A Discussion of the FABOLUS-FASTER Trial:
Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over Prasugrel: A Multicenter Randomized Open-Label Trial in Patients with ST-Elevation Myocardial Infarction Referred for Primary Percutaneous Intervention
I. CLD talks with Marco Valgimigli, MD, PhD, FESC, Professor of Cardiology at Cardicentro Ticino, Lugano, Switzerland.
Dr. Valgimigli, you were involved in designing the FABOLUS-FASTER study.1 What was the rationale behind this study?
We have seen many studies based on cangrelor, on glycoprotein (GP) IIb/IIIa inhibitors, including tirofiban and many studies based on prasugrel, but we have never had a comparative assessment of the capability of these 3 drugs, which was the main goal in setting up this study. Many studies, including a previous FABOLUS study about 10 years ago called FABOLUS Pro, have tested the speed with which oral P2Y12 inhibitors provide platelet inhibition in ST-elevation myocardial infarction (STEMI) patients. FABOLUS Pro was the first study to demonstrate that prasugrel, at least in STEMI, is not as potent immediately after administration as expected. At that time, we expected 90% inhibition after 30 minutes, which was what people were claiming with respect to third-generation P2Y12 inhibitors, such as prasugrel. But in fact, at least early after drug administration, we saw a very limited capability for prasugrel to inhibit platelets, a finding that has been reproduced by many other studies including both prasugrel and ticagrelor. Today, the picture is very clear. Both prasugrel and ticagrelor are much slower to inhibit platelets in STEMI patients. The next logical question is whether parenteral antiplatelet agents are necessary in order to provide complete inhibition of platelet aggregation shortly after drug administration. The answer is most likely yes. Independent studies testing GP IIb/IIIa inhibitors, as well as cangrelor, have shown that about 10 minutes after the drug is given intravenously, the platelet inhibition level reaches 80-90%.
Prior to FABOLUS-FASTER, no randomized study has assessed the capability of cangrelor to inhibit platelets in STEMI patients, specifically, by means of light transmission aggregometry, which remains the gold standard for assessing platelet aggregation. The studies that were the basis for providing the on-label regimen for cangrelor only included elective patients undergoing percutaneous coronary intervention (PCI), healthy volunteers, or patients with acute coronary syndromes (ACS), and only a few patients with ST-segment elevation in ACS. That was the rationale for FABOLUS-FASTER. We wanted to see whether the capability of these two parenteral drugs was non-inferior with respect to the degree of platelet inhibition in STEMI, and also asked, what if patients chewed the tablets of prasugrel instead of taking them as integral tablets, as per the label? We set up a multicenter study and recruited 122 STEMI patients allocated randomly in 3 groups: the GP IIb/IIIa inhibitor tirofiban, cangrelor, or prasugrel. The prasugrel group was subsequently divided into receiving the drug in an integral tablet form or chewing the tablets before ingesting them. The study was set up for 3 independent primary hypotheses: (1) the non-inferiority of cangrelor versus tirofiban; (2) the capability of both parenteral drugs, tirofiban and cangrelor, to be superior to chewed prasugrel; (3) chewed prasugrel would be superior to integral prasugrel.
What were the results of FABOLUS-FASTER?
All the study arms were associated with some degree of inhibition of platelet aggregation, but we were surprised to find one study arm demonstrate a huge difference. Chewing prasugrel, instead of giving prasugrel as an integral tablet, is, in fact, associated with slightly higher inhibition, but it is a marginal difference, which in our study did not even reach statistical significance. We also measured the prasugrel active metabolite. The pharmacokinetic data show that if you chew prasugrel, indeed there is an earlier peak of prasugrel active metabolite. However, this earlier peak does not translate into a major difference with respect to platelet aggregation. So chewing prasugrel may help, but you should not expect significant help. Cangrelor is associated with a 3-fold higher inhibition as compared to chewed prasugrel. We were expecting 95% inhibition with cangrelor, which is the level of inhibition described earlier for the use of this drug. However, we saw a much lower level of inhibition with cangrelor in STEMI patients. The big surprise from the study is that the non-inferiority of cangrelor versus tirofiban was not met. Tirofiban was clearly superior to cangrelor. Among the 4 regimens, the mean level of platelet inhibition that can be achieved at 30 minutes is in the range of 6-7% with standard prasugrel, 12-14% with chewed prasugrel, 34% with cangrelor, and 95% with tirofiban. There is a huge gradient clearly in favor of parenteral drugs over normal (oral) drugs, but also indicating that the parenteral drugs may themselves differ quite dramatically.
