Aspirin, Clopidogrel, and Ticagrelor in Acute Coronary Syndromes

Jeffrey S. Berger, MD*

Dual antiplatelet therapy is the cornerstone in the management of patients with acute
coronary syndromes (ACS). Ticagrelor, an oral, direct, reversibly binding, P2Y12 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 interac-
tion between ticagrelor and higher aspirin dose is linked to the level of P2Y12 inhibition and
the potential prothrombotic effects of high-dose aspirin through the suppression of pros-
tacyclin. 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. Ó 2013 Elsevier Inc. All rights reserved. (Am J
Cardiol 2013;112:737e745)

Acute coronary syndromes (ACS), including myocar- Aspirin

dial infarction and unstable angina, are a substantial clin-
Aspirin mediates its cardioprotective effects through the
ical problem, representing the primary or secondary
irreversible inhibition of cyclooxygenase (COX)-1 in the
diagnosis in 1.172 million hospitalizations annually in the
arachidonic acid pathway, subsequently blocking the produc-
United States.1 Platelet activation plays a key role in the
tion of thromboxane A2, a platelet agonist, thereby reducing
development of both atherosclerosis and ACS.2,3 Platelets
thrombus formation.11,12
adhere to the damaged walls of blood vessels at sites of
The use of aspirin has been shown unequivocally to reduce
endothelial cell activation and contribute to the develop-
vascular morbidity and mortality in patients with ACS both in
ment of chronic atherosclerotic plaques.2 In addition,
the acute13 and long-term clinical settings.14 In a meta-analysis
platelets trigger the acute onset of arterial thrombosis in
of 16 secondary prevention trials comparing long-term aspirin
response to atherosclerotic plaque rupture.2 Dual anti-
therapy with control in 17,000 high-risk patients, aspirin
platelet therapy is now a cornerstone in the management of
significantly reduced major cardiovascular events by 20%
patients with ACS.4e9 Inhibition of platelet aggregation is
conferring an absolute benefit of 1% per year, reduced stroke by
achieved using aspirin in combination with either a thie-
19%, and vascular mortality by 9%.14 Indeed, the important
nopyridine (clopidogrel or prasugrel) or ticagrelor (which
role of aspirin in ACS is underlined by the nearly two-fold
has been included in the most recently updated guide-
increased risk of adverse events in patients with ACS or
lines4e6,9). Adverse outcomes, including the risk of death,
a history of coronary artery disease who discontinued or did not
in patients with ACS decreased significantly during 1999
adhere to the aspirin therapy (odds ratio 1.82, 95% confidence
to 2006.10 This reduction coincided with the increased use
interval [CI] 1.52 to 2.18; p <0.00001).15
of evidence-based interventions and therapies, including
Aspirin has been the foundation of antiplatelet therapy for
more potent oral antiplatelet agents.10
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.16e18 The doses of
Division of Cardiology and Hematology, Department of Medicine,
aspirin licensed for use with antiplatelet agents currently avail-
New York University School of Medicine, New York, New York. Manu- able for patients with ACS will be reviewed before reviewing
script received January 9, 2013; revised manuscript received and accepted data regarding the optimal aspirin doses in patients with ACS
April 17, 2013. and those recommended in various clinical practice guidelines.
The author did not receive any financial compensation for authoring this
article. Medical writing support was funded by AstraZeneca. Thienopyridines
See page 743 for disclosure information.
*Corresponding author: Tel: þ1 (212) 263-4004; fax: þ1 (212) 263-3988. The thienopyridines, clopidogrel and prasugrel, selec-
E-mail address: Jeffrey.berger@nyumc.org (J.S. Berger). tively inhibit the P2Y12 purinoreceptor and block platelet

0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. www.ajconline.org
http://dx.doi.org/10.1016/j.amjcard.2013.04.055
738 The American Journal of Cardiology (www.ajconline.org)

Table 1
Incidence of the composite of cardiovascular death, myocardial infarction, stroke, and major bleeding in patients in the Clopidogrel in Unstable angina to
prevent Recurrent Events (CURE) study (with clopidogrel) by aspirin dose25
Efficacy/Safety Aspirin Alone Aspirin þ Clopidogrel All Patients

