Conversations in Cardiology: Using bivalirudin? When do we need to check the ACT during PCI?

Read the latest Letter to the Clinical Editor here.

Compiled by Morton Kern from contributions from Drs. Ajay Kirtane, Columbia University, New York Presbyterian Hospital/Columbia University Medical Center, New York City, New York; Samuel M. Butman, Verde Valley Medical Center, Arizona; David Cohen, Saint Luke’s Mid America Heart Institute, Kansas City, Missouri; David Kandzari, Piedmont Hospital, Atlanta, Georgia; Fred Resnic, Lehey Clinic, Boston, Massachusetts; Joseph D. Babb, East Carolina University Brody School of Medicine, Greenville, North Carolina; John Bittl, Ocala, Florida; Gus Pichard, Washington Hospital Center, Washington, D.C.; Gregg W. Stone, Columbia University, New York Presbyterian Hospital/Columbia University Medical Center, New York City, New York; Peter Block, Emory University, Atlanta, Georgia; Peter Ver Lee, Maine Medical Center, Bangor, Maine; Larry S. Dean, University of Washington School of Medicine, Seattle, Washington; Kirk Garratt, Lenox Hill Hospital, New York City, New York; Robert Applegate, Winston-Salem, North Carolina; Mitch Krucoff, Raleigh, North Carolina.

In our continuing series of “Conversations in Cardiology”, we present some controversy about when we should be using the activated clotting time (ACT) and what it means. As with prior conversations, I thank my colleagues and expert contributors who make this exercise valuable and entertaining. Here’s the issue.

One of my colleagues, Dr. Walley Parham of St. Louis, Missouri, wrote me: “There is some discussion in our hospital about obtaining an ACT after bolus and before PCI when using bivalirudin. While this is what is recommended in the manufacturer’s dosing instructions, it is not how I was trained (with you). I have never obtained an ACT when using bivalirudin. 

“How do you use ACTs when performing PCIs with or without the heparin/bivalirudin transition?”

