(Circulation. 1999;100:1667-1672.)
© 1999 American Heart Association, Inc.
Cardiovascular Drugs |
From the Department of Clinical Pharmacology, The Royal College of Surgeons in Ireland, Dublin, Ireland.
Correspondence to Professor Desmond Fitzgerald, Department of Clinical Pharmacology, The Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland. E-mail dfitzgerald{at}rcsi.ie
| Abstract |
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Key Words: antiplatelets clopidogrel ticlopidine
| Introduction |
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Adenosine Diphosphate
ADP is a platelet activator that is
released from red blood cells, activated platelets, and
damaged endothelial cells and that induces platelet
adhesion and aggregation.2 3 The platelet response to
ADP is mediated by a family of membrane-bound nucleotide
receptors called P2 receptors (Figure 2
).
These are further subdivided into P2X ligand-gated ion-channel
receptors and P2Y G-proteinlinked receptors.4 Two
separate subtypes of these receptors, P2X1 and P2Y1, have been cloned
from platelet cDNA libraries. However, only the P2X1 subtype has
been demonstrated at the protein level.5 6 P2X1 induces
transmembrane calcium flux in response to ADP but does not play a major
role in platelet aggregation and is unaffected by the
thienopyridines.7 The cloned P2Y1 receptor behaves in a
similar manner to the platelet ADP receptor when expressed in other
cell types and appears to be important in the platelet response to
ADP.8 9
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There is good evidence to indicate the presence of a third as yet unidentified ADP receptor. Binding studies indicate the presence of both high- and low-affinity P2Y receptors on platelets, and a proportion (30%) of these are insensitive to the thienopyridines.10 Functional experiments with specific P2Y1 antagonists suggest that some of these receptors are linked to the inhibition of adenylate cyclase (P2TAC), whereas a second population (P2TPLC) is linked to activation of phospholipase C, platelet shape change, and intracellular calcium mobilization.11 12 Inhibition of either receptor subtype prevents aggregation, which suggests that coordinated signaling through both these receptors is required for full platelet activation.13 The thienopyridines (1) inhibit ADP-induced inhibition of adenylate cyclase,14 (2) prevent the ADP-induced inhibition of the cytoskeletal associated protein VASP (vasodilator-stimulated phosphoprotein) phosphorylation,15 and (3) prevent the association of labeled G proteins with the platelet membrane.16 In contrast, they fail to inhibit ADP-induced platelet shape change or calcium flux. These data suggest that thienopyridines inhibit the as yet unidentified platelet P2TAC. On the other hand, inhibition of adenylate cyclase does not alter their platelet inhibitory effect, which implicates other mechanisms of action.17 In summary, although thienopyridines appear to act through the ADP receptor, the precise mechanism for their platelet inhibitory effects has not been identified.
Pharmacokinetics
Ticlopidine and clopidogrel require metabolism by the
hepatic cytochrome P450-1A enzyme system to acquire
activity.18 Plasma from treated patients leads to
inhibition of untreated platelets, which indicates the presence of
an active metabolite that has yet to be identified.19
Because of the structural similarities of ticlopidine and clopidogrel,
it is possible that both compounds produce the same active metabolite;
however, this has not been defined. Ticlopidine is rapidly absorbed and
metabolized after an oral dose.20 Its bioavailability is
increased by food and decreased by antacids.21 Clopidogrel
is also extensively metabolized, and peak plasma concentrations of the
main circulating metabolite, an inactive carboxylic acid derivative,
occur at 1 hour. Its bioavailability is unaffected by food.
