Platelet Inhibition With the P2Y12 Inhibitor Cangrelor

You have a long interest in antiplatelet therapy. When did it start?

My interest in antiplatelet therapy began far back in the 1980s when I was a co-investigator in a trial utilizing ticlopidine (Ticlid) as an anti-restenotic agent for plain old balloon angioplasty (POBA). Ticlopidine turned out not to have antirestenotic properties, but did have marked antiplatelet properties and reduced abrupt occlusion after POBA. Since that time, I’ve been involved in a number of clinical trials with a host of antiplatelet agents which culminated in participation as a sub-investigator in the CHAMPION trials (CHAMPION-PCI, CHAMPION PLATFORM, and CHAMPION-PHOENIX) while at Case Western Reserve University Hospitals of Cleveland and the BRIDGE trial, both looking at cangrelor.^1,2 By the time  cangrelor was finally FDA approved on the basis of CHAMPION-PHOENIX³, I had moved  to the University of Arizona and was immediately interested in using this agent,  recognizing cangrelor’s potential (Figure 1) and knowing that it was a drug we needed to have in our formulary. In February of 2014, the University of Arizona hospitals and physician practice plans were acquired by Banner Health, a roughly 30-hospital system ranging throughout the southwestern United States. The University of Arizona Tucson is the academic centerpiece. In order for a drug to be added to the formulary at the University of Arizona, it requires approval by a series of committees, as Banner Health’s policy dictates that if something is on the formulary at any one of the hospitals, then will be on formulary systemwide.

As a result, the system was necessarily cautious about placing this relatively new drug on the formulary of its hospitals without first looking into the data very carefully. We went into prolonged due diligence, during which we had the opportunity to review all of the literature on cangrelor, including a CHAMPION PHOENIX ECONOMICS sub-study that emphasized the importance of recognizing reductions in intraprocedural thrombotic events and bleeding complications as cost setbacks when evaluating the overall cost of percutaneous coronary intervention (PCI).⁴ There was some initial concern over the cost of cangrelor versus other drugs such as glycoprotein (GP) IIb/IIIa inhibitors. However,  that concern was neutralized by consideration of these cost setbacks, and ultimately, we came to the point where cangrelor was approved and it is now in use in cath labs throughout our system. When we were doing our own analysis systemwide, we found that GP IIb/IIIa inhibitors were being used in about 20% of PCIs, which we felt was numerically high and economically costly, even though there is a cost differential between cangrelor and GP IIb/IIIa inhibitors. Clinical trials show GP IIb/IIIa inhibitors are associated with increased bleeding. Certainly there has been some reduction in periprocedural bleeding with the shift to radial access that is occurring throughout the United States interventional practice. We are behind the rest of the world in terms of the transition from femoral, especially in patients with acute coronary syndromes (ACS) and cardiogenic shock, with large devices of course still requiring femoral access. ST-elevation myocardial infarction (STEMI) intervention, ACS intervention, and routine diagnostic catheterization procedures are all undergoing a shift to the radial approach, but the last data I was aware of suggest that approximately  40% of catheterization procedures in the U.S. are performed transradially. This is certainly not the case here at our institution, where radial access is at the 85 to 95% rate. Certainly, a number of the bleeding episodes after PCI occur through the oral platelet inhibition agents at a later time, but there is still a risk of acute bleeding. Much of the use of GP IIb/IIIa inhibitors in the acute setting involves not just an intracoronary bolus but also a short-term infusion of anywhere from 4 to 12 hours after the procedure, and that is usually when there is a problem with periprocedural bleeding. CHAMPION-PHOENIX compared cangrelor with clopidogrel, which has now been largely supplanted in most practices by ticagrelor. It found no increased incidence of major bleeding with cangrelor, which is a much more potent platelet inhibitor than clopidogrel, although there was a slight increase in mild or “nuisance” bleeding, which is not the significant bleeding that requires transfusion or interruption of platelet inhibition.

Did you set certain protocols or best use for cangrelor within your hospital system?

Yes. Given the cost differential between cangrelor and the GP IIb/IIIa inhibitors, the system was very cost conscious. We created a Venn diagram, which is essentially an algorithm for cangrelor use (Figure 2). Based on the literature, it appears as though ACS, STEMI, cardiogenic shock, and high risk or complex angioplasty are the most appropriate niches for cangrelor use. Our systemwide experience and algorithm suggest that cangrelor will be best used in the highest risk, complex patients, especially STEMI and shock, most notably those patients who are post arrest and unconscious, and those patients where there is no time in the rush to the cath lab to get an NG tube down and give oral platelet inhibition. These scenarios are where we take advantage of the very rapid onset and very high degree of platelet inhibition afforded by cangrelor. We started out being very conscious and restrictive with the use of cangrelor in our cath labs. In 2015, Gregg Stone presented an abstract at the European Society of Cardiology meeting that more recently has been published in the European literature⁵, demonstrating that the higher the angiographic risk and the more complex the percutaneous procedure, the more benefit is obtained from cangrelor. His group defined some very specific angiographic subsets showing that measurably higher complexity patients benefited the most from use of cangrelor.

What about cangrelor’s time to platelet inhibition once administered?

