© 2000 American Heart Association, Inc.
Thrombosis |
Acute Antithrombotic Effect of a Front-Loaded Regimen of Clopidogrel in Patients With Atherosclerosis on Aspirin
From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, NY.
Correspondence Dr J.H. Chesebro, Director of Clinical Research, Zena and Michael A. Wiener Cardiovascular Institute, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574. E-mail james.chesebro{at}mssm.edu
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Abstract |
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Abstract—There is a need for a rapid antithrombotic effect after the administration of antiplatelet drugs in the setting of acute coronary syndromes and percutaneous interventions. Clopidogrel, a new thienopyridine derivative, is an efficient antiplatelet agent. However, the standard regimen of clopidogrel (75 mg/d) requires 2 to 3 days before significant antithrombotic effects. Patients with stable arterial disease on chronic aspirin therapy (n=20) were treated with clopidogrel either with a front-loaded regimen, 300 mg the first day and 75 mg/d the next 7 days, or with a standard regimen, 75 mg/d for 8 days. Blood thrombogenicity was assessed by quantification of platelet-thrombus formation in an ex vivo perfusion chamber, by ADP-induced platelet aggregation, and by ADP-induced fibrinogen binding. At 2 hours, mean total thrombus area with the standard regimen was not significantly reduced. In contrast, at 2 hours, the mean total thrombus area with the front-loaded regimen was significantly decreased by 23.1±8.5% versus baseline (P<0.05). ADP-induced platelet aggregation (with 5 and 10 µmol/L) was also significantly (P<0.05) reduced with the front-loaded regimen at 2 hours, with the mean platelet aggregation being 82.2±4.4% and 81.8±4.5%, respectively, versus baseline. Similarly, flow cytometry demonstrated a significant decrease (P<0.05) in the ADP-induced fibrinogen binding (with 0.12 and 0.6 µmol/L) at 2 hours in this front-loaded regimen group (36.1±2.0% and 53.2±9.3%). With the standard regimen, platelet activity was not significantly reduced at 2 hours. Our data suggest that a front-loaded regimen of clopidogrel added to aspirin achieves a significant antithrombotic effect at 2 hours in patients with known atherosclerotic disease on chronic aspirin therapy. This provides a rationale for using front-loaded clopidogrel in combination with aspirin in percutaneous coronary interventions.
Key Words: platelet aggregation inhibitors • thrombus • atherosclerosis
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Introduction |
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The central role of platelets in arterial thrombosis is well established.1 Platelet activity and thrombin and thromboxane generation are markedly increased after myocardial infarction, thrombolysis, unstable angina, and percutaneous coronary interventions.1 2 Numerous studies have shown that antiplatelet agents like aspirin or ticlopidine are effective for secondary prevention of coronary and cerebrovascular events.3 Combined antiplatelet therapy with aspirin and ticlopidine improves clinical outcome after stent implantation compared with aspirin alone or aspirin plus full anticoagulation.4 5 6 7 New antiplatelet drugs, including glycoprotein IIb/IIIa antagonists and clopidogrel, a new ADP-receptor antagonist, also reduce coronary events.8 9
Aspirin inhibits cyclooxygenase, whereas clopidogrel inhibits the binding of ADP to its platelet receptor, which leads to reduced binding of fibrinogen to glycoprotein IIb/IIIa receptors.10 11 Given the different mechanisms of action and proven safety of these combined drugs, combined therapy appears logical and has already given encouraging results in nonrandomized comparisons in patients undergoing coronary stenting.12 13 14 15
There is a need for rapid efficacy after the administration of antiplatelet drugs in the setting of percutaneous interventions and acute coronary syndromes. However, the standard regimen of clopidogrel (75 mg/d) requires 2 to 3 days before significant effects occur in platelet aggregation.16
The major objective of this study was to investigate whether a front-loaded regimen of clopidogrel added to aspirin could achieve a significant antithrombotic activity 2 hours after its administration. Antithrombotic activity was assessed by evaluating (1) the quantitative growth of thrombus in a well-validated ex vivo perfusion chamber, (2) ADP-induced platelet aggregation, and (3) ADP-induced fibrinogen binding by flow cytometry in patients with atherosclerosis receiving chronic aspirin therapy.17
No clinical or experimental study has assessed, in patients with atherosclerosis, the acute antithrombotic effect of the combination of clopidogrel and aspirin (load and no-load) compared with aspirin alone. Therefore, the secondary objective was to compare the antithrombotic effect at day 8 of the standard regimen of clopidogrel versus the antithrombotic effect of baseline aspirin therapy alone in atherosclerotic patients on chronic aspirin therapy.
