Dual antiplatelet therapy is the cornerstone in the management of patients with acute coronary syndromes (ACS). Ticagrelor, an oral, direct, reversibly binding, P2Y 12 receptor antagonist, is approved for the prevention of atherothrombotic events in adult patients with ACS. In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was associated with significant reductions in cardiovascular events, cardiovascular mortality, and all-cause mortality compared with clopidogrel. A subanalysis of PLATO trial data identified a geographic region interaction (p = 0.045), indicating reduced efficacy of ticagrelor versus clopidogrel in North American patients. This effect could be due to chance, but may be explained by an interaction of ticagrelor with high aspirin doses, which are commonly used in the United States. In patients taking low-dose maintenance aspirin, ticagrelor was more effective than clopidogrel in decreasing cardiovascular events regardless of the geographic region. A proposed hypothetical mechanism for the interaction between ticagrelor and higher aspirin dose is linked to the level of P2Y 12 inhibition and the potential prothrombotic effects of high-dose aspirin through the suppression of prostacyclin. A review of data regarding aspirin use for secondary prevention of events in ACS demonstrated that low aspirin doses (75 to 160 mg/day) are consistently favored for short- and long-term use because of the lack of a dose-response relationship between increasing aspirin dose and improved efficacy, and a higher incidence of gastrointestinal bleeding with increasing aspirin dose. The use of low aspirin doses reflects good clinical practice and is encouraged in current guidelines.
Acute coronary syndromes (ACS), including myocardial infarction and unstable angina, are a substantial clinical problem, representing the primary or secondary diagnosis in 1.172 million hospitalizations annually in the United States. Platelet activation plays a key role in the development of both atherosclerosis and ACS. Platelets adhere to the damaged walls of blood vessels at sites of endothelial cell activation and contribute to the development of chronic atherosclerotic plaques. In addition, platelets trigger the acute onset of arterial thrombosis in response to atherosclerotic plaque rupture. Dual antiplatelet therapy is now a cornerstone in the management of patients with ACS. Inhibition of platelet aggregation is achieved using aspirin in combination with either a thienopyridine (clopidogrel or prasugrel) or ticagrelor (which has been included in the most recently updated guidelines ). Adverse outcomes, including the risk of death, in patients with ACS decreased significantly during 1999 to 2006. This reduction coincided with the increased use of evidence-based interventions and therapies, including more potent oral antiplatelet agents.
Aspirin
Aspirin mediates its cardioprotective effects through the irreversible inhibition of cyclooxygenase (COX)-1 in the arachidonic acid pathway, subsequently blocking the production of thromboxane A 2 , a platelet agonist, thereby reducing thrombus formation.
The use of aspirin has been shown unequivocally to reduce vascular morbidity and mortality in patients with ACS both in the acute and long-term clinical settings. In a meta-analysis of 16 secondary prevention trials comparing long-term aspirin therapy with control in 17,000 high-risk patients, aspirin significantly reduced major cardiovascular events by 20% conferring an absolute benefit of 1% per year, reduced stroke by 19%, and vascular mortality by 9%. Indeed, the important role of aspirin in ACS is underlined by the nearly two-fold increased risk of adverse events in patients with ACS or a history of coronary artery disease who discontinued or did not adhere to the aspirin therapy (odds ratio 1.82, 95% confidence interval [CI] 1.52 to 2.18; p <0.00001).
Aspirin has been the foundation of antiplatelet therapy for many years. However, there is an ongoing debate regarding the optimum maintenance dose of aspirin for the secondary prevention of events in patients with ACS. The doses of aspirin licensed for use with antiplatelet agents currently available for patients with ACS will be reviewed before reviewing data regarding the optimal aspirin doses in patients with ACS and those recommended in various clinical practice guidelines.
Thienopyridines
The thienopyridines, clopidogrel and prasugrel, selectively inhibit the P2Y 12 purinoreceptor and block platelet activation for the lifespan of the platelet because of their irreversible binding to the receptor. Both compounds are prodrugs, requiring biotransformation into their active form by hepatic cytochrome P450 (CYP) enzymes, particularly the CYP3A4 isozyme.
