Cardiology

Antiplatelet Therapy: Adenosine Diphosphate Receptor Antagonists

General (including evidence of efficacy)

P2Y12 inhibitors

Adenosine diphosphate (ADP) is one of the main platelet-activating factors. Platelet ADP signaling pathways are mediated by the P2Y1 and P2Y12 receptors, which play a key role in platelet activation and aggregation processes. The P2Y1 and P2Y12 are G-coupled receptors and are both required for platelet aggregation.

However, ADP-stimulated effects are mediated mainly by P2Y12receptor activation, which leads to sustained platelet aggregation and stabilization of the platelet aggregate. The P2Y1 receptor is responsible for an initial weak and transient phase of platelet aggregation and change in platelet shape.

Inhibition of the platelet P2Y12 signaling pathway is crucial, particularly in the setting of PCI, as shown in seminal studies with ticlopidine, a first generation thienopyridine. In fact, the combination of aspirin and ticlopidine showed to be associated with better outcomes, in particular the prevention of thrombotic complications, than aspirin monotherapy or aspirin plus warfarin in patients undergoing coronary stenting.

This is in line with the fact that arterial thrombotic complications are primarily platelet-mediated, thus supporting the role of enhanced platelet inhibition in stented patients, which is achieved with dual antiplatelet therapy. Inhibiting COX-1 and P2Y12-mediated signaling is in fact associated with synergistic effect platelet inhibitory effects.

Ticlopidine has two major disadvantages. First, ticlopidine has a limited safety profile with considerable rates of bone marrow suppression leading to agranulocytosis, rash, and gastrointestinal effects.

Second, ticlopidine achieves its platelet inhibitory effects slowly given that the drug cannot be given with a high enough loading dose due to its potential toxicity. These factors encouraged the development of a second generation thienopyridine, clopidogrel, to overcome these limitations.

Clopidogrel is currently the most commonly used P2Y12 receptor inhibitor. It has a more favorable safety profile compared with ticlopidine, as first shown in the CLASSICS (The Clopidogrel Aspirin Stent International Cooperative Study) trial. However, its main limitation is the broad interindividual variability in its antiplatelet effects.

This has led to the development of novel oral P2Y12 receptor inhibitors, including prasugrel, a third generation thienopyridine, and ticagrelor, a first-in-class cyclopentyltriazolopyrimidines (CPTP). Moreover, an intravenous P2Y12receptor inhibitor, cangrelor, has also been developed for clinical use. The mechanism of action and clinical profile of these agents are described below.

Clopidogrel: The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial evaluated the efficacy of clopidogrel (75 mg daily) versus aspirin (325 mg daily) in reducing the risk of ischemic outcomes in patients with different atherosclerotic disease manifestations (coronary artery disease, peripheral vascular disease, and cerebrovascular disease). The results showed a significantly lower annual rate of the composite end point (vascular death, myocardial infarction [MI], or ischemic stroke) with clopidogrel.

Because aspirin and clopidogrel act through different mechanisms to inhibit platelet activity, the potential synergy of these two agents has been explored in several large-scale clinical trials, particularly in high-risk patients presenting with an acute coronary syndrome(ACS) or undergoing percutaneous coronary interventions (PCI), showing greater efficacy of this strategy.

The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial evaluated the short-term and long-term effects of clopidogrel in combination with aspirin compared with aspirin alone in the prevention of ischemic complications in patients with UA/NSTEMI. It showed a 20% relative risk reduction in the primary composite outcome.

A subgroup analysis of patients from the CURE study who underwent PCI (PCI-CURE) showed that clopidogrel pretreatment significantly reduced post-PCI cardiovascular death or MI, with a 31% overall relative risk reduction. The CREDO (Clopidogrel for the Reduction of Events During Observation) trial was specifically designed to evaluate the benefit of clopidogrel in patients undergoing elective PCI.

Patients who were given aspirin plus clopidogrel for 12 months experienced a 26.9% reduction in the relative risk of vascular events versus aspirin alone. The benefit of clopidogrel in addition to aspirin was also confirmed in the setting of patients presenting with STEMI in the CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy) and COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) trials. However, it was not shown to be associated with an incremental benefit in patients not presenting with ACS or undergoing PCI.

