P2Y12 inhibitors overview
Ticlopidine, clopidogrel, and prasugrel are prodrugs converted to active metabolites through oxidation by the hepatic cytochrome P-450 system.
Ticlopidine is now rarely prescribed due to the potential risk of neutropenia or the rare occurrence of thrombotic thrombocytopenic purpura.
The active metabolites irreversibly inhibit the binding of adenosine diphosphate (ADP) to platelet P2Y12 receptors, thereby preventing platelet aggregation.
Pharmacological property of P2Y12 inhibitors
Receptor
Blockade
Prodrug
Half-life of
parent drug
Half-life of
active
metabolite
Binding site
Administration
route
Frequency
Onset of
action
Offset of
action
CYP drug
interaction
Approved
settings
Clopidogrel
Irreversible
Yes
about 6 h
30 mins
ADP binding site
oral
Once daily
2-8 h
5-10 d
CYP2C19
ACS (invasive and noninvasively managed), stable CAD, PCI, PAD, and ischemic stroke
Prasugrel
Irreversible
Yes
< 5 min
Distribution half-life, 30–60 mins
Elimination half-life, 2–15 h
ADP binding site
oral
Once daily
30 min–4 h
7–10 d
No
ACS undergoing PCI
Ticagrelor
Reversible
No
6-12 h
8–12 h
Allosteric binding site
oral
Twice daily
30 min–4 h
3-5 d
CYP3A4
ACS (invasive or noninvasively managed) or history of MI
Cangrelor
Reversible
No
3-6 min
N/A
Undetermined
oral
Bolus plus infusion
about 2 min.
60 min
No
PCI in patients with or without ACS
Clopidogrel
Kurihara A. et al. Drug Metab. Rev. 37(S2):99 (2005)
Tang M. et al. JPET 319:1467-1476 (2006)
Active metabolite
Clopidogrel is a second-generation thienopyridine prodrug. After intestinal absorption, about 85% is hydrolyzed into an inactive metabolite by human carboxylase-1. The remaining 15% is converted into the active thiol metabolite through a two-step oxidation by hepatic cytochrome P-450 isoenzymes, mainly CYP2C19, which irreversibly blocks the ADP-binding site on the P2Y12 receptor.
Starting without loading dose with a daily dose of 75 mg will achieve the desired level of platelet inhibition within 3 to 5 days.
The loading dose of 300 mg achieves effective platelet inhibition within 4 to 6 hours, while a loading dose of 600 mg achieves this within 2 hours.
Clinical trial of clopidogrel in patients with STEMI
The Addition of Clopidogrel to Aspirin and Fibrinolytic Therapy for Myocardial Infarction with ST-Segment Elevation (CLARITY-TIMI 28) trial enrolled 3491 patients, who presented within 12 hours after the onset of an ST-elevation myocardial infarction and randomly assigned them to receive clopidogrel (300-mg loading dose, followed by 75 mg once daily) or placebo. Patients received a fibrinolytic agent, aspirin, and heparin based on body weight. Angiography was scheduled 48 to 192 hours after starting the medication.
The primary efficacy endpoint was a composite outcome of an occluded infarct-related artery (Thrombolysis in Myocardial Infarction flow grade of 0 or 1), death, or recurrent myocardial infarction before angiography.
In the study, the primary efficacy endpoint occurred in 21.7 percent of the placebo group and 15.0 percent of the clopidogrel group, indicating a 6.7 percentage point reduction and a 36 percent decrease in odds with clopidogrel therapy (95 percent confidence interval: 24 to 47 percent; P < 0.001).
After 30 days, clopidogrel therapy lowered the odds of the composite endpoint—including death from cardiovascular causes, recurrent myocardial infarction, or urgent revascularization—by 20 percent, from 14.1 percent to 11.6 percent (P = 0.03). The rates of major bleeding and intracranial hemorrhage were similar in both groups.
ST resolution substudy of CLARITY-TIMI-28 trial (The ECG CLARITY–TIMI 28 Study)
An ST Resolution (STRes) electrocardiographic substudy from the CLARITY-TIMI 28 trial found no significant difference in complete ST Resolution rates at 90 minutes between clopidogrel (38.4%) and placebo (36.6%).