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Methods |
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Patient Population
The study population included patients with stable coronary or peripheral arterial disease (n=20). All patients were receiving chronic aspirin therapy (325 mg/d) for
3 months. The presence of coronary artery disease was
documented by coronary angiography, history of previous
myocardial infarction, or typical angina pectoris with a positive
stress test. The existence of peripheral disease was
documented by lower-extremity claudication, previous
peripheral angioplasty, bypass grafting, or >50%
stenosis in any artery distal to the aortic bifurcation by
angiography or ultrasound. Exclusion criteria included hemoglobin <12
g%, history suggestive of recurrent blood loss, or poorly controlled
hypertension (>180/100 mm Hg). The study was approved by the
Institutional Review Board, and all patients signed informed consent to
participate. The selected patients were randomized to 1 of 2 treatment groups in a double-blind, placebo-controlled design. The front-loaded regimen group received a loading dose of 300 mg (four 75-mg capsules) of clopidogrel on the first day, followed by 75 mg/d for the next 7 days. The standard regimen group received a loading dose of 3 identical placebo capsules plus a 75-mg clopidogrel capsule on the first day followed by 75 mg/d of clopidogrel for the next 7 days. All patients continued taking 325 mg/d of aspirin for the duration of the study. The CAPRIE Trial used a dose of 75 mg/d clopidogrel, which is approved by the FDA.8 The effects of the 2 treatments were studied at serial time points throughout the study and were compared with their respective pretreatment values. This design allowed each patient to serve as his or her own control. The investigators performing the perfusion and platelet studies, described further below, were blinded as to treatment assignment.
Quantification of Platelet-Thrombus Formation
Quantification of platelet-thrombus formation was assessed
at baseline, after 2 hours, and on day 8. The effect of clopidogrel on
ex vivo arterial thrombus formation was assessed by
measuring the area of thrombus formation in a perfusion chamber. The
description, validity, and reliability of the Badimon perfusion system
to study thrombus formation on defined thrombogenic substrates under
stable rheological conditions were reported
previously.17 18 19 In brief, a 19-gauge needle was
carefully inserted into an antecubital vein. After the first 5 mL of
blood had been discarded, the needle was connected to the perfusion
chamber. Native, nonanticoagulated blood was directly perfused from the
antecubital vein to the perfusion chambers at a constant flow rate with
a peristaltic pump (Masterflex, Cole-Parmer Instruments) distal to the
chambers. The Plexiglas perfusion chamber consists of a cylindrical
flow channel (1-mm diameter, 2.5-cm length) that allows the blood to
flow over the thrombogenic substrate. All perfusions were performed for
a period of 5 minutes at a flow rate of 10 mL/min (calculated shear
rate of 1690/s; Reynolds number of 60; average blood velocity 21.2
cm/s). The selected dynamic conditions model the local rheology
associated with mildly stenosed coronary arteries. Previous
work has demonstrated that these rheological conditions result in
consistent levels of platelet
deposition.18
To mimic the in vivo situation of severe arterial injury, porcine aortic tunica media was used as the substrate to trigger thrombus formation. Segments of porcine aorta were cut into segments (2.8x0.8 cm) and surgically prepared to expose the deeper components of the arterial wall as previously described.17
The histological assessment of thrombus formation was performed by histomorphometry as previously described.17 18 19 In brief, after blood perfusion, the segments were removed from the chambers, fixed in 4% paraformaldehyde, and embedded in paraffin. Sections (5 µm) were cut and stained with a combined Masson’s trichrome-elastin to visualize the total thrombus formed on the exposed substrates. Morphometric analysis of thrombus was conducted at 400-fold magnification. Images were digitized with a Sony DKC-5000 camera using Adobe Photoshop 4.0 software on a PowerMacIntosh 8500 computer. The thrombus area on each section was measured by computerized planimetry using Image Pro-plus software (Media Cybernetic). Results are given as the average of the analyzed sections (n=6) per chamber and expressed as the percentage of thrombus area compared with baseline. The measurements were performed by a single investigator blinded to the assigned therapy.
Platelet Aggregation
Platelet aggregation was performed at baseline, 2 hours, 6
hours, day 2, and day 8. Blood (16 mL) was drawn from an antecubital
vein through a 19-gauge needle into 2 mL of 110 mmol/L trisodium
citrate solution. Platelet-rich plasma and platelet-poor plasma
were prepared by differential centrifugation.
