What Are Optimal P2Y12 Inhibitor and Schedule of Administration in Patients With Acute Coronary Syndrome?

Abstract

Guidelines recommend treatment with a P2Y₁₂ platelet adenosine diphosphate receptor inhibitor in patients undergoing elective or urgent percutaneous coronary intervention (PCI), but the optimal agent or timing of administration is still not clearly specified. The P2Y₁₂ inhibitor was initially used for its platelet anti-aggregatory action to block thrombosis of the recanalized coronary artery or deployed stent. It is now recognized that these agents also offer potent cardioprotection against a reperfusion injury that occurs in the first minutes of reperfusion if platelet aggregation is blocked at the time of reperfusion. But this is difficult to achieve with oral agents which are slowly absorbed and often require time-consuming metabolic activation. Patients with ST-segment elevation myocardial infarction who usually have a large mass of myocardium at risk of infarction seldom have sufficient time for upstream-administered oral agents to achieve a therapeutic P2Y₁₂ level of inhibition by the time of balloon inflation. However, optimal treatment could be assured by initiating an IV cangrelor infusion shortly prior to stenting followed by subsequent post-PCI transition to an oral agent, that is, ticagrelor, once success of the recanalization and absence of need for surgical intervention are confirmed. Not only should this sequence provide optimal protection against infarction, it should also negate bleeding if coronary artery bypass grafting should be required since stopping the cangrelor infusion at any time will quickly restore platelet reactivity. It is anticipated that cangrelor-induced myocardial salvage will help preserve myocardial function and significantly diminish postinfarction heart failure.

Acute myocardial infarction (AMI) and postinfarction heart failure continue to be the leading causes of disability and death. It was recognized decades ago that the loss of contractile myocardium was a major contributor to postinfarction heart failure. Salvage of ischemic myocardium at risk of infarction by urgent reperfusion therapy was proven in the Thrombolysis In Myocardial Infarction (TIMI) trials to greatly improve outcomes in these patients. Today percutaneous coronary intervention (PCI) and coronary artery stenting are routine procedures for the treatment of both AMI and chronic stable angina pectoris. Because there is an increased risk of occlusive thrombus formation caused by coronary artery plaque rupture in diseased coronary arteries or in deployed coronary stents, it has become routine to treat these patients with agents that interfere with thrombogenesis both during and following PCI. Anticoagulants such as heparin are routinely employed for acute care. Recognizing the contribution of platelets to clot formation, long-term prevention of intracoronary thrombi is now commonly accomplished with drugs that prevent platelet aggregation. Glycoprotein IIb/IIIa inhibitors (GPIs) are potent antiplatelet agents, but their short half-lives make them suitable for only acute care. Antagonists of the platelet’s P2Y₁₂ adenosine diphosphate (ADP) receptor have proven to be effective blockers of platelet aggregation for both acute and chronic care. These include ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor. The less potent COXII blocker acetylsalicylic acid (ASA), that is, aspirin also directly inhibits aggregation. Whereas the GPIs and cangrelor are intravenous preparations, ASA and the other 4 P2Y₁₂ antagonists are oral medications. It is now universally accepted that both anticoagulants and antiplatelet agents are to be used in patients with AMI treated with and without stents.

The timing of administration of the antiplatelet agents has yet to be firmly established. Current guidelines recommend oral P2Y₁₂ treatment should be upstream of PCI, but how far upstream is not specified. Because performing PCI on an anticoagulated patient treated with upstream antiplatelet agents can increase the risk of bleeding, it has been asked whether the benefit outweighs the potential bleeding risk? Anticoagulation with heparin alone may suffice for stent deployment, while P2Y₁₂ inhibition that is needed for chronic treatment can be started only after successful recanalization has been confirmed. A recent analysis by Allencharril et al ¹ concluded that, “If indeed the full anti-platelet effect is needed only a few hours after restoration of macrovascular coronary flow and not immediately after reperfusion, oral agents administered at the time of PCI likely suffice.” There are, however, several theoretical and practical considerations that influence the decision of when to administer these drugs.