The optimal timing of initiation of clopidogrel therapy has been a topic of debate. Most data on clopidogrel pretreatment in patients undergoing PCI derive from studies using a 300-mg loading dose of clopidogrel. These included the PCI-CURE, and PCI-CLARITY trials.

These trials, however, differed in clinic settings and timing of pretreatment. The CREDO trial represented the only one of these trials designed exclusively in patients undergoing PCI.

A posthoc analysis of this study showed that a benefit of clopidogrel pretreatment was achieved only if pretreatment occurred 12 to 15 hours prior to PCI. In a meta-analysis of these three randomized trials, clopidogrel pretreatment before PCI was shown beneficial and safe regardless of whether a GP IIb/IIIa inhibitor was used at the time of PCI.

This data has been challenged with the introduction of high loading dose regimens of clopidogrel into clinical practice, questioning whetherpretreatment can be obviated if a 600-mg loading dose is used. However, only small sample sizetrial data suggest that 600 mg given at the time of PCI can obviate the need for pretreatment in PCI patients.

Prasugrel: Prasugrel was extensively studied in the TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel) trial, which showed that prasugrel plus aspirin was significantly more effective than clopidogrel plus aspirin in preventing short- and long-term (up to 15 months) ischemic events (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in moderate to high risk ACS patients, with and without ST segment elevation, undergoing PCI.

These events were mainly driven by a reduction in myocardial infarction. There was also a significant reduction in early (<30 days) and late (>30 days up to 15 months) with prasugrel, irrespective of stent type (bare metal or drug-eluting), and reduced rates of urgent target vessel revascularization.

In the overall study population, this ischemic benefit occurred at the expense of an increased risk of bleeding, including fatal bleeding. However, the net benefit still showed an advantage of prasugrel over clopidogrel. Subgroup analysis showed that patients with diabetes mellitus and those with STEMI derived greatest ischemic benefit from prasugrel therapy, without any increase in major bleeding events.

In the TRITON trial, patients needed to have theircoronary anatomy known prior to initiation of treatment, with the exception of patients undergoing primary PCI in whom pretreatment was allowed. The benefit of prasugrel pretreatment is currently under investigation. The TRILOGY ACS trial showed that prasugrel did not have a role in medically managed ACS patients.

Ticagrelor: Ticagrelor was extensively studied in the PLATO (Platelet Inhibition and Outcomes) trial, which assessed the efficacy and safety of a 1-year treatment with ticagrelor plus aspirin versus clopidogrel plus aspirin in patients with and without ST segment elevation ACS. Patients included in the trial were admitted with either a STEMI intended for primary PCI (38%) or with UA/NSTEMI intended for an invasive or medical approach (62%).

Ticagrelor: Ticagrelor was extensively studied in the PLATO (Platelet Inhibition and Outcomes) trial, which assessed the efficacy and safety of a 1-year treatment with ticagrelor plus aspirin versus clopidogrel plus aspirin in patients with and without ST segment elevation ACS. Patients included in the trial were admitted with either a STEMI intended for primary PCI (38%) or with UA/NSTEMI intended for an invasive or medical approach (62%).

Patients were randomized to treatment with either a ticagrelor or clopidogrel for prevention of cardiovascular events. At 12 months, ticagrelor showed a significant reduction in the primary end point (composite of cardiovascular death, nonfatal MI, or nonfatal stroke).

Of note, there was also a significant reduction in cardiovascular death and overall death in ticagrelor-treated patients. There was also a significant reduction in MI and stent thrombosis.

In the PLATO trial, pretreatment with clopidogrel was allowed. Patients were randomized prior to knowing coronary anatomy. No significant difference in the rates of major bleeding using study definition criteria was found between the ticagrelor and clopidogrel groups, but ticagrelor was associated with a higher rate of major bleeding not related to CABG, including more instances of fatal intracranial hemorrhage.

