cases at the operator’s discretion. The infusion of bivalirudin was discontinued at the conclusion of the procedure. The activated clotting time (ACT) was checked at the conclusion of the case and patients were given a heparin bolus of 1,000 Units for each 25 seconds ≤ 250 seconds. Upon completion of the case, the radial arterial sheath was immediately removed and hemostasis was achieved with application of a hemostatic bracelet. The femoral sheath was removed 2 hours post procedure in the recovery area and manual compression applied for hemostasis. Endpoints. The goal of our study was to determine the safety of the low-dose heparin regimen for radial access coronary intervention. The primary endpoints of the study included the incidence of major and minor bleeding and radial artery occlusion. Radial artery occlusion was defined by symptom-led ultrasonographic confirmation of arterial occlusion. Major bleeding was defined as a ≥ 5 gm/dL drop in hemoglobin, any overt bleeding, an access-site hematoma > 5 cm, intra-abdominal, intracranial or intraocular bleeding, or requirement of a blood transfusion. Minor bleeding was defined as an access-site hematoma Results We evaluated 155 patients in the radial group and 100 patients in the femoral group. Baseline patient demographics are shown in Table 1, as above. Most of the baseline characteristics were similar on the two groups. There were more patients with hypertension, hyperlipidemia and diabetes in the radial group. The mean age of the population was 63 ± 11 years (males 68%, weight 88 ± 18 kg) and 66 ± 12 years (males 56%, weight 82 ± 16 kg) in the radial and femoral groups, respectively. Ninety-two percent of the radial and 98% of the femoral cases were elective. The vessels treated were similar in the two groups (Table 2). The mean ACT at the end of infusion was 376 ± 47seconds in the radial group and 331 ± 18 seconds in the femoral group. Consistent with previously published data, patients who underwent radial PCI had slightly longer fluoroscopy times compared to the femoral procedures. However, this was not statistically significant (p = 0.5). There was only 1 case of documented radial artery occlusion that resolved following 2 weeks of low-molecular-weight heparin (LMWH). There were no reported events of any major bleeding in our study population (Table 3). Six patients in the radial group and 5 in the femoral group reported minor bruising. There were no reported events of blood transfusion, death or target vessel revascularization up to 30 days of follow up. When compared to the outcomes with data from the REPLACE 2 trial, we observed a lower risk of bleeding complications in our patient population (Table 4). There was a slightly higher incidence of thrombocytopenia in our patient population.

Discussion

We assessed the usage of bivalirudin in the transradial approach for PCI. In this single-center study we concluded that use of low-dose UFH (2,500 Units) in combination with standard-dose bivalirudin is feasible for ad-hoc coronary intervention via the transradial route. The risk of radial artery occlusion with this modified regimen remains low at 1%, which is similar to the incidence reported in some of the earlier studies. This is not associated with any increase in the incidence of immediate bleeding complications or adverse outcomes up to 30-day follow-up. Vascular access-site-related issues remain a source of significant morbidity in patients undergoing PCI. Transradial access overcomes the limitations of femoral access by allowing for benefits to the patients with early ambulation, less discomfort and bleeding issues. In our center’s current practice, all patients are hospitalized overnight post PCI to monitor for post-PCI MI, acute stent thrombosis and access-site-related complications, the latter being a major concern. Jabara et al demonstrated the feasibility of same-day discharge after coronary intervention performed via the transradial route.¹¹ In their experience with use of radial access for PCI in 450 patients (41% with use of bivalirudin), the incidence of acute complications, i.e., within 24 hours post PCI, was low. The incidence of access-site complications was only 2.4%, and they were all minor bruising or small hematomas that resolved with manual compression and would not have resulted in prolonged hospitalization. It is apparent that the widespread use of radial access for cardiac catheterization would result in early discharge and would help curtail healthcare costs. Radial artery occlusion post cardiac angiography may complicate 3–10% of the cases, and UFH in a dose of 5,000 Units is traditionally used to limit this risk. Traditionally, UFH has been the standard therapy, even though there are no randomized, controlled trials to establish its status as being the therapy of choice. Thus, all new therapies are compared to UFH and are used either in addition to or as a substitute for UFH. The role of bivalirudin has not been established in diagnostic procedures. In a small study group of 66 patients, Mann et al showed that using 1,000–2,500 Units of UFH with bivalirudin in radial PCI is safe. Similarly, in the STRIDE study group, 186 patients were administered 5,000 Units of UFH followed by bivalirudin.¹¹ While in the latter study the incidence of bleeding complications was the same as previously established, there may be concerns about the safety profile of this regimen when applied broadly. We have provided data demonstrating the use of low-dose UFH and standard-dose bivalirudin in ad-hoc transradial PCI without increasing the risk of bleeding, and at the same time providing safety in terms of preventing radial artery occlusion. In our experience, the incidence of access-site hematoma was 1.9%, which is within the incidence range of 0.6–9.5% reported in other studies.^12,13 Even when these events occurred, they did not lead to prolongation of the hospital stay. The incidence of hematoma was independent of demographic characteristics and duration of the procedure. None of the patients in this study group had any major bleeding or required transfusion. These results, in corroboration of the results from a large meta-analysis by Agostoni et al, support the safety of transradial PCI, denoting that radial access should be the default access in contrast to femoral access, which may pose a significant risk of major access-site complications approaching 3%.¹³ One patient in the radial arm had documented evidence of radial artery occlusion that required no specific intervention, and he was asymptomatic at 30-day follow-up. A three-fold elevation of CK was used as the definition of post-procedural MI. The incidence of post-procedural MI was around 3%, which was similar to the incidence in the femoral group and comparable to the results seen in the REPLACE-2 and other bivalirudin trials where they used a three- to five-fold elevation of CK as the definition of post-procedural MI. There were no deaths, stent thromboses or urgent target vessel revascularizations in any of the patients in our study. The study was not powered to evaluate the above-mentioned outcome variables. Study limitations. There are a few limitations to this study. First, this being a retrospective observational study, data may be influenced by the patient’s recollection of events and documentation of adverse events during and after the procedure. Secondly, the sample size, though modest, was not powered to evaluate outcomes. Thirdly, we used clinical symptoms as a guide to assess the incidence of radial artery occlusion as opposed to routine ultrasonography.

