A new, more concentrated format of tirofiban will soon become available to deliver the FDA-approved, high-dose bolus of 25 mcg/kg at the start of treatment: pre-mixed, ready-to-use, 250 mcg/mL in a 15 mL vial.
Emmanouil S. Brilakis, MD, PhD
Dr. Brilakis, can you tell us about the Veterans Affairs (VA) North Texas Health Care System?
The Dallas VA is one of the largest VAs in the country, with a high volume of percutaneous coronary interventions (PCIs). It has a full complex PCI/chronic total occlusion (CTO) program, a full peripheral program, and a full structural program offering transcatheter aortic valve replacement (TAVR) and MitraClip (Abbott Vascular). It offers comprehensive care, in all aspects of cardiac care.
How does the use of glycoprotein IIb/IIIa inhibitors fit into your practice?
Glycoprotein IIb/IIIa agents are often used in acute coronary syndromes (ACS), mainly ST-elevation myocardial infarction (STEMI), as well as in patients with a large thrombus burden. They may also be used as a bailout for patients who have a thrombotic complication during PCI. We almost never use glycoprotein IIb/IIIa inhibitors in CTOs, as in these procedures sometimes the wire can go outside the vessel, which is typically not a problem, but can become an issue with aggressive antiplatelet therapy. Currently, the main use of glycoprotein IIb/IIIa inhibitors is for ACS and thrombotic complications.
Can you talk more about glycoprotein IIb/IIIas being used for thrombosis in an acute setting?
Acute thrombotic complications can benefit from use of glycoprotein IIb/IIIa inhibitors. For example, in bifurcation stenting, the side branch can become occluded. This is a classic example of where a glycoprotein IIb/IIIa can be useful, because you want to re-canalize the side branch, and thrombus forming at the ostium can be a problem. Also, sometimes we have acute vessel closure due to dissection or some patients experience acute stent thrombosis during the procedure. These may be patients who have a large lipid core plaque burden. We did imaging studies utilizing near-infrared spectroscopy and optical coherence tomography (OCT) before and after stenting. When we stented lipid-rich lesions, thrombus was quite likely to form inside the freshly implanted stent. More work is needed in this area, but we believe that for these patients, the use of more aggressive antiplatelet therapy such as glycoprotein IIb/IIIa inhibitors can be advantageous.
Another use is when the patient is not preloaded with aspirin and clopidogrel, and is found to need percutaneous coronary intervention (PCI) after diagnostic angiography. There is increased risk for stent thrombosis in such patients. Some operators will defer the PCI and do it on another day, but an alternative strategy (especially for many of those patients who come from many miles away), is to give them a glycoprotein IIb/IIIa inhibitor, aspirin and high-dose clopidogrel (or prasugrel), and proceed with ad hoc PCI.
Is tirofiban the primary glycoprotein IIb/IIIa inhibitor at the Dallas VA?
We have both tirofiban and eptifibatide, but not abciximab, which we stopped using several years ago. We mainly use tirofiban because of lower cost.
Medicure is going to offer a new, concentrated format of tirofiban — 250mcgs/mL in a 15mL vial. Is this going to be a valuable format for the delivery of this drug?
I think so. A little technical challenge with the medication right now is that the medication comes in a fairly large volume, so it takes a little longer to infuse and administer. Having it in a more concentrated format will make it easier to give intravenously, but more importantly, easier if we want to give it intracoronary, which we do sometimes when the patient presents with STEMI and has a large intracoronary thrombus burden. For that use, which is off-label, it would be nice to have the more concentrated form so we don’t have to give a large volume of medication in the coronary artery.
How does this compare to administering the double bolus of eptifibatide?
It is much easier. Logistically, it is easier to give a single bolus than to have to do two boluses. Some PCIs in patients with ACS or large thrombus burden can be challenging with a lot of things going on at the same time. Having one less task to worry about is definitely a good thing.
Some centers like to keep abciximab or cangrelor on hand for renally compromised patients. How do you handle these patients at the Dallas VA?
We do not have abciximab and we are just now getting cangrelor, so we don’t have experience using it. For patients with renal insufficiency we currently reduce the dose of glycoprotein IIb/IIIa inhibitors and discontinue the infusion at the end of the procedure.
