Combination TherapyCombination Therapyin Acute Coronary Diseasein Acute Coronary Disease

Elizabeth Gabrielle PA-SElizabeth Gabrielle PA-SLock Haven UniversityLock Haven University

February 2009February 2009

Cardiovascular DiseaseCardiovascular Disease

Leading cause of mortality and morbidity Leading cause of mortality and morbidity worldwide.worldwide.

Estimated that 17 million people die of Estimated that 17 million people die of cardiovascular disease each year.cardiovascular disease each year.

Incidences of major cardiovascular events Incidences of major cardiovascular events increase with age.increase with age.

Includes: Includes: – High Blood Pressure, High Blood Pressure, Coronary Artery Coronary Artery

DiseaseDisease, Heart Failure, Congenital , Heart Failure, Congenital Cardiovascular Defects, and Stroke.Cardiovascular Defects, and Stroke.

Coronary Artery DiseaseCoronary Artery Disease (CAD) (CAD)

Principle type of Principle type of heart disease.heart disease.

In 2005:In 2005:– 445,687 people 445,687 people

died from CAD died from CAD – 68.3% of all 68.3% of all

heart disease heart disease deaths.deaths.

AspirinAspirin(acetyl salicylic acid)(acetyl salicylic acid)

Works on both Works on both cyclooxygenase cyclooxygenase pathways.pathways.

Permanently Permanently deactivates deactivates cyclooxygenase-1 cyclooxygenase-1 pathway resulting pathway resulting in antiplatelet in antiplatelet effects.effects.

Antiplatelet drug of Antiplatelet drug of choice.choice.

ClopidogrelClopidogrel(also known as Plavix)(also known as Plavix)

Thienopyridine derivativeThienopyridine derivative

Selectively and irreversibly Selectively and irreversibly inhibits the binding of inhibits the binding of adenosine diphosphate adenosine diphosphate (ADP).(ADP).

Deactivates glycoprotein Deactivates glycoprotein IIb/IIIa complex.IIb/IIIa complex.

Glycoprotein IIb/IIIa Glycoprotein IIb/IIIa complex allows fibrinogen complex allows fibrinogen binding to platelet.binding to platelet.

Inhibits platelet Inhibits platelet aggregation.aggregation.

Current IndicationsCurrent Indications

Individually aspirin and clopidogrel Individually aspirin and clopidogrel are used for secondary prevention of are used for secondary prevention of cardiovascular events.cardiovascular events.

Only indication of combination Only indication of combination therapy is for the treatment of therapy is for the treatment of patients with ACS undergoing patients with ACS undergoing percutaneous coronary intervention percutaneous coronary intervention (PCI) with or without stent placement.(PCI) with or without stent placement.

ProblemProblem

With aspirin alone the relative risk reduction of With aspirin alone the relative risk reduction of death, MI, and stroke is only approximately 20%.death, MI, and stroke is only approximately 20%.

How can we improve this?How can we improve this?

QuestionQuestion

In adult patients 65 years old and In adult patients 65 years old and older with documented coronary older with documented coronary artery disease, artery disease, withoutwithout PCI, is daily PCI, is daily aspirin therapy alone compared to aspirin therapy alone compared to daily aspirin therapy combined with daily aspirin therapy combined with clopidogrel more effective at clopidogrel more effective at decreasing incidences of cardiac decreasing incidences of cardiac events?events?

Clinical Trials:Clinical Trials:Combination TherapyCombination Therapy

Three double blinded randomized Three double blinded randomized controlled trials.controlled trials.

Trial 1: Clopidogrel in Unstable Angina to Trial 1: Clopidogrel in Unstable Angina to Prevent Recurrent Events Prevent Recurrent Events (CURE)(CURE)

Trial 2: Clopidogrel for High Trial 2: Clopidogrel for High Arthrothrombotic Risk and Ischemic Arthrothrombotic Risk and Ischemic Stabilization, Management, and Avoidance Stabilization, Management, and Avoidance (CHARISMA)(CHARISMA)

Trial 3: Clopidogrel and Metoprolol in Trial 3: Clopidogrel and Metoprolol in Myocardial Infaction Myocardial Infaction (COMMIT)(COMMIT)

CURECURE

Patients:Patients: 12,562 with non-ST 12,562 with non-ST elevation acute coronary syndrome.elevation acute coronary syndrome.

Therapy:Therapy: Clopidogrel 300 mg Clopidogrel 300 mg followed by 75 mg daily and aspirin followed by 75 mg daily and aspirin 75-325 mg daily vs. aspirin alone75-325 mg daily vs. aspirin alone

Outcome:Outcome: Cardiovascular death, Cardiovascular death, non-fatal MI, stroke at 9 months after non-fatal MI, stroke at 9 months after onset of treatment.onset of treatment.