Clopidogrel
Clopidogrel (300 mg loading dose, then 75 mg/day) is approved for the prevention of atherosclerotic events in patients with non–ST-segment elevation ACS in combination with aspirin (75 to 325 mg/day) in the United States and the European Union. This approval was based on the results of the pivotal Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. In this trial, clopidogrel plus aspirin was associated with a significant 20% reduction in the incidence of the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke compared with placebo plus aspirin in patients presenting <24 hours of onset of non–ST-segment elevation ACS (9.3% vs 11.4%; relative risk 0.80, 95% CI 0.72 to 0.90; p <0.001). However, clopidogrel plus aspirin was associated with a significantly higher incidence of major bleeding compared with placebo plus aspirin (3.7% vs 2.7%; relative risk 1.38, 95% CI 1.13 to 1.67; p = 0.001), although the incidence of life-threatening bleeding events was not significantly different between the groups (2.2% vs 1.8%; p = 0.13). In an analysis of data from the CURE study according to the aspirin dose (≤100, 101 to 199, and ≥200 mg/day), no additional efficacy benefits were seen with increasing aspirin dose, with a trend toward higher event rates with higher aspirin doses irrespective of whether patients received aspirin alone or aspirin plus clopidogrel ( Table 1 ). In addition, the risk of major bleeding significantly increased with increasing aspirin dose, irrespective of whether patients also received clopidogrel. The European Union Summary of Product Characteristics for clopidogrel in non–ST-segment elevation ACS states that
“since higher doses of ASA [aspirin] were associated with higher bleeding risk, it is recommended that the dose of ASA [aspirin] should not be higher than 100 mg.”
| Efficacy/Safety | Aspirin Alone | Aspirin + Clopidogrel | All Patients |
|---|---|---|---|
| Efficacy: composite of cardiovascular death, myocardial infarction, and stroke | |||
| Aspirin ≤100 mg (%) | 10.5 | 8.6 | 9.6 |
| Aspirin 101–199 mg (%) | 9.8 | 9.5 | 9.7 |
| Aspirin ≥200 mg (%) | 13.6 | 9.8 | 11.7 |
| p Value for trend | 0.0016 | 0.17 | 0.0011 |
| HR ∗ for 101–199 vs ≤100 mg (95% CI) | 1.0 (0.82–1.23) | 1.2 (0.98–1.48) | 1.09 (0.95–1.26) |
| HR ∗ for ≥200 vs ≤100 mg (95% CI) | 1.3 (1.08–1.52) | 1.2 (0.95–1.40) | 1.23 (1.08–1.39) |
| Safety: major bleeding | |||
| Aspirin ≤100 mg (%) | 1.9 | 3.0 | 2.4 |
| Aspirin 101–199 mg (%) | 2.8 | 3.4 | 3.1 |
| Aspirin ≥200 mg (%) | 3.7 | 4.9 | 4.3 |
| p Value for trend | <0.0001 | <0.001 | <0.0001 |
| OR † for 101–199 vs ≤100 mg (95% CI) | 1.52 (1.00–2.31) | 1.20 (0.84–1.73) | 1.33 (1.01–1.74) |
| OR † for ≥200 vs ≤100 mg (95% CI) | 1.7 (1.22–2.59) | 1.63 (1.19–2.23) | 1.70 (1.33–2.16) |
∗ Adjusted for gender, weight, hypertension, components of the Thrombolysis In Myocardial Infarction risk score, and rates of angiography, percutaneous coronary intervention, and coronary artery bypass graft.
† Adjusted for gender, weight, hypertension, components of the Thrombolysis In Myocardial Infarction risk score, rates of angiography, percutaneous coronary intervention, and coronary artery bypass graft, and the use of nonsteroidal anti-inflammatory drugs, heparin, glycoprotein IIb/IIIa inhibitors, oral anticoagulants, open-label ticlopidine, or clopidogrel at any time during the study period.
In contrast, the United States prescribing information does not contain such a recommendation.