Any final thoughts?
Many years ago, we used glycoprotein IIb/IIIa inhibitors for pretty much everything, which resulted in high rates of bleeding. But that was before the era of aspirin and clopidogrel preloading, and prasugrel or ticagrelor. Things have now changed. We have better oral medications to inhibit the platelet. So today, glycoprotein IIb/IIIa inhibitors are not being used as much; however, we are still getting patients in whom glycoprotein IIb/IIIa inhibitors are necessary, for example, when we have a complication or in patients coming with STEMI and a large thrombus burden. Moreover, with the use of the radial approach, or ultrasound and micropuncture-guided femoral access, the risk for access complications has decreased. While it is currently a much smaller patient group that receives glycoprotein IIb/IIIa inhibitors than before, when you need it, you really need it, especially since we are treating increasingly complex patients and lesions.
Martin Zenni, MD
Dr. Zenni, can you tell us about your lab and practice?
We are at the University of Florida in Jacksonville, a 700-bed teaching hospital that is the hub for many satellite offices and is also a referral hospital for many of the sick in Northeast Florida, with referrals from Daytona, southeast Georgia, and out west, as far as Lake City. We have 6 interventional cardiologists, including myself.
You wrote about your use of tirofiban as far back as in 2000.1 It sounds like you have a long history of using this drug.
Yes, we were one of the major hospitals that did research trial work with Centecor, which was the parent company of abciximab. We were involved in many of the pivotal trials with abciximab including the EPIC, EPILOG, EPISTENT, and SPORT trials. While very efficacious, abciximab was very expensive. That, along with reconstituting and filtering the medication, resulted in a time delay, often when you needed it in a hurry. It was a great drug, but I don’t think anyone has used it in our lab in years. We switched to tirofiban years ago, because it was very cost effective, efficacious, simple to use, and we were also doing research with it. Many cath labs at that time had adopted eptifibatide after the ESPRIT trial data was presented. However, we adopted tirofiban, because we thought it was an excellent drug with impressive data in the PRISM, PRISM PLUS, and TACTICS trials regarding the upstream use of tirofiban with acute coronary syndromes (ACS) with or without percutaneous coronary intervention (PCI). We also participated in TARGET and TACTICS, two of the trials designed to look at tirofiban and PCI.
That was in the early 2000s?
Yes, a long time ago. I started using tirofiban at the RESTORE dose. I also had great success using it intracoronary (IC) when faced with no reflow or reduced TIMI flow. Later, we learned from the TARGET and the TENACITY trials (and others) that 25 mcg/kg is the preferred bolus dose of tirofiban needed to achieve optimal platelet inhibition. At the time, it got me thinking: tirofiban is a really cost-effective drug that can be given very quickly, with great ease of use. At a minimum, we can use the RESTORE dose of 10 mcg/kg, and I can give it peripherally intravenous (IV), IC, or use some combination of the two to get exactly the antiplatelet effect (IV or IC) that is best for the patient. If I achieved what I wanted with regard to coronary flow, reperfusion, platelet inhibition, and passivation of the artery, then I stopped with the 10 mcg/kg (RESTORE dose) and didn’t go to the full 25 mcg/kg (TENACITY dose) and increase the risk of the bleeding just to satisfy the newly approved dose. I found that for many patients, 10 mcg/kg worked very well. I could then escalate up with successive aliquots of 5 or 10 ccs (IC or IV) tirofiban to get up to that 25 mcg/kg range and only when the cath films said I needed more antiplatelet inhibition. I felt comfortable with either dose, as long as my activated clotting time (ACT) was less than 250 seconds. If the ACT was greater than 250 seconds, I would stop at the 10 mcg/kg (RESTORE dose), particularly with femoral access. I found this approach useful with patients at higher risk for bleeding. For patients presenting with ST-elevation myocardial infarction (STEMI), high-risk ACS patients with reduced flow, stent thrombosis, or plaque rupture with thrombus or slow flow, particularly if they were on minimal or suboptimal antiplatelet therapy, I still use tirofiban when necessary. In the early 2000s, there was no way to give ticagrelor or prasugrel, because we didn’t have them yet. If a patient came in “hot”, they may have had an aspirin in the emergency department and little else. You had to give some antiplatelet medication and tirofiban worked well.