Cangrelor is like many of the other ultra-short acting, rapid onset/rapid offset of action drugs that we use, like esmolol and nipride in acute and critical care STEMI. We begin with a bolus infusion and then a drip throughout the procedure. Within 2 to 5 minutes of initiating the bolus, we achieve 90-98% platelet inhibition, higher than that achieved by any other antiplatelet agents. It was initially thought that prasugrel and ticagrelor achieved very high levels of platelet inhibition, within 80-90%, within 1 to 2 hours of administration. It turns out that in subsets of very sick patients such as patients who have received opioids, are beginning hypothermia, for example, post arrest, or have severe heart failure, cardiogenic shock, and so on, that onset of action is actually closer to 2 to 4 hours. That leaves a significant gap during the most vulnerable period for these patients with a fresh stent and ruptured plaque. Except for the use of cangrelor, these very sick patients are not adequately receiving P2Y12 inhibition. Unlike clopidogrel and prasugrel, cangrelor is not a prodrug; it is an immediately acting drug that occupies the ADP site of the P2Y12 receptor.

Can you describe the P2Y12 receptor?

Think of the receptor as being shaped like a crown. If you drop a ball into the central part of the crown, that is the ADP site of the receptor. Clopidogrel, prasugrel, and cangrelor occupy that central site. Ticagrelor, however, is a dogbone-shaped molecule that binds across the side arms of the crown-shaped P2Y12 receptor. In fact, this permits the ideal “handshake” with cangrelor, because you can begin ticagrelor platelet inhibition whenever desired while the cangrelor infusion has been initiated. If you wish, you can give ticagrelor immediately, at the same time as the onset of the cangrelor infusion, at any time during the PCI procedure, or as soon as possible at the end of the procedure. It is recommended that the cangrelor infusion be given for up to 2 hours, so if you choose to give the ticagrelor at the end of the procedure, you still have a couple hours to get an NG tube down, or for a previously unconscious or heavily sedated patient to wake up to take oral medication. There was initially some concern for the period when we turn off the cangrelor infusion at the end of the procedure and begin oral agents, that there would be a crossover vulnerable period of somewhat lesser platelet inhibition — a window of less than adequate protection, during what we call the transition period. Careful outcomes studies, however, have shown that there is no recurrence or excess of acute events such as stent thrombosis or recurrent MI during this crossover period. At our institution, we are comfortable following the current labeling. We give the oral agent, usually ticagrelor, during or at the end of the procedure, and finish the infusion. Cangrelor occupancy at the ADP receptor will then rapidly diminish. This being the case, we could alternatively give clopidogrel or prasugrel shortly after the end of the procedure. You certainly wouldn’t want to give clopidogrel or prasugrel during the procedure when cangrelor is in use, as they would compete for the receptor site. The CANTIC study⁶ showed no drug-drug interaction between ticagrelor and cangrelor. Cangrelor’s degree of platelet inhibition is higher and faster than even crushed ticagrelor.

Do opioids affect cangrelor?

The impact from opioids probably has most to do with gastroparesis and impaired gastrointestinal absorption of the oral agents, as well as effects on platelet circulation. Our routine cath lab sedative protocol used to be Versed and fentanyl — of course, the FDA sent out its first white paper in 2018 cautioning about the effects of morphine, and there is now an extended cautionary note  to include fentanyl. This is another reason to be concerned about giving conventional oral agents if patients are going to receive opioids for pain or sedation, especially in very sick patients who need a high degree of platelet inhibition immediately.

Cangrelor is administered in the cath lab. Would EMS ever administer it?

No, although that has been under discussion. There has been a change in terms of the immediate use of upfront administration of P2Y12 inhibitors in the setting of ACS, meaning NSTEMI and STEMI. A number of trials have shown that bleeding complications are increased, especially because many of these trials were done during the solely transfemoral cath era. Outcomes were not improved by the immediate, upfront emergency department preloading of the oral agents. Theoretically you could preload with cangrelor, but there doesn’t seem to be any reason to do so, because of its extremely rapid onset of action. In the cath lab, we usually wait to start antiplatets until after we have seen the anatomy and make the decision as to whether the patient is going to be treated with PCI as opposed to surgical revascularization. Nationally, about 11% of patients who come with ACS to the cath lab require or are candidates for cardiothoracic surgery.⁷ Cardiac surgeons are appropriately highly sensitive to bleeding and blood product replacement requirements, and are naturally unhappy with interventional cardiologists if they have given antiplatelet agents in the cath lab, and then send the patient to urgent cardiac surgery or cause need for washout of oral agents.  The use of cangrelor affords us the ability to give the drug immediately after deciding that we are going to choose to intervene rather than operate on the patient or, bridge the patient to the OR without necessitating a delay. The BRIDGE trial⁸ looked at patients with ACS who were sent to cardiothoracic, mostly coronary bypass, surgery within the next several days after being in the cath lab. The trial showed positive outcomes for patients when cangrelor was immediately shut off prior to bypass surgery in terms of chest tube output and blood product utilization. It was no different than placebo; however, this is not currently a labelled indication, so we are not encouraging it. I can tell you that we have done this on a compassionate use basis on a couple of occasions. We have not used cangrelor for bridging to noncardiac surgery early after PCI, which is another area people are exploring, considering whether this is something that could be done. The data on antiplatelet therapy for noncardiac surgery shortly after stenting in patients on antiplatelet agents are muddy, and it is an area without much literature or consensus.