On the basis of the results of the CLopidogrel as Adjunctive ReperfusIon TherapY (CLARITY-TIMI 28) and ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) studies, clopidogrel was also approved for use in patients with ST-segment elevation myocardial infarction in the United States and the European Union.
Prasugrel
In the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 study, prasugrel reduced the risk of the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke by 19% compared with clopidogrel (9.9% vs 12.1%; hazard ratio 0.81, 95% CI 0.73 to 0.90; p <0.001) in patients with moderate- to high-risk ACS scheduled to undergo percutaneous coronary intervention. The use of aspirin was required in patients participating in the TRITON-TIMI38 study and a dose of 75 to 162 mg/day was recommended. On the basis of the results of this study, prasugrel (60 mg loading dose followed by 10 mg/day) plus aspirin was approved for use in patients with ACS scheduled for percutaneous coronary intervention in the United States and the European Union. However, interestingly, both the United States prescribing information and the European Summary of Product Characteristics recommend aspirin 75 to 325 mg in combination with prasugrel, despite lower aspirin doses being recommended in the trial. The efficacy of prasugrel was evident regardless of aspirin dose, and there was no correlation between aspirin dose and higher risk for non–coronary bypass graft–related Thrombolysis In Myocardial Infarction major or minor bleeding in the TRITON-TIMI 38 study.
Ticagrelor
Ticagrelor, a cyclopentyl-triazolo-pyrimidine, is a direct-acting, reversibly-binding, orally available P2Y 12 receptor antagonist. Ticagrelor (180 mg loading dose then 90 mg twice daily) plus aspirin is approved to reduce the rate of thrombotic cardiovascular events in patients with ACS (unstable angina, non–ST-segment elevation ACS, and ST-segment elevation myocardial infarction) in the United States and European Union according to the results of the PLATelet inhibition and patient Outcomes (PLATO) study. In the PLATO study, ticagrelor plus aspirin reduced the incidence of the primary composite end point of myocardial infarction, stroke and death from vascular causes in patients with ACS compared with clopidogrel plus aspirin (9.8% vs 11.7%; hazard ratio 0.84, 95% CI 0.77 to 0.92; p <0.001).
In a prespecified analysis, the efficacy of ticagrelor plus aspirin was significantly higher than that of clopidogrel plus aspirin in 30 of 33 subgroups. However, the clinical benefit of ticagrelor versus clopidogrel appeared to be attenuated in patients weighing less than the median weight for their gender (p for interaction = 0.04), those not taking lipid-lowering drugs at randomization (p for interaction = 0.04), and those enrolled in North America (p for interaction = 0.045). The interactions for weight-by-sex and lipid-lowering therapy did not exhibit qualitative differences and are considered to have limited clinical significance. The region interaction suggested that ticagrelor plus aspirin was less effective than clopidogrel plus aspirin in North America (primary end point 11.9% vs 9.5%, respectively; hazard ratio 1.27, 95% CI 0.92 to 1.75; p = 0.1459). The reasons behind this geographic interaction have been explored. Although this interaction may have arisen by chance, it may also be due to the high maintenance dose of aspirin used in the United States; more patients in the United States (53.6%) took a median maintenance aspirin dose ≥300 mg/day than the rest of the world (1.7%, Table 2 ). The PLATO study protocol recommended that all patients should receive aspirin (75 to 100 mg/day), unless there were tolerability issues; up to 325 mg/day was allowed after stenting for up to 6 months. The recommended maintenance aspirin dose with ticagrelor is 75 to 150 mg/day following a loading dose in the European Union and 75 to 100 mg/day in the United States.
| Aspirin Dose (mg) | US (n = 1,261 ∗ ) | Non-US (n = 16,186 ∗ ) | ||||
|---|---|---|---|---|---|---|
| Ticagrelor, n | Clopidogrel, n | Total, n (%) | Ticagrelor, n | Clopidogrel, n | Total, n (%) | |
| ≥300 | 324 | 352 | 676 (53.6) | 140 | 140 | 280 (1.7) |
| >100–<300 | 22 | 16 | 38 (3.0) | 503 | 511 | 1,014 (6.3) |
| ≤100 | 284 | 263 | 547 (43.4) | 7,449 | 7,443 | 14,892 (92) |
As described above, it is clear that different practice patterns of aspirin dose exist and different doses of aspirin are licensed for use with clinically available P2Y 12 inhibitors. Thus, the purpose of this article is to further review aspirin dosing in patients with ACS.
