Since your last discussion with CLD in 2015,1 there have been significant changes in practice and approaches to adjunct pharmacotherapy during percutaneous coronary intervention (PCI) in the U.S., including a shift to radial access PCI, and a resurgence of heparin as the preferred anticoagulant — have there been similar changes in practice within Intermountain Health Care?
Certainly I am seeing more radial access. I think patients like it better. I don’t think it is the end-all, be-all to fix everything; there are still times when you have to use femoral procedures. Regarding heparin, I never was a believer that bivalirudin was significantly superior to heparin, so I never did regularly use it, especially because I am a believer in the value of transient, temporary, IIb/IIIa antagonist treatment during the PCI procedure. Physicians at Intermountain who still want to use bivalirudin can do so, but the use of bivalirudin has dropped precipitously in the last couple of years since the HEAT-PPCI study (unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention) came out. And, as when you and I spoke in 2015, our pharmacists continue to participate in our action decision-making process. We still have multiple pharmacists in the coronary care unit and we have pharmacists that are available in outpatient care, as well as on the floor. They all participate and make recommendations, and we respond accordingly.
Several years ago, Intermountain also moved to tirofiban as its primary glycoprotein (GP) IIb/IIIa inhibitor, and took the approach of reducing the infusion length to 6 hours or less, including recommending tailoring the infusion length to complement the P2Y12 inhibitor used. Could you explain the rationale behind the use of short-infusion tirofiban (6 hours or less) versus the more traditional longer-duration infusion of 12-18 hours?
The short-term infusion approach has been accepted by most of our physicians. In the past, we published a paper where we compared long-term infusion vs short-term infusion of eptifibatide.2 We found a significant reduction in bleeding complications, but no increase in ischemic complications. With that data, and other data that has now become available, when we use tirofiban, we virtually always use short infusion. We now have switched to iCentra (Cerner), a fully integrated electronic health record, and iCentra uses what they call “power plans” in our electronic health record. These are like pre-printed order sets. We have set up power plans for tirofiban, and in the orders are our recommendations. Those recommendations include short-term infusions unless there are specific problems or complications, such as if there is a huge amount of thrombus in an acute myocardial infarction (MI) patient, and then the cardiologist may pursue a longer infusion. The order gives the option of 2-6 hours after the conclusion of the catheterization procedure, unless the physician chooses to change it. This default of a short-term infusion does two things: one, it makes things easy for the physician. Two, for the physicians who don’t know exactly what they want to do, the order provides a reminder of the recommended protocol. We have also switched over to the high-dose bolus and infusion for our upstream patients as well, so at present, we only have one order set for tirofiban. It used to be that there was a different, lower, bolus and infusion of tirofiban recommended if it was upstream acute coronary syndrome (ACS), but now it is the same for both upstream use and if started in the catheterization laboratory (25 mcg/kg bolus followed by 0.15 mcg/kg/min infusion). It makes no sense to go to a lower dose when you are upstream. Tirofiban is a short-acting GP IIb/IIIa inhibitor. It has a half-life of 2 hours, and so, in 2 hours it is half worn off, and in 4 hours, it is almost all worn off. That is good if you don’t want to keep a IIb/IIIa inhibitor going long term; if you shorten the infusion, you are going to have less bleeding, and all studies have confirmed this is the case. Now, what about P2Y12 inhibitors? You definitely need to have adequate antiplatelet therapy when you are placing a stent or doing percutaneous coronary intervention (PCI). Adequate antiplatelet therapy is not obtained by only giving an anticoagulant like heparin or bivalirudin. From an oral antiplatelet perspective, it has been determined that, in order to obtain adequate antiplatelet therapy, it generally requires dual antiplatelet therapy using the combination of aspirin and one of the P2Y12 inhibitors. All the guidelines recommend dual antiplatelet therapy. However, a problem with the oral P2Y12 inhibitors is that they don’t have immediate onset. First of all, they have to be absorbed, then they have to be activated and metabolized — at least clopidogrel and prasugrel do — although that is not the case with ticagrelor. Ticagrelor, once it is in the system, has an immediate effect, because it does not have to be activated by liver metabolism. Clopidogrel requires the most activation, taking about 4 hours, on elective basis with a 600mg load, to be activated. Prasugrel takes less time at about 2 hours, because it only has to be hydrolyzed, instead of the greater activation required by clopidogrel. Notably, these data come from standard stable patients. However, several papers have been published documenting that in the setting of acute MI or ACS, especially if the patient is receiving narcotics such as morphine, which slows down GI motility, absorption can be slowed down significantly for all P2Y12 inhibitors, including ticagrelor. Consequently, if patients are not already on dual antiplatelet therapy when they come in, achieving that status is going to take time and there is going to be a window in which they are not protected. That window usually ends by 6 hours, even in the setting of acute MI. One of the advantages of the short-term infusion of tirofiban is that it gives you more potent antiplatelet therapy right at the time it is needed — during the procedure. Then the operator can ensure the patient is protected with tirofiban until full dual oral antiplatelet therapy with both aspirin and the P2Y12 inhibitor is on board. When tirofiban is then stopped, it will wear off fairly quickly.