However, clopidogrel was more beneficial for patients with early ST Resolution, and there was a higher likelihood of having a partial (OR, 1.4; P = 0.04) or complete (OR, 2; P = 0.001) open artery during late angiography. There was no improvement in those with no ST Resolution at 90 minutes (OR, 0.89; P = 0.48) (P for interaction, 0.003).
Clopidogrel did not increase the rate of complete reopening of occluded infarct arteries when fibrinolysis was administered. Still, it effectively prevented the reocclusion of initially reperfused infarct arteries.
The Addition of Clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled (COMMIT) trial enrolled 45,852 patients admitted to 1,250 hospitals within 24 hours of suspected acute myocardial infarction (MI). Participants were randomly assigned to receive either 75 mg (without a loading dose) of clopidogrel daily (n=22,961) or a matching placebo (n=22,891). All patients were administered a daily dose of 162 mg of aspirin. The trial was conducted exclusively in China.
Of the participants, 93% had ST-segment elevation or bundle branch block, while 7% had ST-segment depression. Treatment lasted until discharge or a maximum of 4 weeks, with an average of 15 days for survivors; 93% completed the treatment. Fibrinolytic therapy was used in 50% of patients and anticoagulants in 74%.
Patients undergoing primary percutaneous coronary intervention (PCI) were excluded from the study.
The study focused on two primary outcomes: (1) the composite of death, reinfarction, or stroke, and (2) death from any cause during the treatment period.
Patients in the clopidogrel group had a lower rate of the composite endpoint of death, reinfarction, or stroke (9.2% vs. 10.1%; P = 0.002) and a significantly reduced death rate (7.5% vs. 8.1%; P = 0.03). There were no significant bleeding issues associated with clopidogrel in this trial.
Clinical trial of clopidogrel in patients with acute coronary syndrome without ST-segement elevation
The CURE trial (Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation) involved 12,562 patients who presented within 24 hours of experiencing symptoms. Participants were randomly assigned to receive either clopidogrel or a placebo, in addition to aspirin, unfractionated heparin, or low-molecular-weight heparin (LMWH). This was regardless of whether the patients were treated with medical therapy, percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG).
In total, 6,259 patients received clopidogrel, starting with an initial dose of 300 mg followed by 75 mg once daily, while 6,303 received the placebo. The duration of treatment for both groups ranged from 3 to 12 months.
The primary outcome measured was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke. This outcome occurred in 9.3 percent of patients taking clopidogrel, compared to 11.4 percent of patients in the placebo group. The relative risk of cardiovascular events with clopidogrel, as compared to placebo, was 0.80, with a 95 percent confidence interval ranging from 0.72 to 0.90 (P < 0.001). Benefit was seen as early as 24 hours, with the Kaplan-Meier curves beginning to diverge after just 2 hours.
The clopidogrel group experienced a higher rate of major bleeding at 3.7 percent compared to 2.7 percent in the placebo group (relative risk: 1.38; P=0.001). However, there was no significant difference in life-threatening bleeding (2.1 percent vs. 1.8 percent, P=0.13) or in hemorrhagic strokes between the groups.
Low dose VS High dose
The Dose Comparisons of Clopidogrel and Aspirin in Acute Coronary Syndromes (CURRENT-OASIS 7) trial examined the effects of different doses of clopidogrel and aspirin in patients with acute coronary syndrome undergoing invasive treatment. The trial employs a 2-by-2 factorial design to randomly assign 25,086 patients with acute coronary syndrome, all of whom are referred for an invasive strategy, to one of four treatment groups.
Participants received either a double dose of clopidogrel, which includes a 600 mg loading dose on the first day, followed by 150 mg daily for six days, and then 75 mg daily thereafter, or a standard dose of clopidogrel, which consists of a 300 mg loading dose followed by 75 mg daily. Additionally, patients were assigned to receive either a higher dose of aspirin (300 to 325 mg daily) or a lower dose (75 to 100 mg daily).
The primary outcome, which included cardiovascular death, myocardial infarction, or stroke within 30 days, occurred in 4.2% of the double-dose clopidogrel group and 4.4% of the standard-dose group (hazard ratio: 0.94; P=0.30).