Efficacy: composite of cardiovascular death, myocardial infarction, and stroke

Aspirin 100 mg (%) 10.5 8.6 9.6
Aspirin 101e199 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 101e199 vs 100 mg (95% CI) 1.0 (0.82e1.23) 1.2 (0.98e1.48) 1.09 (0.95e1.26)
HR* for 200 vs 100 mg (95% CI) 1.3 (1.08e1.52) 1.2 (0.95e1.40) 1.23 (1.08e1.39)
Safety: major bleeding
Aspirin 100 mg (%) 1.9 3.0 2.4
Aspirin 101e199 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 101e199 vs 100 mg (95% CI) 1.52 (1.00e2.31) 1.20 (0.84e1.73) 1.33 (1.01e1.74)
OR† for 200 vs 100 mg (95% CI) 1.7 (1.22e2.59) 1.63 (1.19e2.23) 1.70 (1.33e2.16)

HR ¼ hazard ratio; OR ¼ odds ratio.

* 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.

Table 2
Median maintenance aspirin dose by region in patients participating in the PLATelet inhibition and patient Outcomes (PLATO) study (with ticagrelor)37
Aspirin Dose (mg) US (n ¼ 1,261*) Non-US (n ¼ 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)

>100e<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)

US ¼ United States.
* Patients receiving concomitant aspirin.

activation for the lifespan of the platelet because of their
irreversible binding to the receptor.19,20 Both compounds
are prodrugs, requiring biotransformation into their active
form by hepatic cytochrome P450 (CYP) enzymes, partic-
ularly the CYP3A4 isozyme.20,21
Clopidogrel: Clopidogrel (300 mg loading dose, then
75 mg/day) is approved for the prevention of atherosclerotic
events in patients with noneST-segment elevation ACS in
combination with aspirin (75 to 325 mg/day) in the United
States22 and the European Union.23 This approval was based
on the results of the pivotal Clopidogrel in Unstable angina
to prevent Recurrent Events (CURE) study.24 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 noneST-segment
elevation ACS (9.3% vs 11.4%; relative risk 0.80, 95% CI
0.72 to 0.90; p <0.001).24 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 ¼ 0.001),
although the incidence of life-threatening bleeding events
was not significantly different between the groups (2.2% vs
1.8%; p ¼ 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 clopidogrel25
(Table 1). In addition, the risk of major bleeding signifi-
cantly increased with increasing aspirin dose, irrespective of
whether patients also received clopidogrel.25 The European
Union Summary of Product Characteristics for clopidogrel
in noneST-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.”23
In contrast, the United States prescribing information
does not contain such a recommendation.22
On the basis of the results of the CLopidogrel as
Adjunctive ReperfusIon TherapY (CLARITY-TIMI 28)26
and ClOpidogrel and Metoprolol in Myocardial Infarction
Trial (COMMIT)27 studies, clopidogrel was also approved
for use in patients with ST-segment elevation myocardial
infarction in the United States22 and the European Union.23
 Review/Aspirin Dose With Ticagrelor in ACS 739

Table 3
Summary of meta-analyses conducted by the Antiplatelet Trialists’ Collaboration
Year of Meta-Analysis Number of Key Findings
Studies (Patients)

1988 25 (29,000)
- 300e325 mg/day aspirin as effective as 900e1,500 mg/day aspirin in reducing the risk of new vascular
events (24% and 23% risk reduction, respectively)39
- Consistent trend for a lower incidence of gastrointestinal bleeding in patients receiving aspirin 300 mg
vs >300 mg/day40
1994 145 (70,000) - 75e325 mg/day aspirin reduced vascular events in high-risk patients41
- No direct evidence that higher doses of aspirin (500e1,500 mg/day) were more effective than lower doses
(75e325 mg/day) in high-risk patients41
2002 287 (>200,000) - Long-term aspirin use significantly reduced vascular mortality and morbidity42
- Indirect comparisons showed reductions in the risk of vascular events of 32%, 26%, and 19% in patients
receiving aspirin at 75e150, 160e325, and 500e1,500 mg/day, respectively42