Advantages of Intravenous Inhibitors of Platelet Aggregation

In a patient with AMI, the coronary artery is occluded by thrombus. To prevent clot propagation and occlusion of branches, anticoagulation is initiated with an agent such as heparin when the patient is first seen by medical personnel. There is no controversy at this point. But then there is the presumed need for prophylactic administration of agents which will prevent clots from forming in diseased arteries and the stents typically implanted in patients with AMI. This role has been assigned to agents that prevent platelet aggregation. They are useful for chronic treatment as they are orally administered, and the bleeding risk has been accepted. Because infarct size is proportional to the duration of the ischemic period, most centers have reduced their door-to-balloon time to ∼60 minutes, but this interval is not likely to be shortened much further. Ideally, inhibition of thrombus formation should occur as early as possible to prevent progression of thrombosis. Indeed heparin and aspirin are given upon diagnosis. But the potent platelet inhibitors are critical adjuvants to heparin because heparin does not prevent platelet aggregation on ruptured plaques or stents which can act as seeds for thrombi. Attenuation of this thrombosis can easily be accomplished with intravenous agents, GPI and cangrelor, which cause immediate inhibition of platelet function. Both have short plasma half-lives and are administered as infusions. Either can be introduced just before PCI and the infusion continued for several hours which would permit an orderly transition to an oral agent after the PCI for long-term treatment.

Limitations of Oral Platelet Inhibitors Clopidogrel and Prasugrel

Many interventionalists still choose to use the more convenient oral P2Y₁₂ antagonists in lieu of the intravenous preparations which indeed may not be available in all cardiac treatment facilities. And this is where the controversy begins. First, there is the issue of absorption, a consideration for all oral drugs. Gastrointestinal motility may be diminished in critically ill patients with AMI ^2,3 and morphine may further decrease motility and increase the time needed for drug absorption. ³ As a result, absorption may take hours, and this process will vary among patients.

The need for metabolic activation can further delay the production of a therapeutic plasma concentration. Clopidogrel and prasugrel are thienopyridines, irreversible inhibitors of platelet aggregation and pro-drugs which require in vivo metabolic activation. Clopidogrel requires 2 metabolic steps before the active metabolite is formed. Activation of clopidogrel is caused by the CYP450 system, but, unfortunately, genetic polymorphisms are present in some individuals that cause them to be incapable of making this conversion. ^{4 -6} Percutaneous coronary intervention patients with low or no response to clopidogrel, as expected, have increased risk of ischemic events following PCI ^{7 -10} and more stent thromboses. ¹¹ Prasugrel is activated after only 1 metabolic conversion, and there are no enzyme-deficient individuals. These metabolic conversions require time and further delay the onset of effect.

So when should either clopidogrel or prasugrel be administered? If given to the patient just before PCI in the catheterization suite, it will be certain that the antiplatelet effect will not be optimal during the stent deployment which typically takes only about 30 minutes. The anti-platelet agent would ideally have to be administered 2 or more hours before a planned PCI to ensure that platelet aggregation will be fully blocked at the time of PCI. Of course, 2-hour upstream treatment would seldom be possible in the patient being treated with primary PCI for ST-segment elevation MI (STEMI). But if it were possible, the subsequent invasive procedure and postprocedure recovery would be done with anticoagulation and significant blockade of platelet aggregation leading to a greater chance of procedural or other bleeding with no way to restore platelet reactivity. This latter fear is the major reason for hesitating to recommend upstream administration of these anti-platelet aggregation drugs even when the PCI is elective. The onset of inhibition of aggregation can be accelerated by greatly increasing the loading dose as is routinely done with the irreversible inhibitor clopidogrel (600 mg), ¹² but then the bleeding risk is further increased as the eventual dose becomes overly effective at blocking platelet aggregation. ^12,13

Ticagrelor and Cangrelor

Ticagrelor is not a thienopyridine but rather a member of the cyclopentyltriazolopyrimidine class. It does not require metabolic conversion, and, unlike clopidogrel and prasugrel, is a reversible inhibitor of the P2Y₁₂ platelet receptor. Cangrelor, the intravenous platelet receptor inhibitor, is also a member of this class. Because metabolic conversion to an active metabolite is not necessary, ticagrelor’s effect on platelets is seen more quickly after administration than that of clopidogrel or prasugrel. ^2,3 However, ticagrelor is still an oral drug, and, therefore, subject to the same delayed absorption as the other oral preparations. ³

Uncertainty About Timing of Drug Administration Related to Paucity of Data

So when should these oral preparations be administered to maximize therapeutic effects and minimize undesirable side effects? Appropriate randomized, blinded studies are not available to definitively address this issue. Ideally, there would be a trial comparing blinded upstream administration of the agent to administration shortly before or even after PCI. Importantly, platelet activity would be monitored before, during, and after PCI to determine the state of platelet inhibition at these crucial times. The appearance of postischemic events could be correlated with the measured platelet activity. Although no such trial has been conducted, there have been a few attempts to compare upstream to provisional (peri-PCI) administration of antiplatelet drugs without consistent documentation of platelet functional effects. Some of the more revealing studies will be summarized.

