Dr. J. Brent Muhlestein can be contacted at JBrent.Muhlestein@imail.org.

Disclosure: Dr. Muhlestein reports that he participated in a consultancy dinner meeting sponsored by Medicure.

An emphasis on consensus and partnership allows Intermountain Health Care to unite under treatment guidelines, establish protocols, and save money, all while providing quality patient care.   

Can you tell us about the creation of the guidelines for acute coronary syndrome (ACS) at Intermountain Health Care?

The guidelines for ACS (Figure 1), and also the antiplatelet and anticoagulant guidelines for coronary stent placement, have been around for a long time at Intermountain Health Care. The guidelines are in place at every one of our institutions taking care of heart patients. Our first guidelines for ACS were formulated almost ten years ago, under the direction of Dr. Donald Lappe, chairman of the department of cardiovascular medicine and also the director of the cardiovascular clinical program for all of Intermountain Health Care. Dr. Lappe assigned the creation of the guidelines to myself and Dr. Jeffrey Anderson, chairman of the guidelines committee for the American Heart Association/American College of Cardiology (AHA/ACC) guidelines and a co-author of the unstable angina/non-ST-elevation myocardial infarction guidelines. We went on to develop our own guidelines and with the aid of Dr. Lappe, simplified them extensively. We followed the AHA/ACC guidelines as much as possible, but the ACC/AHA guidelines often list a variety of options with the statement that any one is an acceptable choice. In an effort to standardize treatment, we decided to pick just one option in these situations to emphasize in our guidelines. Prior to implementation, we sent out the proposed guidelines to all of the cardiologists throughout Intermountain Health Care and received feedback. We tried to respond to everyone in order to get consensus, rather than moving ahead on just a majority vote. We actually worked very hard to get consensus, and it was only then that the guidelines were finalized and sent out to all care managers, cath lab supervisors, nursing supervisors, emergency departments, and so forth, so that everyone was on the same page.

What is the history of glycoprotein (GP) IIb/IIIa antagonist use at Intermountain Health Care?

We have been using IIb/IIIa antagonists ever since EPIC, the very first outcomes trial of an agent in this class. When abciximab came out, we began using it, especially in ACS patients, but abciximab had its problems, and we eventually switched to eptifibatide.  

What were the problems with abciximab?

Abciximab has challenges associated with thrombocytopenia. It is a long-acting drug, meaning it doesn’t wear off, and it has problems associated with bleeding complications. Also, abciximab is even more expensive than eptifibatide. We didn’t eliminate abciximab completely, because it can be used in patients with severe renal dysfunction, whereas tirofiban and eptifibatide are mostly cleared renally. If you have moderate renal dysfunction, dosing of these agents must be adjusted, and if you have severe renal dysfunction, then tirofiban and eptifibatide should probably not be used at all. Specifically, eptifibatide is contraindicated and tirofiban is not defined in patients undergoing dialysis.

How did tirofiban come to replace eptifibatide in your guidelines?

We were using eptifibatide and happy with it, but eptifibatide kept going up in price. So, in 2012, after a review of how much it cost to cover all the eptifibatide that was used, our pharmacy submitted a proposal to us with an estimate of how much money we might save by switching to tirofiban. We thought about it for quite some time and evaluated the effect of switching over, because everything throughout our system was standardized for eptifibatide. The question was, would we gain enough in cost savings to cover the pain associated with making a big change for an entire institution? We hadn’t yet quite decided to move ahead, but then tirofiban had more studies come out reconfirming its similarity to eptifibatide.¹ In late 2013, Medicure also received a separate indication for use of high-dose bolus tirofiban in the cath lab, although even before that indication, we had decided that there was enough data to make the switch. And then, the price of eptifibatide went up again. The pharmacy re-approached us with their proposal and we agreed to switch. However, before making the change to the guidelines, we followed the same pattern for consensus we always use to alter the guidelines. We sent out a proposal from the leadership to our cardiologists, discussing the utilization of eptifibatide vs tirofiban, and asked for feedback. We said that we didn’t see a big difference in the clinical efficacy between tirofiban and eptifibatide, so with X amount of dollars we can save, we asked, would you be willing to switch to tirofiban? All of our cardiologists said yes. After the change was approved in the first quarter of 2013, the pharmacy switched out from eptifibatide to tirofiban, and today, we use tirofiban whenever we used to use eptifibatide. 

How was the transition to tirofiban’s high-dose bolus?