• Mort Kern, Long Beach, CA: This is a good question and very relevant to daily practice. Bivalirudin will increase the ACT, but it is not used to guide dosing, just to verify some degree of anticoagulation.  If the patient was on heparin before coming to the lab and ad hoc PCI was to follow, ACT would give some idea of state of anticoagulation while transitioning to bivalirudin. ACT would be documentary, but not diagnostic. I believe this was correct information.
• Ajay Kirtane, New York City, NY: Mort, correct. It helps to determine whether [bivalirudin] was given. We have found cases of non-functional IVs, etc., in this way. For patients that have been given heparin pre-procedure, we do not routinely check ACT. We often just give bivalirudin (e.g. in ST-elevation myocardial infarction, per HORIZONS-AMI protocol). I suppose if ACT were therapeutic for PCI one could proceed without bivalirudin, but that’s the subject for another debate.
• Sam Butman, Verde Valley, AZ:  I agree, the only use I know of, and it has come up with our emergency department at least once, is to assure you that the bivalirudin bolus was given. Since we give a standard bolus and infusion of bivalirudin when a patient might have been on some heparin, an ACT is usually not done…although I could imagine some scenarios where it might be. This should be eye-opening if others have drastically different views and experiences.
• David Cohen, Kansas City, KS: I agree with Ajay and have had a few cases over many years when, for one reason or another bivalirudin was ordered but not administered and it was picked up this way [checking an ACT]. Also keep in mind that if you go back in history, in the REPLACE-2 trial, it was mandated to check an ACT after the initial bivalirudin bolus, and the protocol stated that if the ACT was <230 that you were to administer an additional bolus (I believe it was 0.3 mg/kg). If you check the data from the trial, about 2-3% of patients actually received the second bolus. So, if you want to use bivalirudin in the way it was tested in the pivotal trials, checking the ACT and reacting to the value are both relevant.
• David Kandzari, Atlanta, GA: We had a recent run of thrombotic events with sub-therapeutic ACTs with bivalirudin and so now mandate that staff request an ACT for all cases. We also rebolus if ACT is less than 230 seconds (s). It’s funny to see how much physicians complain (myself included) about the time it takes from the case to obtain the ACT (as if it’s so onerous). 
• Fred Resnic, Boston, MA: We just had a case of an infiltrated/non-functional IV this weekend, after bivalirudin had been administered during primary PCI for anterior STEMI. The ACT was very helpful, and I truly believe it helped us avert potentially catastrophic acute stent thrombosis. If I had ever considered not checking an ACT, this case has convinced me otherwise. 
• Joe Babb, Greenville, NC: I also concur with Ajay. Many years ago, in the routine heparin era, we had two cases in quick succession in which heparin was given, PCI performed, and virtually immediate vessel thrombosis occurred, because the ACT had not been checked and the IVs had infiltrated. That changed our lab protocol to require routine ACT post heparin and pre PCI. I think the same applies to bivalirudin.  As Ajay said, it confirms drug effect.
• John Bittl, Ocala, FL: We obtain a measurement at the end of the PCI procedure and recognize that the only useful information obtained from an ACT measurement is binary — to determine whether or not the patient actually received an anticoagulant (with anti-IIa activity).
• Gus Pichard, Washington, D.C.: We started using bivalirudin in 2001, and have used routinely on almost all cases for many years. We always check ACT: soon after bolus and every 30-40 min during the procedure (if it lasts that long). We published many years ago that bleeding was higher in those that also received heparin, so now, if they come on heparin we do ACT: we do not give bivalirudin until the ACT gets below 230. We highly recommend doing it routinely. Easy, cheap, and a very useful guide.
• Gregg Stone, New York City, NY: Excellent conversation. I agree that the main reason to check the ACT is to make sure that the bivalirudin has been administered. Studies have shown no relationship between the ACT on bivalirudin, and either ischemia or bleeding (unlike with heparin). However, I would still give bivalirudin even if the patient has received heparin and the ACT is >230. Heparin activates platelets, whereas bivalirudin inherently blocks both thrombin-induced and collagen-induced platelet activation. And we¹ and others² have shown that adding bivalirudin on top of a high ACT after heparin does NOT increase bleeding.
• Peter Block, Atlanta, GA: There is another important reason, like it or not. I have reviewed a legal case where ACT was not drawn and a thrombotic event occurred. Plaintiff claimed there was no proof that bivalirudin actually entered the patient (faulty IV). I recognize that doing ACT with bivalirudin is a variant of defensive medicine, but after that case, we do it routinely to document that bivalirudin is in.
• Gus Pichard, Washington, D.C.: Gregg, thanks for your teaching on this. The Dangas paper¹ you mentioned is a HORIZONS analysis, where patients got heparin before, then randomized to heparin+2b3a or bivalirudin alone, and indeed the bivalirudin group has less bleeding. There is some old data of ours (you were a coauthor probably) where we found that bivalirudin alone, vs bivalirudin+heparin, had less bleeding.³ I agree that higher ACT does not bring on more bleeding. The main reason for ACT is to insure adequate anticoagulation.
• Peter Ver Lee, Bangor, ME: We check ACT, but only to confirm they have gotten the drug. I guess we are lucky in that our nurses are very good about making sure a patient has two IVs and both are working. We have not had a catheter thrombosis in a long time. But we don’t use much bivalirudin. I am more of the mindset of Paul Teirstein, where we use it only in the cases where the risk of bleeding is high. If someone is loaded on thienopyridine and aspirin, use small doses of heparin and work fast. An ACT over 230 is good.  
• Gregg Stone, New York City, NY: Gus, in addition to demonstrating the superiority of giving bivalirudin in patients who had previously received heparin, the HORIZONS data also showed that among the bivalirudin patients who had received heparin, the ACT before administering the bivalirudin didn’t matter. From the paper: “Impact of baseline ACT before bivalirudin. Among switch patients, the ACT at the beginning of catheterization before bivalirudin administration was <200 s in 637 patients (63.8%) and ≥200 s in 362 patients (36.2%); a pre-procedure pre-bivalirudin ACT was not available in 179 patients. In these 2 subgroups, the median baseline ACT before bivalirudin was 158 and 257 s, respectively (p<0.0001), and the median peak ACT after bivalirudin was 355 and 394 s, respectively (p< 0.0001). The rates of major bleeding and ischemic complications after switching from unfractionated heparin to bivalirudin were not related to the pre-procedure ACT”¹ (Table 1). So you should always give the bivalirudin after heparin, regardless of ACT (meaning you don’t need to check the ACT before giving the bivalirudin) — so, one less step. But I do agree with checking the ACT after you give the bivalirudin just to make sure it has actually gotten in. 

