Antiplatelet therapy to support PCI

# Overview
Dual anti-platelet therapy (aspirin and oral P2Y12 inhibitors) is the main therapy for the prevention of thrombotic complications in patients with PCI. It has been recommended to avoid routine P2Y12 inhibitor treatment in patients with stable angina whose coronary anatomy is unknown. Antiplatelet medications are divided into those which can be used orally or intravenously. Clopidogrel, ticagrelor and prasugrel are the common present-day oral P2Y12 inhibitors with different dosage, characteristics and considerations. On the other hand, aspirin has been used as a key agent in prevention of coronary thrombosis with balloon angioplasty and in patients with chronic vascular disease. Usage of aspirin is recommended in the periprocedural period due to its effect on reducing ischemic complications after PCI. Intravenous antiplatelets such as abciximab, eptifibatide, tirofiban, and cangrelor have been studied in different clinical trials. Among these medications only cangrelor is a P2Y12 inhibitor and the other ones are glycoprotein IIb/IIIa inhibitor. Antiplatelet therapy in STEMI patients who had been treated with fibrinolytics who are undergoing PCI is high risk due to higher rate of bleeding and ischemia. However, clopidogrel was studied in conjunction with fibrinolytic therapy and led to 46% lower rate of cardiovascular death, recurrent MI and stroke within the 30 days after PCI with an unchanged rate of minor and major bleeding.

# Antiplatelet Therapy to Support PCI
- Dual anti-platelet therapy (aspirin and oral P2Y12 inhibitors) is the main therapy for the prevention of thrombotic complications in patients with PCI.
- There is no evidence to support routine pretreatment with a P2Y12 inhibitor in patients with stable angina before coronary angiography when the coronary anatomy is not known. This statement is important since a considerable proportion of patients who has been sent for PCI still may require CABG and pretreatment with P2Y12 inhibitor will delay the surgery.

## Oral Antiplatelets
- The following are the contemporary oral P2Y12 inhibitors used in PCI:
Clopidogrel
Ticagrelor
Prasugrel
- Clopidogrel
- Ticagrelor
- Prasugrel
- The following table shows the loading and maintenance dose of oral antiplatelet drug in patients who are undergoing PCI:
- Aspirin has been used as a key agent in prevention of coronary thrombosis with balloon angioplasty and in patients with chronic vascular disease.
- Due to the effects of aspirin on reducing ischemic complications after PCI its usage is recommended in the periprocedural period.
- Among the medications above, clopidogrel is the least potent. Therefore, a longer duration after the loading dose is required to start its effect on platelet inhibition.
- Based on a clinical trial (The CREDO), a loading dose of clopidogrel in addition to treatment up to 9 months after elective PCI are able to reduce many complications such as MI, stroke, and death. Furthermore, this study showed that there is a trend in further decreasing the ischemic events and complications when a preloading dose of 300 mg clopidogrel was administered more than 3 hours before PCI. However, a 600 mg loading dose is preferred due to a shorter time to platelet inhibition.
- Based on 2021 ACA revascularization guideline, it is recommended that patients receive a loading dose of these medications either before PCI or otherwise during PCI.
- A trial named PLATO (Trial to Assess The Study of Platelet Inhibition and Patient Outcomes) suggests that lower doses of aspirin (less than 100 mg) should be used for patients treated with ticagrelor.
- As two trials (TRITON-TIMI-38 and PLATO) showed, prasugrel and Ticagrelor are more effective in reducing the rate of death from vascular causes, MI, and stroke compared to clopidogrel. Furthermore, these agents were associated with a lower rate of stent thrombosis. 
- TRITON-TIMI-38 and PLATO trials demonstrated that the non-CABG major bleeding was higher with prasugrel. Therefore, usage of prasugrel due to higher rate of bleeding should be done with caution in older patients.
- The TRITON study reported no net benefit of prasugrel compared with clopidogrel among patients with low body weight (<60 kg) or those older than 75 years old. Based on 2021 ACA revascularization guideline, treatment with prasugrel should be cautious in patients weighing less than 60 kg or in patients older than 75 years old. Furthermore, this study demonstrated the net harm with using prasugrel in patients with previous transient ischemic attack or cerebrovascular accident. Therefore, prasugrel is contraindicated in patients with a history of transient ischemic attack or stroke.

