Yale-New Haven Health System Designates Tirofiban as the Primary Glycoprotein IIb/IIIa Inhibitor

I. Samuel S. Hahn, MD

How do you typically use glycoprotein (GP) IIb/IIIa inhibitors in your current practice? 

Our overall utilization is fairly low now when compared with peak utilization rates in the 1990s and early 2000s. The majority of use is in patients with ST-elevation myocardial infarction (STEMI) or with angiographic evidence of thrombus. Our utilization is approximately 20% of all percutaneous coronary interventions (PCIs). Of those cases where we do use GP IIb/IIIas, about 60% is a bolus-only strategy vs 40% bolus + infusion. Our infusions typically run 6-18 hours, depending upon the indication.

How did Yale-New Haven Health System come to the decision to transition to tirofiban as the preferred GP IIb/IIa inhibitor?

Our Pharmacy & Therapeutics Committee, led by our cardiac specialty pharmacists, did a literature review comparing high-dose bolus (HDB) tirofiban with double bolus eptifibatide, and determined they were therapeutically equivalent. After we were satisfied they were clinically equivalent, we selected the agent that was most cost effective, which was clearly HDB tirofiban.

With the initial launch of the concentrated bolus vial of tirofiban, where did you see potential use for this format at your hospital?

The concentrated bolus vial has made administration of the bolus dose very easy.  Given the concentration and recommended dose, the volume of drug to be given is the patient’s weight in kg/10 (e.g., 8 mL for an 80 kg patient). This has made dose calculation virtually error free and also facilitated intracoronary dosing for those physicians who believe in this route of administration.

Given that tirofiban was already on formulary, can you describe the process of adopting this new format into the cath lab? 

The bolus vial was very rapidly adopted in the cath lab, since the majority of our GP IIb/IIIa use is in a bolus-only strategy. This has made stocking and administering the drug very straightforward.

What properties of the concentrated bolus vial of tirofiban stand out as particularly useful for your practice?

The concentration is perfect since it allows easy dosing based upon the patient’s weight in kg.

Does the concentrated bolus vial format address any previous administrative issues and/or concerns with the IV bag format of tirofiban?

The bolus vial is much easier to draw up and the lower volume of administration makes drug delivery a simple IV push vs previously when we had to program our “smart pumps” to calculate and deliver the drug.

Does the concentrated bolus vial format of tirofiban complement contemporary bleeding avoidance strategies?

Yes, given our propensity to use a bolus-only strategy, we waste less drug by using the bolus vial and we have found that most bleeding complications, both serious and nuisance, occur during the infusion rather than after the bolus.

Did the adoption of tirofiban align with your effort to reduce costs while maintaining quality care?

Absolutely. Given the therapeutic equivalence, we have saved approximately $125K in the past 12 months by switching to tirofiban just at Yale-New Haven Hospital. The savings system-wide are even higher.

What advice would you give to any hospitals looking into adopting the concentrated vial format of tirofiban?

First: I have no vested interests in any of the pharmaceutical companies nor do I have any consulting arrangements! I would definitely recommend making the switch. There is no disadvantage to using HDB tirofiban and the ease of single bolus administration combined with the cost savings are clear benefits.

Any final thoughts?

I think the next frontier should be the comparison of HDB tirofiban (bolus only) versus cangrelor. Cangrelor is much more expensive, less potent, and offers only a limited half-life advantage. As we know, when the decision is made to go to “urgent CABG”, the time frame to go from the cath lab to getting “on pump” is typically the next day and more than 3-4 hours in the vast majority of situations — long enough for sufficient recovery of platelet function (in patients with normal renal function). A randomized comparison between the two agents would be extremely interesting.

II. Ralph J. Riello III, PharmD, BCPS

Can you tell us about your position?

I am the cardiovascular critical care pharmacist at Yale-New Haven Health System and have been for a few years now. We encompass a fairly large hospital system: Bridgeport Hospital, Greenwich Hospital, the recently acquired Lawrence+Memorial and Westerly Hospital, and we also have the Saint Raphael Campus. The main Yale-New Haven area is actually split between two campuses, each with a cath lab, but Greenwich and Bridgeport have one also. Lawrence+Memorial has a cath lab that is primary and elective PCI-capable, so they’ve been part of our tirofiban and tirofiban concentrated bolus vial roll out. Westerly has a cath lab as well, but they are not licensed for PCI, so would not need to use tirofiban. The units I own are the cardiac intensive care unit and much of the heart and vascular center. I also oversee the cardiac cath lab, which is how I ended up getting so involved in the tirofiban initiative. 

Tirofiban is the primary GP IIb/IIIa agent.