Major bleeding occurred in 2.5% of patients in the double-dose clopidogrel group compared to 2.0% of patients in the standard-dose clopidogrel group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01).
Clinical trials of clopidogrel in patients with atherosclerotic vascular disease
The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Trial is a randomized, blinded, international trial that evaluated the effectiveness of clopidogrel (75 mg daily) versus aspirin (325 mg daily) in reducing the risk of ischemic stroke, myocardial infarction, and vascular death. It also assessed the relative safety of these medications. The study included patients with atherosclerotic vascular disease, such as recent ischemic stroke or myocardial infarction, and followed them for 1 to 3 years.
19,185 patients were recruited over three years, with 1,960 experiencing first events in the outcome cluster. The intention-to-treat analysis found that patients treated with clopidogrel had an annual risk of ischemic stroke, myocardial infarction, or vascular death of 5.32%, compared to 5.83% for those on aspirin. This represents a significant relative-risk reduction of 8.7% for clopidogrel (p = 0.043; 95% CI: 0.3–1.65), with an on-treatment analysis showing a 9.4% reduction. No significant differences in safety profiles were observed between the two treatments.
Long-term clopidogrel use is more effective than aspirin in reducing the risks of ischemic stroke, myocardial infarction, or vascular death in patients with atherosclerotic vascular disease, with a comparable safety profile to aspirin.
The Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) trial enrolled 15,603 patients with cardiovascular disease or multiple risk factors who were randomly assigned to receive either clopidogrel (75 mg daily) plus low-dose aspirin or a placebo with low-dose aspirin. They were followed for a median of 28 months, with the primary endpoint being a combination of myocardial infarction, stroke, or cardiovascular death.d myocardial infarction, stroke, or death from cardiovascular causes.
The primary efficacy endpoint rate was 6.8% for clopidogrel plus aspirin and 7.3% for placebo plus aspirin (relative risk, 0.93; 95% confidence interval, 0.83 to 1.05; P=0.22).
The Trial indicates that combining clopidogrel with aspirin does not provide any additional benefit compared to using aspirin alone.
Genetic polymorphism
People with diabetes, obesity, advanced age, and specific genetic variations in the cytochrome P-450 system are more likely to exhibit hyporesponsiveness to clopidogrel.
Hyporesponders tend to have higher rates of recurrent cardiac events, which include stent thrombosis and acute myocardial infarction (MI).
CYP2C19 polymorphisms are present in about one-third of Caucasians and are more common in Asians. The *C2 allele, a "reduced-function allele," reduces the effectiveness of clopidogrel in inhibiting platelet aggregation, which is associated with a higher risk of adverse outcomes in patients treated with clopidogrel.
CYP2C19 alleles that lead to a nonfunctional protein include *2, *3, *4, and *5, while CYP2C19*17 is associated with very rapid CYP2C19 activity.
A study of the Thai population revealed the following allele frequencies for CYP2C19: *1/*1 (40.72%), *1/*2 (35.10%), *1/*3 (6.85%), *2/*2 (7.32%), *2/*3 (5.61%), and *1/*17 (4.30%). Homozygous CYP2C19 *3/*3 was identified in one patient in the study, representing 0.10% of the sample. Based on these frequencies, it is predicted that 40.72% of patients are extensive metabolizers, 41.95% are intermediate metabolizers, 13.03% are poor metabolizers, and 4.30% are ultra-rapid metabolizers.
Drug-drug interaction with Clopidogrel
CYP2C19 is involved in the metabolism of proton-pump inhibitors, including omeprazole, a commonly prescribed drug.
Clopidogrel can lead to gastrointestinal side effects like bleeding, dyspepsia, and ulceration. To reduce risks in high-risk patients, proton pump inhibitors (PPIs) are often co-prescribed.
Combining these medications may create interaction risks. Clopidogrel is a prodrug activated by the enzyme CYP2C19, while proton pump inhibitors (PPIs) like omeprazole and esomeprazole inhibit this enzyme. This inhibition may lead to decreased plasma levels of active clopidogrel. Consider using pantoprazole, or rabeprazole instead.
The Clopidogrel with or without Omeprazole in Coronary Artery Disease (COGENT) trial randomly assigned patients requiring dual antiplatelet therapy to receive clopidogrel with either omeprazole or a placebo, in addition to aspirin.