## Intravenous Antiplatelets
- The following table shows the loading and maintenance dose of intravenous antiplatelet drug in patients who are undergoing PCI:
- Cangrelor is a potent intravenous P2Y12 inhibitor with several characteristics, such as being a direct, reversible, and short-acting medication that has a rapid onset with a rapid restoration (within 1 hour of discontinuation) of platelet function. These features of cangrelor, make it a predictable, rapid and profound platele inhibitor.
- Cangrelor is an effective treatment in preventing stent thrombosis, especially in the following patients:
In patients who did not received any pretreatment with a P2Y12 inhibitor.
In patients whose absorption of oral medications may be inhibited.
In patients who are unable to take oral medications.
- In patients who did not received any pretreatment with a P2Y12 inhibitor.
- In patients whose absorption of oral medications may be inhibited.
- In patients who are unable to take oral medications.
- A trial, named CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), investigated the effect of cangrelor in comparison to clopidogrel. These investigations did not show any reduction in the primary outcomes such as death, MI, and ischemia-driven revascularization at 48 hours with cangrelor. However, cangrelor resulted in a reduction in prespecified secondary outcomes of stent thrombosis and death. 
- On the other hand, a pooled patient-level meta-analysis] of the CHAMPION trials demonstrated a lower rate of the composite endpoint of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours with cangrelor than with clopidogrel.
- Cangrelor treatment has been associated with a 41% reduction in stent thrombosis.
- Although CHAMPION trials did not show any differences in major bleeding between cangrelor and clopidogrel, minor bleeding was more frequent in the cangrelor group.

### Glycoprotein IIb/IIIa Receptor Inhibitors
- Glycoprotein IIb/IIIa receptor inhibitors are direct antiplatelet agents that target the glycoprotein IIb/IIIa, an integrin complex found on platelets.
- Numerous clinical trials have been done in the setting of glycoprotein IIb/IIIa inhibitors among ACS patients prior to the use of potent P2Y12 inhibitors or before routine stenting. However, benefits of glycoprotein IIb/IIIa receptor inhibitors have been diminished in the era of shorter revascularization times and use of potent dual antiplatelet therapy (DAPT).
- Based on the 2021 ACA Revascularization Guideline, glycoprotein IIb/IIIa inhibitors could be reserved for patients with a large thrombus burden, no-reflow or slow flow attributable to distal embolization of thrombus.
- Ischemic events did not reduce after treatment with a glycoprotein IIb/IIIa receptor inhibitor and a clopidogrel load in patients with stable ischemic heart disease.
- ISAR-REACT (iNtra- coronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) trial showed a similar outcome in a group that received abciximab and a 600mg loading dose of clopidogrel and another group that only received clopidogrel. Furthermore, major bleeding was not significantly different among the two groups. Nevertheless, severe thrombocytopenia was significantly higher in the abciximab group.
- A subgroup analysis of the ESPRIT (Enhance Suppression of the Platelet IIB/IIIA receptor with Integrilin Therapy) trial did not revealed any benefit in the primary endpoint of death, MI, urgent target-vessel revascularization, and thrombotic bailout with eptifibatide at 48 hours among patients who undergone PCI for stable angina.

## Antiplatelet Therapy In Patients Who Were Treated With Fibrinolytic Therapy
- Risk of bleeding and ischemia is elevated in STEMI patients who had been treated with fibrinolytics and are planned to undergo PCI.
- Clopidogrel is the only medication that has been studied in patients immediately after the administration of fibrinolytic therapy.
- Based on the CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy) trial, clopidogrel was studied in conjunction with fibrinolytic therapy which led to 46% lower rate of cardiovascular death, recurrent MI and stroke within the 30 days after PCI with an unchanged rate of minor and major bleedings.
- However, there is some evidence associated with greater inhibition of platelet reactivity when ticagrelor is used compared with clopidogrel.
- Although PLATO trial demonstrated superiority of ticagrelor over clopidogrel in patients who received fibrinolytic therapy, there are limited data regarding the safety of ticagrelor treatment immediately after fibrinolytic therapy.
- Furthermore, another trial (The TREAT) showed no inferiority of ticagrelor over clopidogrel regarding TIMI major bleeding, fatal bleeding, and intracranial bleeding.

# 2021 ACA Revascularization Guideline

# 2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)
2011 AHA guidelines recommend the use of antiplatelet therapy aspirin (Level of Evidence: B) and P2Y12 receptor inhibitor (clopidogrel, prasugrel and ticagrelor) (Level of Evidence: A) to support PCI in patients with ACS. Few randomised trials have been conducted showing comparison of clopidogrel with aspirin and other P2Y12 inhibitors (prasugrel and ticagrelor) in terms of clinical benefit and risk of bleeding when given in patients undergoing PCI. However, there is limited data comparing new P2Y12 receptor inhibitors (prasugrel and ticagrelor) for downstream and upstream therapy in patients undergoing PCI with non ST elevation MI in terms of clinical benefit and adverse effects. Hence, a new large scale randomised open label trial called DUBIUS is in process in Italy comparing two new P2Y12 inhibitors prasugrel and ticagrelor for pretreatment in patients with non ST elevation MI undergoing PCI. It is a trial designed for superiority comparing downstream therapy over upstream therapy in terms of NACE (net adverse cardaic effect) and risk of major bleeding (BARC 3, 4 and 5). Another endpoint considered in the trial is non inferiority comparison between prasugrel and ticagrelor in terms of potency of the drug for clinical benefit and NACE.

## Oral Antiplatelet Therapy (DO NOT EDIT)

## Dual Antiplatelet Therapy Compliance and Stent Thrombosis (DO NOT EDIT)