Chronic stable angina treatment clopidogrel

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4] Phone:617-632-7753; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [5]; John Fani Srour, M.D.; Jinhui Wu, M.D.; Lakshmi Gopalakrishnan, M.B.B.S.

Overview

Thienopyridines, such as clopidogrel and ticlopidine, selectively inhibit ADP-induced platelet aggregation and are used as an alternative to aspirin in patients with significant risk of arterial thrombosis.

Mechanisms of benefit

• Clopidogrel is a thienopyridine derivative which prevents adenosine diphosphate–mediated activation of platelets by selectively and irreversibly inhibiting the binding of adenosine diphosphate to its platelet receptors and thereby, blocking adenosine diphosphate–dependent activation of the glycoprotein IIb/IIIa complex.

• Ticlopidine, another thienopyridine derivative, decreases platelet function in patients with stable angina but, unlike aspirin, has not been shown to decrease adverse cardiovascular events.

Indication

Clopidogrel is used in patients with contraindication to aspirin or aspirin intolerance.

Drug interactions

• Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with an increased risk of bleeding and therefore, close monitoring is required.

• Atorvastatin via ADP mediated platelet activation inhibits clopidogrel. However, this inhibition is not observed with low dose atorvastatin (10mg).

• Clopidogrel is metabolized via CYP-3A4, hence drugs that inhibit (erythromycin) or induce (rifampicin) CYP-34A alter the plasma levels of clopidogrel.

Adverse effects

• Clopidogrel:

• Gastrointestinal bleed
• Active bleeding

• Ticlopidine:

• Neutropenia
• Thrombocytopenia

Supportive trial data

• The CAPRIE trial, a randomized blinded study of 19,185 patients with atherosclerotic vascular disease assessing the efficacy of clopidogrel versus aspirin therapies, showed a modest difference in the effectiveness between clopidogrel and aspirin. There was a relative risks reduction of 8.7% in favor of clopidogrel therapy among patients with established atherosclerotic vascular disease in reducing the combined risk of ischemic stroke, myocardial infarction and vascular death.

• The CURE trial, a randomized placebo controlled studying involving 12,562 who received either clopidogrel or placebo in addition to aspirin for 3-12 months after the first 24 hours of onset of symptoms, demonstrated the efficacy and safety of adding clopidogrel (a loading dose of 300 mg, followed by 75 mg daily) to aspirin in the long-term management of patients with acute coronary syndromes without ST-segment elevation.

• The CHARISMA trial, a randomized placebo controlled study involving 2,163 patients, reported dual anti platelet therapy with clopidogrel plus aspirin was not significantly effective in comparison to aspirin alone in reducing the rate of myocardial infarction, stroke, or cardiovascular death in patients with established vascular disease or at high risk for developing vascular disease.

2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines and the 1999 ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina (DO NOT EDIT)

Class I

"1. Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with an increased risk of bleeding and should be monitored closely. (Level of Evidence: B) "

Class IIa

"1. Clopidogrel when aspirin is absolutely contraindicated. (Level of Evidence: B) "

ESC Guidelines- Pharmacological therapy to improve prognosis in patients with stable angina (DO NOT EDIT)

Class IIa

"1. Clopidogrel as an alternative antiplatelet agent inpatients with stable angina who cannot take aspirin (e.g. aspirin allergic). (Level of Evidence: A) "

Concomitant use of Proton pump inhibitors and Thienopyridines

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.

”

Related Chapters

• The Chronic Stable Angina Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines

Sources

• The ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina

• The ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina

• Guidelines on the management of stable angina pectoris: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology

• The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina

• ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines