GP IIb/IIIa Inhibitors

Strategies to Circumvent the Delayed Mechanism of Action of Oral Antiplatelets in the Cardiac Catheterization Lab

Cath Lab Digest talks with Mahir Elder, MD, Clinical Professor at Wayne State University School of Medicine, Detroit, Michigan; Clinical Professor at Michigan State University College of Osteopathic Medicine, East Lansing, Michigan.

Cath Lab Digest talks with Mahir Elder, MD, Clinical Professor at Wayne State University School of Medicine, Detroit, Michigan; Clinical Professor at Michigan State University College of Osteopathic Medicine, East Lansing, Michigan.

Recently, there was a change in the prescribing information (PI) of all the oral P2Y12 receptor inhibitors (i.e., oral antiplatelets) mentioning the impact of opioids such as morphine on their antiplatelet effect. How important is this issue in the cath lab?

The ongoing opioid crisis in this country, along with the judicial use of morphine in patients with acute coronary syndrome, have created an environment where it is important to bring awareness to physicians and medical staff about morphine, and its associations with delayed onset of action with the oral antiplatelet agents. There is an association, even after adjusting for the propensity to receive morphine, and even with patients not tolerating oral intake, i.e., vomiting. Recent data suggests that patients with ST-elevation myocardial infarction (STEMI) who are administered morphine are associated with delayed onset of action for oral antiplatelet agents due to a decrease in absorption of oral antiplatelets.1 Effects of morphine on platelet inhibition are consistent across both of the most common antiplatelet therapeutic agents used in the cath lab, such as prasugrel and ticagrelor.

What are the clinical implications of not having the full benefit of an oral antiplatelet during the periprocedural timeframe in an ACS patient?

There is not proper platelet inhibition that we normally expect to have with patients who have acute coronary syndrome and STEMI. Due to the interaction with morphine and other opioids, we expect these patients are going to display a window of vulnerability. It is important that we have protection (i.e., platelet aggregation inhibition) during this time period; otherwise, there is an increased risk of complications such as auto thrombosis or even late phase thrombosis, which can be detrimental to the patient.

Do you pretreat with the oral antiplatelets?

In patients with STEMI, the standard therapy has been to pretreat patients as soon as they are either identified as ST-elevation or acute coronary syndrome, and most of that is done upstream, so there is a loading dose of antiplatelet therapy prior to the intervention. Statistically, most of the time it is done by EMS or in the emergency department (ED). Patients who have STEMI and are not loaded with antiplatelets in the ED are vulnerable. These patients must be loaded immediately upon arrival in the cath lab in anticipation of intervention. However, the concern is that when antiplatelets are given late in the cath lab, very valuable time is lost. For the patient arriving to the cath lab with a STEMI, most likely stent placement will occur — subject to the risk of acute thrombosis. It is a time period where the patient is not covered by an antiplatelet, because by the time the antiplatelet therapy is administered and becomes therapeutic in the cath lab, there is a window of 1-2 hours where the patient is left unprotected.

What about the need for coronary artery bypass graft (CABG) surgery?

Some older data suggest patients undergoing antiplatelet therapy within a 5-day period have a higher risk of mortality because of bleeding if they are being considered for CABG. Most recently, what tends to be standard across the country is that very rarely do patients actually undergo emergency CABG. If you look at the whole country over the last 10 to 15 years, the number of patients that undergo emergency CABG, for patients that are either STEMI or elective cases of acute coronary syndrome, is very low.2,3 There are data suggesting that if patients undergo an elective procedure, and if they are on antiplatelets, that waiting five days to decrease mortality from secondary bleeding may be of benefit.4-6

Is there enough awareness surrounding the delayed onset of action of oral antiplatelets in high risk acute coronary syndrome patients?

I think we have done a very good job emphasizing the importance of dual antiplatelet therapy (DAPT). It wasn’t easy. It took years of different publications, raising awareness, and patient education, and we in interventional cardiology have done a good job. There is opportunity for improvement where I think we are lacking, which is in greater awareness of late onset with patients on oral antiplatelet therapy in the cath lab, especially with decreasing door-to-balloon times.  The evolution of antiplatelet therapy has changed such that the time to onset has shortened, which is beneficial for patients, but there is still a time to onset window or time frame that is placing certain vulnerable patients at a higher risk.

The RAPID7 and RAPID II8 studies by Parodi et al have shown a delay in the onset of oral antiplatelets, such as prasugrel and ticagrelor, in high-risk acute coronary syndrome patients undergoing PCI. Can IV parenteral regimens be used to “bridge the gap” until the oral antiplatelets become therapeutic in the presence of opioids?