Thienopyridines
The thienopyridines, clopidogrel and prasugrel, selectively inhibit the P2Y 12 purinoreceptor and block platelet activation for the lifespan of the platelet because of their irreversible binding to the receptor. Both compounds are prodrugs, requiring biotransformation into their active form by hepatic cytochrome P450 (CYP) enzymes, particularly the CYP3A4 isozyme.
Clopidogrel
Clopidogrel (300 mg loading dose, then 75 mg/day) is approved for the prevention of atherosclerotic events in patients with non–ST-segment elevation ACS in combination with aspirin (75 to 325 mg/day) in the United States and the European Union. This approval was based on the results of the pivotal Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. In this trial, clopidogrel plus aspirin was associated with a significant 20% reduction in the incidence of the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke compared with placebo plus aspirin in patients presenting <24 hours of onset of non–ST-segment elevation ACS (9.3% vs 11.4%; relative risk 0.80, 95% CI 0.72 to 0.90; p <0.001). However, clopidogrel plus aspirin was associated with a significantly higher incidence of major bleeding compared with placebo plus aspirin (3.7% vs 2.7%; relative risk 1.38, 95% CI 1.13 to 1.67; p = 0.001), although the incidence of life-threatening bleeding events was not significantly different between the groups (2.2% vs 1.8%; p = 0.13). In an analysis of data from the CURE study according to the aspirin dose (≤100, 101 to 199, and ≥200 mg/day), no additional efficacy benefits were seen with increasing aspirin dose, with a trend toward higher event rates with higher aspirin doses irrespective of whether patients received aspirin alone or aspirin plus clopidogrel ( Table 1 ). In addition, the risk of major bleeding significantly increased with increasing aspirin dose, irrespective of whether patients also received clopidogrel. The European Union Summary of Product Characteristics for clopidogrel in non–ST-segment elevation ACS states that
“since higher doses of ASA [aspirin] were associated with higher bleeding risk, it is recommended that the dose of ASA [aspirin] should not be higher than 100 mg.”
| Efficacy/Safety | Aspirin Alone | Aspirin + Clopidogrel | All Patients |
|---|---|---|---|
| Efficacy: composite of cardiovascular death, myocardial infarction, and stroke | |||
| Aspirin ≤100 mg (%) | 10.5 | 8.6 | 9.6 |
| Aspirin 101–199 mg (%) | 9.8 | 9.5 | 9.7 |
| Aspirin ≥200 mg (%) | 13.6 | 9.8 | 11.7 |
| p Value for trend | 0.0016 | 0.17 | 0.0011 |
| HR ∗ for 101–199 vs ≤100 mg (95% CI) | 1.0 (0.82–1.23) | 1.2 (0.98–1.48) | 1.09 (0.95–1.26) |
| HR ∗ for ≥200 vs ≤100 mg (95% CI) | 1.3 (1.08–1.52) | 1.2 (0.95–1.40) | 1.23 (1.08–1.39) |
| Safety: major bleeding | |||
| Aspirin ≤100 mg (%) | 1.9 | 3.0 | 2.4 |
| Aspirin 101–199 mg (%) | 2.8 | 3.4 | 3.1 |
| Aspirin ≥200 mg (%) | 3.7 | 4.9 | 4.3 |
| p Value for trend | <0.0001 | <0.001 | <0.0001 |
| OR † for 101–199 vs ≤100 mg (95% CI) | 1.52 (1.00–2.31) | 1.20 (0.84–1.73) | 1.33 (1.01–1.74) |
| OR † for ≥200 vs ≤100 mg (95% CI) | 1.7 (1.22–2.59) | 1.63 (1.19–2.23) | 1.70 (1.33–2.16) |
∗ Adjusted for gender, weight, hypertension, components of the Thrombolysis In Myocardial Infarction risk score, and rates of angiography, percutaneous coronary intervention, and coronary artery bypass graft.
