Unstable angina non ST elevation myocardial infarction thienopyridines

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Associate Editors-in-Chief: Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.; Smita Kohli, M.D.

Overview

Thienopyridines are a class of drugs that inhibit ADP receptor/P2Y 12, and function as antiplatelet agents.

Thienopyridines

A number of drugs from this class are currently being studied for use in ACS patients. Agents available in this category include:

• Ticlopidine, which is one of the first drugs studied in this class but has lost some popularity due to 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. The trial enrolled a total of 19,185 patients who were randomized to receive ASA 325 mg per day or clopidogrel 75 mg per day 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 ischemic stroke, myocardial infarction, or vascular death.
• The results of the CURE trial further reinforced the benefits of clopidogrel in patients with unstable angina/NSTEMI.

Dosing

• A loading dose of 300 mg is typically used. Some studies have used higher doses (600 - 900 mg) but despite showing improved outcomes, have also shown an increased incidence of side effects.
• The duration of treatment recommended at present is a maintenance dose of either 75 mg daily clopidogrel or 10 mg daily prasugrel for a minimum of 12 months in patients undergoing PCI with either BMS or DES.
• It is recommended to empirically withhold the drug for 5 days before CABG.

Disadvantages

• A limiting factor in the use of clopidogrel, is its inter-individual response variability with the presence of hyporesponders, which has growing concern in patients who have undergone PCI, and its impact on the incidence of subsequent stent thrombosis.

Prasugrel in the Management of Unstable Angina/NSTEMI

Mechanism of Benefit

• It hasa similar mechanism of action as clopidogrel, but has a more potent antiplatelet effect.

Clinical Trial Data

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

Indications

• Prasugrel is being increasingly used in high risk patients with ACS undergoing PCI.
• It is also used in patients who have failed clopidogrel therapy.
• In high-risk situations such as in patients with history of diabetes or prior MI, in which its effect appears to be greater.

Contraindications

• Prasugrel 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 benefits except for some 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 for at least seven days after discontinuing the drug.

Dosing

• The duration of treatment recommended at present is maintenance dose of either 75 mg daily clopidogrel or 10 mg 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 10 mg daily. Lowering the maintenance dose to 5 mg 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. It showed improved outcomes in patients on Ticagrelor in both STEMI and NSTEMI groups 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- ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines (DO NOT EDIT)

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Clopidogrel reduces major CV events compared with placebo or aspirin. Dual antiplatelet therapy with clopidogrel and aspirin, compared with aspirin alone, reduces major CV events in patients with established ischemic heart disease, and it reduces coronary stent thrombosis but is not routinely recommended for patients with prior ischemic stroke because of the risk of bleeding. Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding. Patients with prior GI bleeding are at highest risk for recurrent bleeding on antiplatelet therapy. Other clinical characteristics that increase the risk of GI bleeding include advanced age; concurrent use of anticoagulants, steroids, or nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin; and Helicobacter pylori infection. The risk of GI bleeding increases as the number of risk factors increases. Use of a PPI or histamine H2 receptor antagonist (H2RA) reduces the risk of upper GI bleeding compared with no therapy. PPIs reduce upper GI bleeding to a greater degree than do H2RAs. PPIs are recommended to reduce GI bleeding among patients with a history of upper GI bleeding. PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy. Routine use of either a PPI or an H2RA is not recommended for patients at lower risk of upper GI bleeding, who have much less potential to benefit from prophylactic therapy. Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications. Pharmacokinetic and pharmacodynamic studies, using platelet assays as surrogate endpoints, suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of clopidogrel. The strongest evidence for an interaction is between omeprazole and clopidogrel. It is not established that changes in these surrogate endpoints translate into clinically meaningful differences. Observational studies and a single randomized clinical trial (RCT) have shown inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs. A clinically important interaction cannot be excluded, particularly in certain subgroups, such as poor metabolizers of clopidogrel. The role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and PPIs has not yet been established.

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