Cangrelor: The role of cangrelor as adjunctive antiplatelet therapy in patients requiring PCI has been tested in three large-scale phase III clinical trials. Although, the first two trials, namely the CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition)-PCI and the CHAMPION-PLATFORM trials were interrupted for futility and failed to document any ischemic benefit of cangrelor over DAPT with aspirin and clopidogrel, pitfalls in study end point definitions (i.e., MI definition) may have contributed to these results. In fact, a pooled analysis of the CHAMPION-PCI and CHAMPION-PLATFORM trials, which used the Universal Definition of MI to define MI events, showed a significant reduction in the primary end point with the use of cangrelor.

The hypothesis-generating data from this analysis led to the design of the CHAMPION PHOENIX trial, which evaluated if addition of cangrelor on top of DAPT with aspirin and clopidogrel in patients undergoing PCI could reduce the occurrence acute ischemic complications. The study included P2Y12 receptor inhibitor naïve patients across the spectrum of CAD manifestations (stable angina, NSTE-ACS and STEMI). After angiography, patients were randomized to receive either cangrelor bolus followed by infusion or clopidogrel loading dose (administered before or immediately after the PCI, as per institutional standard). Adjunctive cangrelor therapy significantly reduced the primary efficacy end point (a composite of death from any cause, MI, ischemia-driven revascularization, or stent thrombosis) at 48 hours, primarily driven by a reduction in the hazard of MI and stent thrombosis.

The rate of severe bleeding at 48 hours was not significantly increased by cangrelor with GUSTO criteria, as well as with other definitions of bleeding. However, the rate of major bleeding according to the more sensitive ACUITY criteria was significantly higher in patients treated with cangrelor, primarily driven by a higher incidence of hematoma at the site of vascular access. The clinical benefit of adjunctive cangrelor therapy was consistent at 30 days and across multiple pre-specified sub-groups, such as different clinical presentation (stable angina, NSTE-ACS, or STEMI), dose and timing of clopidogrel loading, stent type, and duration of study drug infusion.

Differences between drugs within the class

Thienopyridines: Ticlopidine, clopidogrel, and prasugrel are first, second, and third generation thienopyridines, respectively. Thienopyridines are oral pro-drugs, and thus need to be metabolized by the hepatic cytochrome P450 (CYP) system to form an active metabolite that irreversibly inhibits the P2Y12 receptor.

Clopidogrel is the most broadly used thienopyridine. The U.S. Food and Drug Administration's (FDA) approved loading and maintenance dosages forclopidogrel are 300 mg and 75 mg once daily, respectively. However, in clinical practice in the setting of PCI, a 600-mg loading is most commonly used.

Clopidogrel requires a two-step oxidation by the CYP system to generate an active metabolite. However, approximately 85% of the prodrug is hydrolyzed by esterases to an inactive carboxylic acid derivative and only about 15% of the prodrug is metabolized into an active metabolite.

Multiple CYP enzymes are involved in this process: CYP3A4, CYP3A5, CYP2C9, CYP1A2 isoenzymes are involved in one oxidation step; whereas CYP2B6 and CYP2C19 are involved in both steps. Although clopidogrel has a half-life of only 8 hours, it has an irreversible effect on platelets and thus lasts for its life-span (7 to 10 days).

The FDA-approved loading and maintenance dosagesof prasugrel are 60 mg and 10 mg once daily, respectively. Prasugrel has a more efficient metabolism than clopidogrel. After oral ingestion, the prodrug is exposed to hydrolysis by carboxyesterases, mainly in the intestine, which gives origin to an intermediate thiolactone which then requires only a one-step hepatic metabolism.

CYP isoenzymes involved in this process include CYP3A, CYP2B6, CYP2C9, and CYP2C19. Thus the active metabolite of prasugrel is generated more rapidly and effectively.

This more favorable pharmacokinetic profile translates into better pharmacodynamic effects, showing more potent platelet inhibition, lower interindividual variability, and a faster onset of antiplatelet activity compared with clopidogrel, even when the latter is used at high doses (≥600 mg).