The transition was quite simple. We already had a paper in place, which is online and posted everywhere, regarding bolus protocols: dosing, loading, and infusions. The pharmacy set up that system and they facilitated the transition. When the switch was made to tirofiban, for me, from a physician standpoint, all I had to do was say, “Let’s load this patient on eptifibatide” (it did take me a while to get into the habit) and then the staff would say, “Well, we don’t have eptifibatide anymore, we have tirofiban.” I’d just say, “Ok, then, let’s load tirofiban.” Our staff was inserviced by pharmacy regarding all bolus protocols. I don’t ever have to write down tirofiban’s actual bolus and dosing. I just say, bolus plus infusion, and staff works through our protocol, adjusting for creatinine and any other issues. The only thing the physician has to decide is when to stop the infusion, because that is a clinical decision based on the patient rather than a protocol decision. 

How are specific scenarios for GP IIb/IIIa use addressed in the Intermountain Health Care guidelines?

While our guidelines do address the specific use of IIb/IIIa antagonists, we give physicians the option of choosing. We stratify use by whether patients are ACS or elective percutaneous coronary intervention (PCI), whether these are patients who will be getting stents, and whether or not patients are already loaded with dual antiplatelet therapy. This is based on the results of the ACUITY trial, which tested bivalirudin alone vs heparin plus IIb/IIIa antagonists, and found that from an efficacy standpoint, bivalirudin by itself was probably fine in most situations and was better from a bleeding standpoint, but only in cases in which the patients were preloaded with dual antiplatelet therapy. As a result, our guidelines recommend that IIb/IIIa antagonists should be utilized with unfractionated heparin or with bivalirudin, when patients, especially ACS patients, have not been preloaded with dual antiplatelet therapy. In ACS or high-risk patients that are effectively loaded, we will still consider GP IIb/IIIa antagonists and heparin. In addition, based on the results of a number of studies, including the BRIEF-PCI study², we have adopted short-term infusion of IIb/IIIa antagonists into our guidelines. We don’t necessarily infuse for the full 18 to 24 hours; instead, shorter-term infusions are recommended unless patients are high risk. The IIb/IIIa antagonist can be discontinued four hours after clopidogrel load, or two hours after prasugrel or ticagrelor load. For the highest risk cases, the infusion can continue for up to 12 to 18 hours. We published an abstract³ looking at the outcome of patients with short-term infusions vs long-term infusions, and documented no significant increase in the risk of ischemic complications, along with a significant reduction in bleeding complications, such that, if short-term IIb/IIIa antagonists are given, there is no greater risk of bleeding than with bivalirudin monotherapy. 

Are there any other benefits to a shorter-term IIb/IIIa infusion timing besides a reduction in bleeding complications?

It is cheaper to use in the short term. Bivalirudin isn’t necessary, so overall spending on that drug is less. After the results of the most recent bivalirudin study, HEAT-PPCI⁴, comparing bivalirudin plus bailout IIb/IIIa antagonists vs heparin plus bailout IIb/IIIa antagonists (really a comparison of bivalirudin vs heparin), we have reduced bivalirudin use and are often just using heparin instead. That has resulted in perhaps a little more short-term IIb/IIIa antagonist use. However, that is not to say that bivalirudin is not a good drug. Bivalirudin is a good drug, but it is not a platelet inhibitor, and acute coronary thrombus is mostly platelet aggregation. I am giving you my bias, which is that you need to have adequate platelet inhibition. What has led us to like the short-term IIb/IIIa antagonist even more has been the data showing that acute STEMI patients, especially, are not preloaded with dual antiplatelet therapy. When acute STEMI patients come in, you want to load them, and even the more rapid onset drugs, like prasugrel and ticagrelor, take longer to act, especially in a situation where patients get morphine, because morphine significantly slows down the absorption of these agents. In this scenario, there is an even greater potential advantage for giving short-term IIb/IIIa antagonists, which can cover platelet inhibition until the dual antiplatelet therapy with P2Y12 inhibition actually kicks in. There was a study looking exactly at this method of use, where the administration the high-dose bolus of tirofiban, followed by a short infusion and concomitant prasugrel bridges the first hours in which prasugrel alone fails to provide complete platelet inhibition.⁵

In your story, it is interesting that your pharmacy came to you and proposed the use of tirofiban as a clinically equivalent alternative that was more cost effective. Is this type of proposal common?

