Rationale and Role of High Loading Dose Clopidogrel in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

doi:10.4236/pp.2012.34066

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Pharmacology & Pharmacy, 2012, 3, 481-484

http://dx.doi.org/10.4236/pp.2012.34066 Published Online October 2012 (http://www.SciRP.org/journal/pp) 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: *[email protected], *[email protected]

Received March 28th, 2012; revised June 18th, 2012; accepted July 14th, 2012

ABSTRACT

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.

Rationale and Role of High Loading Dose Clopidogrel in Patients with Acute Coronary

Syndrome Undergoing Percutaneous Coronary Intervention

482

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)

[21].

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

12.5

10.0

7.5

5.0

2.5

0.0

Events

(

)

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

clopidogrel.

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

[24].

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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