How has the way that you have used glycoprotein IIb/IIIa inhibitors changed over time?
It has changed, because so many patients are coming in to the cath lab with a STEMI on little or no antiplatelet therapy, or perhaps with stent thrombosis. They may be on clopidogrel or not compliant with it, or perhaps they may be a non-responder to clopidogrel, now assessed with buccal swab genetic testing. They may not have had a stent put in properly or could have very late stent thrombosis due to neoatherosclerosis on some antiplatelet therapy or dual antiplatelet therapy (DAPT). Almost everyone now is treated with an oral antiplatelet drugs, so they come to the cath lab on optimal antiplatelet therapy, i.e., DAPT. If they are on prasugrel or ticagrelor, together with aspirin and heparin, we are not going to pull glycoprotein IIb/IIIa agents off the shelf, because we figure their platelets are fairly inhibited. But, if I get into trouble or if I see a lot of clot, I will often use a small bolus of tirofiban, 10mcg/kg, often IC. If I am done working and I see more clot, more no reflow, I might go up to 25 mcgs/kg. It helps if you choose a radial approach, because you don’t have to worry about the groin exploding and losing 3-6 liters of blood into a big thigh or retroperitoneum.
If there is no reflow, any medication IV or given through the guide is not going to get to the microcirculation there, because there is no flow in the artery. One of the unique features of tirofiban is that it has a neutral pH balance. You can advance an over-the-wire balloon or a FineCross catheter (Terumo) down the artery and pull the wire out, and then deliver aliquots of 5 ccs of tirofiban through that catheter directly into the distal vessel or microcirculation. If there is no flow in the artery, often tirofiban, together with nipride, adenosine, or verapamil, helps improve coronary flow and “clean up the artery” much quicker than if you attempt to give something through the guide; it’s just not going to get where it needs to be in order to work. So if there is no reflow, tirofiban is very good to use in the microcirculation, together with other antispasm or vasodilatory medications. If platelets are aggregating in a certain spot, infusing tirofiban right into that area helps to passivize the artery. So a typical bolus of 10mcgs/kg might be 20 ccs in an 80kg individual. I might give 2 aliquots of 5 ccs each down the coronary; the other 10 ccs might be given peripherally. I should point out that this is all anecdotal; nonetheless, this stepped approach has really worked well for me over the years.
One of my other favorite uses is if I have a high-risk diabetic patient and they come in with a non-ST-elevation MI, say over the weekend. I worry they might have severe triple-vessel coronary artery disease and surgical anatomy. By guideline, oral ticagrelor or clopidogrel is recommended up front on the weekend. Often you cath the patient and they do in fact have surgical anatomy. Now you are stuck with that patient for 5 days (since they received clopidogrel or ticagrelor), having to withdraw these medications prior to surgery in order to let platelet function recover. In these cases, if it is going to be 24-48 hours until cath, I still think there is a limited role for the glycoprotein IIb/IIIa inhibitors to use upstream. I would rather see that patient get aspirin, heparin, and tirofiban, and not have to wait for an oral drug to wear off in the case of surgical anatomy where coronary artery bypass graft surgery (CABG) needs to be performed. Because the guidelines lean strongly towards oral P2Y12 inhibitors, the use of the glycoprotein inhibitors has decreased and fallen out of favor. Still, I can tell you that once a week there is a diabetic patient that comes in under this particular scenario and is stuck waiting for CABG.
If a patient is not on optimal oral antiplatelet therapy and it is a fairly complex case in a thrombotic milieu, I prefer to have optimal antiplatelet therapy on board. Certainly tirofiban is one of those options or perhaps cangrelor, which can also minimize thrombotic complications until ischemic protection is conferred by DAPT. We have found other strategies here at the University of Florida that help in STEMI ACS. For example, our group (Dr. Angiolillo) published the “CRUSH” paper where we crush ticagrelor in the setting of a STEMI.2 By crushing it, instead of giving two oral intact pills, absorption is faster and the time to adequate platelet inhibition shortened. We demonstrated superior antiplatelet effects at an hour with this simple maneuver. The body doesn’t have to absorb the ticagrelor by first breaking a tablet down. If the patient is receiving morphine (dilaudid or fentanyl), or if the patient is vomiting or the gastric transit time is reduced, absorption of the oral antiplatelet medicines isn’t as fast as with stable coronary artery disease presentations. We have shown that during STEMI or ACS, absorption is slowed, and sometimes, an IV drug like tirofiban (or cangrelor), can bridge this therapeutic gap. While cangrelor is shorter acting with excellent data, it is less cost effective than tirofiban, particularly with the pre-mixed availability of tirofiban.
