Mechanism Of Action
Clopidogrel is an inhibitor of platelet activation and
aggregation through the irreversible binding of its active metabolite to the
P2Y12 class of ADP receptors on platelets.
Clopidogrel must be metabolized by CYP450 enzymes to
produce the active metabolite that inhibits platelet aggregation. The active
metabolite of clopidogrel selectively inhibits the binding of adenosine
diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent
ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby
inhibiting platelet aggregation. This action is irreversible. Consequently,
platelets exposed to clopidogrel's active metabolite are affected for the
remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced
by agonists other than ADP is also inhibited by blocking the amplification of
platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be
seen 2 hours after single oral doses of Plavix. Repeated doses of 75 mg Plavix
per day inhibit ADP-induced platelet aggregation on the first day, and
inhibition reaches steady state between Day 3 and Day 7. At steady state, the
average inhibition level observed with a dose of 75 mg Plavix per day was
between 40% and 60%. Platelet aggregation and bleeding time gradually return to
baseline values after treatment is discontinued, generally in about 5 days.
Elderly (≥ 75 years) and young healthy subjects had
similar effects on platelet aggregation.
Renally Impaired Patients
After repeated doses of 75 mg Plavix per day, patients
with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and
moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed
low (25%) inhibition of ADP-induced platelet aggregation.
Hepatically Impaired Patients
After repeated doses of 75 mg Plavix per day for 10 days
in patients with severe hepatic impairment, inhibition of ADP-induced platelet
aggregation was similar to that observed in healthy subjects.
In a small study comparing men and women, less inhibition
of ADP-induced platelet aggregation was observed in women.
Clopidogrel is a prodrug and is metabolized to a
pharmacologically active metabolite and inactive metabolites.
After single and repeated oral doses of 75 mg per day,
clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary
excretion of clopidogrel metabolites.
Effect Of Food
Plavix can be administered with or without food. In a
study in healthy male subjects when Plavix 75 mg per day was given with a
standard breakfast, mean inhibition of ADP-induced platelet aggregation was
reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the
presence of food, while there was a 57% decrease in active metabolite Cmax.
Similar results were observed when a Plavix 300 mg loading dose was
administered with a high-fat breakfast.
Clopidogrel is extensively metabolized by two main
metabolic pathways: one mediated by esterases and leading to hydrolysis into an
inactive carboxylic acid derivative (85% of circulating metabolites) and one
mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize
clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism
of the 2-oxoclopidogrel intermediate metabolite results in formation of the
active metabolite, a thiol derivative of clopidogrel. The active metabolite is
formed mostly by CYP2C19 with contributions from several other CYP enzymes,
including CYP1A2, CYP2B6 and CYP3A. The active thiol metabolite binds rapidly
and irreversibly to platelet receptors, thus inhibiting platelet aggregation
for the lifespan of the platelet.
The Cmax of the active metabolite is twice as high
following a single 300 mg clopidogrel loading dose as it is after four days of
75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after
dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active
metabolite deviates from dose proportionality: 4-fold the dose results in
2.0-fold and 2.7-fold the Cmax and AUC, respectively.
Following an oral dose of 14C-labeled
clopidogrel in humans, approximately 50% of total radioactivity was excreted in
urine and approximately 46% in feces over the 5 days post dosing. After a
single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6
hours. The half-life of the active metabolite is about 30 minutes.
Effect Of Other Drugs On Plavix
Clopidogrel is metabolized to its active metabolite in
part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results
in reduced plasma concentrations of the active metabolite of clopidogrel and a
reduction in platelet inhibition.
Proton Pump Inhibitors (PPI)
The effect of proton pump inhibitors (PPI) on the
systemic exposure to the clopidogrel active metabolite following multiple doses
of Plavix 75 mg evaluated in dedicated drug interaction studies is presented in
Figure 1: Exposure to Clopidogrel Active Metabolite
Following Multiple Doses of Plavix 75 mg Alone or with Proton Pump Inhibitors
pharmacokinetic parameters measured in these studies showed that the
interaction was highest with omeprazole and least with dexlansoprazole.
Effect Of Plavix On Other Drugs
In vitro studies have shown that the glucuronide metabolite of
clopidogrel is a strong inhibitor of CYP2C8. Concomitant administration of
repaglinide with Plavix increased the systemic exposure to repaglinide (AUC0-∞)
by 5.1-fold following the loading dose (300 mg) and by 3.9-fold on day 3 of the
maintenance dose (75 mg) of Plavix [see DRUG INTERACTIONS].