Is cangrelor’s lower inhibition level from this study specific to STEMI patients?
I think so. When we saw the data with the level of inhibition with cangrelor being so much lower than expected, I questioned the results. I created a set of measures by using cangrelor in patients without STEMI. In those patients, I did see the 95% level of inhibition. The lower level of inhibition with cangrelor as compared to tirofiban appears to be specific to STEMI. When I saw these data, I then went back to the early studies in the literature and saw that STEMI patients had never before been investigated with respect to the level of platelet inhibition achieved with cangrelor at light transmission aggregometry. We now know that STEMI patients respond sub-optimally to cangrelor, for whatever reason.
Is this the first time that STEMI patients have been isolated in this way, in terms of their reaction to a particular drug?
Before FABOLUS-FASTER, there was another mechanistic yet important study, the CANTIC study.2 CANTIC compared cangrelor versus ticagrelor, but the study was relatively small and was powered for superiority, with cangrelor being superior to ticagrelor (this was shown). In FABOLUS-FASTER, we showed the same, that cangrelor is superior to prasugrel. What is missing in CANTIC is a third arm with GP IIb/IIIa inhibitors. In addition, only a point-of-care testing was used in CANTIC (VerifyNow [Instrumentation Laboratory]), which is a very reliable point-of-care testing, but we know light transmission aggregometry (LTA) is the gold standard. LTA is what we used in FABOLUS-FASTER. These two major study differences may explain the surprise of our data.
In light of the FABOLUS-FASTER results, what should change?
It is extremely important to understand the safety of these different treatment options, because tirofiban stands out as the drug with the highest potential to be associated to a lowest ischemic risk. FABOLUS-FASTER suggests that tirofiban is most likely associated to a higher potency and, therefore, a higher likelihood of protecting the patient from ischemic complications. FABOLUS-FASTER, for the first time, is showing that if you are in trouble because of a large thrombus burden or because the patient is very high ischemic risk, probably the drug that you should be using is tirofiban, rather than cangrelor. On the other hand, a clinician may argue, “What is the risk of bleeding if you use tirofiban instead of cangrelor?”
Could clinicians rely on historical data regarding tirofiban and bleeding risk?
That is a great question and the answer is no. Glycoprotein IIb/IIIa inhibitors have been extensively investigated, with the first study done back in 1994. You can imagine how many hundreds of studies have investigated this class of compounds. GP IIb/IIIa inhibitors have been traditionally used in a bolus followed by very long infusion. When these drug were developed, the only oral antiplatelet agent available was aspirin. We didn’t have clopidogrel, prasugrel, or ticagrelor, so in those days, a very long protection of the patient after an acute MI made sense. The contemporary method of GP IIb/IIIa inhibitor use would be a bolus and very short infusion or even no infusion. The bleeding risks that the clinicians are expecting to be associated with GP IIb/IIIa inhibitors are likely much lower than expected, as long as these drugs are used in the more contemporary manner of a bolus and very short (or no) infusion. We only need to protect the patient during the PCI itself in order to provide enough time for oral P2Y12 inhibitors to start working.
Can you describe any further differences between tirofiban and cangrelor?