A 60-mg loading dose of prasugrel achieves 50% platelet inhibition by 30 minutes and 80% to 90% inhibition by 1 to 2 hours. Similarly to other thienopyridines, prasugrel is characterized by irreversible effects on platelets and thus lasts for its lifespan (7 to 10 days).

Nonthienopyridines: Ticagrelor is the first nonthienopyridine forming part of a new class of P2Y12 inhibitors called CPTP approved for clinical use. The FDA-approved loading and maintenance dosages of ticagrelor are 180 mg and 90 mg twice daily, respectively.

Ticagrelor is anorally administered, direct acting, and reversible inhibitor of the P2Y12 receptor. Although ticagrelor has direct-acting effects (no metabolism required), approximately 30% of its effects are attributed to a metabolite generated by the CYP system, involving the CYP3A4 isoenzyme.

Ticagrelor is rapidly absorbed and exerts its effects on P2Y12-mediated signaling acting as a noncompetitive ADP antagonist and inhibiting platelet inhibition via allosteric modulation of the receptor. Also, ticagrelor has shown faster, more potent, and less variable platelet inhibition than clopidogrel.

A 180-mg loading dose of ticagrelor achieves 80% to 90% platelet inhibition by 1 to 2 hours. Ticagrelor has a half-life of 7 to 12 hours, requiring twice daily dosing. Although the slope of offset of ticagrelor effects is rapid, approximately 5 days are needed after ticagrelor withdrawal to return to baseline platelet function.

Cangrelor is an analogue of adenosine triphosphate (ATP) and is the first reversible intravenous P2Y12 inhibitor. It directly binds to the P2Y12receptor in a predominantly competitive manner without the need for being metabolized. Cangrelor achieves very potent (>80%) antiplatelet effects reaching steady-state concentrations within a few minutes and is characterized by a linear dose-dependent pharmacokinetic profile which leads to very stable pharmacodynamic effects. Owing to its very short half-life (3-5 minutes), cangrelor has a fast offset of action, with platelet aggregation returning to baseline levels within 60 minutes.

Administration

P2Y12 inhibitors: Administration and Duration

Clopidogrel: The approved loading and maintenance doses of clopidogrel are 300 mg and 75 mg, respectively. Since these doses were derived from pharmacodynamic studies showing levels of platelet inhibition that paralleled those achieved by ticlopidine—for which higher doses were not applicable in clinical practice due to potential toxicity—several pharmacodynamic and clinical investigations have assessed the impact of higher dosing regimens.

Numerous studies have shown that clopidogrel loading doses ≥600 mg are associated with more prompt and potent platelet inhibition than 300 mg. This has shown to be associated with greater reduction in ischemic events, mainly driven by a reduction in periprocedural myocardial infarction.

Accordingly, practice guidelines support the use of a 600-mg loading dose in the setting of PCI. Pharmacodynamic studies have also assessed a 150-mg clopidogrel maintenance dose, which is also associated with more potent platelet inhibition compared with 75 mg.

However, there is limited clinical data to support its routine use. The CURRENT-OASIS 7 (The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organizatin to Assess Strategies in Ischemic Syndromes) trial evaluated the efficacy and safety of double-dose clopidogrel (600-mg loading dose following of 150-mg daily for 7 days) versus standard dose (300 mg following 75 mg) in patients with ACS. Although in the overall study population there was no significant difference in the primary endpoint (composite of cardiovascular death, myocardial infarction, or stroke) at 30 days between patients receiving double-dose versus standard-dose clopidogrel, in PCI patients the double-dose clopidogrel was associated with a significant reduction in the primary endpoint and in rates of stent thrombosis compared with the standard-dose regimen.

In patients presenting with an ACS, clopidogrel 75 mg daily should be given for at least 12 months irrespective of treatment management (medical, PCI, coronary artery bypass graft [CABG]). In the setting of PCI, clopidogrel 75 mg daily should also be given for at least 12 months after drug-eluting stent (DES) implantation and for a minimum of 1 month and ideally up to 12 months with use of a bare-metal stent (BMS).

Guidelines recommend continuation of therapy beyond 12 months in DES-treated patients depending on patient risk. Therapy should be considered on an individualized basis. Shorter durations, however, may also be considered if patients are at increased risk of bleeding.