It is certainly common at Intermountain. We work very closely with our pharmacy and have regular meetings together. They help us devise our guidelines, formulate our protocols, and facilitate appropriate medical care with all of our patients. We have specific cardiovascular pharmacists on every floor, overseen by a director who helps us a great deal. Pharmacy is a critical component of our management team. They attend our conferences, we do joint research projects, and they are co-authors on our papers. They are part of the team. It wasn’t unusual for our pharmacy to approach us. It was just part of our natural management, with collaboration and cooperation between different, important health care team members.

Can you share some of the history of tirofiban in interventional cardiology?

Tirofiban (at the time, owned by Merck) started off with the PRISM-PLUS study, published in the New England Journal of Medicine in 1998⁶, which got it approved in full to use in ACS, starting with upstream treatment. Then Merck wanted to compete with abciximab, and did a head-to-head study of abciximab vs tirofiban with a lower 10mcg/kg bolus in patients undergoing PCI in the cath lab, starting dosage in the cath lab. But tirofiban didn’t have the right bolus dose figured out yet and abciximab won that study. Many people felt another study could help get the right bolus dose of tirofiban. It has advantages over abciximab and with the right bolus dose, it was felt that tirofiban could compete with abciximab. Tirofiban has demonstrated higher levels of platelet inhibition at 10 minutes with greater patient response⁷, along with reduced TIMI minor bleeding and incidence of thrombocytopenia¹. But Merck had not typically been involved with short-term infusion drugs. They decided that it wasn’t really in their best interest to pursue tirofiban, so they sold it to another company, which eventually sold it to a Canadian company, Medicure. Studies were done in ACS patients undergoing PCI showing that tirofiban at the 25mcg/kg bolus was equivalent to other IIb/IIIa antagonists while being a lot cheaper. The FDA approved the high-dose bolus for PCI in October 2013. The high-dose bolus of tirofiban has an equal recommendation to eptifibatide in the 2014 ACC/AHA Non-ST-Elevation-ACS guidelines, 2013 ACC/AHA ST-Elevation Myocardial Infarction (STEMI) guidelines, and 2011 ACC/AHA/SCAI Percutaneous Coronary Intervention (PCI) guidelines.

Do you have any advice if a facility is looking at switching to tirofiban?

The most important thing we did before switching was getting consensus and buy-in from all the physicians, so that the physicians didn’t feel like anything was being ramrodded through. We did our homework beforehand to make certain that we would not cause any reduction in quality of care, because quality of care for our patients is of prime importance. Once we became convinced that the quality of care using high-bolus dose tirofiban was no different than with the use of eptifibatide, then we worked with everyone to get a consensus opinion, and then we acted. So that is my recommendation — don’t just send out an email that says, “Eptifibatide is taken off the formulary and tirofiban is now on the formulary, so you have to use tirofiban.” Don’t do that! There was a great deal of work done beforehand so that everyone agreed this was a good idea. I believe all physicians are happy to help institutions save money, if they feel that they are still able to give the best quality of care to their patients. 

References

1. Valgimigli M, Biondi-Zoccai G, Tebaldi M, van’t Hof AW, Campo G, Hamm C, ten Berg J, et al. Tirofiban as adjunctive therapy for acute coronary syndromes and percutaneous coronary intervention: a meta-analysis of randomized trials. Eur Heart J. 2010 Jan; 31(1): 35-49. doi: 10.1093/eurheartj/ehp376.
2. Fung AY, Saw J, Starovoytov A, Densem C, Jokhi P, Walsh SJ, et al. Abbreviated infusion of eptifibatide after successful coronary intervention The BRIEF-PCI (Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention) randomized trial. J Am Coll Cardiol. 2009 Mar 10; 53(10): 837-845. doi: 10.1016/j.jacc.2008.09.060.
3. 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:  A14373.
4. Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, et al.; HEAT-PPCI trial investigators. Unfractionated heparin vs bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014 Nov 22; 384(9957): 1849-1858. doi: 10.1016/S0140-6736(14)60924-60927.
5. Valgimigli M, Tebaldi M, Campo G, Gambetti S, Bristot L, Monti M, Parrinello G, Ferrari R; FABOLUS PRO Investigators. Prasugrel vs tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. JACC Cardiovasc Interv. 2012 Mar; 5(3): 268-277. doi: 10.1016/j.jcin.2012.01.006.
6. PRISM-PLUS study investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS). N Engl J Med. 1998 May 21;  338(21): 1488-1497.
7. Danzi GB, Capuano C, Sesana M, Mauri L, Sozzi FB. Variability in extent of platelet function inhibition after administration of optimal dose of glycoprotein IIb/IIIa receptor blockers in patients undergoing a high-risk percutaneous coronary intervention. Am J Cardiol. 2006 Feb 15;97(4):489-493.