Tirofiban has a relatively short half-life, not as short as cangrelor, but still quite short. Once you stop the infusion, in 2-3 hours, you return to normal. It is not a very long-lasting effect, which is why tirofiban is very appealing, since it is very fast on, but also very quickly offset. In that respect, it is very similar to cangrelor. On the other hand, unlike cangrelor, tirofiban does not have any issue with respect to drug-to-drug interaction for oral P2Y12 inhibitors, which is an issue with cangrelor. We know that cangrelor cannot be given concomitantly to prasugrel or clopidogrel. Cangrelor can only be given concomitantly to ticagrelor, because otherwise there is a negative drug-to-drug interaction. You need to wait for cangrelor to be stopped and only at that moment can prasugrel be given, which is exactly what we did in our study. There will be a further dip in platelet inhibition a few hours after cangrelor infusion has been stopped, which we also noted. During cangrelor infusion, there was a proportion of non-responsiveness in the range of 50-58%. When cangrelor was stopped and prasugrel was given, at the end of that infusion, in the following two hours, that rate of poor responsiveness went even higher, because cangrelor was already off and it was not enough time for prasugrel to kick in. The result is a so-called vulnerable period, in which the patient can even be potentially exposed to a rebound of ischemic events. This phenomenon is not seen with tirofiban. Tirofiban has no negative drug-to-drug interaction and you can give whatever pills you want, at whatever moment, which is very convenient from a clinical standpoint.
How have you incorporated FABOLUS-FASTER results into your practice?
I was already using tirofiban in a selective manner before seeing the results of the study. From time to time, I was switching to cangrelor without knowing whether one drug was better than the other. Now, after having seen the results of this study, I prefer using tirofiban instead of cangrelor. I only use cangrelor in very select group of patients, such as those who experienced an out-of-hospital cardiac arrest. These patients are associated to an extremely high bleeding risk and tirofiban is a potent anti-thrombotic agent, so I still think that cangrelor, despite my not having seen supportive data, is probably an ideal drug with respect to the pharmacology for this specific patient population.
Any final thoughts?
I posted a survey on Twitter asking about changes to practice as a result of the study. More than 200 people responded. The survey winner, as I was expecting, was tirofiban, but many also said, “Based on [FABOLUS-FASTER] data, I don’t want to use cangrelor anymore.” Despite being a relatively small study, we already have feedback from colleagues and peers that this study is convincing with respect to clinical practice. We should also be concerned and aware that even crumbling or chewing the tablets of oral P2Y12 inhibitors is not associated with a great speed of action. To inhibit platelets in your patient during STEMI treatment, you need to give parenteral drugs — that is my take-home message.
FABOLUS-FASTER is already an important study, but it cannot be seen as a definitive study. The next step should be to conduct a study powered on clinical endpoints in order to compare tirofiban versus cangrelor in STEMI patients. It will help us understand the bleeding risks and the benefit for both treatments.
II. CLD talks with Ralph J. Riello III, PharmD, BCPS, Cardiovascular Critical Care Pharmacist, Coronary Intensive Care Unit (CICU), Department of Pharmacy Services, Yale-New Haven Health System, New Haven, Connecticut.
Dr. Riello, can you tell us about your role?
I am the clinical pharmacy specialist in cardiovascular critical care at Yale New Haven Hospital, where I have been covering the coronary intensive care unit (CICU), as well as the cardiac catheterization laboratory for over the past 5 years. I also sit on the anticoagulation and cardiology pharmacy and therapeutics subcommittees, as well as Yale’s Heart and Vascular Center steering committee. These committees are responsible for development and implementation of many of our health-system’s drug use policies and acute care management protocols for P2Y12 and glycoprotein (GP) IIb/IIIa inhibitors, both in and out of the cath lab.
What is your impression of the main findings of the FABOLUS-FASTER study?