Yes. One standard right now are IV glycoprotein (GP) IIb/IIIa inhibitors. There are three commonly used GP IIb/IIIa inhibitors in the U.S., and one in particular can achieve 95% platelet inhibition within the first 10 minutes.9 That is also beneficial over multiple aspects. A GP IIb/IIIa inhibitor helps bridge the high-risk patients that are vulnerable for platelet aggregation in a very short period; it helps with that window of vulnerability. Typically, a GP IIb/IIIa inhibitor is used in patients with a delayed onset of oral antiplatelet therapy or for those who could not absorb the administered oral antiplatelet therapy, meaning patients that are intubated, patients that have an excessive amount of opioids, patients that vomit, and those who can’t tolerate the antiplatelet therapy. These are the types of patients who are clinically vulnerable and using GP IIb/IIIa inhibitors can help cover a time period where these patients are at an increased risk for thrombosis.

Some clinical evidence supports crushing antiplatelet pills as one way to shorten that window of vulnerability.

There have been some studies regarding crushing pills for patients10-12, and we do see higher plasma levels of the antiplatelet therapy as an active metabolite when it is crushed compared to integral tablets. However, these reports were mainly in healthy patients. What we don’t know is how it affects higher risk patients, such as patients who may have difficulty swallowing, the elderly, patients with prior stroke or dysphasia, or who are sedated or intubated. It is important to note that there are some limitations with antiplatelet therapy when it can’t be swallowed.10-12 Fortunately, it is not as frequent. I work at two major medical centers, and the majority of the time, patients can be compliant with P2Y12 receptor inhibitors without difficulty in absorption. But there are a number of patients, whether elderly (and our patient population is getting older), with a prior stroke, who are sedated or intubated, or have dysphasia, who can’t take oral medication. There’s also a type of patient that we will see, commonly in the Northeast (or colder states), where in the wintertime, they may come in with hypothermia. They may have temperatures of 33 to 36 degrees Celsius, and this may also influence platelet inhibition effect of the oral antiplatelets. It may be related to the hepatic cytochrome P450 system. Under these circumstances, the antiplatelet effect of the P2Y12 inhibitors is decreased, and there is delayed absorption and altered pharmacological transformation during this time period. That’s why these patients, especially the ones that are resuscitated patients, may exhibit a sluggish response to the P2Y12 receptor inhibitors.13 Ultimately, there is a number of patients at higher risk and for multiple reasons. We have to identify early on that these patients will have some difficulty with delayed absorption, or, perhaps will need IV antiplatelet coverage in the first few hours.

Who is responsible for identifying these patients?

It is a team approach. When the patient arrives at the hospital, there has to be complete communication and continuity of care. It is the responsibility of every individual or healthcare provider who actually sees or touches the patient. There is information that will be obtained by EMS, the ED, nursing staff, other healthcare professionals, that needs to be communicated to the interventional cardiologist upstream, prior to the patient coming to the cath lab, that there may be an absorption complication. It truly takes a collaborative effort and is a multidisciplinary process. Everybody is communicating that this is a high-risk patient, that just vomited, and most likely did not absorb the administered oral P2Y12 receptor inhibitor. Or that these patients that took the oral antiplatelet need to be reloaded, or, if they are rushed to the cath lab, then we need to have coverage. Since interventional cardiologists are downstream, it is the upstream medical providers that may have this important and valuable information. Unfortunately, not until recently has that been communicated properly and because of that, it could be detrimental to the patient’s health.

What clinical considerations must be taken when choosing the appropriate IV parenteral regimen for circumventing the delayed onset of the oral antiplatelets?

There are currently three GP IIb/IIIa inhibitors available in the U.S. and unfortunately, one is on what looks to be permanent shortage (abciximab).14 The other two are tirofiban hydrochloride (Aggrastat) and eptifibatide (Integrilin). Both are effective at decreasing platelet inhibition at 95% and 90%, respectively.15,16 What makes my decision easier is the patient’s clinical scenario. For example, if a patient has renal insufficiency, it is an easier decision to use a GP IIb/IIIa inhibitor where we can easily adjust the dosing and yet still achieve adequate platelet protection. As another example, we still use the tirofiban bolus dosing on our renal insufficiency patients — the bolus dosing remains the same and only the infusion dosing is altered. Tirofiban can still be used with caution in patients undergoing hemodialysis, whereas eptifibatide is contraindicated for these patients. We would lean toward giving the patient tirofiban in that case. Another indication for using one versus the other is the prep time. If time is of the essence and patients need to have the GP IIb/IIIa inhibitor urgently, tirofiban, which is administered as a single bolus followed by an infusion (no minimum time, up to 18 hours) rather than eptifibatide, which needs to be administered as a double bolus given 10 minutes apart, followed by a minimum infusion of 12 hours. Also, tirofiban comes as a premixed solution and is available in a bolus, vial, or bag format, which we select depending on our dosing and administration needs for the patient. It is stored at room temperature and has a long shelf life (3 years). GP IIb/IIIa inhibitors are effective and obtain platelet inhibition levels between 90 and 95% within 10 minutes. The choice between the two typically depends on availability within the hospital, and if both are available, then clinical correlation based on appropriate therapy tailored specifically for each patient.