How have you evaluated the clinical and safety profile of the tirofiban GP IIb/IIIa short infusion approach?
We have already published data regarding the safety and efficacy of short-term infusion vs long-term infusion of GP IIb/IIIa inhibitors, based on observational data.2 At the time, there was a big press towards the use of bivalirudin and quite a few of our physicians chose to use bivalirudin. Some other physicians, like myself, thought, I still want to be protected. I want adequate antiplatelet therapy all the way through the entire procedure, especially the first, highest-risk part, so I will use a short-term infusion of tirofiban, and I will use heparin, not bivalirudin. It turns out we had a good number of patients at Intermountain who underwent both strategies and so we decided to review observational data regarding the use of a short-term infusion of tirofiban with heparin vs use of bivalirudin without a IIb/IIIa antagonist. Most patients started dual antiplatelet therapy at the time of the procedure. They weren’t pretreated with dual antiplatelet therapy, except for a small percent. We also noted whether clopidogrel, prasugrel or ticagrelor was used, and then we looked at the outcomes of the patients out to one year (our data have already been published in abstract form3 and we are now working on a manuscript). What we found was that, from a bleeding standpoint, the use of a short-term infusion of tirofiban actually resulted in less bleeding complications than the use of bivalirudin. A lot of people seem to have forgotten this, because it was a long time ago now, but when you use a IIb/IIIa antagonist, you don’t need to have nearly as much anticoagulation. You don’t need an activated clotting time (ACT) that is greater than 300. The target is between 180 and 200; that is 3,000-4,000 units of heparin. When you use a IIb/IIIa antagonist like tirofiban, you should reduce the amount of heparin that you give. If you are not doing any IIb/IIIa antagonist, then the ACT needs to be greater than 300. This means that if operators end up giving high amounts of heparin, it is going to increase the risk of bleeding, potentially even when there is a short-term infusion. As a result, our internal guidelines all say to use low-dose heparin and a targeted ACT between 180 and 200. Our average ACT is significantly lower than many of the studies, which may contribute to the reduction in bleeding we noted. But I still think the most important thing was stopping the IIb/IIIa antagonist when it is no longer needed. In regards to efficacy, for the most part there was equivalent efficacy between the two strategies, except that all-cause mortality was reduced with the short-term infusion of tirofiban compared to bivalirudin, which is interesting. If you remember, there were several studies where the proposal was that bivalirudin resulted in a reduction of all-cause mortality. How did it do that? They proposed that maybe it was because of less bleeding complications. It may be the case that short-term infusion of tirofiban with lower dose heparin may result in even less bleeding than the use of bivalirudin. Therefore, that may be where our benefit in all-cause mortality came from. We did use all comers, and the benefit did not vary based on their presentation, whether they presented with MI or something else. Major bleeding complications in the setting of radial artery procedures were zero in both groups, so no one had major bleeding who had radial artery access. But then, these strategies are also both low bleeding risk strategies. Bivalirudin by itself is a low bleeding risk strategy, and short-term infusion of tirofiban with lower dose heparin is also a low bleeding risk strategy. In the setting of a low risk bleeding strategy and radial artery procedures, we didn’t have any major bleeds at all. That gives justification for doing radial procedures, when it is easily feasible. Certainly in the setting in which you do not have dual antiplatelet therapy on board before the procedure, the thought is that you should probably use a short-term infusion of tirofiban and low dose heparin. Some people say, well, if the patient is not really sick, we will get P2Y12 action, so we may not need to use this strategy in stable patients. Although I still use it in stable patients. Those patients where you may not need to use a short-term infusion of tirofiban are those already on dual antiplatelet therapy. Perhaps it’s from my experience in the past before we had GP IIb/IIIa inhibitors, where we would run into problems of significant thrombus. Granted, you can bail it out by doing a rescue IIb/IIIa, but that is a hassle, and I would rather it never happens. The patients who need it the most are the patients who are ACS, who are not already on dual antiplatelet therapy, and that is an area where I think all of our physicians agree that that is necessary and they do it under those circumstances.