What do you recommend for others who are interested in starting with cangrelor?

If you want to avoid bleeding, I would make a strong argument that you should use cangrelor. It is a really simple drug to use. You spike a vial, give a bolus and then a drip which goes to the end of the procedure or a maximum of two hours, and that is it. Although the drug is somewhat more costly than the available small molecule IIb/IIIa inhibitors, it halts the thrombotic cascade much earlier. Using GP IIb/IIIa inhibitors are like sending in the aerial tankers and the smoke jumpers to put out a raging forest fire. They act at the end of the thrombotic cascade. In layman’s terms, using cangrelor is like Smokey the Bear preventing anything from growing beyond a smoldering campfire. To me, it makes a lot of sense to inhibit the cascade right at the very start with cangrelor, rather than waiting until the forest fire is burning out of control. Again, if you look at the cost offsets of using cangrelor versus the currently available IIb/IIIa inhibitors, offsets such as preventing death, MI, urgent revascularization, lack of bleeding and the possibility of a stent thrombosis, means cangrelor ends up being cost neutral when compared with a GP IIb/IIIa inhibitor.⁹

Since cangrelor halts progression earlier in the thrombotic cascade, is timing an issue?

If someone has hung out at home for 4 to 6 hours and has a STEMI with a large thrombus burden, there may still be a role for some bailout use of GP IIb/IIIa inhibitors, or occasionally the off-label use of intracoronary IIb/IIIa inhibitors. My bias would still be according to the data from the CHAMPION trials. It is paramount to get adequate P2Y12 inhibition onboard at the beginning of your interventional procedure in order to prevent the entire clotting cascade. We have seen a number of patients getting multivessel PCI in a setting of ACS or STEMI, and one recent patient who didn’t do very well, a case which we reviewed in our quality committee. This particular patient had disease with very nasty looking lesions in both circumflex and the left anterior descending (LAD) coronary arteries. They came to the lab in cardiogenic shock. It appeared as though the circumflex was the culprit lesion. Angioplasty and stenting in the circumflex was undertaken after giving oral ticagrelor in the cath lab at the beginning of the case. After completing the circumflex procedure, attention was then directed  to the LAD. While the LAD was being stented, the circumflex stent clotted off. An LAD stent was placed, and attention went to opening the circumflex stent. While doing so, the LAD stent clotted off. Activated clotting times (ACTs) were therapeutic. Clearly, the reason was an inadequate degree of platelet inhibition from the very beginning. We have seen a number of these cases — and this was also seen in the CHAMPION-PHOENIX trial — where the presence of intraprocedural stent formation  is a harbinger of subsequent complete stent thrombosis, a situation requiring more than just the slow onset of action of the oral agents. 

1. Steg PG, Bhatt DL, Hamm CW, et al; CHAMPION Investigators. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet. 2013 Dec 14; 382(9909): 1981-1992. doi: 10.1016/S0140-6736(13)61615-3.
2. Angiolillo DJ, Firstenberg MS, Price MJ, et al; BRIDGE Investigators. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012 Jan 18; 307(3): 265-274. doi: 10.1001/jama.2011.2002.
3. Abtan J, Steg PG, Stone GW, et al; CHAMPION PHOENIX Investigators. Efficacy and safety of cangrelor in preventing periprocedural complications in patients with stable angina and acute coronary syndromes undergoing percutaneous coronary intervention: the CHAMPION PHOENIX trial. JACC Cardiovasc Interv. 2016 Sep 26; 9(18): 1905-1913. doi: 10.1016/j.jcin.2016.06.046.
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5. Stone GW, Généreux P, Harrington RA, et al. Impact of lesion complexity on peri-procedural adverse events and the benefit of potent intravenous platelet adenosine diphosphate receptor inhibition after percutaneous coronary intervention: core laboratory analysis from 10 854 patients from the CHAMPION PHOENIX trial. Eur Heart J. 2018 Dec 7; 39(46): 4112-4121. doi: 10.1093/eurheartj/ehy562.
6. 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 Apr 2; 139(14): 1661-1670. doi: 10.1161/CIRCULATIONAHA.118.038317.
7. Stone GW, McLaurin BT, Cox DA, et al; ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006 Nov 23;355(21): 2203-2216.
8. Angiolillo DJ, Firstenberg MS, Price MJ, et al; BRIDGE Investigators. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012 Jan 18; 307(3): 265-274. doi: 10.1001/jama.2011.2002.
9. Jensen IS. Cost-consequence analysis of cangrelor use in high angiographic risk percutaneous coronary intervention (PCI) patients: a US hospital perspective. TCT Abstracts Posters 2018. TCTMD/Slides. Available online at https://www.tctmd.com/slide/cost-consequence-analysis-cangrelor-use-high-angiographic-risk-percutaneous-coronary. Accessed September 13, 2019.