Decisions on Glycoprotein IIb/IIIa Inhibitors and the Use of Tirofiban in ACS Patients

Does the VA have standard guidelines for the diagnosis and subsequent management of ACS? Would these guidelines differ from guidelines used at other institutions (i.e. non-VA institutions)?

The VA/DoD [Department of Veterans Affairs/Department of Defense] have guidelines for management of acute coronary syndrome (ACS), but they date from 2003. As a result, there is no mention of bivalirudin, prasugrel, or ticagrelor, and instead a heavy emphasis on the use of glycoprotein inhibitors (GPIs) for anyone with a positive troponin, ST segment change, or recurrent angina. Although 13 years seems like a long time ago, perhaps what was most striking was that not much else has changed in the guidelines:  https://www.healthquality.va.gov/guidelines/CD/ihd/ihd_sum_combined.pdf

How heavily should we weigh the ability of a GP IIb/IIIa inhibitor to disaggregate a pre-existing thrombus burden, which cannot be achieved with a P2Y12 inhibitor or an anticoagulant? Has the focus on the central role of the platelet in ACS has somewhat shifted in importance in recent years?

Nothing is more satisfying to an interventional cardiologist than seeing a thrombus disappear before their eyes. This can be achieved with GPIs, especially intracoronary abciximab, but also with thrombus aspiration. Intuitively, if thrombus is the proximate cause of ACS, then the more thrombus is removed or dissolved, the better, and I will confess that I share this belief. The clinical data of thrombus aspiration (TASTE, TOTAL) or intracoronary abciximab unfortunately have not confirmed this belief to date. Nevertheless, most interventional cardiologists, faced with a large thrombus, would favor using GPIs to help reduce the thrombus burden.

I think that the focus on the platelet in ACS has changed over the years with drug development. Initially, with only heparin available, drug development was focused on GPIs and oral P2Y12 inhibitors (clopidogrel). For more than a decade, as clopidogrel was the standard, attention and clinical trials turned to antithrombins such as bivalirudin and enoxaparin. Now an intense focus on the platelet is back, with new agents (prasugrel, ticagrelor, vorapaxar, cangrelor) targeting the platelet’s role in thrombus generation.

What would you consider an adequately pre-treated ACS patient prior to PCI?

Pre-treatment is a very nonspecific/vague term, encompassing everything from having a clopidogrel load 6 days before a percutaneous coronary intervention (PCI) (PCI-CURE trial), to immediately on presentation for a ST-elevation myocardial infarction (STEMI), to administering it right on the table after the diagnostic cath. We know from pharmacokinetic studies that it takes clopidogrel 6 hours to reach therapeutic antiplatelet efficacy, and 2 hours for prasugrel and ticagrelor. In STEMI patients, the times may be doubled for prasugrel and ticagrelor, as shown in two small trials.^1,2 As a PCI might take only 30 minutes, it is unlikely that there is a significant difference between loading on the table and loading immediately after PCI, but one would be considered pretreatment and the other would not. 

I would consider someone who received clopidogrel 600 mg 6 hours prior to cath, or prasugrel or ticagrelor 2 hours before cath, to have been adequately pre-treated. This is effectively impossible for STEMI patients, and becoming less common for non-STEMI (NSTEMI)/ACS. Despite American College of Cardiology (ACC)/American Heart Association (AHA) guidelines favoring pretreatment with clopidogrel for all patients prior to PCI, the reality is that <50% of patients in the United States receive pretreatment. This is because: a) the evidence is borderline and controversial, especially with the ACCOAST trial results of pretreatment with prasugrel, b) the newer oral agents have a faster and more potent onset of action, and c) no cardiologist wants to be left holding on to the 10% of NSTEMI patients that end up needing coronary artery bypass graft surgery (CABG) and have to wait 5 days for their P2Y12 inhibitor to wear off.

If you cannot adequately pretreat with a P2Y12 inhibitor, do you follow the AHA/ACC guideline recommendation to use a GP IIb/IIIa inhibitor? What is your preferred antiplatelet therapy for NSTE-ACS patients?