Conclusion

In this retrospective observational study we have demonstrated the feasibility of using 2,500 Units of heparin in combination with bivalirudin for transradial PCI. In our small patient group from a single center, we did not find any increased risk of bleeding or radial artery occlusion when using low-dose heparin and bivalirudin for ad-hoc PCI. These results need to be confirmed in larger randomized, controlled trials.

References

1. Singh M, Rihal CS, Gersh BJ, et al. Twenty-five-year trends in in-hospital and long-term outcome after percutaneous coronary intervention: A single-institution experience. Circulation 2007;115:2835–2841. Epub 2007 May 28.
2. Kiemeneij F, Laarman GJ, Odekerken D, et al. A randomized comparison of percutaneous transluminal coronary angioplasty by the radial, brachial and femoral approaches: The ACCESS study. J Am Coll Cardiol 1997;29:1269–1275.
3. Louvard Y, Lefevre T, Allain A, et al. Coronary angiography through the radial or femoral approach: The CARAFE study. Catheter Cardiovasc Interv 2001;52:181–187.
4. Jolly SS, Amlani S, Hamon M, et al. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: A systematic review and meta-analysis of randomized trials. Am Heart J 2009;157:132–140. Epub 2008 Nov 1.
5. Campeau L. Percutaneous radial artery approach for coronary angiography. Cathet Cardiovasc Diagn 1989;16:3–7.
6. Kiemeneij F, Laarman GJ. Percutaneous transradial artery approach for coronary stent implantation. Cathet Cardiovasc Diagn 1993;30:173–178.
7. Rao SV, Ou FS, Wang TY, et al. Trends in the prevalence and outcomes of radial and femoral approaches to percutaneous coronary intervention: A report from the National Cardiovascular Data Registry. J Am Coll Cardiol Intv 2008;1:379–386.
8. Doyle BJ, Ting HH, Bell MR, et al. Major femoral bleeding complications after percutaneous coronary intervention: Incidence, predictors, and impact on long-term survival among 17,901 patients treated at the Mayo Clinic from 1994 to 2005. J Am Coll Cardiol Intv 2008;1:202–209.
9. Fuchs S, Kornowski R, Teplitsky I, et al. Major bleeding complicating contemporary primary percutaneous coronary interventions-incidence, predictors, and prognostic implications. Cardiovasc Revasc Med 2009;10:88–93.
10. Lincoff AM, Bittl JA, Harrington RA, Feit F, et al; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863.
11. Jabara R, Gadesam R, Pendyala L, et al. Ambulatory discharge after transradial coronary intervention: Preliminary U.S. single-center experience (Same-day TransRadial Intervention and Discharge Evaluation, the STRIDE Study). Am Heart J 2008;156:1141–1146. Epub 2008 Oct 9.
12. Bertrand OF, Larose E, Rodés-Cabau J, et al. Incidence, predictors and clinical impact of bleeding after transradial coronary stenting and maximal antiplatelet therapy. Am Heart J 2009;157:164–169.
13. Agostoni P, Biondi-Zoccai GG, de Benedictis ML, et al. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures; Systematic overview and meta-analysis of randomized trials. J Am Coll Cardiol 2004;44:349–356.

————————————————————

From ^*Long Island Jewish Medical Center, New Hyde Park, New York; ^§Boston University School of Medicine, Boston, Massachusetts; and ^£The George Washington University School of Medicine and Health Sciences, Washington, D.C. The authors report no conflicts of interest regarding the content herein. Manuscript submitted October 12, 2010, provisional acceptance given November 22, 2010, final version accepted December 21, 2010. Correspondence address: Avneet Singh, MD, Department of Cardiology, 270-05, 76th Avenue, New Hyde Park, New York, NY 11040. E-mail: asingh1@nshs.edu