Unstable angina / non ST elevation myocardial infarction thienopyridines


 * Associate Editors-in-Chief: Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.; Smita Kohli, M.D.

Thienopyridines
A number of drugs are currently being studied for use in ACS patients. Agents available in this category include:
 * Ticlopidine, one of the first agents studied in this class, has become less popular now because of its role in causing neutropenia, thrombotic thrombocytopenic purpura and gastrointestinal side effects.
 * Clopidogrel is another extensively studied drug which has been shown to improve outcomes in Unstable angina/NSTEMI patients.
 * Most recently, Prasugrel has been approved by FDA for use in patients undergoing PCI.
 * Another drug in this class which is pending FDA approval is Ticagrelor

Clopidogrel in the Management of Unstable angina/NSTEMI
Mechanism of action:
 * This class of drugs inhibits platelet aggregation and reduces blood viscosity by inhibiting adenosine diphosphate (ADP) action on platelet receptors, specifically the P2Y12 component of the ADP receptor.

Clinical trial data:
 * Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial led to widespread use of Clopidogrel in ACS and stroke patients. Trial enrolled a total of 19,185 patients who were randomized to receive ASA 325 mg per d or clopidogrel 75 mg per d in patients with atherosclerotic vascular disease(manifested as recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease). Follow up ranged from 1-3 yrs. Results showed that long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death.
 * The results of the CURE trial further reinforced the benefits of Clopidogrel in patients with Unstable angina/NSTEMI.

Clopidogrel Dosing:
 * A loading dose of 300mg is typically used, although some studies have used higher dose(600-900mg) and shown improved outcomes, but also increase incidence of side effects.
 * Duration of treatment recommended at present is maintenance dose of either 75mg daily Clopidogrel or 10mg daily Prasugrel for minimum 12 months in patients undergoing PCI with either BMS or DES.
 * It is recommended to empirically with-hold the drug for 5days before planning for CABG.

Disadvantage of Clopidogrel:
 * A limiting factor in the use of clopidogrel is its inter-individual variability in response (hyporesponders) which has growing concern in patients with PCI and its impact on the incidence of stent thrombosis.

Prasugrel in the Management of Unstable angina/NSTEMI
Mechanism of benefit:
 * It has similar mechanism of action but more potent antiplatelet effect.

Clinical trial data:
 * TRION-TIMI 38 trial which was a multicenter, randomized, double blind study enrolling 13,608 patients with moderate to high-risk ACS led to the FDA approval and its inclusion in ACC/AHA guidelines for PCI as one of the recommended thienopyridine agent. Results of this study showed that in patients with acute coronary syndromes with scheduled percutaneous coronary intervention,Prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.

Prasugrel Indications:
 * Prasugrel is being increasingly used in high risk patients with ACS undergoing PCI.
 * Also in patients with failed clopidogrel therapy.
 * In high-risk situations such as with history of diabetes or prior MI, in which its effect appears to be greater and its use may be considered.

Prasugrel Contraindications:
 * In patients with history of stroke, TIA and other bleeding disorders.
 * Prasugrel is usually not recommended in patients ≥75 years of age because of the increased risk of fatal and intracranial bleeding and uncertain benefit except in high-risk situations (see above).
 * Prasugrel should not be started in patients who are likely to undergo urgent CABG. Patient should not be taken for surgery at least for 7days following stoppage of the drug.

Prasugrel Dosing:
 * Duration of treatment recommended at present is maintenance dose of either 75mg daily Clopidogrel or 10mg daily Prasugrel for minimum 12 months in patients undergoing PCI with either BMS or DES.
 * Dose adjustment of prasugrel is required in patients weighing <60 kg as they have increased risk of bleeding secondary to increased exposure to active metabolites when consuming 10mg daily. Lowering the maintenance dose to 5mg daily should be considered, although at present there are no prospective studies about its effectiveness and safety at this dose.