The main findings of the FABOLUS-FASTER trial1 were actually quite surprising and exciting. The trial results have challenged some of our earlier understanding of pharmacodynamics for antiplatelet agents. We have seen from earlier cangrelor pharmacodynamic studies that when used as an adjunct to percutaneous coronary intervention (PCI), cangrelor provided excellent percentages of inhibition of platelet aggregation rapidly, at above 90%, with very little residual platelet reactivity as well. Similarly, crushed prasugrel in the earlier CRUSH study3 showed higher percentages of the active prasugrel metabolite, and we learned how that correlated to a better inhibition of platelet aggregation percentage and lower residual platelet reactivity. Yet the FABOLUS-FASTER trial turned both those earlier understandings on their heads, and did so in the most critical population of patients going to the cath lab with ST-elevation myocardial infarction (STEMI). First, tirofiban is superior to cangrelor with respect to inhibition of platelet aggregation in STEMI patients. Second, chewed prasugrel did not provide higher inhibition of platelet aggregation over whole prasugrel, despite having more active metabolite present. The results of FABOLUS-FASTER mean the interventional cardiology community has a lot of exciting findings to think about, that will ultimately impact practice.
What are the implications of these data for current practice and/or future research?
I think the impact of FABOLUS-FASTER on interventional cardiology will probably be to give preferential weight to tirofiban over cangrelor — at least as an adjunct to PCI for STEMI. Second, the practice will probably become to only crush prasugrel if absolutely necessary, such as if the patient has difficulty swallowing or a feeding tube is present. As this was a pharmacokinetics/pharmacodynamics (PK/PD) study intentionally underpowered to detect differences in clinical endpoints like bleeding or ischemic events, I hope the findings were encouraging enough to motivate study sponsors or clinical investigations to pursue a larger outcomes trial. GP IIb/IIIa inhibitors, being generally rapid and potent platelet inhibitors, may produce clinically meaningful reductions in endpoints like stent thrombosis, without increasing the risk for clinically relevant bleeding in a head-to-head trial with cangrelor. I would also love to see future research involve all of the available P2Y12 inhibitors as options, since ticagrelor and clopidogrel are still widely used, despite the recent ISAR-REACT 5 trial4 last year.
STEMI patients fall under the acute MI hospitalization umbrella, and many institutions are moving to new Medicare reimbursement and payment models that reward and emphasize value and quality of care. A cost-effectiveness analysis of cangrelor versus tirofiban would tell a very compelling story about potential cost savings by using tirofiban over new, more expensive agents.
At Yale New Haven Hospital, are these agents included in your acute coronary syndromes treatment protocol?
The FABOLUS-FASTER PCI trial could not have been published at a more opportune time for us here at Yale New Haven Hospital. We recently conducted a medication-use evaluation across the health system of all cangrelor cases. The goal was to better define the clinical context for appropriate use as an adjunct to PCI and also as a bridge in recently stented patients on dual antiplatelet therapy (DAPT) that have urgent surgery or procedures requiring temporary cessation of antiplatelet therapy. As we were in the throes of revisiting our formulary guidelines for use of intravenous (IV) antiplatelet agents, the publication of FABOLUS-FASTER reaffirmed our preferred place in therapy for tirofiban over cangrelor — the newer, more expensive agent. We have both agents on formulary and stocked in cath labs across all of our delivery networks. Ever since we switched from eptifibatide to tirofiban several years ago, tirofiban has remained the workhorse of IV antiplatelet therapy in and around the cath lab, and also for bridge therapy. We added cangrelor to formulary after it was FDA-approved, but restricted its use to pharmacist order entry, meaning the cardiology team wishing to use cangrelor needs to first plead their case and most importantly, answer the question, why not tirofiban first? Based on the findings from FABOLUS-FASTER and input from our interventional cardiology stakeholders in the pharmacy and therapeutics subcommittees, we have drafted preliminary criteria for use of cangrelor. A pharmacist like me would approve cangrelor use and it would be predominantly for patients who are not candidates for tirofiban — meaning an allergy or history of pronounced thrombocytopenia to GP IIb/IIIa agents in the past. Cases can be made for patients with significant renal failure and a history of bleeding where the perceived potency of tirofiban may warrant consideration for cangrelor instead, but of course, that is evaluated on an individual, case-by-case basis.
How do you optimize expenditure and utilization of these agents?