What has been the reaction within Intermountain Health Care to the short infusion GP IIb/IIIa approach and your analysis?
Our protocols are set up so that within the internal website of Intermountain, we have a cardiology area, and within that, we have clinical guidelines and care process models. We have guidelines and recommendations for what to do in the cath lab and every other area within cardiology. We keep updating those guidelines, and when we update and change them, we have a conference call with representatives and anybody else who wants to join, for all the different cath labs throughout Intermountain Health Care. We discuss what the recommendations are now, what our care process model advises, and see if people have any suggestions or changes, and then generally come to a consensus. Once that happens, everyone approves it and we work with the iCentra people to set up, in essence, premade orders that will match our recommendations. That makes it easy for the physicians to follow what is in our protocols, because that is the way the orders are written up. It doesn’t mean they have to do it, but it has to be a choice they make, to say in this circumstance, “I don’t want to do what the guidelines have recommended from Intermountain, because of x reasons” and they have to change the orders. Physicians can do anything any way they want, but when it is not something special, what they are going to get is what is in our care process model.
Our short infusion strategy was implemented based on data from other studies, especially the BRIEF PCI (brief infusion of eptifibatide following PCI) study. At first, we made it available, but never forced anyone to do anything. Then we did our own studies, and we presented our studies not only to the world, but also to our own colleagues, and the short infusion strategy became accepted to the point that now it is basically all that is done at Intermountain.
Do you think there are misconceptions about GP IIb/IIIa inhibitors that could be addressed through analysis of your data, and lead to practice change within the U.S.?
One misconception is thinking that with dual antiplatelet therapy, the need for GP IIb/IIIa inhibitors is getting less and less. My general analysis and overall experience is that is a mistake. IIb/IIIa inhibitors are still extremely valuable in many circumstances. Some misinterpretation of the EARLY ACS trial has led people to be less excited about IIb/IIIa inhibitors, and not be using them as much as they should. But I think the use of a short-term infusion of tirofiban with low dose heparin is tremendously beneficial in making your cases go smoothly and steadily. If you already have a IIb/IIIa inhibitor on board, you know you are not going to run into thrombotic complications. You can stop it when you are done, it all goes away, and you can have your cake and eat it, too.
- Muhlestein JB. Switching from eptifibatide to tirofiban use in ACS: reducing cost while maintaining quality of care. Cath Lab Digest. 2015 Mar; 23(3): 1,14. Available online at https://www.cathlabdigest.com/article/Switching-Eptifibatide-Tirofiban-Use-ACS-Reducing-Cost-While-Maintaining-Quality-Care. Accessed February 13, 2018.
- Rigby B, May HT, Bair TL, Anderson JL, Whisenant BK, Lappé DL, Muhlestein JB. Clinical outcomes of percutaneous coronary intervention in patients receiving short term or prolonged infusions of eptifibatide or bivalirudin: results from the Intermountain Heart Registry. Circulation. 2013; 128(suppl 22): A14373.
- Muhlestein JB, May HT, Bair TL, et al. Abstract 15074: safety and efficacy of peri-procedural heparin plus short term infusion of tirofiban versus bivalirudin in patients undergoing percutaneous coronary intervention: results from the Intermountain Heart Collaborative Study. Circulation. 2016; 134: A15074. Available online at http://circ.ahajournals.org/content/134/Suppl_1/A15074. Accessed February 14, 2018.
Disclosure: Dr. Muhlestein reports being a member of the speaker’s bureau for BMS and that he speaks about twice per year regarding Eliquis.
Dr. J. Brent Muhlestein can be contacted at JBrent.Muhlestein@imail.org.