Currently, tirofiban is provided in pre-mixed IV bags at a concentration of 50 mcg/mL; a new, more concentrated format (pre-mixed, ready-to-use, at 250 mcg/mL in a 15 mL vial) will soon become available to deliver the FDA-approved high-dose bolus (HDB) of 25 mcg/kg at the start of treatment. What are your initial impressions of this format?
Most of the time, it is bolus-only use, so there is some excess medication in the IV bag that may remain in excess. With this new vial format, my sense is that it is structured for you to give the bolus and bolus only to avoid excess. You are not going to do upstream therapy with a 24-hour or 48-hour treatment of the drug, so the new format will definitely help with facilitating the bolus. I think the new vial will make it easier in the cath lab for bolus-only administration.
Are you mostly tirofiban in your lab?
We have tirofiban and cangrelor. We don’t have eptifibatide. I don’t know of anyone using a dose of abciximab in the last 4 years in our lab.
It sounds like cost has been a long-time concern at your lab.
Over the years, we have learned to be frugal and reasonable with our approaches. Abciximab was incredibly expensive at a couple thousand dollars vs three to four hundred dollars with tirofiban. Even eptifibatide was running closer to eight hundred dollars when we did the cost analysis. For a long time, we just stopped using glycoprotein IIb/IIIa inhibitors, and now they have resurfaced in a limited fashion with radial access and the need to get immediate antiplatelet inhibition.
Any advice for labs that might start using tirofiban?
It is safe. It can be given intracoronary. If you are a radial operator, bleeding is reduced and the ACT is less crucial to keep under 250, but certainly keep an ACT ceiling of 300. You do still have to worry about intracranial bleeding, but most of the bleeding we saw in these older studies were groin hematomas and retroperitoneal bleeding, which are now very rare. Radial access allows you to be more aggressive with your anticoagulant and antiplatelet therapy. As I mentioned above, cangrelor is a wonderful addition to our antiplatelet armamentarium; the problem is simply a matter of cost. It is more expensive (nearly twice as expensive at our institution) than tirofiban. I also like the fact that a simple bolus of tirofiban lasts for 4 to 6 hours and then reverses, which is plenty of time for the patient to absorb clopidogrel, etc., providing ample bridge time particularly if the patient is vomiting or unable to swallow pills (especially if intubated). This provides a nice overlap of time as the tirofiban reverses, which can help reduce very acute stent thrombosis. Tirofiban’s pH balance is neutral, it is cost-effective, simple to use and titrate, and now it is easy to administer with the pre-mixed concentrated bolus vial. It is a very nice option to have in the cath lab.
- Zenni MM, Gilmore PS. Intracoronary administration of tirofiban to facilitate clot lysis during percutaneous coronary intervention. J Invasive Cardiol: Clinical Case Update. 2000 Apr;2.
- Franchi F, Rollini F, Cho J, et al. Impact of escalating loading dose regimens of ticagrelor in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of a prospective randomized pharmacokinetic and pharmacodynamic investigation. J Am Coll Cardiol Intv. 2015; 8(11): 1457-1467.
Disclosure: Dr. Brilakis reports consulting/speaker honoraria from Abbott Vascular, Asahi, Cardinal Health, Elsevier, GE Healthcare, and St. Jude Medical; research support from InfraRedx and Boston Scientific; spouse is employee of Medtronic. Dr. Zenni reports no conflicts of interest regarding the content herein.
Dr. Emmanouil Brilakis can be contacted at email@example.com.
Dr. Martin Zenni can be contacted at firstname.lastname@example.org.