Can you comment on the significance of the 2014 ACC/AHA NSTEMI guidelines where a class 1A recommendation is given for GP IIb/IIIa inhibitors in patients not adequately pretreated with an oral antiplatelet?

The 2014 guidelines do give a class IA recommendation for patients who are not adequately pretreated with the P2Y12 receptor inhibitors or are unable to absorb it.17 These are patients in whom you can use a GP IIb/IIIa inhibitor. Otherwise, for non-STEMI it is still a class IIA indication.18 There is a niche where you can use a GP IIb/IIIa inhibitor in these patients, an awareness that we would like to bring to readers. There is an opportunity when the patients are exposed, or have that window of vulnerability, that they can be covered with the GP IIb/IIIa inhibitor class and it is supported by the guidelines.

Can an oral antiplatelet inhibitor be used concomitantly with small molecule GP IIb/IIIa inhibitors?

Yes. The oral antiplatelet inhibitors work on one pathway in platelets, whereas GP IIb/IIIa inhibitors work on another pathway in platelet aggregation. Oral antiplatelets target P2Y12 receptors that are responsible for upstream activation and aggregation of platelets. On the other hand, GP IIb/IIIa inhibitors are physiologically different in that they block the downstream common pathway, which is the final pathway, driven by the GP IIb/IIIa receptors binding platelets together via fibrinogen crosslinking during the process of thrombus formation. Blocking this final common pathway allows for better platelet aggregation inhibition. So both can be used, as they target different receptors and consequently different pathways in platelet aggregation. We often use them in conjunction without any major complications. Ultimately, the advantage of the GP IIb/IIIa inhibitors is that they do not allow fibrinogen to link GP IIb/IIIa receptors between platelets, whereas the oral antiplatelets do not affect the final pathway; rather, they block some of the P2Y12 receptors involved in platelet activation and aggregation. Each class of drugs has a mechanism of action affecting different platelet pathways and can be used concomitantly in order to achieve desired levels of platelet aggregation. Each affect two different mechanisms, both of which can be beneficial in blocking platelet aggregation.

Would a bolus and short infusion of a small molecule GP IIb/IIIa inhibitor provide potent platelet protection during the delayed onset of the oral antiplatelets, while mitigating the potential for bleeding?

We have found that in the first 10 minutes of using a GP IIb/IIIa inhibitor you will achieve 95% inhibition. It can be administered as a bolus and an infusion (shorter or longer) depending on the patient case. In particular, in patients that are elderly, that 95% with the GP IIb/IIIa inhibitor is, sometimes, all you really need as that first inhibition until digestion and the absorption of oral antiplatelets occurs. It certainly can be used as a bolus and very often is used in that manner. Having said that, there are other mechanisms for these agents. Sometimes GP IIb/IIIa inhibitors are used as what we call a bailout, typically in patients that might have a dissection and have risk of thrombosis or actually have intracoronary thrombosis. The GP IIb/IIIa inhibitors can help prevent the propagation of thrombus due to a coronary complication.

Any final thoughts?

We are really in this all together and it must be a team approach. Identifying high risk patients is crucial. As an interventional cardiology team (cardiologists, nurses, cardiovascular technologists, radiologic technologists, and fellows), we are downstream, and we are very dependent on the information our upstream colleagues get about the patient that can be integral to treating those patients at high risk. It is important that we work collaboratively and that information is shared, so we can identify these high risk patients and make appropriate adjustments.

How did it happen for your team?