CYP2C19 is involved in the
formation of both the active metabolite and the 2-oxo-clopidogrel intermediate
metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet
effects, as measured by ex vivo platelet aggregation assays, differ according
to CYP2C19 genotype. Patients who are homozygous for nonfunctional alleles of
the CYP2C19 gene are termed “CYP2C19 poor metabolizers.” Approximately 2% of White
and 4% of Black patients are poor metabolizers; the prevalence of poor
metabolism is higher in Asian patients (e.g., 14% of Chinese). Tests are
available to identify patients who are CYP2C19 poor metabolizers.
A crossover study in 40 healthy
subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated
pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per
day and 600 mg followed by 150 mg per day, each for a total of 5 days.
Decreased active metabolite exposure and diminished inhibition of
platelet aggregation were observed in the poor metabolizers as compared to the
Table 3: Active Metabolite Pharmacokinetics and
Antiplatelet Responses by CYP2C19 Metabolizer Status
||300 mg (24 h)
|600 mg (24 h)
|75 mg (Day 5)
|150 mg (Day 5)
||300 mg (24 h)
|600 mg (24 h)
|75 mg (Day 5)
|150 mg (Day 5)
||300 mg (24 h)
|600 mg (24 h)
|75 mg (Day 5)
|150 mg (Day 5)
|* Intermediate metabolizers
have one but not two nonfunctional alleles.
† Ultrarapid metabolizers have at least one gain-of-function allele.
‡ Inhibition of platelet aggregation with 5 mcM ADP; larger value indicates
greater platelet inhibition.
§ Vasodilator-stimulated phosphoprotein - platelet reactivity index;
smaller value indicates greater platelet inhibition. Values are mean (SD).
Acute Coronary Syndrome
The CURE study included 12,562
patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24
hours of onset of the most recent episode of chest pain or symptoms consistent with
ischemia. Patients were required to have either ECG changes compatible with new
ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T
to at least twice the upper limit of normal.
Patients were randomized to receive Plavix (300-mg
loading dose followed by 75 mg once daily) or placebo, and were treated for up
to one year. Patients also received aspirin (75-325 mg once daily) and other
standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not
permitted for three days prior to randomization.
The patient population was largely White (82%) and
included 38% women, and 52% age ≥ 65 years of age. Only about 20% of
patients underwent revascularization during the initial hospitalization and few
underwent emergent or urgent revascularization.
The number of patients experiencing the primary outcome
(CV death, MI, or stroke) was 582 (9.3%) in the Plavix-treated group and 719
(11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of
10%-28%; p <0.001) for the Plavix-treated group (see Table 4).
Table 4: Outcome Events in the CURE Primary Analysis
||Plavix (+ aspirin)*
|Placebo (+ aspirin)*
|Relative Risk Reduction (%) (95% CI)
|Primary outcome (Cardiovascular death, MI, stroke)
|All Individual Outcome Events †
|* Other standard therapies were
used as appropriate.
† The individual components do not represent a breakdown of the primary and
coprimary outcomes, but rather the total number of subjects experiencing an
event during the course of the study.
Most of the benefit of Plavix occurred in the first two
months, but the difference from placebo was maintained throughout the course of
the trial (up to 12 months) (see Figure 2).
Figure 2: Cardiovascular Death, Myocardial Infarction,
and Stroke in the CURE Study
The effect of Plavix did not
differ significantly in various subgroups, as shown in Figure 3. The benefits
associated with Plavix were independent of the use of other acute and long-term
cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein
IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE
inhibitors. The efficacy of Plavix was observed independently of the dose of
aspirin (75-325 mg once daily). The use of oral anticoagulants, nonstudy
antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.
Figure 3: Hazard Ratio for Patient Baseline
Characteristics and On-Study Concomitant Medications/Interventions for the CURE
Figure 3: Hazard Ratio for
Patient Baseline Characteristics and On-Study Concomitant
Medications/Interventions for the CURE Study (continued)
The use of Plavix in CURE was
associated with a decrease in the use of thrombolytic therapy (71 patients
[1.1%] in the Plavix group, 126 patients [2.0%] in the placebo group; relative
risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the
Plavix group, 454 patients [7.2%] in the placebo group, relative risk reduction
of 18%). The use of Plavix in CURE did not affect the number of patients
treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in
the Plavix group, 2324 patients [36.9%] in the placebo group; relative risk
reduction of 4.0%).
In patients with STEMI, the
safety and efficacy of Plavix were evaluated in the randomized,
placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients
presenting within 24 hours of the onset of the symptoms of myocardial
infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression
or left bundle-branch block). Patients were randomized to receive Plavix (75 mg
once daily) or placebo, in combination with aspirin (162 mg per day), for 28
days or until hospital discharge, whichever came first.