Intravenous GPI and Cangrelor Shortly Before PCI Optimize Benefits in all ACS

Several investigations of the intravenous GPIs, tirofiban, eptifibatide, and abciximab, are informative. In the earlier studies, GPI infusions begun shortly before PCI in patients with STEMI significantly decreased post-ischemic complications (death, recurrent MI, need for surgical revascularization, and possible stroke) at 30 days and 6 months and even out to 1 year. ^{14 -16} This advantage of GPI was also seen if the coronary artery lesion was stented rather than just ballooned. ¹⁷ Because benefit was also seen in patients without stenting, it would appear that the benefit was not just related to the prevention of stent thrombosis. The efficacy of GPI was further validated when upstream administration of GPI was contrasted with an infusion begun before or shortly after intracoronary balloon inflation. Patients with moderate- and high-risk acute coronary syndromes in the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) timing trial by Stone et al. ¹⁸ received a bolus and then prolonged infusion of eptifibatide or tirofiban 12 to 18 hours before PCI or eptifibatide or abciximab 5 to 10 minutes before balloon inflation. There was an equal number of ischemic events (death, recurrent MI, and need for surgical revascularization) with upstream and delayed GPI administration. These results suggest that there was no added benefit from extended treatment prior to balloon inflation.

Giugliano et al ¹⁹ also evaluated possible differential effects of upstream eptifibatide (more than 12 hours) before PCI and delayed eptifibatide started after angiography but prior to PCI in patients being revascularized for both unstable angina pectoris and non-STEMI (NSTEMI). Seventy percent of patients were also treated with a loading dose of clopidogrel, usually, 300 mg. Fifty-seven percent of the study population underwent PCI (2666 in the early group and 2723 in the delayed group). Although patients who underwent PCI in the early-eptifibatide group had fewer primary and secondary end points than those in the delayed-eptifibatide group (Kaplan–Meier rates 8.0% vs 10.5%), the difference was not significant. Any possible benefit of upstream use of GPI was negated by nearly 50% more major bleeding than in the delayed group and 100% more when only bleeding not related to coronary artery bypass grafting (CABG) is considered.

Recanalization in STEMI With or Without Platelet Inhibition

Heestermans et al ²⁰ compared administration of tirofiban a mean of 94 minutes before balloon inflation with infusion a mean of 37 minutes after balloon inflation in patients with STEMI. There were more than 800 patients in each group. Infarct size was significantly smaller, death or recurrent MI at 30 days significantly less, and death significantly less in the upfront group suggesting a benefit for upstream loading compared to treatment after PCI. Bleeding rates were comparable. The beneficial clinical effect of pre-PCI GPI is not unique to this class of drugs. The intravenous P2Y₁₂ inhibitor cangrelor is similarly protective when infused shortly before PCI, ^21,22 and addition of a GPI has no additive effect. ²² This would indicate that platelet inhibition at the time of PCI in STEMI patients does reduce postischemic complications. Some of this benefit may be related to direct cardioprotection from reduced platelet reactivity in the first minutes of reperfusion which may reduce the reperfusion injury and thus infarct size. That benefit might be unique to STEMI patients who have abrupt reperfusion of deeply ischemic myocardium. Cardioprotective effects of platelet inhibitors will be discussed below.

Oral Agent: Upstream Clopidogrel for Maximal Effect in NSTEMI

The use of oral antiplatelet agents in acute coronary syndrome has been extensively explored. Although intravenous agents have been noted to be quite efficacious, a transition from intravenous to oral medication is needed for long-term treatment of patients following PCI and stenting. Therefore, one wonders if treatment could be initiated and maintained with a single oral agent. Historically, the most widely used platelet P2Y₁₂ receptor inhibitor has been clopidogrel, although recently published guidelines ²³ now label it as a second-tier treatment option behind prasugrel and ticagrelor because of its less effective blockade of platelet function and its troubling incidence of disabling genetic polymorphisms. Multiple studies have demonstrated clopidogrel’s efficacy in PCI patients. ^{24 -28} But, as expected, patients with either low or no response to clopidogrel have increased risk of ischemic events when compared to normal responders. ^{7 -11} As discussed above, Heestermans et al ²⁰ provided convincing evidence that there is a long-term benefit to having platelets blocked prior to PCI as opposed to afterward. Therefore, if upstream administration is needed, the question becomes, “How far upstream?”

