Pharmacology & Pharmacy, 2012, 3, 481-484 Published Online October 2012 ( 1
Rationale and Role of High Loading Dose Clopidogrel in
Patients with Acute Coronary Syndrome Undergoing
Percutaneous Coronary Intervention
Sam T. Mathew1*, Gayathri Devi Subbaiah2, Prasanth Vasantha Viswanadhan3, Vinod Balan4
1Accenture Pharmaceutical Services, Bangalore, India; 2Department of Pharmaceutics, Sikkim Manipal University, Bangalore, India;
3Department of Pharmaceutics, Gautham College of Pharmacy, Bangalore, India; 4Department of Pharmaceutical Chemistry, Push-
pagiri College of Pharmacy, Thiruvalla, Kerala, India.
Email: *, *
Received March 28th, 2012; revised June 18th, 2012; accepted July 14th, 2012
Antiplatelet therapy, which red uces platelet activation and aggregation, is the corner stone of treatment for patients un-
dergoing percutaneous coronary intervention (PCI). Clopidogrel is an established oral antiplatelet medication of thie-
nopyridine class, which inhibits blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular
disease. Many studies have revealed that high loading dose clopidogrel in patients undergoing PCI. This review article
investigates the rationale and role of high loading dose clopidogrel in patients undergoing PCI.
Keywords: Clopidogrel; Antiplatelet Therapy; Percutaneous Coronary Intervention
1. Introduction
The term acute coronary syndrome (ACS) refers to any
group of clinical symptoms compatible with acute myo-
cardial ischemia and includes unstable angina (UA), non-
ST-segment elevation myocardial infarction (NSTEMI),
and ST-segment elevation myocardial infarction (STEMI)
[1]. Antiplatelet therapy, which reduces platelet activa-
tion and aggregation, integral steps in the formation of a
thrombus after plaque disruption, is the corner stone of
treatment for patients undergoing percutaneous coronary
intervention (PCI) [2 , 3] .
Clopidogrel is an established oral antiplatelet medica-
tion of thienopyridin e class, which inhibits blood clots in
coronary artery disease, peripheral vascular disease, and
cerebrovascular disease. The active metabolite of clopi-
dogrel inhibits platelet activation to a modest degree and
with wide variability in platelet response by noncompeti-
tively inhibiting the binding of adenosine diphosphate
(ADP) to the P2Y12 receptor (ADP-receptor antagonist)
that participates in the activation of the GP IIb/IIIa com-
plex [4]. The use of clopidogrel ( at a loading dose of 300
mg followed by a maintenance dose of 75 mg/day) is
now a key component of treatment strategies used in the
management of ACS, particularly for patients who un-
dergo PCI and require peri- and postprocedural thrombus
prevention. At this loading dose, inhibition of platelet
aggregation to ADP is approximately 30%, and the time
to peak effect is approximately 4 to 6 hours [5].
2. Clopidogrel in Acute Coronary Syndrome
Risk Reduction
Two pivotal clinical trials-Clopidogrel vs. Aspirin in Pa-
tients at Risk of Ischemic Events (CAPRIE) and Clopi-
dogrel in Unstable angina to prevent Recurrent Events
(CURE) have established the clinical benefits of clopi-
dogrel [6].
Patients (n = 19,185) with atherosclerotic vascular
disease, including recent myocardial infarction (MI), re-
cent ischemic stroke (IS), or established peripheral artery
disease (PAD) were evaluated in the CAPRIE study [6].
The annual IS and MI risk in clopidogrel treated group
was 5.32%, and that in the aspirin treated group was
5.83% with a relative risk reduction of 8.7% vs. aspirin
(p = 0.0431). The CURE trial was a double-blind, pla-
cebo-controlled, international, randomized trial of short-
and long-term therapy with clopidogrel vs. placebo, in
addition to aspirin and other contemporary therapies in
patients with NSTE ACS. This trial [7] randomly as-
signed patients (n = 12,562) with UA or NSTEMI to re-
ceive either aspirin alone (75 - 325 mg/day) or aspirin
plus clopidogrel (300 mg loading dose, th en 75 mg/day).
The incidence of cardiovascular death, MI, or stroke was
*Corresponding a uthor.
Copyright © 2012 SciRes. PP
Rationale and Role of High Loading Dose Clopidogrel in Patients with Acute Coronary
Syndrome Undergoing Percutaneous Coronary Intervention
20% lower for both low-risk and high risk patients who
received aspirin plus clopidogrel (11.4%) than for those
who received aspirin alone (9.3%; p < 0.0001). Benefit
was seen as early as 24 hours after the initiation of treat-
ment and continued throughout the trial’s one year treat-
ment period. The prespecified subgroup analysis, Percu-
taneous Coronary Intervention in the Clopidogrel in Un-
stable angina to prevent Recurrent Events (PCI-CURE),
found that treatment with clopidogrel before PCI was
also associated with a substantial ben efit; the red u ction in
cardiac events was 31% at 30 days and at one year. Ad-
ministration of clopidogrel therapy for a mean period of
8 months after PCI was also associated with a reduction
in cardiovascular death, MI, or need for any revasculari-
zation (p = 0.03) [8].