Conclusion:Conclusion:CURECURE

Results:Results:– Cardiovascular Death, Non-fatal MI, Cardiovascular Death, Non-fatal MI,

StrokeStrokeCombined Therapy 9.3% Combined Therapy 9.3% Aspirin Alone Therapy 11.4% Aspirin Alone Therapy 11.4% Odds Ration 0.80 CI (0.72-0.90)Odds Ration 0.80 CI (0.72-0.90)

Evidence of benefitEvidence of benefit from combined from combined treatment.treatment.

Mainly due to a decrease risk of non-Mainly due to a decrease risk of non-fatal MI and cardiovascular death.fatal MI and cardiovascular death.

Results:Results:CURE CURE

CHARISMACHARISMA

Patients:Patients: 15,200 patients with 15,200 patients with coronary artery disease.coronary artery disease.

Therapy:Therapy: Clopidogrel 75 mg and Clopidogrel 75 mg and aspirin 75-162 mg daily vs. aspirin aspirin 75-162 mg daily vs. aspirin alone for 28 monthsalone for 28 months

Outcome:Outcome: Cardiovascular death, MI, Cardiovascular death, MI, Stroke.Stroke.

Conclusion:Conclusion:CHARISMACHARISMA

Results:Results: – Cardiovascular death, MI, StrokeCardiovascular death, MI, Stroke

Combined Therapy: 6.8% Combined Therapy: 6.8% Aspirin Alone Therapy: 7.3%Aspirin Alone Therapy: 7.3% Odds ratio 0.93 (0.83-1.05)Odds ratio 0.93 (0.83-1.05)

Only a Only a smallsmall reduction in the risk of reduction in the risk of having a cardiovascular event during having a cardiovascular event during long term follow up.long term follow up.

Results:Results:CHARISMACHARISMA

COMMITCOMMIT

Patients:Patients: 45,852 patients admitted 45,852 patients admitted to the hospital within 24 hours of a to the hospital within 24 hours of a suspected MI without undergoing PCI.suspected MI without undergoing PCI.

Therapy:Therapy: Clopidogel 75 mg and Clopidogel 75 mg and aspirin 162 mg vs. aspirin alone for aspirin 162 mg vs. aspirin alone for up to four weeks.up to four weeks.

Outcome:Outcome: Cardiovascular death, Cardiovascular death, reinfarction, Stroke.reinfarction, Stroke.

Conclusion:Conclusion:COMMITCOMMIT

Results:Results: -Cardiovascular events, reinfarction, -Cardiovascular events, reinfarction, strokestroke Combined Therapy 9.2%Combined Therapy 9.2% Aspirin Alone Therapy 10.1 %Aspirin Alone Therapy 10.1 % Odds Ratio 0.91 (0.86-0.97)Odds Ratio 0.91 (0.86-0.97)

There There waswas a significant reduction in a significant reduction in death, reinfarction, and stroke.death, reinfarction, and stroke.

What are the Risks?What are the Risks?

Bleeding RiskBleeding Risk

ClopidogrelClopidogrel– Neutropenia Neutropenia – Thrombocytopenic Purpura (TTP)Thrombocytopenic Purpura (TTP)

Usually occurs within two weeks of drug initiation.Usually occurs within two weeks of drug initiation. High mortality if not treated promptly.High mortality if not treated promptly.

Bleeding RiskBleeding Risk

AspirinAspirin– Twofold increase in the risk of upper-gastrointestinal-Twofold increase in the risk of upper-gastrointestinal-

tract bleeding with a dose of 75mg-100mg.tract bleeding with a dose of 75mg-100mg.– Higher doses increase the risk of bleeding by a factor Higher doses increase the risk of bleeding by a factor

of 4-10 because it causes more gastric lesions.of 4-10 because it causes more gastric lesions.

Combined Bleeding RiskCombined Bleeding Risk

All studies concluded that there was All studies concluded that there was an increased risk of bleeding in the an increased risk of bleeding in the populations receiving combined populations receiving combined therapy compared to those receiving therapy compared to those receiving only aspirin.only aspirin.

However, in patients who specifically However, in patients who specifically had ACS the benefits outweighed had ACS the benefits outweighed major bleeding risks.major bleeding risks.

Application into PracticeApplication into Practice

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

Further StudiesFurther Studies

1. Does the risk of bleeding increase 1. Does the risk of bleeding increase with long term therapy?with long term therapy?

2. What is the optimal duration of 2. What is the optimal duration of combination therapy?combination therapy?

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