Unstable angina / non ST elevation myocardial infarction antiplatelet therapy

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

Overview of Antiplatelet Therapy in UA / NSTEMI
Antiplatelet therapy plays a major role in the management of UA/NSTEMI. This class of medication is directed towards one of the three pathways listed below:
 * Decreasing Thomboxane A2 formation(Aspirin)
 * Inhibiting the P2Y12 component of the adenosine diphosphate (ADP) receptor pathway(thienopyridines)
 * Direct inhibitors of platelet aggregation (GP IIb/IIIa inhibitors)

Aspirin
One of the medications which has consistently been shown to reduce mortality in ACS or CAD patients is ASA. Until recently, no trial had directly compared the efficacy of different doses of ASA in patients who present with UA / NSTEMI. But CURRENT OASIS 7 trial, which was a randomized, multicenter, multinational trial enrolling 25,087 patients with ACS showed no difference in cardiovascular outcomes of death from MI or stroke between low dose aspirin(75-100mg) compared to high dose aspirin(300-325mg) at the end of 30 days. The Second International Study of Infarct Survival (ISIS-2) trial led to the recommendation that ASA be initiated immediately in the ED once the diagnosis of ACS is made or suspected. Aspirin therapy can also be initiated in prehospital setting when ACS is suspected. However, on the basis of previous randomized trials, the current recommendation for initial dose of aspirin is 162-325mg. Non enteric coated formulaitons are preferred due to rapid buccal absorption. For safety (e.g., gastrointestinal bleeding), a couple of large observational studies have found that the rate of bleeding appears to be lower with low-dose aspirin(75-100mg daily) as compared with high dose aspirin (325 mg daily) in patients receiving medical therapy, percutaneous coromary intervention (PCI) or coronary artery bypass grafting (CABG). Thus, after an initial loading dose of 162 to 325 mg, a dose of 75 to 100 mg daily appears sufficient. In patients who have an allergy or who cannot tolerate aspirin, use of clopidogrel is recommended. On the basis of current available data, lifelong continuation of aspirin should be encouraged unless a contraindication develops.

Thienopyridines
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. 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 UA/NSTEMI patients. 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 UA/NSTEMI. 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. It is recommended to empirically with-hold the drug for 5days before planning for CABG.

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. A number of drugs are currently being studies for use in ACS patients. Most recently, Prasugrel has been approved by FDA for use in patients undergoing PCI. It has similar mechanism of action but more potent antiplatelet effect. 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 is being increasingly used in high risk patients with ACS undergoing PCI and also in patients with failed clopidogrel therapy. 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. It is contraindicated 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 such as with history of diabetes or prior MI, in which its effect appears to be greater and its use may be considered. 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.

Another drug in this class which is pending FDA approval is Ticagrelor. 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.

Glycoprotein IIb/IIIa Inhibitors
GP IIb/IIIa inhibitors inhibit the fibrinogen-mediated cross linkage of platelets, which is the final common pathway of platelet aggregation. Three agents currently available are Abciximab, Eptifibatide and Tirofiban, all three of which are now included by the ACC/AHA guidelines for use in PCI. All three agents are for intravenous usage and are given by bolus and continuous infusion. ISAR-REACT 2 trial studied Abciximab in NSTEMI patients. This was a multicenter, randomized, double-blind, placebo-controlled study enrolling 2022 patients with non-ST-segment elevation ACS undergoing PCI. Results showed that Abciximab reduces the risk of adverse events in patients with non-ST-segment elevation ACS undergoing PCI after pretreatment with 600 mg of clopidogrel. The benefits provided by abciximab appear to be confined to patients presenting with an elevated troponin level. The benefit of GP IIb/IIIa inhibition appears greater when used in high-risk patients and in those with ST segment changes. The benefit was also seen in high risk patients with or without revascularization. Abciximab is not recommended if PCI is not planned. Eptifibatide and Tirofiban are preferred agents when delay in coronary angiography and PCI is anticipated.

Optimal timing of GP IIb/IIIa inhibition remains controversial with no clear data available from current trials. More so, most of the trials related to timing of GP IIa/IIIb inhibitors involve patients with STEMI and hence cannot be applied to all ACS patients. Most recently, EARLY ACS trial revealed that in patients who had acute coronary syndromes without ST-segment elevation, the use of eptifibatide 12 hours or more before angiography was not superior to the provisional use of eptifibatide after angiography. The early use of eptifibatide was associated with an increased risk of non-life-threatening bleeding and need for transfusion. Potential benefit with this class of drugs also led to study of oral GP IIa/IIIb inhibitors. A major study involving Orbofiban(an oral GP IIb/IIIa inhibitor) failed to demonstrate improved outcomes and was associated with increased mortality.

A major side effect of GP IIb/IIIa inhibitors is thrombocytopenia and hence increased bleeding. Therefore, platelet monitoring is indicated during its use.

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

Class I
1. Aspirin should be administered to UA/NSTEMI patients as soon as possible after hospital presentation and continued indefinitely in patients who tolerate it. (Level of Evidence: A)

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

3. Patients with definite UA / 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)

4. For UA / 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)

5. For UA / 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)

6. A loading dose of thienopyridine is recommended for UA / 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)

7. The duration and maintenance dose of thienopyridine therapy should be as follows:
 * In UA / 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 IIa
1. For UA / NSTEMI patients in whom an initial conservative strategy is selected and who have recurrent ischemic discomfort with clopidogrel, ASA, and anticoagulant therapy, it is reasonable to add a GP IIb/IIIa antagonist before diagnostic angiography. (Level of Evidence: C)

2. For UA / NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit administration of an IV GP IIb/IIIa inhibitor if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 hours earlier than planned catheterization or PCI. (Level of Evidence: B)

Class IIb
1. For UA / NSTEMI patients in whom an initial conservative (i.e., noninvasive) strategy is selected, it may be reasonable to add eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy. (Level of Evidence: B)

2. Prasugrel 60 mg may be considered for administration promptly upon presentation in patients with UA / 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)

3. The use of upstream GP IIb/IIIa inhibitors may be considered in high-risk UA / NSTEMI patients already receiving ASA and a thienopyridine who are selected for an invasive strategy, such as those with elevated troponin levels, diabetes, or significant ST-segment depression, and who are not otherwise at high risk for bleeding. (Level of Evidence: B)

4. In patients with definite UA / 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)

Class III
No Benefit

1. Abciximab should not be administered to patients in whom PCI is not planned. (Level of Evidence: A)

2. In UA / NSTEMI patients who are at low risk for ischemic events (e.g., TIMI risk score ≥2) or at high risk of bleeding and who are already receiving ASA and clopidogrel, upstream GP IIb/IIIa inhibitors are not recommended. (Level of Evidence: B)

Harm

1. In UA / 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)}}