Myocardial Infarction major or minor bleeding in the

Figure 1. Rates of the composite end point of vascular death, myocardial
infarction, and stroke by open-label median maintenance aspirin dose (and
randomly assigned, blinded treatment) in patients enrolled in the PLATelet
inhibition and patient Outcomes study, estimated using Kaplan-Meier
methods.37 Hazard ratio (HR) is ticagrelor versus clopidogrel. ASA ¼
aspirin.
Prasugrel: In the TRial to assess Improvement in
Therapeutic Outcomes by optimizing platelet inhibitioN
with prasugreleThrombolysis 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 clo-
pidogrel (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.28
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.28 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 States29
and the European Union.30 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.28e30 The
efficacy of prasugrel was evident regardless of aspirin dose,
and there was no correlation between aspirin dose and higher
risk for nonecoronary bypass grafterelated Thrombolysis In
TRITON-TIMI 38 study.31
Ticagrelor: Ticagrelor, a cyclopentyl-triazolo-pyrimidine,
is a direct-acting, reversibly-binding, orally available P2Y12
receptor antagonist.32,33 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, noneST-segment elevation ACS,
and ST-segment elevation myocardial infarction) in the
United States34 and European Union35 according to the
results of the PLATelet inhibition and patient Outcomes
(PLATO) study.36 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 clo-
pidogrel plus aspirin (9.8% vs 11.7%; hazard ratio 0.84,
95% CI 0.77 to 0.92; p <0.001).36
In a prespecified analysis, the efficacy of ticagrelor plus
aspirin was significantly higher than that of clopidogrel plus
aspirin in 30 of 33 subgroups.36,37 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 ¼ 0.04), those not taking
lipid-lowering drugs at randomization (p for interaction ¼
0.04), and those enrolled in North America (p for
interaction ¼ 0.045).36 The interactions for weight-by-sex
and lipid-lowering therapy did not exhibit qualitative
differences and are considered to have limited clinical
significance.37 The region interaction suggested that tica-
grelor 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 ¼
0.1459).37 The reasons behind this geographic interaction
have been explored.37 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).37 The PLATO study protocol38 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 main-
tenance aspirin dose with ticagrelor is 75 to 150 mg/day
740 The American Journal of Cardiology (www.ajconline.org)

Figure 2. Hazard ratios and 95% CI comparing ticagrelor and clopidogrel for the primary efficacy outcome according to region (United States [US] and
noneUS) and the dose category for median maintenance aspirin dose.37 *Hazard ratio (HR) was not calculated owing to small number of events. ASA ¼
aspirin; E ¼ denotes number of events; N ¼ denotes number of patients.

Figure 3. Mechanism of action of aspirin. Arachidonic acid is converted to unstable intermediates prostaglandin G2 by COX and prostaglandin H2 by
hydroperoxidase (HOX). Low-dose aspirin selectively inhibits COX-1, whereas high-dose aspirin inhibits both COX-1 and COX-2. Prostaglandin H2 is
converted by tissue-specific isomerases to multiple prostanoids that activate specific cell membrane receptors.12

following a loading dose in the European Union35 and 75 to The Evolution of Aspirin Dosing for Secondary
100 mg/day in the United States.34 Prevention of Events in ACS
As described above, it is clear that different practice
The use of aspirin for the prevention of vascular
patterns of aspirin dose exist and different doses of aspirin
morbidity and mortality has evolved over many years. The
are licensed for use with clinically available P2Y12 inhibi-
original tablet version of aspirin was developed in 1900 and
tors. Thus, the purpose of this article is to further review
sold in the United States as a 5-grain pill (w325 mg)—the
aspirin dosing in patients with ACS.
 Review/Aspirin Dose With Ticagrelor in ACS 741

Figure 4. Schematic representation of the effects of aspirin and P2Y12 receptor antagonists on platelet pathways, to explain the putative mechanism behind the
interaction between aspirin and P2Y12 receptor antagonists.53 (A) Under normal physiologic conditions, there is balance between antiaggregatory and proaggregatory
influences on the platelet. Prostaglandin I2 is antiaggregatory through the stimulation of adenylyl cyclase (AC) secondary to activation of platelet prostaglandin I2
receptors (prostacyclin [IP] receptors). Thromboxane A2 (TxA2), produced by COX within the platelet, is proaggregatory acting through platelet thromboxane A2
(TP) receptors. Activation of platelet thromboxane A2 receptors also promotes the release of adenosine diphosphate (ADP) from platelets, which further drives
aggregation. ADP produces its proaggregatory effects through activation of platelet ADP receptors (P2Y12 receptors) and inhibition of platelet AC. Activation of
P2Y12 receptors drives more production of thromboxane A2 and more release of ADP. (B) In the presence of aspirin, platelet COX is blocked, abolishing the
thromboxane A2 pathway of aggregation, but the P2Y12 pathway is unaffected. Overall, there is a reduction in the proaggregatory drive. There is also a reduction in
the antiaggregatory influence because of the reduction in the production of prostaglandin I2 by the blood vessel wall in response to aspirin. (C) In the presence of
a P2Y12 receptor antagonist, AC inhibition is reduced, and so the antiaggregatory effects of prostaglandin I2 are enhanced. As the effects of the thromboxane A2
pathway are amplified through the P2Y12 pathway the proaggregatory effects of thromboxane A2 are also reduced, as is thromboxane A2 production. (D) In the
presence of both aspirin and a P2Y12 receptor antagonist there may be some small additional reductions in the proaggregatory influences by the complete removal of
thromboxane A2 production; however, there is also a loss of prostaglandin I2, which might lead to an even greater reduction in the antiaggregatory influence.