† Adjusted for gender, weight, hypertension, components of the Thrombolysis In Myocardial Infarction risk score, rates of angiography, percutaneous coronary intervention, and coronary artery bypass graft, and the use of nonsteroidal anti-inflammatory drugs, heparin, glycoprotein IIb/IIIa inhibitors, oral anticoagulants, open-label ticlopidine, or clopidogrel at any time during the study period.
In contrast, the United States prescribing information does not contain such a recommendation.
On the basis of the results of the CLopidogrel as Adjunctive ReperfusIon TherapY (CLARITY-TIMI 28) and ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) studies, clopidogrel was also approved for use in patients with ST-segment elevation myocardial infarction in the United States and the European Union.
Prasugrel
In the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 study, prasugrel reduced the risk of the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke by 19% compared with clopidogrel (9.9% vs 12.1%; hazard ratio 0.81, 95% CI 0.73 to 0.90; p <0.001) in patients with moderate- to high-risk ACS scheduled to undergo percutaneous coronary intervention. The use of aspirin was required in patients participating in the TRITON-TIMI38 study and a dose of 75 to 162 mg/day was recommended. On the basis of the results of this study, prasugrel (60 mg loading dose followed by 10 mg/day) plus aspirin was approved for use in patients with ACS scheduled for percutaneous coronary intervention in the United States and the European Union. However, interestingly, both the United States prescribing information and the European Summary of Product Characteristics recommend aspirin 75 to 325 mg in combination with prasugrel, despite lower aspirin doses being recommended in the trial. The efficacy of prasugrel was evident regardless of aspirin dose, and there was no correlation between aspirin dose and higher risk for non–coronary bypass graft–related Thrombolysis In Myocardial Infarction major or minor bleeding in the TRITON-TIMI 38 study.
Ticagrelor
Ticagrelor, a cyclopentyl-triazolo-pyrimidine, is a direct-acting, reversibly-binding, orally available P2Y 12 receptor antagonist. Ticagrelor (180 mg loading dose then 90 mg twice daily) plus aspirin is approved to reduce the rate of thrombotic cardiovascular events in patients with ACS (unstable angina, non–ST-segment elevation ACS, and ST-segment elevation myocardial infarction) in the United States and European Union according to the results of the PLATelet inhibition and patient Outcomes (PLATO) study. In the PLATO study, ticagrelor plus aspirin reduced the incidence of the primary composite end point of myocardial infarction, stroke and death from vascular causes in patients with ACS compared with clopidogrel plus aspirin (9.8% vs 11.7%; hazard ratio 0.84, 95% CI 0.77 to 0.92; p <0.001).
In a prespecified analysis, the efficacy of ticagrelor plus aspirin was significantly higher than that of clopidogrel plus aspirin in 30 of 33 subgroups. However, the clinical benefit of ticagrelor versus clopidogrel appeared to be attenuated in patients weighing less than the median weight for their gender (p for interaction = 0.04), those not taking lipid-lowering drugs at randomization (p for interaction = 0.04), and those enrolled in North America (p for interaction = 0.045). The interactions for weight-by-sex and lipid-lowering therapy did not exhibit qualitative differences and are considered to have limited clinical significance. The region interaction suggested that ticagrelor plus aspirin was less effective than clopidogrel plus aspirin in North America (primary end point 11.9% vs 9.5%, respectively; hazard ratio 1.27, 95% CI 0.92 to 1.75; p = 0.1459). The reasons behind this geographic interaction have been explored. Although this interaction may have arisen by chance, it may also be due to the high maintenance dose of aspirin used in the United States; more patients in the United States (53.6%) took a median maintenance aspirin dose ≥300 mg/day than the rest of the world (1.7%, Table 2 ). The PLATO study protocol recommended that all patients should receive aspirin (75 to 100 mg/day), unless there were tolerability issues; up to 325 mg/day was allowed after stenting for up to 6 months. The recommended maintenance aspirin dose with ticagrelor is 75 to 150 mg/day following a loading dose in the European Union and 75 to 100 mg/day in the United States.