The primary endpoints were
death from any cause and the first occurrence of re-infarction, stroke or
The patient population was 28%
women and 58% age ≥ 60 years (26% age ≥ 70 years). Fifty-five percent
(55%) of patients received thrombolytics and only 3% underwent PCI.
As shown in Table 5 and Figure 4 and Figure 5 below,
Plavix significantly reduced the relative risk of death from any cause by 7%
(p=0.029), and the relative risk of the combination of re-infarction, stroke or
death by 9% (p=0.002).
Table 5: Outcome Events in COMMIT
||Plavix (+ aspirin)
|Placebo (+ aspirin)
|Odds ratio (95% CI)
|Composite endpoint: Death, MI, or Stroke*
||0.91 (0.86, 0.97)
||0.93 (0.87, 0.99)
||0.81 (0.69, 0.95)
||0.89 (0.70, 1.13)
|* 9 patients (2 clopidogrel and 7 placebo) suffered both
a nonfatal stroke and a nonfatal MI.
† Nonfatal MI and nonfatal stroke exclude patients
who died (of any cause).
Figure 4: Cumulative Event Rates for Death in the COMMIT Study*
Figure 5: Cumulative Event
Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT
The effect of Plavix did not differ
significantly in various prespecified subgroups as shown in Figure 6. The
effect was also similar in non-prespecified subgroups including those based on
infarct location, Killip class or prior MI history. Such subgroup analyses
should be interpreted cautiously.
Figure 6: Effects of Adding Plavix to Aspirin on the
Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups
for the COMMIT Study
Recent Myocardial Infarction,
Recent Stroke, Or Established Peripheral Arterial Disease
The CAPRIE trial was a
19,185-patient, 304-center, international, randomized, double-blind,
parallel-group study comparing Plavix (75 mg daily) to aspirin (325 mg daily).
To be eligible to enroll, patients had to have: 1) recent history of myocardial
infarction (within 35 days); 2) recent histories of ischemic stroke (within 6
months) with at least a week of residual neurological signs; and/or 3)
established peripheral arterial disease (PAD). Patients received randomized
treatment for an average of 1.6 years (maximum of 3 years).
The trial's primary outcome was
the time to first occurrence of new ischemic stroke (fatal or not), new
myocardial infarction (fatal or not), or other vascular death. Deaths not
easily attributable to nonvascular causes were all classified as vascular.
Table 6: Outcome Events in the CAPRIE Primary Analysis
|Ischemic stroke (fatal or not)
|MI (fatal or not)
|Other vascular death
As shown in Table 6, Plavix was
associated with a lower incidence of outcome events, primarily MI. The overall
relative risk reduction (9.8% vs 10.6%) was 8.7%, p=0.045. Similar results were
obtained when all-cause mortality and all-cause strokes were counted instead of
vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who
survived an on-study stroke or myocardial infarction, the incidence of
subsequent events was lower in the Plavix group.
The curves showing the overall
event rate are shown in Figure 7. The event curves separated early and
continued to diverge over the 3-year follow-up period.
Figure 7: Fatal or Nonfatal
Vascular Events in the CAPRIE Study
The statistical significance
favoring Plavix over aspirin was marginal (p=0.045). However, because aspirin
is itself effective in reducing cardiovascular events in patients with recent
myocardial infarction or stroke, the effect of Plavix is substantial.
The CAPRIE trial enrolled a
population that had recent MI, recent stroke, or PAD. The efficacy of Plavix
relative to aspirin was heterogeneous across these subgroups (p=0.043) (see
Figure 8). Nonetheless this difference may be a chance occurrence because the
CAPRIE trial was not designed to evaluate the relative benefit of Plavix over
aspirin in the individual patient subgroups. The benefit was most apparent in
patients who were enrolled because of peripheral arterial disease and less
apparent in stroke patients. In patients who were enrolled in the trial on the
sole basis of a recent myocardial infarction, Plavix was not numerically
superior to aspirin.
Figure 8: Hazard Ratio and 95% CI by Baseline
Subgroups in the CAPRIE Study
No Demonstrated Benefit Of Plavix
Plus Aspirin In Patients With Multiple Risk Factors Or Established Vascular
The CHARISMA trial was a 15,603
subject, randomized, double-blind, parallel group study comparing Plavix (75 mg
daily) to placebo for prevention of ischemic events in patients with vascular
disease or multiple risk factors for atherosclerosis. All subjects were treated
with aspirin 75-162 mg daily. The mean duration of treatment was 23 months. The
study failed to demonstrate a reduction in the occurrence of the primary
endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%)
patients in the Plavix group versus 573 (7.4%) patients in the placebo group
experienced a primary outcome event (p=0.22). Bleeding of all severities was
more common in the subjects randomized to Plavix.