Platelet concentration in platelet-rich plasma was adjusted to
2.5x1011/L by the addition of platelet-poor
plasma. ADP (Chronolog) at concentrations of 5 and 10 µmol/L
served as an agonist to trigger platelet aggregation. The
aggregation response was recorded for 6 minutes after addition of
the agonist in an aggregometer (Chrono-log model 440, Chrono-log Corp).
Platelet aggregation was expressed as the mean percentage of
maximum platelet aggregation compared with baseline.
Flow Cytometry
Platelet activation was assessed at baseline, 2 hours, day
2, and day 8. Samples were prepared within 1 hour of collection.
FITC-conjugated chicken anti-fibrinogen antibody (10 µL;
Wak-Chemie Medical GmbH) was added to 3 tubes containing 230
µL HEPES buffer or HEPES-EDTA buffer for the negative
control.20 Thereafter, 20 µL platelet-rich plasma
was added and incubated for 10 minutes at room temperature. Twenty
microliters of a solution of ADP in HEPES buffer (0, 0.12, and 0.6
µmol/L) was added to each sample tube, and 20 µL of HEPES-EDTA
buffer was added to the negative control. After exactly 10 minutes of
incubation, 2 mL of ice-cold HEPES buffer was added to each tube.
Samples were analyzed within the next 3 hours in a
Becton-Dickinson flow cytometric analyzer. Activated
platelets are expressed as a percentage, and the results are
expressed as the relative fibrinogen binding compared with
baseline.
Blood Samples
Blood was collected at baseline and day 8 for complete blood
examination. Blood (4.5 mL) was also collected in SCAT tubes
(Hematologic Technologies Inc) containing PPACK, EDTA, and aprotinin.
Repeated blood samples for prothrombin fragment 1+2, a marker of
thrombin generation, were obtained from the 20 patients at baseline, 2
hours, and day 8. Aliquots of plasma were stored at -70°C until
analysis with ELISA (Enzygnost, Dade Behring).
Statistical Analysis
As already mentioned, the study design allowed each patient to
serve as his or her own control (pretreatment versus posttreatment).
Continuous variables were expressed as percentage of baseline±SEM
and compared by a paired Student’s t test (within-group
comparisons). Statistical significance was considered as a 2-tailed
probability <0.05.
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Results |
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Study Population and Hematological Parameters
Twenty patients with stable coronary or peripheral arterial disease were studied; all of them completed the platelet reactivity data and 16 of them the perfusion chamber data. Baseline characteristics of these patients are summarized in the Table
. No
statistically significant differences were observed between the groups.
In particular, use of antianginal and hypolipidemic drugs did not
differ between groups.
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There were no adverse events related to the medication. All patients received aspirin (325 mg/d) with the clopidogrel. In particular, no bleeding, gastrointestinal upset or rash was noted. Hematocrit, white cell count, and platelet count were measured in EDTA-blood at baseline and at day 8 and did not change significantly.
Effects of Clopidogrel Treatments on Thrombus Area
The effects of the 2 regimens on thrombus formation were assessed
at 2 time points (2 hours and day 8) and compared with their respective
baseline (aspirin-treated) values (Figure 1). No significant difference was
observed in the mean thrombus formation between the 2 groups at
baseline, indicating the homogeneity of the study groups. At 2 hours,
mean thrombus area with the standard regimen was decreased by
9.9±7.9% but was not significantly different from baseline (aspirin
alone, P=NS). In contrast, at 2 hours, the mean thrombus
area in patients receiving the front-loaded regimen was 23.1±8.5%
less than the mean pretreatment value (P<0.05). As
expected, the mean thrombus areas were significantly
(P<0.05) reduced at day 8 in both groups compared with the
baseline (22.2±6.9% with the standard regimen and 29.1±9.1% with
the front-loaded regimen).
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Effects of Clopidogrel Treatments on Platelet Aggregation
Mean maximum percentages of ADP-induced platelet aggregation
at baseline were comparable in both groups (Figure 2A and 2B). No significant inhibition of
ADP-induced platelet aggregation was noted at 2 and 6 hours with
ADP 5 and 10 µmol/L with the standard regimen of clopidogrel
(mean platelet aggregation: 86.9±8.0%, 95.0±4.7% and
89.3±6.8%, 96.5±3.2%, respectively). At day 2, significant
inhibition was achieved, the mean platelet aggregation with ADP 5
and 10 µmol/L being 66.3±6.2% and 82.6±6.7%,
respectively.