In the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 4 trial, Sibbing et al ²⁹ treated all NSTEMI patients with ASA and 600 mg of clopidogrel. The time interval between administration of these drugs and the PCI is not indicated, but platelet aggregation studies were performed just before PCI. Patients treated with clopidogrel were noted to have either high platelet reactivity (HPR) or no HPR. Thus, patients with persistent HPR had not responded to clopidogrel, possibly because of inadequate time for absorption from the gut or presence of a genetic polymorphism. Patients in each group were then randomized to either co-treatment with abciximab or bivalirudin before PCI. There were between 100 and 200 patients in each of the 4 groups. Following abciximab treatment which also inhibits platelet aggregation, ischemic complications were not different in HPR and no HPR subgroups. However, all adverse clinical end points were significantly more frequent in bivalirudin patients with HPR than those with no HPR (22.0% vs 5.0%, P < .0001). Thus, the presence of inhibited platelet reactivity at the time of recanalization was beneficial during PCI whether it was related to either clopidogrel or abciximab. But in HPR patients treated with bivalirudin which has no platelet antiaggregatory effect, the protection was negligible. The need for timely upstream administration of a P2Y₁₂ antagonist is obvious. But can we extrapolate these findings to the setting of urgent primary PCI in patients with STEMI who have a high ischemic burden and little time for upstream loading?

Oral Agent: Upstream Prasugrel in NSTEMI Insures Adequate Platelet Blockade but Bleeding Risk Increases

Prasugrel is more potent than clopidogrel ^30,31 and its efficacy is not affected by CYP450 polymorphisms. ³⁰ Therefore, it has several advantages over clopidogrel. And it was shown to be better than clopidogrel at preventing ischemic complications of cardiovascular death, nonfatal MI, and nonfatal stroke at 15 mos (10.0% vs 12.4%, P = .02) in the large Triton-TIMI 38 study. ³² In A Comparison of prasugrel at the time oif percutaneous Coronary intervention Or as pre-treatment At the time of diagnosis in patients with non-ST-segment elevation myocardial infarction (ACCOAST) trial of prasugrel treatment of NSTEMI patients, the timing of drug administration was either early before diagnostic coronary angiography or delayed until after diagnostic angiography but before PCI. ³³ In the early group in which diagnostic coronary angiography was undertaken 2 to 48 hours following randomization, either 30 mg of prasugrel or placebo was administered. If PCI was needed after the angiogram, those patients previously treated with prasugrel received an additional 30 mg, whereas patients in the untreated control group were given 60 mg. The interval between the second loading dose and PCI is unknown. Ischemic complications and the frequency of stent thrombosis at 7 and 30 days were similar in both early and delayed groups. Major bleeding was significantly more frequent in the pretreatment group, although one-half of all episodes were related to urgent CABG and one-half of non-CABG-related TIMI major bleeding events were caused by vascular access-site bleeding. What is missing in this large cohort is the determination of adequacy of platelet receptor blockade, especially in those patients fully treated between diagnostic coronary angiography and PCI. But in a very small subgroup, platelet reactivity was measured before the treatment, at the time of arterial access (median of 4.8 h after the first loading dose), and again at the time of PCI and 1 hour later. Not surprisingly at 4.8 hours after the first loading dose patients who had received 30 mg of prasugrel had a substantial blockade of platelet aggregation, whereas platelet aggregation was normal in placebo-treated patients. Thirty minutes after the second loading dose and the PCI, there was a minimal effect on platelet aggregation in the delayed treatment group. But after an additional 30 minutes, platelet aggregation was substantially blocked in this group, and there was no longer any difference between early and delayed treatment groups. Thus, oral prasugrel acted in less than 1 hour to block platelet aggregation. This very rapid effect undoubtedly accounted for the absence of increased ischemic complications in the delayed group when compared to individuals treated upstream. This similarity of clinical outcome was observed despite lack of an effective antiplatelet effect at reperfusion in the delayed group. In NSTEMI where there is much less myocardium at risk of infarction, platelet inhibition at the moment of reperfusion does not appear to be as critical.

In the ISAR-REACT 5 trial, ³⁴ the effect of prasugrel was again evaluated in patients with acute coronary syndromes. In all patients, 46.2% had NSTEMI, 41.1% had STEMI, and 12.7% had unstable angina. Patients were randomized to be treated with loading doses of either prasugrel or ticagrelor. The complicated treatment algorithm resulted in administration of the antiplatelet agent immediately after randomization in all STEMI patients. In patients without ST-segment elevation, ticagrelor was likewise administered immediately after randomization, whereas prasugrel administration was delayed until after diagnostic angiography. In none of the groups is the interval between ingestion of the P2Y₁₂ antagonist and coronary recanalization known. Furthermore, GPI agents were used in 12.3% of patients undergoing PCI. When clinical outcomes (death, MI, and stroke) after 1 year of follow-up of all patients were combined, prasugrel was significantly better than ticagrelor. But when patients were segregated according to presenting syndrome, prasugrel was favored over ticagrelor, but the differences were not significant.