genesis of the “higher cardiovascular” dose commonly used
today.17 An 81-mg tablet for children was arbitrarily
selected as a quarter of the adult dose and became available
in 1922.17 Given the long-term use of aspirin as an anti-
platelet therapy and its inclusion in many clinical trials,
several meta-analyses conducted by the Antiplatelet Tria-
lists’ Collaboration have highlighted key effects with
different aspirin doses, which are listed in Table 3.
Although aspirin is generally well tolerated, the most
common serious adverse event associated with its use is
bleeding, particularly gastrointestinal bleeding. The mech-
anism of gastrointestinal bleeding associated with aspirin is
related to the inhibitory effect of aspirin on COX-1 and
COX-2. In addition to their role in thromboxane A2
production, COX-1 and COX-2 are involved in the
production of cytoprotective prostaglandins in the gastric
mucosa.17,43 Inhibition of COX-1 and COX-2 in gas-
tric mucosal cells by aspirin decreases the production of
these cytoprotective prostaglandins. Almost 50% inhibition
of gastric prostaglandin levels is achieved with aspirin
30 mg/day, and maximal inhibition at w1,300 mg/day.44
Data from the Clopidogrel optimal loading dose Usage to
Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for
InterventionS (CURRENT-OASIS 7 study)45 challenged the
general perception that patients with ACS (non-ST-segment
elevation or ST-segment elevation myocardial infarction)
require a higher dose of aspirin following ACS. The
CURRENT-OASIS 7 study investigated outcomes in patients
with ACS scheduled to undergo angiography <72 hours of
hospital arrival and randomized to receive aspirin 300 to
325 mg/day or 75 to 100 mg/day with clopidogrel for
30 days.45 There was no significant difference in the incidence
of cardiovascular death, myocardial infarction, or stroke at
30 days between the high- and low-dose aspirin groups (4.2%
vs 4.4%; hazard ratio 0.97, 95% CI 0.86 to 1.09; p ¼ 0.61).
Although the incidence of major bleeding was not associated
with aspirin dose, minor bleeding (5.0% vs 4.4%; hazard ratio
1.13, 95% CI 1.00 to 1.27; p ¼ 0.04) and major gastrointestinal
bleeding (0.4% vs 0.2%; p ¼ 0.04) were significantly
increased in the high- versus low-dose aspirin groups.
A retrospective analysis of data from patients with acute ST-
segment elevation myocardial infarction in the Global Use of
Strategies to Open Occluded Arteries (GUSTO) I and III
studies46 found no short-term (24-hour, 7-day, and 30-day)
benefit with a high initial aspirin dose (325 mg) versus a lower
dose (162 mg). In addition, the high aspirin dose was shown to
742 The American Journal of Cardiology (www.ajconline.org)
Table 4
Recommendations for aspirin maintenance doses for patients with ACS in current clinical guidelines
Guideline Recommended Aspirin
Maintenance Dose (mg/day)
NSTE ACS
ESC5 75e100
ACCF/AHA6,57 75e162
STEMI
ESC7 75e100
ACC/AHA8,58 75e162
NSTE ACS and STEMI
ACCP4,9 75e100
ACC ¼ American College of Cardiology; ACCF ¼ American College of Cardiology Foundation; ACCP ¼ American College of Chest Physicians; AHA ¼
American Heart Association; CAD ¼ coronary artery disease; ESC ¼ European Society of Cardiology; NSTE ¼ noneST-segment elevation; STEMI ¼ ST-
segment elevation myocardial infarction.
significantly increase in-hospital moderate or severe bleeding
(adjusted odds ratio 1.14, 95% CI 1.05 to 1.24; p ¼ 0.003)
versus the low dose.
On the basis of the analyses described above, a generally
consistent finding is the lack of a dose-response relationship
between increasing aspirin dose and improved short- or long-
term efficacy. This conclusion is in line with data demon-
strating that the antithrombotic effect of aspirin is saturable:
a single 100 mg dose of aspirin or w30 mg daily over 1 week
almost completely suppresses platelet thromboxane A2
production.47 Thus, aspirin doses 75 to 100 mg/day are in
excess of the dose required for the full pharmacodynamic effect
of aspirin. The general consensus from these data is that low-
dose aspirin (doses ranging between 75 and 160 mg/day) is
favored for long-term secondary prevention in patients with
ACS.3,12,17,48,49
Clopidogrel and Aspirin
An overview of real-world treatment practice showed that