Current recommendations on duration of dual antiplatelet therapy are not based on prospective randomized data. Registry data have shown conflicting results, with some suggesting that shorter durations of clopidogrel therapy (e.g., 6 months) are as effective as longer durations of therapy (e.g., 12 months), while others suggest a continuing benefit of prolonging clopidogrel therapy beyond 1-year in DES-treated patients.

There are several ongoing, large-scale, randomized trials that are addressing the optimal duration of dual antiplatelet therapy in DES-treated patients. In a posthoc analysis from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) trial, patients with a history of a prior myocardial infarction achieved a 24% relative risk reduction in ischemic events with a prolonged therapy up to 3 years.

This has also raised the question of whether prolonging dual antiplatelet therapy may be depend on the clinical setting, where a patient presenting with an ACS may potentially derive continuing benefit from prolonged treatment. However, prospective randomized trials are warranted to define this.

Recent data suggest that the duration of dual antiplatelet therapy may depend on the type of DES being used. In fact, encouraging data derived from second generation DES have shown a more favorable safety profile compared with earlier generation DES. Prasugrel. The recommended dose of prasugrel is 60-mg loading dose and 10-mg maintenance dose.

A dose modification (5-mg maintenance dose) is recommended in low-weight patients (<60 kg) by the FDA and European Medical Agency (EMA). The EMA recommends a 5-mg maintenance dose also in the elderly (>75 years of age), while the FDA recommends considering a 10-mg maintenance dose in elderly patients at high risk for ischemia, such as a history of diabetes or prior myocardial infarction (MI).

The same considerations made for clopidogrel with regards to duration of therapy apply for prasugrel. Ticagrelor: Treatment with ticagrelor should be initiated with a single 180-mg loading dose and then continued at 90-mg twice daily.

Treatment is recommended for up to 12 months. Of interest, a predefined subgroup analysis of patients enrolled in the PLATO trial has shown a borderline significant interaction with enrollment by geographic area driven by a trend toward more efficacy of clopidogrel rather than ticagrelor among patients recruited in North America.

It has been suggested that this may be attributed to the use of a higher aspirin dose regimen (e.g., 325 mg), which was more prevalent in North America and which may have limited the efficacy of ticagrelor. Therefore, low aspirin doses (e.g., <100 mg) are recommended in ticagrelor treated patients. Ticagrelor needs to be withheld for 5 days in patients requiring surgery. The same considerations made for clopidogrel with regards to duration of therapy apply for ticagrelor.

Cangrelor should be administered as a 30 mcg/kg bolus plus 4 mcg/kg/min infusion. This should be initiated before PCI and continued for at least 2 hours or for the duration of PCI, whichever is longer.

Indications and contraindications

ACS and PCI guidelines for use of P2Y12 receptor inhibitors are summarized in Table 1. Information on cangrelor has still not been incorporated in the guidelines. Currently, guidelines argue against routine platelet function and genetic testing to tailor antiplatelet treatment regimens, which should be based on evidence derived from large scale clinical investigations.

Figure 1.

Guideline recommendations for available P2Y12 antagonists

Clopidogrel:Adding clopidogrel to aspirin has shown to be particularly beneficial in the settings of PCI and across the spectrum of ACS manifestations. Current ACS and PCI guidelines recommend treatment with a P2Y12 receptor inhibitor as soon as possible.

Drug regulating agencies have mandated a boxed warning for clopidogrel based on pharmacodynamic studies showing a drug interaction between proton pump inhibitors (mainly omeprazole and esomeprazole), as well as the presence of reduced antiplatelet effects among patient carriers of loss-of-function CYP2C19 alleles.

Prasugrel: Prasugrel is indicated to reduce the rate of thrombotic cardiovascular events, including stent thrombosis, in patients with ACS who are to be managed with PCI. Patients with prior stroke or transient ischemic attack (TIA), high risk of bleeding, and prasugrel hypersensitivity are absolute contraindications for prasugrel use.