Oral Agent: Upstream Ticagrelor in STEMI Patients Has Few Benefits, but Is “Upstream” Really Upstream?

Ticagrelor is not a pro-drug, and, therefore, the only impediment to initiation of its platelet antiaggregatory effect is absorption from the gut. In the landmark PLATelet inhibition and patient Outcomes (PLATO) trial, ³⁵ in more than 18 000 patients with acute coronary syndrome followed for 1 year, ticagrelor treatment at presentation resulted in fewer vascular deaths, MIs, or strokes than clopidogrel (9.8% vs 11.7%, P < .001). Two trials to compare upstream and delayed administration have been reported. In the Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial Infarction to open Coronary artery (ATLANTIC) trial, STEMI patients were treated with either ticagrelor or placebo upstream in the ambulance, and then in the cardiac catheterization suite before PCI. Patients previously treated with ticagrelor received a placebo, whereas those previously given a placebo were treated with a loading dose of ticagrelor. ³⁶ In a small subset of upstream and delayed treatment patients, platelet reactivity was measured. There were no differences between the groups in the proportion of patients with resolution of ST-segment elevation before PCI, the proportion of patients with resumption of TIMI 3 flow in the infarct-related artery at the time of initial coronary angiogram or postischemic complications at 30 days. However, the incidence of stent thrombosis was significantly lower in the upstream group. In two-thirds of patients radial artery access was used, and there was no difference in major bleeding episodes. Notably, the median difference in timing of ticagrelor’s administration between upstream and delayed groups was only 31 minutes and the median interval between administration of the second loading dose and PCI was 28 minutes. In light of these small differences in timing of ticagrelor administration in the 2 groups, it is not surprising that there was no effect on platelet reactivity at PCI in either group. Changes in platelet reactivity only began to appear 1 hour after PCI, first mainly in the upstream group. Certainly prevention of reperfusion injury due to platelet inhibition at the time of reperfusion would not have occurred in either group. Thus, upstream ticagrelor was safe but resulted in few benefits. The short time between ticagrelor administration in upstream and delayed groups diminishes the impact of these observations.

Koul et al ³⁷ performed a similar investigation with ticagrelor administered upstream or in the cardiac catheterization suite in STEMI patients. Thirty-eight percent of those not treated with ticagrelor received clopidogrel. There were no differences in ischemic complications or frequency of stent thrombosis in the groups. Also, bleeding rates were not different. It is uncertain what was the interval between ticagrelor administration in the pretreatment and pre-PCI groups. It was estimated that in nearly one-half of the patients the interval was more than 1 hour. Nor is the interval between ticagrelor administration and PCI known. These studies of timing of administration of anti-platelet therapies do not permit a definitive recommendation. GPI and cangrelor are effective when administered shortly before PCI. But oral prasugrel and ticagrelor appear to be minimally more effective when administered upstream of PCI in STEMI patients, although it is uncertain whether “upstream” can really be achieved in these patients. Upstream treatment is more promising in NSTEMI when oral agents can be given far enough upstream to provide platelet inhibition at the time of balloon inflation. Procedure-associated bleeding appears to be less of a problem with radial artery access. But the appropriate randomized trial with monitoring of platelet reactivity has not been done, and probably cannot be done in STEMI patients in whom every effort is being made to do PCI with little delay.

P2Y₁₂ Antagonists Are Cardioprotective: A New Wrinkle

The oral antiplatelet agents clopidogrel and ticagrelor and the intravenous agent cangrelor are extremely cardioprotective in animal models and dramatically reduce myocardial infarct size after the release of a coronary occlusion of 30 to 60 minutes. ³⁸ This cardioprotective effect is quite robust and has been documented in mice, ³⁹ rats, ⁴⁰ rabbits, ⁴¹ pigs, ^{42 -44} and non-human primates. ⁴⁵ The protection is thought to use a mechanism similar to that in ischemic preconditioning which was the first intervention that unambiguously made the heart resistant to ischemia-induced infarction in animal experiments.