The primary gastrointestinal endpoint included bleeding, symptomatic ulcers, obstruction, or perforation, while the primary cardiovascular endpoint encompassed death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated early due to loss of funding.
A total of 3,873 patients were randomly assigned to the study, with a planned enrollment of 5,000. Of these, 3,761 patients were included in the analyses. Among the participants, 51 experienced a gastrointestinal event, resulting in rates of 1.1% for those receiving omeprazole and 2.9% for the placebo group at the 180-day mark. The hazard ratio for omeprazole was 0.34 (95% CI, 0.18 to 0.63; P < 0.001).
Additionally, the overt upper gastrointestinal bleeding rate was lower among patients taking omeprazole, with a hazard ratio of 0.13 (95% CI, 0.03 to 0.56; P = 0.001). In terms of cardiovascular events, 109 patients were affected. The rates for omeprazole and placebo were 4.9% and 5.7%, respectively, yielding a hazard ratio of 0.99 (95% CI, 0.68 to 1.44; P = 0.96).
Prasugrel
Active metabolite
Farid N.A. et al. Drug Metab. Dispos. 35: 1096-1104 (2007)
Rehmel J.L.F et al. Drug Metab. Dispos. 34: 600-607 (2006)
Williams E.T. et al. Drug Metab. Rev. 39(S1): 254 (2007)
Prasugrel is a third-generation thienopyridine prodrug that converts to its active metabolite more efficiently than clopidogrel. This process involves ultrarapid hydrolysis by human carboxylesterase-2, followed by a single-step oxidation in the liver via cytochrome P450 enzymes. The active metabolite irreversibly blocks the ADP-binding site on the P2Y12 receptor, demonstrating approximately ten times the potency of clopidogrel.
Prasugrel is contraindicated in patients with a history of stroke or a transient ischemic attack, and also active bleeding.
The initial loading dose of prasugrel is 60 mg, while the standard maintenance dose is 10 mg.
For patients with an increased risk of bleeding, such as the elderly (aged 75 years or older) and those with a body weight of less than 60 kg (132 pounds), consider using a maintenance dose of 5 mg instead of the standard 10 mg.
Clinical trial of prasugrel in patients with acute coronary syndrome
The Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes (TRITON TIMI-38) trial studied 13,608 patients with moderate-to-high-risk acute coronary syndromes undergoing percutaneous coronary intervention.
If percutaneous coronary intervention (PCI) was planned in the trial, prasugrel was administered until after the coronary angiography.
Participants were randomly assigned to receive either prasugrel (60 mg loading dose and 10 mg daily maintenance dose) or clopidogrel (300 mg loading dose and 75 mg daily maintenance dose) for 6 to 15 months.
The primary outcome was a combination of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, while the primary safety concern was significant bleeding.
The primary efficacy endpoint was achieved in 12.1% of patients receiving clopidogrel compared to 9.9% of those receiving prasugrel, resulting in a hazard ratio of 0.81 for prasugrel versus clopidogrel (95% confidence interval [CI]: 0.73 to 0.90; P<0.001). Additionally, the prasugrel group experienced significant reductions in various outcomes: myocardial infarction rates were 9.7% for clopidogrel and 7.4% for prasugrel (P<0.001), urgent target-vessel revascularization rates were 3.7% versus 2.5% (P<0.001). Stent thrombosis rates were 2.4% for clopidogrel compared to 1.1% for prasugrel (P<0.001).
However, major bleeding occurred in 2.4% of patients taking prasugrel and 1.8% of those on clopidogrel, leading to a hazard ratio of 1.32 (95% CI: 1.03 to 1.68; P=0.03). The prasugrel group also had a higher rate of life-threatening bleeding (1.4% versus 0.9%; P=0.01), with rates of nonfatal bleeding at 1.1% for prasugrel versus 0.9% for clopidogrel (hazard ratio: 1.25; P=0.23) and fatal bleeding rates at 0.4% for prasugrel compared to 0.1% for clopidogrel (P=0.002).
These findings demonstrate that prasugrel is superior to clopidogrel, supporting the idea that clopidogrel's efficacy is limited compared to prasugrel. However, the more significant platelet inhibitory effect of prasugrel is associated with a higher incidence of severe bleeding.