Ticagrelor: Ticagrelor is indicated for the prevention of atherothrombotic events in patients with ACS (UA, NSTEMI, or STEMI), including patients managed medically and those who are managed with PCI or CABG.

Ticagrelor is contraindicated in patients at high risk of bleeding, in those with history of prior intracranial hemorrhage, and in patients with severe hepatic dysfunction. There are other safety considerations that need to be considered for ticagrelor. Ticagrelor-treated patients experience higher rates of dyspnea and should be used with caution in patients with acute asthma or COPD manifestations.

Patients with severe bradyarrhythmias without a pace maker or internal defibrillator were not enrolled in the trial because ticagrelor is associated with ventricular pauses and therefore should not be used in these patients (patients with sick sinus syndrome, second or third degree AV blocks without a pacemaker). Since ticagrelor is administered twice daily, guidelines indicate precautionary use in noncompliant patients.

Given that ticagrelor is metabolized by CYP3A4, drug interactions may occur with coadministration of strong CYP3A4 inhibitors and inducers. Digoxin levels should also be monitored in ticagrelor treated patients. Ultimately, ticagrelor must be used only with low-dose (≤100 mg) aspirin.

Cangrelor. Cangrelor is approved for clinical use by the FDA as an adjunct to PCI for reducing the risk of peri-procedural MI, repeat coronary revascularization, and stent thrombosis in patients in who have not been treated with a P2Y12 platelet inhibitor and are not being given a GPI. Cangrelor was also approved for clinical use by the EMA for patients undergoing PCI who have not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable.

Undesirable effects

Bleeding complications remain the main concern in patients treated with P2Y12 receptor inhibitors. Bleeding events are increased with dual antiplatelet therapy compared with aspirin alone. In clopidogrel-treated patients, the risk of bleeding has been attributed to the dose of aspirin used; in particular, higher doses of aspirin (>200 mg) were associated with an increased risk of bleeding.

Ticagrelor should be used with low dose aspirin (≤100 mg) as higher doses limited its efficacy. Prasugrel has shown not to be affected by aspirin doses.

Given their greater potency, spontaneous bleeding is increased with prasugrel and ticagrelor. With both agents, the risk of spontaneous bleeding increases over time and these drugs are contraindicated in patients at high risk of bleeding.

In particular, in low-weight patients there was no net clinical benefit of prasugrel because of the increased bleeding risk, suggesting the need for dose modifications in these settings. However, the safety of the 5-mg dose has not been prospectively studied and this dose derives from pharmacokinetic findings.

In the elderly with diabetes or a prior MI, the benefits outweighed the risks supporting the use of prasugrel at standard dosing in the elderly with these characteristics. Patients with prior stroke or TIA had an increased risk of intracranial hemorrhage.

Ticagrelor was not associated in a significant increase in overall bleeding events compared with clopidogrel; however, it was associated with a higher rate of spontaneous non-CABG-related major bleeding, including more instances of fatal intracranial bleeding, although overall fatal bleeding was not increased.

Other rare complications of thienopyridines are neutropenia with ticlopidine (0.1%), and the potentially fatal thrombotic thrombocytopenic purpura (TTP), which has been shown mainly using clopidogrel. Other nonbleeding adverse events have shown to be higher with ticagrelor versus clopidogrel, including dyspnea, ventricular pauses, and an increase in serum uric acid and serum creatinine, which have been associated with higher rates of treatment discontinuation.

Although cangrelor reduces periprocedural thrombotic complications without an increase in major bleeding complications, minor bleeding is increased. Cangrelor overdosing, which is common with parenteral antithrombotic agents, was not associated with an increase in bleeding complications, an observation that may be attributed to its very short half life and rapid offset of action.

Alternative approaches

In case of allergic reactions to clopidogrel, hypersensitivity to ticlopidine and prasugrel may still occur given that they form part of the same class of drugs. Desensitization protocols are currently available for clopidogrel.

n aspirin monotherapy or aspirin plus warfarin in patients undeHowever, anecdotal experience has also shown cases in which such cross-reactivity with other thienopyridine does not occur. Switching from one class (thienopyridine to nonthienopyridine or vice versa) may be a treatment option.

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