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P<0.05 vs 2 hours.In contrast, a significant inhibition of ADP-induced platelet aggregation was observed at 2 hours with the front-loaded regimen of clopidogrel. At this time, the mean platelet aggregation for ADP 5 and 10 µmol/L was 82.2±4.4% and 81.8±4.5%, respectively, compared with baseline (aspirin alone). Further significant inhibition (P<0.05) was observed at 6 hours, with a mean platelet aggregation of 63.5±4.9% and 68.4±5.2% for both concentrations of ADP used. At day 2 and day 8, no further significant inhibition of platelet aggregation was noted.
Effects of Clopidogrel Treatments on Fibrinogen Binding to
ADP-Activated Platelets
There was no significant difference at baseline between the 2
groups (Figure 3A and 3B). With the
front-loaded regimen, platelet activation, as determined by
ADP-induced platelet-fibrinogen binding by flow cytometry, was
significantly reduced (P<0.05) at 2 hours for ADP
concentrations of 0.12 and 0.6 µmol/L, the fibrinogen binding
being 36.1±2.0% and 53.2±9.3%, respectively, compared with
baseline. In contrast, platelet activation was not significantly
reduced at 2 hours in the standard regimen, the fibrinogen binding
being 90.4±7.1% and 74.6±11.8%, respectively.
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Effect of Clopidogrel Treatments on Thrombin Generation
Baseline values of prothrombin fragment F1+2 plasma levels were
similar in both groups at baseline on aspirin (0.79±0.08 nmol/L with
the front-loaded regimen and 0.91±0.09 nmol/L with the standard
regimen). These values remained unchanged when the patients were
treated, at 2 hours and day 8 (0.89±0.11 and 0.86±0.06 nmol/L with
the front-loaded regimen and 0.84±0.09 and 0.86±0.12 nmol/L with the
standard regimen, respectively).
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Discussion |
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We have shown that a front-loaded regimen of clopidogrel (300 mg) added to aspirin achieved a significant antithrombotic activity as early as 2 hours after its administration, as assessed by reduction in thrombus formation and platelet reactivity. We have also demonstrated that the antithrombotic effect at day 8 of a standard regimen of clopidogrel (75 mg/d) in patients with atherosclerosis receiving chronic aspirin therapy is greater than the antithrombotic effect of chronic aspirin therapy alone.
Acute Antithrombotic Effect of a Front-Loaded Regimen of
Clopidogrel
With a front-loaded regimen of clopidogrel (300 mg), it is
possible to achieve a significant antithrombotic effect at 2 hours, an
effect not obtained with the standard regimen, in patients with known
atherosclerotic disease already receiving aspirin. To the best of our
knowledge, this is the first report of quantitative reduction in
thrombus formation in a patient population with documented
atherosclerotic disease receiving aspirin. Previous data in normal
subjects have indicated that a dose of 300 to 400 mg produced a rapid
onset of the pharmacodynamic activity of clopidogrel, with levels of
platelet inhibition close to steady state observed within the first
hours after dosing.21 Our findings confirm and extend
these results in patients with atherosclerotic disease receiving
chronic aspirin therapy. But more importantly, we have shown that the
antithrombotic effect, assessed in a perfusion chamber mimicking an
arterial injury atop a mild stenosis in a
coronary artery, is achieved as early as 2 hours after
front-loaded regimen administration. This provides evidence for the
rapid onset of an antithrombotic effect with a loading dose (300 mg) of
clopidogrel in the treatment of acute coronary syndromes and in
coronary stent implantation. This is important because the
median time from stent implantation to stent thrombosis in patients
treated with ticlopidine and aspirin is 
12 hours.22 To
date, it appears that a standard regimen of ticlopidine or clopidogrel
does not achieve a significant early antithrombotic effect.
We have also demonstrated that although a significant reduction in ADP-platelet aggregation is obtained with 300 mg of clopidogrel after 2 hours, a further significant reduction is achieved at 6 hours. This confirms recent findings showing that a loading regimen of clopidogrel induces maximal inhibition of platelet aggregation at 5 hours.21
The early antithrombotic effect on platelet activation we observed with a loading dose of clopidogrel, as assessed by flow cytometry, is consistent with the reduction in thrombus formation. The reduction in the fibrinogen binding obtained with a front-loaded regimen of clopidogrel is already significant at 2 hours, whereas with the standard regimen, a significant reduction was observed only at day 2. Similarly, an acceleration of platelet inhibition has been shown with a loading dose of a similar agent, ticlopidine (500 mg), in patients undergoing coronary angiography at 24 hours, but no data at 2 hours were provided.23
Prothrombin fragment F1+2 plasma levels were similar throughout the study and between the groups. This is consistent with other published data24 25 showing that thrombin generation is not directly reduced with thienopyridines.