At the two medical centers where I work, we have focused on staff education. We work with the nursing staff to make sure they identify these patients that are at higher risk. It immediately will bring up a red flag. During the time out period, they identify patients that actually took the P2Y12 receptor inhibitors and whether there was a complication, a lack of absorption or a delay. The time out is crucial as the period used to identify high risk patients and institute appropriate treatment. During this intricate time, communication is translated to the entire medical staff and it is the ideal interval where the team adheres to “TIME OUT”, a moment before the procedure when the entire staff listens to vital information and all concur with the plan.During that period, everybody is listening in the cath lab and it is before we do any maneuvering. We have found it is the best time to transmit and share information so we can take appropriate action. When we recognize the high-risk patients, that is when GP IIb/IIIa inhibitors are recommended. We usually have it on standby or in the cath lab so it can be initiated early on. The premixed GP IIb/IIIa inhibitor will just take a few minutes. Most cath labs will have it available in the cath lab. That is important. I want to emphasize that for any cath lab treating STEMI or doing interventional work, having GP IIb/IIIa inhibitors in the cath lab can help in cases that are high risk with delayed onset, which occurs after giving the P2Y12 receptor inhibitors and observing a lack of absorption, or, in very rare instances, as a bailout in patients that undergo complications from a coronary dissection or a thrombus. Having it available in the cath lab and accessible in a timely fashion is going to be beneficial for these patients. 

References
  1. Parodi G, Bellandi B, Xanthopoulou I, et al. Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ Cardiovasc Interv. 2014 Dec 31; 8(1). pii: e001593.
  2. Yang EH, Gumina RJ, Lennon RJ, et al. Emergency coronary artery bypass surgery for percutaneous coronary interventions: changes in the incidence, clinical characteristics, and indications from 1979 to 2003. J Am Coll Cardiol. 2005 Dec 6; 46(11): 2004-2009.
  3. Cornwell LD, Omer S, Rosengart T, et al. Changes over time in risk profiles of patients who undergo coronary artery bypass graft surgery: the Veterans Affairs Surgical Quality Improvement Program (VASQIP). JAMA Surg. 2015 Apr; 150(4): 308-315.
  4. Kurki TS, Kataja M, Reich DL. Emergency and elective coronary artery bypass grafting: comparisons of risk profiles, postoperative outcomes, and resource requirements. J Cardiothorac Vasc Anesth. 2003 Oct; 17(5): 594-597.
  5. Maganti M, Brister SJ, Yau TM, et al. Changing trends in emergency coronary bypass surgery. J Thorac Cardiovasc Surg. 2011 Oct; 142(4): 816-822.
  6. Schumer EM, Chaney JH, Trivedi JR, et al. Emergency coronary artery bypass grafting: indications and outcomes from 2003 through 2013. Tex Heart Inst J. 2016 Jun 1; 43(3): 214-219.
  7. 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 Apr 16;61(15): 1601-1606.
  8. Parodi G, Bellandi B, Valenti R, et al. Comparison of double (360 mg) ticagrelor loading dose with standard (60 mg) prasugrel loading dose in ST-elevation myocardial infarction patients: the Rapid Activity of Platelet Inhibitor Drugs (RAPID) primary PCI 2 study. Am Heart J. 2014 Jun;167(6): 909-914.
  9. Danzi GB, Capuano C, Sesana M, et al. 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.
  10. Parodi G, Xanthopoulou I, Bellandi B, et al. Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. J Am Coll Cardiol. 2015 Feb 10;65(5):511-512.
  11. Alexopoulos D, Barampoutis N, Gkizas V, et al. Crushed versus integral tablets of ticagrelor in ST-segment elevation myocardial infarction patients: a randomized pharmacokinetic/pharmacodynamic study. Clin Pharmacokinet. 2016 Mar; 55(3): 359-367.
  12. 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 May 3; 67(17): 1994-2004.
  13. Ferreiro JL, Sánchez-Salado JC, Gracida M, et al. Impact of mild hypothermia on platelet responsiveness to aspirin and clopidogrel: an in vitro pharmacodynamic investigation. J Cardiovasc Transl Res. 2014 Feb; 7(1): 39-46.
  14. U.S. Food & Drug Administration. FDA Drug Shortages. Available online at https://www.accessdata.fda.gov/scripts/drugshortages/.  Accessed January 15, 2019.
  15. Mardikar HM, Hiremath MS, Moliterno DJ, et al. Optimal platelet inhibition in patients undergoing PCI: data from the Multicenter Registry of High-Risk Percutaneous Coronary Intervention and Adequate Platelet Inhibition (MR PCI) study. Am Heart J. 2007 Aug; 154(2): 344.e1-344.e5.
  16. Danzi GB, Capuano C, Sesana M, et al. 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.
  17. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec 23; 64(24): e139-e228.
  18. Levine GN, Bates ER, Blankenship JC, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011 Dec 6; 58(24): e44-e122.