The AHA/ACC PCI guidelines from 2011 are clear: for patients treated with heparin and not pre-treated with clopidogrel, GPIs should be used for patients with NSTE/ACS (Class I, LOE A) and are reasonable to use in STEMI (Class IIa, LOE A) and stable angina patients (Class IIa, LOE B). In my practice, I will use GPIs liberally in patients with NSTE/ACS and STEMI where thrombus is likely present, and the risk of stent thrombosis is highest. Stable angina patients are less likely to have acute stent thrombosis, so I believe the benefits are less in that setting as long as prasugrel or ticagrelor are administered promptly after PCI.

Which GP IIb/IIIa inhibitor have you selected?

At the University of California (UC)-Irvine Medical Center, we have transitioned to tirofiban because of its ease of use, cost advantage over eptifibatide, and stability. At the Long Beach VA, we are still using eptifibatide out of habit, and because the cost savings were more modest (but still present) due to national VA contract pricing. I do not see any benefit to using abciximab over the small-molecule GPIs, but significant costs both monetary (>3x the price) and clinical (thrombocytopenia).

What infusion length do you typically prefer?

I continue GPIs for 12-24 hours after STEMI because of the increased thrombus burden and risk of stent thrombosis from the high degree of platelet activation after STEMI. For NSTE/ACS or stable angina, I will often use just a bolus only or short infusion of GPIs, as I have confidence in the oral P2Y12 inhibitors achieving efficacy within the 4 hours that GPIs remain active.

Do you feel that shorter infusion times with a GP IIb/IIIa could mitigate the risk of major and minor bleeding? 

I suspect shorter infusion times or bolus-only strategies of GPIs significantly reduce the risk of bleeding complications with GPIs. The Mount Sinai experience³ of 1565 patients with a bolus-only GPI strategy suggested that vascular complications, especially large hematomas and minor bleeding, were reduced compared with a bolus+infusion strategy. Major bleeding had a trend (P=0.09) towards reduction.

I have seen this in clinical practice, where femoral procedures frequently resulted in hematomas when GPIs were continued for days. I believe that the use of long (>24 hour) infusions is a relic of the history of these agents, as they were developed when there was a lack of effective oral P2Y12 inhibitors. Our experience with femoral procedures is relatively small now that we have moved to a radial-first approach to access.

Do the clinical and safety benefits associated with radial access PCI allow the operator to use a more aggressive approach to antiplatelet therapy, especially in the high-risk ACS patient population? Could ACS patients see clinical benefit from this more aggressive antiplatelet treatment strategy?

Yes, absolutely, the radial approach has been proven in multiple randomized trials to reduce major and minor bleeding, and potentially as a result reduce mortality in STEMI. The limited studies of GPIs in radial access⁴ suggest that the risk of bleeding with GPIs is attenuated by the radial approach, while the ischemic benefits of GPIs persist.

GPIs continue to be used in one-third of ACS patients in the U.S. between 2009-2011, according to a National Cardiovascular Data Registry (NCDR) analysis of 970,865 PCIs for ACS.⁵ GPI use was associated with a reduced risk of mortality across multiple risk-adjustment methods (odds ratio [OR] 0.72-0.90), at the cost of twice the risk of major bleeding. With only <3% of PCIs being transradial during that period, one can presume that the risk of bleeding with GPIs would be less in the current era.

Do you feel that the next generation of interventional cardiologists in training consider using GP IIb/IIIa inhibitors or is there a different mindset to your experience at that stage? 

As a rule, fellows in training learn from what they see, and what they see at academic centers varies with their attending physicians. Many academic centers transitioned to bivalirudin monotherapy in the past decade, but the drug has lost some of its luster as the risk of acute stent thrombosis has been highlighted. 

I think that the next generation of interventional cardiologists will be predominantly radial operators and will thus be open to using GPIs, as they will not encounter the bleeding seen with the femoral approach. They will not be anchored in the assumptions of the past.

Drug shortages seem to becoming a more common occurrence in the current medical climate. Has this affected your cath lab in any way? 

