Mercy Medical Center`s Experience: Early Ambulation post PCI with Use of Direct Thrombin Inhibitor, Bivalirudin

It is now widely accepted that early sheath removal after percutaneous coronary intervention (PCI) reduces femoral access site complications and leads to earlier ambulation, possibly earlier discharge, and improved patient satisfaction. Heparin-based anticoagulation therapy requires monitoring of coagulation status to determine readiness for sheath removal, due to the unpredictable nature of heparin. In an effort to increase quality of care for his patients undergoing PCI, as well as reduce the cost of resources in the cath lab, Dr. Sameer Mehta developed a time-based sheath removal protocol for patients who received bivalirudin (Angiomax®) as the base anticoagulant for unstable angina undergoing PCI. Dr. Mehta found that using a two-hour sheath removal protocol led to earlier sheath removal and reduced access site complications. It also permitted planning for the timing of sheath removal (rather than waiting for the ACT to come down) which simplified nursing resource allocation in the post care areas. I started to use bivalirudin as the base anticoagulant for percutaneous coronary interventions (PCI) shortly after it was approved by the FDA in December of 2000. As an investigator for the REPLACE-1 trial, an unblinded trial that used bivalirudin as the base anticoagulant for patients undergoing PCI, I strongly believe that bivalirudin’s properties make it a superior drug to heparin for PCI. These properties include the following: As a direct thrombin inhibitor, bivalirudin inhibits both circulating and clot bound thrombin. With the increase in patient acuity treated with PCI, the ability to inhibit thrombin already in the clot bound state is crucial. Heparin, an indirect thrombin inhibitor, cannot inhibit clot bound thrombin, a major limitation in the PCI setting.¹ Bivalirudin’s bolus dose and infusion provide adequate anticoagulation throughout the entire PCI procedure.² With heparin, we must check ACT levels during the PCI procedure, especially during lengthy procedures, in order to titrate the drug to maintain adequate anticoagulation. The 25-minute half life of bivalirudin, together with the mechanism of action whereby thrombin is temporarily disabled but not permanently altered, leads to a superior bleeding profile, with fewer bleeds reported in all trials done with bivalirudin versus heparin in the PCI setting.^3-5 Bivalirudin has also shown improved ischemic outcomes over heparin in clinical trials. Finally, bivalirudin does not react with heparin antibodies and can be used in patients with a history of Heparin Induced Thrombocytopenia Syndrome (HITS) who are undergoing PCI.⁶ I decided to test bivalirudin’s potential to see if the pharmacokinetic profile would allow us to pull sheaths without having to perform the frequent ACT monitoring required to date with heparin patients. In using bivalirudin as the base anticoagulant, it seemed possible to improve patient outcomes, reduce bleeding, simplify and speed up the sheath removal process, and reduce the number of ACT tests and closure devices used in the lab. In patients who have received bivalirudin, it is possible to calculate when hemostatic function is sufficient to remove sheaths without relying upon an ACT level to measure coagulation status. Once the bivalirudin bolus is administered, plasma concentrations soon reach peak levels and maintain therapeutic concentrations throughout the bolus infusion. When drug is discontinued, plasma levels of the bivalirudin fall rapidly. Data shows that patients have return of hemostatic function within 2 half lives of the drug, or approximately one hour in patients with normal renal function7 (Figure 1). Although drug clearance is slower in patients with moderate (creatinine clearance of 30-60 ml/min) to severe renal function (creatinine clearance 10-30 ml/min), these patients appear to have subtheraputic levels of bivalirudin within 2 hours of discontinuation of drug (Figure 2). Bivalirudin’s mechanism of action explains this phenomenon. A bivalent direct thrombin inhibitor, bivalirudin binds directly to the thrombin molecule in 2 places: the active site and the thrombin binding site. Bivalirudin inhibits both circulating and clot bound thrombin, and does not activate platelets. The bivalirudin molecule is eventually cleaved by thrombin at the active site, leaving bivalirudin still attached to the fibrin binding site. Once cleaved, the bivalirudin molecule frees itself from the binding site, leaving the thrombin molecule intact. With thrombin intact, fibrin is able to compete with and displace bivalirudin from the fibrin binding site, leading to a recovery of hemostatic function. Hence once the drug is discontinued and serum concentrations of bivalirudin fall, hemostatic function returns.