The Role of Aspirin in Cardiovascular Prevention
Aspirin is well recognized as an effective antiplatelet drug for secondary prevention in subjects at high risk of cardiovascular events. However, most patients receiving long-term aspirin therapy still remain at substantial risk of thrombotic events due to insufficient inhibition of platelets, specifically via the thromboxane A2 pathway. Although the exact prevalence is unknown, estimates suggest that between 5.5% and 60% of patients using this drug may exhibit a degree of "aspirin resistance," depending upon the definition used and parameters measured. To date, only a limited number of clinical studies have convincingly investigated the importance of aspirin resistance. Of these, few are of a sufficient scale, well designed, and prospective, with aspirin used at standard doses. Also, most studies do not sufficiently address the issue of noncompliance to aspirin as a frequent, yet easily preventable cause of resistance to this antiplatelet drug. This review article provides a comprehensive overview of aspirin resistance, discussing its definition, prevalence, diagnosis, and therapeutic approaches. Moreover, the clinical implications of aspirin resistance are explored in various cardiovascular disease states, including diabetes mellitus, hypertension, heart failure, and other similar disorders where platelet reactivity is enhanced.
The fascinating history of aspirin-like remedies traces back to antiquity. The Assyrians and the Egyptians were well aware of the analgesic effects of a decoction of myrtle or willow leaves for joint pain. Since the times of Hippocrates, Celsus, Pliny the Elder, Dioscorides, and Galen, remedies made from willow bark were used as antipyretic and antirheumatic therapies. In 1838, the Italian chemist, Rafaelle Piria discovered the active ingredient in willow bark -- salicylic acid. However, it was not until some 60 years later when in 1897, Felix Hoffman, who worked for the Bayer pharmaceutical company in Germany, synthesized the acetylated form of salicylic acid, which was named "aspirin," and became the most widely used drug of all time. Aspirin differed markedly from previous forms of salicylic acid, with improved tolerability and reduced gastrointestinal side effects, and remains widely used as both an anti-inflammatory and antirheumatic drug.
A new era of aspirin usage began in 1971 when Sir John Vane demonstrated that the main mechanism of action was the inhibition of prostaglandin synthesis. The critical importance of this discovery was underlined in 1982 when Vane was awarded the Nobel Prize for Medicine. Subsequent clinical and experimental studies have demonstrated that low-dose aspirin irreversibly acetylates a serine residue at position 530 on the cyclooxygenase-1 (COX-1) enzyme in platelets, thus blocking synthesis of prostaglandin G2/H2 (Fig. 1). This reaction is the first in a series that allows transformation of arachidonic acid into the potent platelet agonist, thromboxane A2, thereby leading to the beneficial clinical effect of aspirin in patients with coronary artery disease and stroke.
(Enlarge Image)
Inhibition of Platelet Thromboxane A2 Pathways by Low-Dose Aspirin. Figure illustration by Rob Flewell.
The importance of aspirin therapy in this setting is sealed by a large meta-analysis from the Antithrombotic Trialists' Collaboration (287 randomized trials of antiplatelet therapy of patients at high risk of occlusive vascular events), which demonstrated a 32% reduction of nonfatal myocardial infarction (MI), nonfatal stroke, and vascular death in patients treated with 75 to 150 mg aspirin daily. Despite such strong evidence, it is increasingly appreciated that some patients still fail to respond adequately to aspirin therapy. This is usually seen by the occurrence of further clinical (thrombotic) events despite aspirin treatment in "usual" prophylactic dosages. Such "aspirin resistance" has also been defined in the laboratory setting by the failure of aspirin to fully inhibit platelet aggregation.
This review provides an overview on the importance of aspirin therapy in primary and secondary prevention of vascular disease and explores the purported role of aspirin resistance and the implications of this for everyday clinical practice.
Aspirin is well recognized as an effective antiplatelet drug for secondary prevention in subjects at high risk of cardiovascular events. However, most patients receiving long-term aspirin therapy still remain at substantial risk of thrombotic events due to insufficient inhibition of platelets, specifically via the thromboxane A2 pathway. Although the exact prevalence is unknown, estimates suggest that between 5.5% and 60% of patients using this drug may exhibit a degree of "aspirin resistance," depending upon the definition used and parameters measured. To date, only a limited number of clinical studies have convincingly investigated the importance of aspirin resistance. Of these, few are of a sufficient scale, well designed, and prospective, with aspirin used at standard doses. Also, most studies do not sufficiently address the issue of noncompliance to aspirin as a frequent, yet easily preventable cause of resistance to this antiplatelet drug. This review article provides a comprehensive overview of aspirin resistance, discussing its definition, prevalence, diagnosis, and therapeutic approaches. Moreover, the clinical implications of aspirin resistance are explored in various cardiovascular disease states, including diabetes mellitus, hypertension, heart failure, and other similar disorders where platelet reactivity is enhanced.
The fascinating history of aspirin-like remedies traces back to antiquity. The Assyrians and the Egyptians were well aware of the analgesic effects of a decoction of myrtle or willow leaves for joint pain. Since the times of Hippocrates, Celsus, Pliny the Elder, Dioscorides, and Galen, remedies made from willow bark were used as antipyretic and antirheumatic therapies. In 1838, the Italian chemist, Rafaelle Piria discovered the active ingredient in willow bark -- salicylic acid. However, it was not until some 60 years later when in 1897, Felix Hoffman, who worked for the Bayer pharmaceutical company in Germany, synthesized the acetylated form of salicylic acid, which was named "aspirin," and became the most widely used drug of all time. Aspirin differed markedly from previous forms of salicylic acid, with improved tolerability and reduced gastrointestinal side effects, and remains widely used as both an anti-inflammatory and antirheumatic drug.
A new era of aspirin usage began in 1971 when Sir John Vane demonstrated that the main mechanism of action was the inhibition of prostaglandin synthesis. The critical importance of this discovery was underlined in 1982 when Vane was awarded the Nobel Prize for Medicine. Subsequent clinical and experimental studies have demonstrated that low-dose aspirin irreversibly acetylates a serine residue at position 530 on the cyclooxygenase-1 (COX-1) enzyme in platelets, thus blocking synthesis of prostaglandin G2/H2 (Fig. 1). This reaction is the first in a series that allows transformation of arachidonic acid into the potent platelet agonist, thromboxane A2, thereby leading to the beneficial clinical effect of aspirin in patients with coronary artery disease and stroke.
(Enlarge Image)
Inhibition of Platelet Thromboxane A2 Pathways by Low-Dose Aspirin. Figure illustration by Rob Flewell.
The importance of aspirin therapy in this setting is sealed by a large meta-analysis from the Antithrombotic Trialists' Collaboration (287 randomized trials of antiplatelet therapy of patients at high risk of occlusive vascular events), which demonstrated a 32% reduction of nonfatal myocardial infarction (MI), nonfatal stroke, and vascular death in patients treated with 75 to 150 mg aspirin daily. Despite such strong evidence, it is increasingly appreciated that some patients still fail to respond adequately to aspirin therapy. This is usually seen by the occurrence of further clinical (thrombotic) events despite aspirin treatment in "usual" prophylactic dosages. Such "aspirin resistance" has also been defined in the laboratory setting by the failure of aspirin to fully inhibit platelet aggregation.
This review provides an overview on the importance of aspirin therapy in primary and secondary prevention of vascular disease and explores the purported role of aspirin resistance and the implications of this for everyday clinical practice.
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