Yes. We added cangrelor to the formulary in September 2016, but under some very narrow indications — basically just for the STEMI patients who may have a cardiac arrest, are intubated, and we can’t give them dual antiplatelet therapy by mouth. So, for the most part, in 99% of our cases, the IV antiplatelet agent we use is tirofiban. 

How did you arrive at that point?

In the fall of 2015, we were looking into the cost of eptifibatide. It had been creeping up probably ever since about 2013, which is when the high-dose bolus of tirofiban became available. As eptifibatide’s wholesale acquisition costs kept rising, it popped up on our radar of agents to perform a formulary class review — meaning let’s look at what we are using, how much, and what other options exist. I wrote the monograph characterizing all our GP IIb/IIIa use. We are very fortunate to be part of a large purchasing coalition in the Northeast that brokers excellent deals with drug manufacturers, and right around the time that the cost of eptifibatide was creeping up, we also noticed the cost of tirofiban had become incredibly affordable. We saw a tremendous opportunity for cost savings with tirofiban, without compromising efficacy or safety. Both eptifibatide and tirofiban are equally recommended in the guidelines, and both have similar data for safety and efficacy, so we were happy to be able to keep the same quality, but also cut down on costs and make our lives a little easier from a pharmacy operational standpoint. Once you take eptifibatide bottles out of the fridge, they are only good for a certain amount of time. Tirofiban is stored at room temperature, so there are no issues with keeping things refrigerated in the cath lab. Tirofiban had a longer shelf life, which of course pleased our pharmacy operational staff, who have to go in and out of the cath lab to constantly load these agents when they are being used. We saw maybe a 10-15% cost savings just by switching alone, which equated to $50/patient if they were going to be given a bolus and continued on that infusion, or even $100 savings/patient for a bolus-only approach, which most of our interventionalists prefer. We pitched the switch to tirofiban to our Pharmacy & Therapeutics committee (P&T) and it sailed through. Our cardiologists had no issues and P&T saw a chance to save money without compromising safety and efficacy, so it was a no-brainer. Our P&T committee is one of the main committees at the hospital that decides what agents are on formulary and what protocols we use — basically every single decision chain at the hospital needs to be run through the P&T committee and approved in order to be implemented.

How were physicians involved?

Our health system is enormous and there are far too many committees to spend all your time involved in all issues. We do try and divide up practice-changing decisions based on a subcommittee. The cardiology subcommittee is a group that I have worked with for years because I was the CCU pharmacist, I was in the cath lab, and the physicians knew me. When I was in charge of the monograph, I engaged the physicians early and up front, asking them for their thoughts. We received no pushback about switching, basically because we looped them into the conversation very early on. There were, of course, some concerns. Any time you are doing anything new, there are going to be questions. That was up to us to handle, so pharmacy did a lot of the in-servicing and education. We made the full P&T monograph available on the intranet, with all the granular data down to the very last detail of each study. Pharmacy also made a nice, easy-to-understand in-service that we shared with all the cath lab staff, from nursing to interventional cardiologists, to even the non-interventional cardiologists who receive these patients on the floor, especially in the cardiac ICU, where maybe patients are coming up from the lab with these agents on board, and we don’t want the physician to be surprised. We wanted to keep everyone in the loop from the get-go, and we started to roll out education very early on. 

What are the indications for tirofiban use?

Most of the data for GP IIb/IIIa agents comes from NSTEMI patients. Our physicians used to continue the infusion for 36 hours, sometimes even up to 72 hours. However, we now have ticagrelor as our first-line oral P2Y12 agent, which of course is much more rapid-acting than clopidogrel, so we don’t need to continue these agents for much longer beyond the cath lab. In fact, we set our order screens to cut off the infusion by default after 6 hours, which is when, no matter what the agent, it is fully active. With the launch of tirofiban, use slid into mainly STEMI patients. Our interventionalists use it for anterior wall myocardial infarctions — so a big infarct affecting the whole left ventricle, or any time they don’t feel confident they got the whole thrombus, or maybe a patient came in with a large thrombus burden. We do see a lot of bolus-only approach, which was probably why the concentrated bolus vial of tirofiban has gone over so well. Maybe about 400 of our PCI cases — we do maybe 2000/year — were all just only bolus-only approach. Some of our interventionalists at Bridgeport give tirofiban intracoronary, so we had noticed a lot of waste with the bags, probably, on average, almost 50mLs/case, so almost half the tirofiban bags were just being discarded, because they were bolusing off the bag and infusion pump, and discarding the rest of it. Waste in pharmacy is blasphemy. The half-a-bag of tirofiban waste applies to any time a bolus-only approach is used, which is a majority of cases. The concentrated bolus vial filled that bolus-only approach waste-creation gap probably more than it filled the issue of volume needed to administer an intracoronary bolus. In fact, intracoronary tirofiban use was well discussed previously in a 2014 CLD article.¹ As Dr. McDaniel from Emory mentions in that article, tirofiban used to require quite a bit of volume to draw off the bag into a syringe to administer intracoronary, but now, with the availability of the tirofiban concentrated bolus vial, our Bridgeport interventionalists or anyone else choosing to administer tirofiban via the intracoronary route would no longer have that issue of volume. It definitely provides an added convenience, but the intracoronary volume issue affects a much smaller pool of patients than all of the waste generated by the far more common intravenous bolus-only strategy. The use of GPIs in our labs was mainly just bolus-only with patients going up to the floors to be medically managed. The concentrated vial really filled in that gap. We were wasting half the bag with our bolus-only approach, and when you stretch that out to maybe 400 cases/year, that’s a decent amount of change from something that is not being optimally used. It was another opportunity for cost savings — not just switching from eptifibatide to tirofiban, but now, a year later, switching to the bolus vial. Now we have even more room to not just save money, but also cut down on costs and make things more convenient for our interventionalists, who prefer the bolus-only approach anyway.