Antithrombotic Effect of Clopidogrel Administration in
Atherosclerotic Patients Receiving Chronic Aspirin Therapy
We showed that the antithrombotic effect of treatment with
clopidogrel for 8 days (75 mg/d) in patients with
atherosclerosis receiving chronic aspirin therapy is
greater than the antithrombotic effect of chronic aspirin therapy
alone. In animal models, clopidogrel has antithrombotic effects in both
arterial and venous thrombosis.26 27 28 29 In a
porcine ex vivo model of high shear–induced stent thrombosis,
intravenous clopidogrel produced a dose-dependent
inhibition of stent thrombosis.30 In nonhuman primates,
clopidogrel reduced thrombosis in a baboon model of
arterial thrombosis.31 To the best of our
knowledge, only 1 study focused on the inhibition of thrombogenesis by
clopidogrel in humans.24 In this study, a standard regimen
of clopidogrel significantly inhibited thrombus formation in healthy
male subjects after 2 weeks of a standard regimen of clopidogrel. We
found that the inhibition was significant at day 8 in patients with
atherosclerosis receiving chronic aspirin therapy when
a standard regimen of clopidogrel was used.
Large-scale, randomized, placebo-controlled trials have clearly
established that oral aspirin therapy decreases the risk of thrombotic
events in patients with symptomatic atherosclerotic disease
by 20% to 25%.3 Because aspirin is only a
cyclooxygenase
inhibitor,32 its effectiveness is limited,
because it fails to block platelet activation by other important
agonists such as shear stress, thrombin, collagen, and ADP. Clopidogrel
is an ADP-receptor antagonist that is free of the
hematological side effects of ticlopidine therapy.8
Clopidogrel acts by irreversibly inactivating platelet ADP
receptor–initiated signaling in a dose-dependent
manner.33 In a large-scale, randomized clinical trial,
clopidogrel was shown to be significantly more effective than and at
least as safe as aspirin in decreasing arterial
thrombo-occlusive episodes in patients with symptomatic
atherosclerotic disease.8 However, aspirin and clopidogrel
interfere with different pathways of platelet activation.
Therefore, to improve the antithrombotic effect, the combination of
these 2 drugs has been suggested. Additive antithrombotic effects of
clopidogrel and aspirin have been demonstrated in experimental models
in the rabbit.34 Interestingly, clopidogrel and aspirin
have produced additive antithrombotic effects as assessed by
measurements of 111In-labeled platelets and
125I-labeled fibrin deposition in a porcine ex
vivo model of high shear–induced stent thrombosis.28 In
our study, the combination of aspirin and clopidogrel significantly
improved the antithrombotic effect of aspirin alone in patients
receiving chronic aspirin therapy. The rheological conditions (1690/s)
we used mimicked those typical of a mildly stenosed coronary
artery. These rheological conditions were selected because 70% of
the plaques responsible for an acute myocardial infarction have <50%
stenosis.35
Limitations
Our data support the added benefit of combining clopidogrel with
aspirin on thrombus formation without any bleeding complications.
However, this is a pilot study, and large-scale clinical trials are
needed to further clarify the efficacy and safety of the combination of
aspirin and clopidogrel.
Conclusions
Our data suggest that a front-loaded regimen of clopidogrel 300 mg
added to aspirin achieves a significant antithrombotic effect at 2
hours, an effect not achieved with the standard regimen, in patients
with known atherosclerotic disease on chronic aspirin therapy. This
supports the efficacy of a loading dose of clopidogrel in acute
coronary syndromes and percutaneous
coronary interventions.
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Acknowledgments |
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This work was supported by grants from the French Federation of Cardiology (G.H.), The Sociedad Española de Cardiologia (J.I.O.), The National Heart Foundation of Australia (SA Branch) (S.G.W.), Sanofi-Synthelabo, and Bristol-Myers Squibb. The authors would like to thank Stella Palencia for her excellent assistance and the staff at the Clinical Research Center for their help.
Received May 22, 2000; accepted June 7, 2000.
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