Most of the clinical investigations of platelet inhibitors have centered on rethrombosis and bleeding. These are common complications following PCI and are directly related to the adequacy of the anti-thrombotic effect that platelet inhibitors were designed to provide. However, vascular complications of coronary occlusion and stent thrombosis which result in MI would not be expected to be affected by a cardioprotective intervention, and, therefore, are not robust end points for outcome studies of cardioprotection. Postinfarction heart failure is related to infarct size and should be directly affected by a cardioprotective intervention. Documentation of both out-patient and in-patient heart failure should be the most sensitive clinical end point for a cardioprotection trial. But, unfortunately, this was seldom addressed in the past clinical trials of platelet inhibitors following primary PCI. As a result, the possible contribution of cardioprotection to the clinical success of platelet inhibitors in AMI until recently has not been considered.

Much is known about the mechanism of conditioning’s cardioprotection and has been previously summarized. ⁴⁶ Briefly, there are 2 phases: a triggering phase before a lethal ischemic insult and a mediator phase at reperfusion. In the triggering phase, brief periods of myocardial ischemia cause the release of adenosine, opioids, and bradykinin which initiate complex signaling cascades involving mitochondrial K_ATP channels, reactive oxygen species (ROS), and activation of protein kinase C. At reperfusion increased affinity of adenosine A_2B receptors allow them to be populated which in turn inhibit glycogen synthase kinase-3β via Akt and extracellular regulated kinase. Glycogen synthase kinase-3β inhibition blocks the formation of lethal mitochondrial permeability transition pores (mPTP), the putative end-effectors of cardioprotection. Mitochondrial permeability transition pore is a high conductance pore that dissipates the transmembrane proton/electrochemical gradient that drives adenosine triphosphate (ATP) generation when open. Pore formation would lead to ATP depletion, enhanced ROS production, failure of membrane ion pumps, solute entry, organelle swelling, and ultimate mitochondrial rupture and cardiomyocyte necrosis. It is now known that the mediator pathway can actually still be instituted at the time of reperfusion if conditions are just right. Low pH during myocardial ischemia blocks mPTP formation. Reperfusion does not wash out acidic metabolites immediately, so it is still possible to trigger cardioprotective signaling if it is done before tissue pH rises. ⁴⁷

Although appropriate clinical trials have never been done, there is suggestive evidence that this phenomenon of cardioprotection is also seen in man. ³⁸ But there is an important caveat. Intravenous cangrelor or intraperitoneal ticagrelor is extremely protective in animals only when administered prior to reperfusion. If the P2Y₁₂ antagonist is introduced 10 minutes after reperfusion, then all cardioprotection is lost ⁴¹ presumably because the mPTP will have already formed. Therefore, infarct size reduction is dependent on the P2Y₁₂ antagonist being present in the first few minutes of reperfusion.

Although platelet P2Y₁₂ receptor blockers were initially used clinically for their anticoagulant properties, the serendipitous discovery of their off-target cardioprotective properties significantly enhances the value of these agents. Infarct size is a primary determinant of the postischemic course of primary PCI patients. Thus, this cardioprotective benefit of antiplatelet treatment would be the most apparent in the setting of primary PCI in which infarction has been terminated by abrupt reperfusion. The amount of contractile mass lost is a primary determinant of postischemic recovery and the appearance of postinfarction heart failure. ^48,49 This is not a trivial problem. In the 2015 CIRCUS trial, nearly 30% of patients presenting with an anterior STEMI either died or developed new or worsening heart failure in the year following their PCI. ⁵⁰ Hence, clinical trials in anterior STEMI patients would likely be the most revealing about the possible benefit of platelet inhibition at the time of reperfusion. In the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction (CIRCUS) trial, one-half of the patients by design were treated with cyclosporine, but virtually all of them had received a loading dose of a P2Y₁₂ inhibitor prior to recanalization. There was no benefit from cyclosporine despite its having been shown to reduce infarct size in many animal models. ^{51 -54} It is possible that the P2Y₁₂ inhibitor had already conditioned these patients rendering cyclosporine treatment redundant.

It is instructive to evaluate the status of another cardioprotective intervention which already has been applied clinically. Remote ischemic conditioning (RIC) is achieved by repeated inflation and deflation of a blood pressure cuff on an arm or thigh to create several cycles of local ischemia and reperfusion prior to recanalization of an occluded coronary artery. This remote conditioning has been reported to reduce infarct size in preclinical animal models ^55,56 as well as man. ^{57 -60} Cardioprotection in patients treated with RIC has been demonstrated by documenting either smaller rises in cardiac enzymes after STEMI ^{58 -60} or smaller infarcts and greater myocardial salvage indices as measured by cardiac magnetic resonance several days after PCI. ^57,59,60 A small study suggests that RIC can significantly diminish cardiac mortality and the appearance of heart failure. ⁶¹ However, a recent larger clinical study in 5115 patients with STEMI failed to document any advantage of RIC on clinical outcomes 1 year after PCI. ⁶² Slightly more hospitalizations for heart failure actually occurred in the RIC group (192 vs 182) indicating no benefit. However, because out-patient heart failure events were not documented, the true effect on heart failure may have been somewhat obscured.