I am so glad you asked about costs. With cangrelor being the latest and greatest IV antiplatelet agent on the market, it certainly generated some buzz when we added it to formulary as an attractive option for the cath lab. But it has a fairly high sticker price of about $700 per 50 mg vial at our institution. As an adjunct to PCI, where our interventionalists often continue a weight-based maintenance infusion for 2 hours after the initial bolus, a 90 kg patient can come out to over $1,000 per case or about 1-2 vials per PCI. At an institution that performs well over a thousand PCIs per year, with about 20% of those PCIs for STEMI, those costs can certainly add up. Tirofiban, however, is much more affordable for our health system at about $40 per 5 mg vial. Even with an extended 6-hour post PCI infusion, tirofiban comes out to well under $100 per case for that same patient. If the cath lab further optimizes use of the concentrated bolus vials and infusions, that translates to substantial costs savings by comparison. With under $100 per case for tirofiban and about a $1,000 for cangrelor, that is a big difference, especially over the course of a year for a busy cath lab or primary PCI center.
How has the current pandemic affected use of these agents?
It has been well documented that fear of the Covid-19 pandemic has been keeping many acute MI patients at home, as they worry that seeking healthcare may risk exposure to the coronavirus. Acute coronary syndrome patients who may have been non-STEMI are holding off calling 911, with delaying care for chest pain leading to worse downstream consequences. Since the pandemic has largely been controlled in Connecticut, we are starting to see an uptick in STEMI admissions and patients with Q waves on their electrocardiogram indicating they may have had a coronary event in the past, but they had opted to not seek care. These patients present with a much larger clot burden and higher acuity of care, necessitating IV antiplatelet bailout therapy, all circumstances that likely warrant use of adjunctive IV antiplatelet agents. So the pandemic is bringing more opportunities where interventionalists feel the need to supplement platelet inhibition with tirofiban or cangrelor. We have certainly been using a lot of GP IIb/IIIa agents in our cath labs lately.
Any final thoughts?
Cardiology pharmacists overseeing active primary PCI centers at other institutions should take a look at their hospital’s IV antiplatelet policies and expenditures, because preferential use of tirofiban and/or adding more stringent criteria for cangrelor use is a pretty safe bet to optimize cost savings. But cost is not the only opportunity. The FABOLUS-FASTER data shows superior platelet inhibition for tirofiban in high-risk STEMI patients, so it not only makes sense from a cost perspective, but now we have early clinical or at least pharmacodynamic data in support as well. As many new pharmacy residents are just starting their residency year at hospitals all over the country, revisiting cath lab protocols for IV antiplatelet use based on the FABOLUS-FASTER PCI data would be a great project to tackle and present results in order to spread the word.
This article is supported by Medicure.
Disclosures: Dr. Valgimigli reports consulting fees/honoraria from Abbott Vascular, Amgen Inc., Alvimedica, Bayer Healthcare Pharmaceuticals, Bristol-Myers Squibb SA, CorFlow, Daiichi Sankyo, Vifor, Idorsia, iVascular, Terumo; speaker’s bureau: AstraZeneca.
Dr. Marco Valgimigli can be contacted at firstname.lastname@example.org.
Dr. Riello reports he is a consultant for AstraZeneca, Janssen, Johnson & Johnson, and Portola.
Dr. Ralph Riello can be contacted at email@example.com.
- Gargiulo G, Esposito G, Avvedimento M, et al. Cangrelor, tirofiban, and chewed or standard prasugrel regimens in patients with ST-segment elevation myocardial infarction. Primary results of the FABOLUS-FASTER trial. Circulation. 2020; 142: 441-454. doi.org/10.1161/CIRCULATIONAHA.120.046928
- Franchi F, Rollini F, Rivas A, et al. Platelet inhibition with cangrelor and crushed ticagrelor in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation. 2019; 139(14): 1661-1670. doi:10.1161/CIRCULATIONAHA.118.038317
- Rollini F, Franchi F, Hu J, et al. Crushed prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary intervention: the CRUSH study. J Am Coll Cardiol. 2016; 67(17): 1994-2004. doi:10.1016/j.jacc.2016.02.045
- Schüpke S, Neumann FJ, Menichelli M, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med. 2019; 381(16): 1524-1534. doi:10.1056/NEJMoa1908973