Administer prasugrel as a pre-treatment upon presentation at the emergency room.
The Pretreatment with Prasugrel in Non–ST-Segment Elevation Acute Coronary Syndromes (ACCOAST) trial enrolled 4,033 patients with non-ST elevation acute coronary syndromes (NSTE ACS) and positive troponin levels, scheduled for coronary angiography within 2 to 48 hours. Patients were randomly assigned to receive either a 30 mg loading dose of prasugrel before angiography (pretreatment group) or a placebo (control group). If percutaneous coronary intervention (PCI) was performed, the pretreatment group received an additional 30 mg of prasugrel, while the control group received 60 mg.
The primary efficacy endpoint, which includes death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7, showed no significant difference between the two groups (hazard ratio with pretreatment: 1.02; 95% CI: 0.84 to 1.25; P=0.81).
In contrast, the key safety endpoint of major bleeding episodes, as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria, was significantly higher with pretreatment (hazard ratio: 1.90; 95% CI: 1.19 to 3.02; P=0.006), with rates of TIMI major bleeding and life-threatening bleeding not related to CABG increasing by factors of 3 and 6, respectively.
There is no clear benefit was observed when prasugrel tablets loading dose was administered prior to diagnostic coronary angiography compared to at the time of PCI
Ticagrelor
Ticagrelor is a reversible blocker of the P2Y12 platelet receptor that acts directly on the platelet. It also produces an active metabolite with potency comparable to the parent drug's.
Following an acute coronary syndrome (ACS) event:
Loading dose: 180 mg orally once
Maintenance dose: 90 mg orally twice a day for 1 year
Maintenance dose after 1 year: 60 mg orally twice a day
Clinical trial of Ticagrelor in patients with acute coronary syndrome
The Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes (PLATO) trial was a multicenter, double-blind, randomized study comparing ticagrelor and clopidogrel in preventing cardiovascular events in 18,624 patients with acute coronary syndromes, with or without ST-segment elevation. Patients received a loading dose of 180 mg of ticagrelor followed by 90 mg twice daily or 300 to 600 mg of clopidogrel followed by 75 mg daily.
At 12 months, the primary endpoint—a composite of death from vascular causes, myocardial infarction (heart attack), or stroke—occurred in 9.8% of patients taking ticagrelor, compared to 11.7% taking clopidogrel (hazard ratio, 0.84; P<0.001).
Significant differences were also observed in secondary endpoints: myocardial infarction occurred in 5.8% of the ticagrelor group versus 6.9% for clopidogrel (P=0.005), and death from vascular causes was 4.0% versus 5.1% (P=0.001). However, rates of stroke were similar (1.5% vs. 1.3%; P=0.22).
Ticagrelor also reduced the overall death rate (4.5% vs. 5.9% with clopidogrel; P<0.001). There was no significant difference in major bleeding rates between the two groups, but ticagrelor was linked to a higher rate of non-CABG related bleeding (4.5% vs. 3.8%; P=0.03), including more fatal intracranial bleeding.
Pre-treatment of Ticagrelor in patients with ST-elevation MI
The Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction (ATLANTIC) trial, An international, multicenter, randomized, double-blind study involving 1,862 patients with ongoing ST-elevation myocardial infarction (STEMI) lasting less than 6 hours, compared prehospital treatment (in the ambulance) with in-hospital treatment (in the catheterization laboratory) using ticagrelor.
Primary endpoints included the proportion of patients with less than 70% resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and those without TIMI flow grade 3 in the infarct-related artery at initial angiography. Secondary endpoints assessed major adverse cardiovascular events and definite stent thrombosis at 30 days.
The median time from randomization to angiography was 48 minutes, with a 31-minute difference between treatment strategies. There were no significant differences in the primary endpoints or major adverse cardiovascular events between the prehospital and in-hospital groups. After PCI, 42.5% of prehospital patients and 47.5% of in-hospital patients showed less than 70% ST-segment elevation resolution. Definite stent thrombosis rates were lower in the prehospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Major bleeding events were low and similar in both groups.
Results showed no significant differences in outcomes or major adverse cardiovascular events between the two treatment strategies. The median time to angiography was 48 minutes, and the treatment approaches differed by 31 minutes.