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The Pharmacist’s Perspective

Cath Lab Digest talks with Katy Mathews Cox, PharmD, BCPS (AQ Cardiology)*, who was the cardiovascular clinical pharmacist at Intermountain Health Care overseeing the change to tirofiban.

What was the dollar amount pharmacy proposed they might save by moving away from eptifibatide? 

At the time that we launched the transition, the expected cost savings were around $450,000 for the system (with $200,000 for Intermountain Medical Center alone). We have 4 primary percutaneous coronary intervention (PCI) facilities within our system. Intermountain Medical Center typically comprises the largest population of PCI cases each year. Our system contemplated this transition for a couple of years, and during that time, there were changes that affected the potential cost savings that we anticipated from the transition. Most of the changes in practice (locally and nationally) affected how much eptifibatide we were using. Our anticipated cost savings were calculated based on our eptifibatide spend (since tirofiban and eptifibatide are in the same small peptide glycoprotein IIb/IIIa inhibitor class). Details of these “changes in practice” are as follows:

1. Bivalirudin utilization was becoming prominent with primary PCI across the country. When bivalirudin use went up, glycoprotein IIb/IIIa inhibitor use went down, thereby decreasing cost savings.  It is important to note that after the tirofiban transition occurred, the results of the HEAT-PPCI¹ (favoring heparin over bivalirudin in a ST-elevation myocardial infarction [STEMI] population) changed bivalirudin prescribing behaviors dramatically. 
2. Upstream use of glycoprotein IIb/IIIa inhibitors was becoming less common following the publication of the EARLY-ACS trial² for patients with non-STEMI (NSTEMI). This change in practice also decreased how much eptifibatide we were using.
3. The introduction of more potent oral P2Y12 inhibitors such as prasugrel and ticagrelor decreased the need for prolonged glycoprotein IIB/IIIa inhibitor infusions in the post PCI setting.

The actual savings were $250,000 in 2013 (during the conversion) and $350,000 in 2014. As mentioned above, the likely culprit for less-than-predicted cost savings is due to changes in prescribing practices.

Dr. Muhlestein mentions that staff followed a protocol in administering the high-dose bolus of tirofiban. How did the pharmacy work with the cath lab staff to facilitate the transition from eptifibatide to the tirofiban high-dose bolus and how did staff react to the change?

We have heard a lot of positive feedback from nursing staff regarding the ease of administration with tirofiban over eptifibatide:

• It is a single bolus (no need to do two boluses ten minutes apart as with eptifibatide);
• The bolus comes out of same bag as the infusion (far fewer bag/vial changes);
• The bolus is delivered via the pump, and automatically switches to the maintenance infusion (eptifibatide requires bolus vials with delivery via syringes, and a separate infusion vial);
• Tirofiban is stored at room temperature (eptifibatide can’t be outside of the fridge for more than 2 months).
• One of the most landmark contributions to this transition came from collaborating with the IT department to execute bolus administration with our Sigma Spectrum pumps. We piloted the pump settings with my cath lab staff before we trained the other sites. One of my Intermountain Health Care cath lab champions assisted me as we trained with the other sites (on-site). We also worked with nurse educators to coordinate “skills pass-off” for IV administration. 

Do you have any comment on the role played by pharmacy in the transition to tirofiban at Intermountain Health Care?

It is important to mention that we all needed to agree on the transition, because it is a huge process to change formulary at a system level. It was necessary to have the support of the cardiologists to help communicate guideline updates (with tirofiban as a suitable small molecule glycoprotein inhibitor) and allow open discussion at system forums (such as grand rounds). Pharmacy had a critical role with updating order sets and protocols, but worked closely with cardiology to ensure consensus with revisions. Pharmacy worked closely with the cath lab staff (prior to the transition) to identify any potential areas that might lead to error with the transition.

References

1. Giugliano RP, White JA, Bode C, Armstrong PW, Montalescot G, Lewis BS, et al; EARLY ACS Investigators. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med. 2009 May 21; 360(21): 2176-2190. doi: 10.1056/NEJMoa0901316.
2. Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, et al.; HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014 Nov 22; 384(9957): 1849-1858. doi: 10.1016/S0140-6736(14)60924-60927.

*Katy Mathews Cox, PharmD, BCPS (AQ Cardiology) is currently the Critical Care Pharmacist – Cardiology, Director – PGY1 Pharmacy Practice Residency, at Baylor University Medical Center’s Department of Pharmacy, in Dallas, Texas.