Drug shortages have not affected our cath lab, thanks to our very effective pharmacy management and large network. In our university and VA labs, drug costs are relatively modest compared with staffing and equipment costs, so we have not be subjected to any financial pressures in this regard to date. However, in our Pharmacy & Therapeutics Committee, cost and relative efficacy are topics of constant discussion.

The cost of pharmacotherapy is also increasingly a cause of concern for health care providers. Is interventional cardiology more or less immune?

In the VA and University of California systems, we have not encountered significant pressures to cut drug costs in the cath lab for one-time use or intravenous drugs for ACS. I believe the feeling is that the potential savings are modest and not worth the risk of either antagonizing the cardiologists, so if we want bivalirudin instead of heparin, then generally we can get it. For equivalent drugs, though, such as eptifibatide and tirofiban, we are strongly encouraged to choose one for simplicity and consistency for the cath lab staff, and we chose tirofiban. 

The new oral P2Y12 agents are relatively restricted by private and public insurers. I have had more than one Medicaid patient get discharged on prasugrel, not get it for a week because of a prolonged preauthorization process, and present with stent thrombosis. As a result, more than I would like, I will use clopidogrel, because it has been “good enough” for most patients in the past, and I can be sure the patient can get it. At the VA, we have an active plan to transition patients off of prasugrel and on to clopidogrel after a month (when the risk of stent thrombosis diminishes), in the absence of risk factors (multiple, long, or bifurcation stents, STEMI patients).

If the major benefit of prasugrel and ticagrelor over clopidogrel is a rapid onset of action that obviates the need to pretreat, then GPIs that last 4-6 hours can potentially be used to bridge a patient to the point of clopidogrel activity. This could be useful if you do not have prasugrel or ticagrelor in the lab, or you are not sure your patient will be able to obtain anything but clopidogrel once they leave the hospital.

Does your use of tirofiban as your preferred GP IIb/IIIa inhibitor fit into a reduction of costs while maintaining high-quality healthcare?

Yes, certainly. When I presented the option of tirofiban to our pharmacy as a less expensive but equally efficacious agent to replace eptifibatide, they were all ears.

Any final thoughts?

Transradial PCI is truly a game changer that has largely enabled me to be as aggressive as I want or need to be with antithrombotics. For STEMI patients, I want to use the most powerful and fast-acting antiplatelet agents, because platelet activation and risk of thrombosis are highest.

I think that we are in an interesting time with many antiplatelet options, most of which will never be directly compared against each other. In particular, any discussion of the intravenous P2Y12 agent cangrelor should in my opinion include the GPIs, as they share the benefits of immediate and potent antiplatelet efficacy, and relatively prompt recovery of platelet function on discontinuation (in other words, no delays to CABG), at the cost of increased bleeding. Where they will differ is in their dollar cost, where GPIs, especially tirofiban, may be a fraction of the cost of cangrelor.

References

1. Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) Primary PCI Study. J Am Coll Cardiol. 2013; 61(15): 1601-1606. doi:10.1016/j.jacc.2013.01.024.
2. Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2012 Dec; 5(6): 797-804. doi: 10.1161/CIRCINTERVENTIONS.112.972323.
3. Kini AS, Chen VH, Krishnan P, Lee P, Kim MC, Mares A, et al. Bolus-only versus bolus + infusion of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention. Am Heart J. 2008 Sep; 156(3): 513-519. doi: 10.1016/j.ahj.2008.04.019.
4. Iqbal Z, Cohen M, Pollack C, Goldstein P, Zeymer U, Huber K, et al; ATOLL Investigators. Safety and efficacy of adjuvant glycoprotein IIb/IIIa inhibitors during primary percutaneous coronary intervention performed from the radial approach for acute ST segment elevation myocardial infarction. Am J Cardiol. 2013 Jun 15; 111(12): 1727-1733. doi: 10.1016/j.amjcard.2013.02.020.
5. Safley DM, Venkitachalam L, Kennedy KF, Cohen DJ. Impact of glycoprotein IIb/IIIa inhibition in contemporary percutaneous coronary intervention for acute coronary syndromes: insights from the National Cardiovascular Data Registry. JACC Cardiovasc Interv. 2015 Oct; 8(12): 1574-1582. doi: 10.1016/j.jcin.2015.04.031.