Ticagrelor monotherapy after three months following percutaneous coronary intervention (PCI) in patients at high risk of bleeding.
The Ticagrelor with or without Aspirin in High-Risk Patients after PCI (TWILIGHT) trial is a non-inferiority trial that evaluated the effects of ticagrelor alone versus ticagrelor combined with aspirin on clinically significant bleeding in high-risk patients post-percutaneous coronary intervention (PCI). After three months on ticagrelor plus aspirin without major bleeding or ischemic events, patients continued on ticagrelor and were randomly assigned to receive either aspirin or a placebo for one year. The primary endpoint was bleeding classified as BARC type 2, 3, or 5, and we also assessed a composite endpoint of death, nonfatal myocardial infarction, or nonfatal stroke, using a noninferiority hypothesis with a margin of 1.6 percentage points.
The trial included 9,006 patients, with 7,119 randomized after three months. Between randomization and one year, the primary endpoint occurred in 4.0% of patients receiving ticagrelor plus placebo and 7.1% of those receiving ticagrelor plus aspirin (hazard ratio: 0.56; P < 0.001).
For BARC type 3 or 5 bleeding, the incidence was 1.0% in the ticagrelor plus placebo group and 2.0% in the ticagrelor plus aspirin group (hazard ratio: 0.49).
Death, nonfatal myocardial infarction, or nonfatal stroke occurred in 3.9% of both groups (difference: −0.06 percentage points; P < 0.001 for noninferiority).
The long-term use of Ticagrelor in patients who have experienced a MI for more than one year.
The Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction (PEGASUS-TIMI 54) trial randomly assigned 21,162 patients, who had experienced a myocardial infarction 1 to 3 years earlier, to receive either ticagrelor at 90 mg or 60 mg twice daily, or a placebo. All participants took low-dose aspirin and were followed for a median of 33 months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke, while the primary safety endpoint was major bleeding as defined by TIMI criteria.
Both doses of ticagrelor (90 mg and 60 mg taken twice daily) significantly lowered the rate of the primary efficacy endpoint compared to placebo, with rates of 7.85% and 7.77%, respectively, versus 9.04% for placebo. The hazard ratios were 0.85 (P=0.008) for 90 mg and 0.84 (P=0.004) for 60 mg.
However, ticagrelor was associated with higher rates of TIMI major bleeding: 2.60% for 90 mg and 2.30% for 60 mg, compared to 1.06% for placebo (P<0.001 for both doses). Rates of intracranial hemorrhage or fatal bleeding were 0.63%, 0.71%, and 0.60% across the groups.
Ticagrelor Inhibits Cellular Uptake of Adenosine
Adenosine is a purine nucleoside primarily produced from the metabolism of adenosine diphosphate (ADP) and adenosine triphosphate (ATP) by the enzymes CD39 and CD73. Its levels increase following cellular stress due to injury, ischemia/reperfusion, or inflammation. Cells take up adenosine through sodium-independent transporters (ENT1/2) and sodium-dependent transporters (CNT2/3) within just a few seconds. Once inside the cells, adenosine is either metabolized into inosine by the enzyme adenosine deaminase or converted into adenine nucleotides by adenosine kinase.
Ticagrelor inhibits the ENT1 transporter, leading to increased responses to adenosine.
Adenosine plays a significant role in the respiratory system's inflammatory processes. Under healthy conditions, low extracellular adenosine levels activate high-affinity receptors (A1 and A2A), which trigger protective responses. However, during inflammation, elevated adenosine levels activate low-affinity receptors (A3 and A2B), which can worsen the inflammatory response.
Pretreatment with P2Y12 inhibitor
(1) Initiate P2Y12 inhibitor treatment upon presentation or hospital admission.
According to the CURE trial: The pre-treatment with clopidogrel reduces early ischemic events and enables benefits from pretreatment before PCI, though it increases the risk of bleeding complications.
The TRITON-TIMI-38 and ACCOAST trials indicate no clear benefit of pre-treating with prasugrel before diagnostic coronary angiography compared to administering it during PCI.
(2) If PCI is planned, postpone P2Y12 inhibitor treatment until after coronary angiography and administer the medication on the catheterization table.
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