• Larry Dean, Seattle, WA: As others have pointed out, we check ACT regardless of the drug that has been given. Nothing has occurred in the bivalirudin era that has solved the age-old problem of IV infiltration or some other process error that leads to inadequate anticoagulation.
• Kirk Garratt, New York City, NY: Some of us give bivalirudin (or heparin, for that matter) through the guide catheter to assure it gets in. I guess I’m an outlier: I’ve used bivalirudin almost exclusively the past decade without ever checking ACT. So far no problems, but perhaps I should start. How many times have any of you needed to re-dose because ACT was too low?
• Bob Applegate, Winston-Salem, NC: Kirk, I guess I have been a lot like you. I use bivalirudin almost exclusively for my PCIs and have not checked an ACT except maybe once or twice in many years, without apparent issues. This dialogue suggests it might be time to change that.  
• David Cohen, Kansas City, KS: As noted in my earlier email, the protocol in REPLACE-2 was to give an additional 0.3 mg/kg bolus if the ACT was <230. So that’s at least one approach.
• Mitch Krucoff, Raleigh, NC: We need to keep in mind that use of ACT with heparin emerged from perfusionists running pumps during bypass, with fairly linear relationship between dose and measurement. No such relationship exists with bivalirudin. Hence, what many do, including many providing comments here, is use the ACT simply to make sure the drug got into the patient. ACT elevation, once drug is in, is often “super therapeutic” i.e., >300 sec, but not related to bleeding, because [the ACT is] not related to dose or anti-thrombotic effect per se. Still, even as an “all or nothing” kind of measurement, we check ACT routinely to confirm we are not doing PCI with “nothing” on board!

Bottom line

It is better to be safe than sorry when giving critical anticoagulation during PCI. If nothing else, an ACT may confirm that the IV, which was hidden under the drapes, did work.

References

1. Dangas GD, Mehran R, Nikolsky E, Claessen BE, Lansky AJ, Brodie BR, Witzenbichler B, Guagliumi G, Peruga JZ, Dudek D, Möckel M, Caixeta A, Parise H, White H, Stone GW. Effect of switching antithrombin agents for primary angioplasty in acute myocardial infarction: the HORIZONS-SWITCH analysis. J Am Coll Cardiol. 2011; 57: 2309-2316.
2. White HD, Chew DP, Hoekstra JW, Miller CD, Pollack CV, Feit F, Lincoff AM, Bertrand M, Pocock  S, Ware J, Ohman EM, Mehran R, Stone GW. Safety and efficacy of switching from either unfractionated heparin or enoxaparin to bivalirudin in patients with non-ST-segment elevation acute coronary syndromes managed with an invasive strategy. Results from either unfractionated heparin or enoxaparin to bivalirudin in patients with non-ST-segment elevation acute coronary syndromes managed with an invasive strategy: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol. 2008; 51: 1734-1741.
3. Cheneau E, Canos D, Kuchulakanti PK, et al. Value of monitoring activated clotting time when bivalirudin is used as the sole anticoagulation agent for percutaneous coronary intervention. Am J Cardiol. 2004; 94: 789-792.