Ticagrelor in the Management of Unstable angina/NSTEMI
Clinical Trial Data:
 * This drug was investigated in a multicenter, double-blind, randomized PLATO trial which enrolled 18,624 patients with ACS. This trial compared Clopidogrel with Ticagrelor and showed improved outcomes in patients on Ticagrelor in both STEMI and NSTEMI group with regards to death from vascular causes, MI and stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding.
 * CHAMPION PCI and CHAMPION PLATFORM trials have studied the role of IV platelet inhibition with Cangrelor and both trials did not show superiority of Cangrelor over Clopidogrel or Placebo, respectively.

==ACC / AHA Guidelines for Antiplatelet therapy in Unstable Angina/NSTEMI (DO NOT EDIT) ==

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Class I
1. Clopidogrel (loading dose followed by daily maintenance dose) should be administered to Unstable angina / NSTEMI patients who are unable to take ASA because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: A)

2. Patients with definite Unstable angina / NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive dual-antiplatelet therapy on presentation. (Level of Evidence: A) ASA should be initiated on presentation. (Level of Evidence: A) The choice of a second antiplatelet therapy to be added to ASA on presentation includes 1 of the following:

Before PCI:
 * Clopidogrel (Level of Evidence: B); or
 * An IV GP IIb/IIIa inhibitor. (Level of Evidence: A) IV eptifibatide or tirofiban are the preferred GP IIb/IIIa inhibitors.

At the time of PCI:
 * Clopidogrel if not started before PCI (Level of Evidence: A); or
 * Prasugrel (Level of Evidence: B); or
 * An IV GP IIb/IIIa inhibitor. (Level of Evidence: A)

3. For Unstable angina / NSTEMI patients in whom an initial invasive strategy is selected, antiplatelet therapy in addition to aspirin should be initiated before diagnostic angiography (upstream) with either clopidogrel (loading dose followed by daily maintenance dose) or an intravenous GP IIb/IIIa inhibitor. (Level of Evidence: A) Abciximab as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is the preferred choice of GP IIb/IIIa inhibitor. (Level of Evidence: B)

4. For Unstable angina / NSTEMI patients in whom an initial conservative strategy is selected, if recurrent symptoms/ischemia, HF, or serious arrhythmias subsequently appear, then diagnostic angiography should be performed. (Level of Evidence: A). Either an IV GP IIb/IIIa inhibitor (eptifibatide or tirofiban (Level of Evidence: A) or clopidogrel (loading dose followed by daily maintenance dose (Level of Evidence: B)) should be added to ASA and anticoagulant therapy before diagnostic angiography (upstream). (Level of Evidence: C)

5. A loading dose of thienopyridine is recommended for Unstable angina/NSTEMI patients for whom PCI is planned. Regimens should be one of the following:
 * Clopidogrel 300 to 600 mg should be given as early as possible before or at the time of PCI (Level of Evidence: A) or
 * Prasugrel 60 mg should be given promptly and no later than 1 hour after PCI once coronary anatomy is defined and a decision is made to proceed with PCI. (Level of Evidence: B)

6. The duration and maintenance dose of thienopyridine therapy should be as follows:
 * In Unstable angina / NSTEMI patients undergoing PCI, clopidogrel 75 mg daily or prasugrel 10 mg daily should be given for at least 12 months. (Level of Evidence: B)
 * If the risk of morbidity because of bleeding outweighs the anticipated benefits afforded by thienopyridine therapy, earlier discontinuation should be considered. (Level of Evidence: C)

Class IIb
1. Prasugrel 60 mg may be considered for administration promptly upon presentation in patients with Unstable angina / NSTEMI for whom PCI is planned, before definition of coronary anatomy if both the risk for bleeding is low and the need for CABG is considered unlikely. (Level of Evidence: C)

2. In patients with definite Unstable angina / NSTEMI undergoing PCI as part of an early invasive strategy, the use of a loading dose of clopidogrel of 600 mg, followed by a higher maintenance dose of 150 mg daily for 6 days, then 75 mg daily may be reasonable in patients not considered at high risk for bleeding. (Level of Evidence: B)

Harm

1. In Unstable angina / NSTEMI patients with a prior history of stroke and/or TIA for whom PCI is planned, prasugrel is potentially harmful as part of a dual-antiplatelet therapy regimen. (Level of Evidence: B)}}