Unstable angina non ST elevation myocardial infarction thienopyridines

Intern Survival Guide

Acute Coronary Syndrome Main Page
Unstable angina / NSTEMI Microchapters
Home
Patient Information
Overview
Classification
Pathophysiology
Unstable Angina
Non-ST Elevation Myocardial Infarction
Differentiating Unstable Angina/Non-ST Elevation Myocardial Infarction from other Disorders
Epidemiology and Demographics
Risk Stratification
Natural History, Complications and Prognosis
Special Groups
Women
Heart Failure and Cardiogenic Shock
Perioperative NSTE-ACS Related to Noncardiac Surgery
Stress (Takotsubo) Cardiomyopathy
Diabetes Mellitus
Post CABG Patients
Older Adults
Chronic Kidney Disease
Angiographically Normal Coronary Arteries
Variant (Prinzmetal's) Angina
Substance Abuse
Cardiovascular "Syndrome X"
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Blood Studies
Biomarkers
Electrocardiogram
Chest X Ray
Echocardiography
Coronary Angiography
Treatment
Primary Prevention
Immediate Management
Anti-Ischemic and Analgesic Therapy
Cholesterol Management
Antitplatelet Therapy
Antiplatelet therapy recommendations
Aspirin
Thienopyridines
Glycoprotein IIb/IIIa Inhibitor
Anticoagulant Therapy
Additional Management Considerations for Antiplatelet and Anticoagulant Therapy
Risk Stratification Before Discharge for Patients With an Ischemia-Guided Strategy of NSTE-ACS
Mechanical Reperfusion
Initial Conservative Versus Initial Invasive Strategies
PCI
CABG
Complications of Bleeding and Transfusion
Discharge Care
Medical Regimen
Post-Discharge Follow-Up
Cardiac Rehabilitation
Long-Term Medical Therapy and Secondary Prevention
ICD implantation within 40 days of myocardial infarction
ICD within 90 days of revascularization
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Unstable angina non ST elevation myocardial infarction thienopyridines On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Unstable angina non ST elevation myocardial infarction thienopyridines
CDC onUnstable angina non ST elevation myocardial infarction thienopyridines
Unstable angina non ST elevation myocardial infarction thienopyridines in the news
Blogs on Unstable angina non ST elevation myocardial infarction thienopyridines
to Hospitals Treating Unstable angina non ST elevation myocardial infarction thienopyridines
Risk calculators and risk factors for Unstable angina non ST elevation myocardial infarction thienopyridines

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 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.

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.

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 7 days following stoppage of the drug.

Dosing

• 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 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- ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines (DO NOT EDIT)

“

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.

”