How was the bolus-only approach adopted?

We did some in-servicing. The math worked out well with the concentrated vial, making it easy to educate the nursing staff. Before, calculating the bolus off the bag, there were so many different changes of hand and opportunities for error. Although I oversee the cath lab from a pharmacy perspective, I am not normally in the cath lab. I am only in the ICU. There isn’t really a strong, pharmacist-breathing-down-my-neck presence in the cath lab like there is on most of the other units in the hospital. So any time you can make things easier for nursing staff to calculate doses and for interventionalists to verbally recommend something, we take advantage of that opportunity. The bolus vial at the 3.75mg/15mL works out so that you basically divide the patient’s weight in kilograms by 10, and that is the exact amount they need to draw in milliliters. It became easy math for nurses to do right there at the lab side and give IV push. Frankly, it made things a lot easier for them and they were happy with the transition.

Did it change your acute coronary syndromes treatment protocol?

We did have to update it. We simplified and instituted some new drug use guidelines around the introduction of GP IIb/IIIas in the lab. We don’t want our interventionalists to feel they are required to do something, but we do offer recommendations. If they know up front that they are going to use a bolus-only approach, in our new guidelines, we recommended that they use the vials. We communicated that it will make their life easier and it will cut down on our cath costs. But if this is a difficult STEMI, the patient is quite sick, and they want to continue the infusion, then please, by all means, use the bags, because that will actually save on our end with costs as well. We added in a differential approach where if you know your strategy up front, you can pick your dosage form based on your plan.

So you do keep the non-concentrated version on formulary as well.

Yes, on formulary we have the 5mg/100mLs and also we have 3.75mg/15mLs, the bolus vial. We have some of the 12/mg/250mLs, but we find that for our average weight patient, we don’t typically use that much.

Do you have any advice for hospitals interested in going down this path?

I think we did a good job of looking at the numbers up front. Look to see what your interventionalists prefer. Ours really did seem to prefer the bolus-only approach. Stretch that out to how many cases a year that covers and then look at the possible cost savings. If your physicians are bolusing off the bags right now, or if they are drawing it out into a syringe, and trying to give it intracoronary, the concentrated vial can make everybody’s lives a lot easier, especially for high-volume PCI centers. We are a fairly large referral center, so we get patients all the way from Rhode Island to eastern New York coming here to get their PCIs. We saw a tremendous opportunity, given all those cases, to realize a significant cost savings with a bolus-only approach and a vial that’s made for that approach. It makes everybody’s life easier.

Any final thoughts?

It was fun to see it all come to fruition. The education and the in-services were excellent. I engaged my pharmacy resident staff to help me out. We also had Dr. Sam Hahn, our interventionalist captain over on the Saint Raphael side. His help with the education on that campus made things really streamlined. We also got a great deal of help from the Medicure medical science liaisons, especially at our sister delivery networks. They actually went to some of our non-teaching community hospitals to provide education. Medicure was immensely helpful with the process of rolling out across several hospitals in a big network to all go live on the same date. It was magnificent to watch that happen all at once, and then see the follow-up, now that it has been two and a half months since this has all happened. Everything’s been going amazingly well. I think we do have to credit Medicure for helping us out on the front end.

References

1. McDaniel M. Tirofiban in acute coronary syndrome: finding value in the cath lab. Cath Lab Digest. 2014; 22(9). Available online at https://www.cathlabdigest.com/articles/Tirofiban-Acute-Coronary-Syndrome-Finding-Value-Cath-Lab. Accessed April 18, 2017.