Animal studies reveal a similar anti-infarct effect with the P2Y₁₂ inhibitors clopidogrel, ⁴¹ ticagrelor, ⁴⁰ and cangrelor ^40,41 suggesting a class effect. Surprisingly, the effect of prasugrel on infarct size has not been studied. We found only 1 report in which prasugrel reportedly decreased infarct size, but a rat model with permanent occlusion of a coronary artery was used. ⁶³ There are several reports suggesting ticagrelor confers added cardioprotection because of its ability to raise tissue adenosine levels. ^{42 -44} Roubille et al ⁶⁴ reported in a relatively small study (30 STEMI patients) that either clopidogrel loading or ischemic postconditioning reduced infarct size and that they had an additive effect when combined. Those patients were actually studied prior to 2005 when door-to-balloon times were much longer than today’s so it is likely that many of those receiving oral clopidogrel did have some platelet inhibition at the time of balloon inflation. Such a study could not be conducted today because it would be unethical to withhold an antiplatelet drug in the control group.

The GPI inhibitors have received little attention in this regard, but there is some evidence that they may be similarly protective. Some early studies suggest an anti-infarct effect in patients ^14,29 and Heestermans et al ²⁰ saw reduced infarct size in patients that were given tirofiban prior to reperfusion compared to those receiving it after reperfusion. Evidence indicates that the cardioprotective targets for the P2Y₁₂ antagonist are the receptors on platelets since a thrombocytopenic rat’s heart can no longer be protected against infarction by ticagrelor. ⁶⁵ If the important preclinical observations noted above are extrapolated to the clinical theater, then adequate blockade of the platelet P2Y₁₂ ADP receptor must be evident in the first minutes of reperfusion to get the anti-infarct effect.

If we assume that the human heart can also be similarly protected against infarction by a P2Y₁₂ inhibitor, then platelets would have to be inhibited prior to balloon inflation. It is unlikely that this could be accomplished with an oral agent with today’s short door-to-balloon time. The delay before these oral agents take effect can be shortened by greatly increasing the dose. The recommended loading dose for clopidogrel is 600 mg which is 8 times the maintenance dose. Increasing the dose from 300 to 600 mg did improve clopidogrel’s clinical benefit after PCI in STEMI patients. ^12,13 But was the protection optimal? All patients will not absorb the drug at the same rate, and we know there are many patients that are unresponsive to clopidogrel. Because of shortened door-to-balloon times, the benefit of any oral upstream P2Y₁₂ treatment may have diminished because of inadequate absorption, but this potential loss of efficacy may be offset by the shortened ischemia time and the latter’s effect on infarction. Here we suggest an alternative approach in which platelet inhibition at the time of balloon inflation could be assured and would provide maximum safety for the patient as well.

Cooperative Action of Intravenous Cangrelor and Oral Ticagrelor

In a small group of patients with STEMI Franchi et al ⁶⁶ treated all with a loading dose of crushed ticagrelor pills after completion of diagnostic coronary angiography and the decision to proceed with PCI. At the same time, patients were randomized to receive an infusion of either cangrelor or placebo. Platelet reactivity was assessed 5 and 30 minutes after beginning the infusion, immediately after PCI, and at various times following the procedure. After only 5 minutes of cangrelor infusion platelet aggregation was significantly blocked, but there was no change in the ticagrelor-only group. After 30 minutes and at the end of the PCI (mean of 41 minutes [21-54 minutes]) platelet reactivity was still at baseline in the ticagrelor-only group but was in the therapeutic range in those receiving cangrelor. At 1 hour after treatment with ticagrelor, a small effect on platelet aggregation in the ticagrelor-only group could be measured; significant blockade of aggregation was documented only after an additional 1 hour. The cangrelor and placebo infusions were suspended after 2 hours. During the next hour platelet aggregation in the ticagrelor-only group was blocked further, while the antiaggregatory effect in those previously treated with cangrelor partially reversed so that platelet aggregation was equally blocked in both groups.