⁷Sheath Removal Protocol The bivalirudin sheath removal protocol I developed is shown in Figure 3. Sheaths are removed by an RN or RT within one hour of discontinuation of bivalirudin, using standard manual pressure techniques. For those patients with impaired renal function, we wait 90 to 120 minutes, as shown in the protocol. Most patients in our cath lab receive bivalirudin as the base anticoagulant, and their sheaths are pulled in the holding area or cath lab. At the time of this study, approximately 40% of our patients received heparin as the base anticoagulant, and the standing sheath pull protocol for heparin patients was to monitor ACT until the level reaches 180 seconds. This can take anywhere from 2-10 hours, but generally is in the 4-hour range, and requires, on average, 2-3 ACT measures to be performed. Some patients are transferred to the floor by this time and have their sheaths removed by staff on the post care unit. Renal Function Many times, patients who present to the cath lab for interventional procedures have some degree of renal failure, which is not always evident from looking at the patient’s chart. In fact, renal impairment is common in patients undergoing PCI, at some estimates occurring in 40% of these patients.⁸ Clinical studies have shown bivalirudin to be safe and effective in patients with renal impairment. However, the degree of renal function should be noted to determine the rate of drug clearance and time of return of hemostasis to better manage a time-based sheath pull protocol. This is especially true if planning to remove sheaths within one hour of bivalirudin discontinuation. It is estimated that within two hours, most patients, except for those who are dialysis dependent, have low enough serum levels of bivalirudin to safely remove sheaths. If creatinine clearance is unknown, or there is suspicion that a patient has an impaired renal status, it is advisable to wait the full 2 hours to remove the femoral sheath. With the few patients we care for who are dialyses-dependent, we take a more cautious approach and monitor blood anticoagulation levels, waiting until an ACT shows a consistent reading of 180 seconds before removing a femoral sheath, similar to what we do with our heparin patients. Sheath Removal Nurses in this study primarily relied upon manual compression or c-clamp for pressure once sheaths were removed. In my practice, about 5% of patients receive a topical closure pad, and very few invasive closure devices are used or in my opinion, needed. The bivalirudin time-based sheath removal protocol has been in place since June 2002. When the protocol was initiated, the nursing staff reviewed proper sheath removal techniques, and designed a data sheet to record access site complications, including hematoma, pseudoaneurysm, surgical repair, ecchymosis, and access site oozing. Nurses reported that the sheath removal process is simpler with patients that have received bivalirudin. As patients are leaving the cath lab at the end of the procedure, nursing staff can calculate when the sheath should be removed and plan that into their time, rather than having to gather resources when the ACT finally drops. Also, the process of actually removing the sheath is easier. Our hold times are more consistent and access site complications are less likely to occur. AFRICA: Study Results We enrolled 186 consecutive patients where PCI was performed by a single operator in the AFRICA trial. All patients receive bivalirudin as the base anticoagulant, administered as a 0.75mg/kg bolus and a 1.75mg/kg/hr infusion for the duration of the procedure. Seven patients received a glycoprotein (GP) IIb/IIIa inhibitor. The majority of patients (184/186) (99%) had their sheaths pulled within two hours of discontinuation of the drug, including those patients who had received a GP IIb/IIIa inhibitor. Sixty-nine percent (69%) of patients had sheaths re-moved within one hour. Access site complications and other bleeding complications were low, as shown in Table 1. There were no pseudo-aneurysms, no retroperitoneal bleedings, or any arteriovenous fistulas. The observed hematomas mentioned in Table 1 were non-expanding and did not require transfusion of blood products. Finally, the bleeding complications were not correlated with duration or time of sheath removal. Conclusions Access site complications continue to be a problem post PCI, despite the many advances made in other areas of care. Sheath removal is time-consuming and resource-intensive. Instituting a protocol for patients that have received bivalirudin during PCI using a time-based sheath removal protocol has resulted in faster sheath removal, fewer access site complications, improved resource allocation for nursing staff in the post care areas, earlier ambulation, and increased patient satisfaction. The authors wish to express their gratitude to Annmarie Galli, MSN, from the Medicines Company for her assistance in preparing this manuscript. The authors also acknowledge an educational grant from the Medicines Company that was provided for this work.

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