high aspirin doses were commonly used in North America.50
Furthermore, a cross-country evaluation of CURE also
demonstrated that use of high aspirin doses was common in
North America, with 86% of patients receiving 200 mg,
whereas low aspirin doses were commonly used in Europe
(>50% of patients in both Western and Eastern Europe
received doses of 100 mg/day). In addition to the previously
mentioned analysis by aspirin dose of the CURE data,
comparing clopidogrel plus aspirin with aspirin alone in
patients with noneST-segment elevation ACS (Table 1),25
a further analysis was undertaken in patients undergoing
percutaneous coronary intervention: PCI-CURE (n ¼ 2,658).
Patients receiving high (200 mg/day) and moderate (101 to
199 mg/day) aspirin doses had similar rates of cardiovascular
death, myocardial infarction, or stroke compared with the low-
dose aspirin group (100 mg/day: 8.6%, 7.4%, and 7.1%,
respectively).51 Major bleeding was increased with high-dose
aspirin (3.9%, 1.5%, and 1.9% in the high-, moderate-, and
low-dose group, respectively) with the risk of major bleeding
more than double in the high-dose versus low-dose groups
(hazard ratio 2.05, 95% CI 1.20 to 3.50; p ¼ 0.009). The net
adverse clinical events (death, myocardial infarction, stroke, or
Duration of Maintenance Level of Evidence
Long term 1A
Indefinite 1A
Indefinite 1A
Indefinite 1A
Not specified 1A (established CAD)
1AeB <1 yr after ACS (depending on
circumstances and other antiplatelet
therapy)
major bleeding) favored low- over high-dose aspirin (8.4% vs
11.0%, hazard ratio 1.31, 95% CI 1.00 to 1.73; p ¼ 0.056).
In the CURRENT-OASIS 7 study, the investigators
observed a nominally significant interaction between the clo-
pidogrel and aspirin dose comparisons with respect to the
primary outcome.45 Among patients assigned to higher dose
clopidogrel, the primary outcome occurred less frequently in
patients receiving the higher dose of aspirin (3.8% vs 4.5%). In
contrast, among patients randomized to standard dose clopi-
dogrel, the primary outcome occurred more frequently in the
higher dose aspirin group (4.6% vs 4.2%). This finding was
unexpected and could have been due to the play of chance.
Ticagrelor and Aspirin
In the PLATO trial investigating ticagrelor plus aspirin
versus clopidogrel plus aspirin for the prevention of
cardiovascular events in patients with ACS, it was recom-
mended that all patients receive a maintenance aspirin dose
of 75 to 100 mg/day (325 mg for 6 months was permitted in
those who received a stent).36 As mentioned above, pre-
specified subgroup analyses from the PLATO trial indicated
that the efficacy of ticagrelor plus aspirin was less compared
with clopidogrel with aspirin for 3 of 33 subgroups; one of
these was geographic region.36,37 Clopidogrel was associ-
ated with a nonsignificant trend for better outcomes in North
America, whereas ticagrelor was associated with better
outcomes in all other regions combined (rest of the world:
42 countries within Europe, the Middle East and Africa,
Asia and Australia, and Central and South America).37
The differences between ticagrelor and clopidogrel with
geographic region were further explored in detail to gain
a better understanding of the possible reasons behind this
observation.37 Systematic errors and differences in trial conduct
were ruled out as explanations for the regional interaction in
PLATO by 2 independent statistical groups.37 However, the
statistical analyses could not rule out the play of chance.37
Median aspirin maintenance dose was the only factor that
explained a substantial fraction (80% to 100%) of the
regional interaction observed in the PLATO study.37 A larger
proportion of patients in the United States took a median
aspirin dose 300 mg/day compared with the rest of the
 Review/Aspirin Dose With Ticagrelor in ACS
world (53.6% vs 1.7%, respectively), which is consistent with
previously published data.25,50 In patients taking low-dose
maintenance aspirin, ticagrelor was associated with a better
efficacy outcome compared with clopidogrel (Figure 1).37
Figure 2 shows the adjusted hazard ratios for the primary
efficacy outcome by aspirin dose. Pooling the primary effi-
cacy results for the overall cohort yielded a hazard ratio of