Alexopoulos et al ⁶⁷ did a similar randomized study in a cohort of STEMI patients and made similar observations. Notably, neither Franchi ⁶⁶ nor Alexopoulos ⁶⁷ observed any major bleeding. Although Mohammad et al ⁶⁸ did not randomize STEMI patients to either a cangrelor or placebo group, they observed continued blockade of platelet aggregation after the 2-hour cangrelor infusion was suspended as a result of ticagrelor administration 41 to 50 minutes before PCI. Clinical outcomes were not examined in any of these studies.

Recommendation for Intravenous Cangrelor Before PCI and Oral Ticagrelor Several Hours Later

These latter 3 studies demonstrated that a smooth transition from the effect of an intravenous to an oral P2Y₁₂ inhibitor is possible. This protocol leads to effective blockade of platelet aggregation in the minutes to hours after PCI and also harnesses the cardioprotective potential of P2Y₁₂ blockade. A small modification of the protocol would make it even more appealing to clinicians. Cardiovascular surgeons have been very vocal about the major bleeds resulting from administration of P2Y₁₂ antagonists to patients that require CABG. They usually opt to wait a few days for the platelet effects of these drugs to dissipate. But a delay is not feasible in the patient with STEMI who requires urgent surgical coronary revascularization. Cangrelor has a plasma elimination half-time of only 3 to 5 minutes following discontinuation, and there is near-full recovery of platelet function in 60 to 90 minutes after infusion termination. ⁶⁹ Any anticoagulation from administered heparin could be reversed with protamine, so these patients could quickly be made ready for a surgical intervention. Therefore, it is suggested that a cangrelor infusion be started shortly before PCI, but ticagrelor administration be delayed until after the PCI when it has been determined that CABG is not needed. Then a loading dose of ticagrelor can be given and the cangrelor infusion continued for 2 to 4 hours. This would be a fairly easy protocol to test against a currently employed loading dose of ticagrelor in STEMI patients. The primary end points would have to include infarct size and the incidence of postinfarction heart failure.

Caution Against Use of Cangrelor With Either Clopidogrel or Prasugrel

The transition noted above from intravenous to oral P2Y₁₂ inhibitors works well when the agents are cangrelor and ticagrelor. There is no competition between these 2 reversible inhibitors. ⁷⁰ However, this is not the case for the irreversible inhibitors clopidogrel ⁷¹ and prasugrel. ⁷⁰ By blocking the receptor cangrelor inhibits the receptor binding necessary for irreversible inhibition of both. Clopidogrel must not be administered until after the cangrelor infusion is stopped, ⁷¹ while prasugrel can be administered up to 30 minutes before the end of the cangrelor infusion, ⁷⁰ thus leading to several unavoidable hours when P2Y₁₂ blockade would be absent or inadequate.

Conclusion

Hence, there is a reasonable and justifiable strategy for the administration of P2Y₁₂ antagonists to patients before primary PCI and coronary artery stenting. In general, the objective is to block platelet aggregation to minimize the risk of thrombosis in the coronary artery and stent in the early moments after stent deployment and to marshal the powerful effects of the drugs’ cardioprotective property in the required few minutes after reperfusion. For elective procedures, upstream administration of the P2Y₁₂ antagonist is sufficient, for example, 90 to 120 minutes for ticagrelor, with the interval before PCI needed for adequate absorption of the oral preparation and metabolism, if required, of the pro-drug to its active metabolite. In addition, the use of the radial artery for arterial access will greatly minimize peri-procedural hemorrhage when upstream oral P2Y₁₂ blockers are used. For the patient with either unstable angina or an NSTEMI, it is likely that the coronary artery will not have been completely occluded thus minimizing deleterious reperfusion injury. Therefore, the efficacy of P2Y₁₂ inhibitor therapy will mainly reflect its anticoagulant properties rather than its cardioprotective qualities.

In urgent situations in which the patient presents with an STEMI early platelet inhibition becomes more important, but logistical considerations make upstream administration problematic because of the limited door-to-balloon time. In this case, it may be prudent to use an intravenous preparation such as cangrelor and then administer oral ticagrelor only after adequate recanalization has been achieved and emergent surgical revascularization has been deemed not to be necessary. There is little doubt that recanalization of STEMI patients after total coronary artery occlusion exposes the heart to reperfusion injury. With a proper dosing schedule, P2Y₁₂ antagonists should provide important cardioprotection to these patients as well as anticoagulation. Increased myocardial salvage should lead to better cardiac function and less post-infarction heart failure. We believe this hypothesis warrants clinical testing.