3. Role of High Loading Dose of Clopidogrel
in ACS Patients Undergoing PCI
Based on the findings of PCI-CURE trial, the Clopido-
grel for the Reduction of Events During Observation
(CREDO) trial and the Clopidogrel as Adjunctive Re-
perfusion Therapy-Thrombolysis in Myocardial Infarc-
tion 28 (CLARITY-TIMI 28) trial, together with the re-
sults of a meta-analysis, the 2005 guidelines from the
ACC, the AHA, and the Society for Coronary Angiogra-
phy and Interventions contain a class I, level of evidence
A recommendation for clopidogrel pretreatment before
PCI [2-9]. Results of these large clin ical trials in patients
with ACS and stable angina revealed beneficial effects
when patients were pretreated with 300 mg of clopido-
grel 6 days before the intervention in the observational
PCI-CURE trial [8], or 3 to 24 hours in the CREDO trial
[10]. Based on these observations, current clinical guide-
lines recommend a 300 mg loading dose of clopidogrel to
be administered the day before a planned PCI, or at least
6 hours before the intervention [2-10]. However, ischemic
cardiovascular events still occur. The recurrences of ische-
mic cardiovascular events may b e due to low response to
antiplatelet therapy and inter-individual variability in
platelet response to clopidogrel [11-15]. Considering these
results, other therapeutic approaches should be consid-
ered for these low-responder patients, such as higher
loading dose and or higher maintenance dose. Several
studies have reported the relationship between clopido-
grel resistance and recurrence of clinical outcomes and
suggested that treatment with a higher loading dose and
maintenance doses of clopidogrel may be more effective
than a 300 mg loading dose. These studies also showed
faster onset of action of 600 mg clopidogrel as compared
with 300 mg loading dose [16- 20].
The Antiplatelet therapy for Reduction of MYocardial
Damage during Angioplasty (ARMYDA-2) trial was the
first randomized trial to evaluate th e clinical significance
of the emerging practice standard of high dose clopido-
grel pretreatment. Patients (n = 255) scheduled to un-
dergo PCI were randomized to receive a 600 mg or 300
mg loading dose of clopidogrel and aspirin. Treatments
were administered 4 - 8 h prior to PCI. The primary en d-
point, thirty day occurrence of death, MI, or target-vessel
revascularization occurred only in 4% of patients in the
600 mg loading dose group where as it was 12% in the
300 mg loading dose group (p = 0.041). It was also ob-
served that the high-loading regimen was associated with
a 50% risk reduction of periprocedural MI (p = 0.044)
A randomized prospective study evaluated the benefit
(clinical outcomes) of a higher loading dose of clopido-
grel on platelet aggregation and recurrent ischemic events
for NSTE ACS patients undergoing coronary stenting.
Patients were randomly received a 300 mg (n = 146) or
600 mg (n = 146) loading dose of clopidogrel at least 12
h before percutaneous coronary intervention. The ADP-
induced platelet aggregation and expression of P-selectin
were significantly lower in patients receiving 600 mg
than in those receiving 300 mg. The cardiovascular out-
comes of this study are presented in Figure 1 [22].
However, despite the ad ministration of a clopidogre l 600
mg loading dose and the routine use of 75 mg clopidogrel
plus aspirin as a maintenance dose, recurrent ischemic
cardiovascular eve nts occurred [21,22].
HAN Ya-ling and co workers [23] conducted a study
to evaluate the short-term efficacy and safety of a 150
mg maintenance dose of clopidogrel following a 600 mg
loading dose in patients with ACS undergoing drug
eluting stent implantation. A 600 mg loading dose was
administered before PCI and patients were randomized to
receive clopidogrel 75 mg or 150 mg for 30 days in addi-
tion to 300 mg aspirin daily. This study concluded that a
high clopidogrel maintenance dose of 150 mg daily fol-
lowing a 600 mg loading dose for the first month after
PCI procedure reduces the risk of stent thrombosis and is
safe in patients with ACS undergoing drug eluting stent
300 mg
600 mg
CVE ACS ST Stroke CV death
ACS = acute coronary syndrome; CV death = cardiovascular death;
CVE = cardiovascular events; ST = stent thrombosis. (Reproduced
from [22]).
Figure 1. Clinical outcomes according to loading dose of
Copyright © 2012 SciRes. PP
Rationale and Role of High Loading Dose Clopidogrel in Patients with Acute Coronary
Syndrome Undergoing Percutaneous Coronary Intervention 483
implantation. A randomized, multi-center, parallel-group
study (ALBION trial [Assessment of the best loading
dose of clopidogrel to blunt platelet activation, Inflam-
mation and Ongoing Necrosis]) evaluated the effects of
three different load ing doses of clopido grel. Patients (n =
103) with non-ST-segment elevation acute coronary syn-
dromes were randomized to receive a 300 mg, 600 mg,
or 900 mg clopidogrel loading dose plus other standard
therapy including aspirin. The results of this study dem-
onstrated that clopidogrel loading doses of >300 mg can
provide faster onset of action and greater levels of inhibi-
tion of platelet aggregation in patients with NSTE-ACS
4. Conclusion
The review of published literatures shows that clopido-
grel, an adenosine diphosphate recep tor antagon ist, ach ieves
platelet inhibition with wide variability in response, and
reduces the chances of death from cardiovascular causes,
MI or stroke compared with placebo in patients with ST
and non-ST segment elevation ACS. Currently, the 300
mg loading dose of clopidogrel given at least six hours
before the procedure with a maintenance dose of 75 mg
represents the conventional antiplatelet regimen before
PCI. However, higher loading (up to 900 mg) and main-
tenance doses (150 mg) of clopidogrel given before PCI
for NSTE ACS is safe and achieve greater degrees of
platelet inhibition in a faster way than standard doses,
and result in a decreased rate of ischemic events. The low
risk of this pharmacological regimen may support its
routine use in patients before planned coronary angio-
plasty and may influence practice patterns with regard to
antiplatelet therapy before percutaneous intervention.
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