Abstract & Commentary
Synopsis: Clopidogrel, an alternative antiplatelet agent used in patients with aspirin intolerance, is especially useful in combination with aspirin after coronary stent procedures.
Source: Jneid H, et al. Arch Intern Med. 2003;163: 1145-1152.
Acute coronary syndromes (ACS) (ie, unstable angina, non-ST and ST segment elevation myocardial infarction, and acute sudden cardiac deaths due to coronary artery disease) are ischemic coronary events caused by the same pathophysiology. Coronary atherosclerosis is the cause of more than 725,000 deaths per year in the United States, and fortunately, this number has been steadily falling due to effective strategies designed to prevent and slow the progression of coronary atherosclerosis including lifestyle modification and pharmacological approaches. Although the lipids play a critical role in atherosclerosis, significant coronary atherosclerosis develops in many people without lipid abnormalities and even continues to progress in people with normal or pharmacologically controlled lipid levels. In addition, coronary arterial inflammation and endothelial dysfunction almost certainly contribute to acute thrombus formation, which appears to be the major mechanism responsible for the onset of ACS.
Jneid and associates critically analyzed the results of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study1 and several other antiplatelet trials to provide guidance to the physician regarding the use of aspirin and/or clopidogrel in patients with ACS. Since acute thrombus formation upon a disrupted atherosclerotic plaque appears to be the major mechanism responsible for the onset of ACS, appropriate inhibition of thrombus formation is crucial in the prevention and treatment of ACS. Platelet aggregation leading to acute thrombosis is a complex process and, therefore, multiple therapeutic agents may be required simultaneously to block at least 2 separate pathways in order to prevent thrombus formation. The CURE study was a randomized, double-blind study involving 482 centers from 28 countries enrolling a total of 12,562 patients diagnosed as having ACS without ST segment elevation. Using clopidrogrel plus aspirin reduced the risk of nonfatal myocardial infarctions, strokes, and death by 20 percent. The myocardial infarction risk reduction rate was reduced by 23 percent and multiple other end points (stroke occurrence, cardiovascular death, refractory ischemia, etc) demonstrated lower event rates.
Comment by Harold L. Karpman, MD, FACC, FACP
Coronary atherosclerotic plaque disruption depends upon both active and passive phenomena.2 The plaques most vulnerable to fracture and disruption are characterized by having a thin fibrous cap, a large atheromatous core, microphage infiltration, and a scarcity of smooth muscle cells. Although lipids play a critical role in atherogenesis, during the 1990s many studies clearly demonstrated that coronary atherosclerosis develops in many people without lipid abnormalities, may continue to progress in people with pharmacologically controlled lipid profiles, and that other mechanisms such as inflammation and endothelial dysfunction may contribute to the formation of atherosclerotic plaques. Beyond prevention and, certainly of equally importance, once plaque disruption occurs, the magnitude and stability of the thrombus which is formed and regulated by the biochemical composition of the lesion, the degree of injury, numerous local conditions, and the presence or absence of certain systemic factors affecting blood thrombogenicity.
Conventional antiplatelet therapy with aspirin is designed to diminish platelet aggregation, however, aspirin is a relatively weak antiplatelet drug and, in addition, up to 10 percent of patients do not respond to the antiplatelet effects of aspirin.3 Aspirin works by inhibiting the formation of thromboxane A2, thereby reducing platelet aggregability. Clopidogrel inhibits ADP-induced platelet aggregation and has been demonstrated to produce a significant 8.7 percent risk reduction in the combined end points of myocardial infarction, ischemic stroke, and vascular deaths4-5 after an average of 1.9 years of follow-up therapy.
From a clinical point of view, current evidence strongly supports the use of aspirin combined with clopidogrel for at least 9-12 months in patients presenting with ACS who have been subjected to PCI therapy. Many clinicians favor even longer-term therapy for selected patients based upon a variety of coronary risk factors. The most recent data support the use of low-dose (81 mg daily) aspirin for secondary prevention; however, higher dose (at least 162 and preferably 325 mg) therapy is recommended for the treatment of ACS. Clopidogrel should be used instead of aspirin in the primary prevention of coronary artery disease only in patients who are intolerant or resistant to aspirin. In all likelihood, the aspirin/clopidogrel combination will prove to be the appropriate form of therapy for all patients with ACS and not just patients who are at high risk; however, definitive recommendations must wait the results of the ongoing Clopidogrel for High Atherothrombic Risk and Ischemic Stabilization Management and Avoidance (CHARISMA) trial, which will compare the results of combination therapy vs aspirin alone in both secondary and in high-risk primary prevention.
Dr. Karpman, Clinical Professor of Medicine, UCLA School of Medicine, is Associate Editor of Internal Medicine Alert.
1. Yusuf S, et al. N Engl J Med. 2001;345:494-502.
2. Fuster V, et al. Lancet. 1999;353 (suppl 2):S115-S119.
3. Gum PA, et al. Am J Cardiol. 2001;88:230-235.
4. CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
5. Creager MA. Vasc Med. 1998;3:257-260.