Combination Therapy in Acute Coronary Disease Elizabeth Gabrielle PA-S Lock Haven University February 2009

Cardiovascular Disease Leading cause of mortality and morbidity worldwide. Leading cause of mortality and morbidity worldwide. Estimated that 17 million people die of cardiovascular disease each year. Estimated that 17 million people die of cardiovascular disease each year. Incidences of major cardiovascular events increase with age. Incidences of major cardiovascular events increase with age. Includes: Includes: –High Blood Pressure, Coronary Artery Disease, Heart Failure, Congenital Cardiovascular Defects, and Stroke.

Coronary Artery Disease (CAD) Principle type of heart disease. Principle type of heart disease. In 2005: In 2005: –445,687 people died from CAD –68.3% of all heart disease deaths.

Aspirin (acetyl salicylic acid) Works on both cyclooxygenase pathways. Works on both cyclooxygenase pathways. Permanently deactivates cyclooxygenase-1 pathway resulting in antiplatelet effects. Permanently deactivates cyclooxygenase-1 pathway resulting in antiplatelet effects. Antiplatelet drug of choice. Antiplatelet drug of choice.

Clopidogrel (also known as Plavix) Thienopyridine derivative Thienopyridine derivative Selectively and irreversibly inhibits the binding of adenosine diphosphate (ADP). Selectively and irreversibly inhibits the binding of adenosine diphosphate (ADP). Deactivates glycoprotein IIb/IIIa complex. Deactivates glycoprotein IIb/IIIa complex. Glycoprotein IIb/IIIa complex allows fibrinogen binding to platelet. Glycoprotein IIb/IIIa complex allows fibrinogen binding to platelet. Inhibits platelet aggregation. Inhibits platelet aggregation.

Current Indications Individually aspirin and clopidogrel are used for secondary prevention of cardiovascular events. Individually aspirin and clopidogrel are used for secondary prevention of cardiovascular events. Only indication of combination therapy is for the treatment of patients with ACS undergoing percutaneous coronary intervention (PCI) with or without stent placement. Only indication of combination therapy is for the treatment of patients with ACS undergoing percutaneous coronary intervention (PCI) with or without stent placement.

Problem With aspirin alone the relative risk reduction of death, MI, and stroke is only approximately 20%. With aspirin alone the relative risk reduction of death, MI, and stroke is only approximately 20%. How can we improve this? How can we improve this?

Question In adult patients 65 years old and older with documented coronary artery disease, without PCI, is daily aspirin therapy alone compared to daily aspirin therapy combined with clopidogrel more effective at decreasing incidences of cardiac events? In adult patients 65 years old and older with documented coronary artery disease, without PCI, is daily aspirin therapy alone compared to daily aspirin therapy combined with clopidogrel more effective at decreasing incidences of cardiac events?

Clinical Trials: Combination Therapy Three double blinded randomized controlled trials. Three double blinded randomized controlled trials. Trial 1: Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial 1: Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial 2: Clopidogrel for High Arthrothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial 2: Clopidogrel for High Arthrothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial 3: Clopidogrel and Metoprolol in Myocardial Infaction (COMMIT) Trial 3: Clopidogrel and Metoprolol in Myocardial Infaction (COMMIT)

CURE Patients: 12,562 with non-ST elevation acute coronary syndrome. Patients: 12,562 with non-ST elevation acute coronary syndrome. Therapy: Clopidogrel 300 mg followed by 75 mg daily and aspirin mg daily vs. aspirin alone Therapy: Clopidogrel 300 mg followed by 75 mg daily and aspirin mg daily vs. aspirin alone Outcome: Cardiovascular death, non- fatal MI, stroke at 9 months after onset of treatment. Outcome: Cardiovascular death, non- fatal MI, stroke at 9 months after onset of treatment.

Conclusion: CURE Results: Results: –Cardiovascular Death, Non-fatal MI, Stroke Combined Therapy 9.3% Aspirin Alone Therapy 11.4% Odds Ration 0.80 CI ( ) Evidence of benefit from combined treatment. Evidence of benefit from combined treatment. Mainly due to a decrease risk of non-fatal MI and cardiovascular death. Mainly due to a decrease risk of non-fatal MI and cardiovascular death.

Results: CURE

CHARISMA Patients: 15,200 patients with coronary artery disease. Patients: 15,200 patients with coronary artery disease. Therapy: Clopidogrel 75 mg and aspirin mg daily vs. aspirin alone for 28 months Therapy: Clopidogrel 75 mg and aspirin mg daily vs. aspirin alone for 28 months Outcome: Cardiovascular death, MI, Stroke. Outcome: Cardiovascular death, MI, Stroke.

Conclusion: CHARISMA Results: Results: –Cardiovascular death, MI, Stroke  Combined Therapy: 6.8%  Aspirin Alone Therapy: 7.3%  Odds ratio 0.93 ( ) Only a small reduction in the risk of having a cardiovascular event during long term follow up. Only a small reduction in the risk of having a cardiovascular event during long term follow up.

Results: CHARISMA

COMMIT Patients: 45,852 patients admitted to the hospital within 24 hours of a suspected MI without undergoing PCI. Patients: 45,852 patients admitted to the hospital within 24 hours of a suspected MI without undergoing PCI. Therapy: Clopidogel 75 mg and aspirin 162 mg vs. aspirin alone for up to four weeks. Therapy: Clopidogel 75 mg and aspirin 162 mg vs. aspirin alone for up to four weeks. Outcome: Cardiovascular death, reinfarction, Stroke. Outcome: Cardiovascular death, reinfarction, Stroke.

Conclusion: COMMIT Results: Results: -Cardiovascular events, reinfarction, stroke  Combined Therapy 9.2%  Aspirin Alone Therapy 10.1 %  Odds Ratio 0.91 ( ) There was a significant reduction in death, reinfarction, and stroke. There was a significant reduction in death, reinfarction, and stroke.

What are the Risks?

Bleeding Risk Clopidogrel Clopidogrel –Neutropenia –Thrombocytopenic Purpura (TTP)  Usually occurs within two weeks of drug initiation.  High mortality if not treated promptly.

Bleeding Risk Aspirin Aspirin –Twofold increase in the risk of upper-gastrointestinal- tract bleeding with a dose of 75mg-100mg. –Higher doses increase the risk of bleeding by a factor of 4-10 because it causes more gastric lesions.

Combined Bleeding Risk All studies concluded that there was an increased risk of bleeding in the populations receiving combined therapy compared to those receiving only aspirin. All studies concluded that there was an increased risk of bleeding in the populations receiving combined therapy compared to those receiving only aspirin. However, in patients who specifically had ACS the benefits outweighed major bleeding risks. However, in patients who specifically had ACS the benefits outweighed major bleeding risks.

Application into Practice Combination therapy of aspirin and clopidogrel in standard long-term therapy of patients with cardiovascular disease should be considered. However it should not be implicated until new data is published. Combination therapy of aspirin and clopidogrel in standard long-term therapy of patients with cardiovascular disease should be considered. However it should not be implicated until new data is published.

Further Studies 1. Does the risk of bleeding increase with long term therapy? 2. What is the optimal duration of combination therapy?

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