1.45 (95% CI 1.01 to 2.09) favoring clopidogrel with main-
tenance aspirin doses 300 mg and a hazard ratio of 0.77
(95% CI 0.69 to 0.86) favoring ticagrelor for maintenance
aspirin doses 100 mg. The interaction between aspirin dose
and treatment was significant (p ¼ 0.00006). Importantly, no
treatment-by-region interaction was observed for major
bleeding (unadjusted p ¼ 0.9048; adjusted p ¼ 0.7798).37
The biological mechanism underlying the interaction
between ticagrelor and high-dose aspirin is currently
unknown. However, a detrimental effect of high doses of
aspirin in patients with ACS has previously been reported.16
Additionally, data from the CURE trial demonstrated a 23%
increased risk for the composite of cardiovascular death,
myocardial infarction, or stroke in patients receiving aspirin
200 versus 100 mg/day (clopidogrel; Table 1).25
Several potential mechanisms of the ticagrelor-aspirin
interaction have been considered. For example, off-target
effects, that is, those mediated by processes independent of
P2Y12 inhibition, are unlikely to play a role in this inter-
action, as shown by in vitro studies demonstrating the
activity of various P2Y12 inhibitors (including ticagrelor)
against a panel of various receptors and enzymes.52 Addi-
tionally, drug-drug interaction studies have demonstrated
that aspirin had no effect on ticagrelor pharmacokinetics and
pharmacodynamics (AstraZeneca, data on file).
In vascular endothelial cells, at low doses aspirin selec-
tively inhibits COX-1 activity, whereas at high doses it also
inhibits COX-2-dependent prostaglandin I2 biosynthesis
(Figure 3).12 Prostaglandin I2 inhibits platelet aggregation
and induces vasodilation.12 Theoretically, more profound
suppression of prostaglandin I2 formation as a function of
dose-dependent inhibition of COX-2 by high doses of
aspirin could attenuate the antithrombotic effect of aspirin
and initiate or predispose to thrombosis (Figure 4).3,12,53,54
Such a phenomenon has been shown with selective COX-2
inhibitors and other nonsteroidal anti-inflammatory drugs.55
This hypothesis suggests that an interaction between aspirin
and P2Y12 inhibitors is a class effect.53 This putative
mechanism is believed to be dependent on the level of
P2Y12 inhibition.53 High-level P2Y12 receptor antagonism
can inhibit both adenosine diphosphateedependent and
platelet thromboxane A2edependent pathways of platelet
activation independently of aspirin.54 Indeed, P2Y12 recep-
tors have been shown to be critical to the generation of
irreversible aggregation through the thromboxane
A2edependent pathway.54,56 Thus, because the dose-
dependent irreversible inhibition of thromboxane A2
synthesis by aspirin reaches maximum effect at a relatively
low dose, aspirin only adds antiplatelet benefit when
combined with suboptimal P2Y12 inhibition, such as that
achieved with clopidogrel, rather than with the near-
complete P2Y12 blockade associated with ticagrelor.53,56 In
contrast, in the presence of strong P2Y12 inhibition, high
doses of aspirin have the potential to produce prothrombotic
743
effects through the loss of prostaglandin I2 (Figure 4).53,54
Further studies investigating the effects of P2Y12 inhibitors
combined with aspirin are required to elucidate the mecha-
nism underlying these effects.
Low aspirin doses are consistent with current clinical
guidelines (Table 4), which recommend maintenance aspirin
doses from 75 mg to not >162 mg in patients with noneST-
segment elevation ACS and ST-segment elevation myocar-
dial infarction.4e9,57,58 Although the mechanism underlying
the interaction between ticagrelor and high aspirin doses is
yet to be determined, the recommendation for lower main-
tenance doses of aspirin in combination with ticagrelor is
supported by a growing body of evidence demonstrating
a general lack of benefit of high maintenance doses of aspirin
in ACS.
Acknowledgment: The author acknowledges the assistance
of Josh Collis and Jackie Phillipson, PhD, of Gardiner-
Caldwell Communications in drafting the review article.
Views expressed in this review represent those of the author.
Disclosures
The author has no conflicts of interest to disclose.
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