Pharmacodynamics
Ticlopidine and clopidogrel prolong bleeding time, inhibit
platelet aggregation, and delay clot retraction.19 By
inhibiting the effects of ADP released from platelet dense granules
and inhibiting granule release, they also inhibit platelet
aggregation induced by other agonists, including
thromboxane analogues, platelet activating factor,
collagen, and low concentrations of thrombin.22 23
However, high concentrations of strong platelet agonists can still
overcome these inhibitory effects.24
Ex vivo, ticlopidine and clopidogrel produce dose- and time-dependent inhibition of platelet aggregation, reaching a maximum of 40% to 60% inhibition of ADP-induced aggregation after 3 to 5 days. Similarly, recovery of platelet function is delayed after discontinuation of these agents, occurring slowly over 3 to 5 days.19 25 Bleeding time is significantly prolonged with both agents and reaches a maximum of 1.5- to 2-fold of baseline at 3 to 7 days.26 27
Side Effects
Diarrhea, nausea, and vomiting are common with ticlopidine and
occur in 30% to 50% of recipients. Skin rash is also a common
problem.28 Neutropenia is the most serious side effect
reported with ticlopidine and occurs in 2.1% of ticlopidine-treated
patients.29 This can be severe (<450 neutrophils per
mm3 in 0.9% of patients) and has resulted in a
number of fatalities.30 Most cases develop within the
first 3 months of therapy and initially may be clinically silent. Full
blood counts should be performed every 2 weeks during the first 3
months of therapy to identify these potential
complications.31 Bone marrow aplasia and thrombotic
thrombocytopenic purpura have also been reported.32 33 34
Fortunately, these are usually reversible after drug withdrawal.
Ticlopidine has also been associated with cholestatic jaundice, the mechanism of which is unknown.35 Elevated levels of liver enzymes rarely occur with ticlopidine, and levels usually return to normal after discontinuation of therapy. Ticlopidine has been reported to increase serum cholesterol by an average of 9%, although without an apparent increase in cardiovascular morbidity.36
Clopidogrel has a more favorable side-effect profile than ticlopidine, and fatal complications have not been reported. Once again, gastrointestinal problems are the commonest side effect. In the CAPRIE trial (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), clinically severe rash was more frequent with clopidogrel than with aspirin (0.26% versus 0.10%, P<0.05), whereas clinically severe gastrointestinal hemorrhage was more common in aspirin-treated patients (0.71% versus 0.49%, P<0.05). Neutropenia was rare and indeed was less frequent in the clopidogrel-treated than the aspirin-treated group. Overall, bleeding was uncommon, and the frequency of any bleeding event was similar for aspirin and clopidogrel (9.27% versus 9.28%).1
Drug Interactions
The combinations of aspirin and ticlopidine or clopidogrel have
synergistic antiplatelet effects.37 38 Similarly,
ticlopidine has been shown to enhance the inhibitory
effects of a glycoprotein IIb/IIIa receptor
antagonist.39 Phenytoin toxicity has been
reported when combined with ticlopidine, probably owing to inhibition
of its metabolism.40 41 Increased
carbamazepine and theophylline levels have also been
reported.42 43
| Clinical Trials |
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In the CAPRIE trial, clopidogrel was slightly superior to aspirin in the prevention of vascular death, nonfatal or fatal stroke, and myocardial infarction in treated patients. In the 6431 patients recruited with a history of a completed atherothrombotic stroke within the previous 6 months, the clopidogrel-treated patients had an average annual event rate of 7.15% compared with 7.71% for aspirin (P=0.26).1
In summary, ticlopidine and clopidogrel are equivalent if not slightly superior to aspirin in the secondary prevention of cerebrovascular disease. The combination of these agents with aspirin may provide additional protection, particularly in patients for whom aspirin therapy is unsuccessful, although this has not been studied directly.
Myocardial Infarction and Unstable Angina
Clopidogrel and ticlopidine are effective in some animal models of
arterial thrombosis and prevent reocclusion and facilitate
clot lysis after thrombolysis.44 45
However, there has only been 1 study that examined ticlopidine in
unstable angina.46 There was a 6.3% (from 13.6% to
7.3%, P=0.009) reduction in the combined end point of
vascular death and nonfatal myocardial infarction with ticlopidine
compared with no antiplatelet therapy in the 652 patients enrolled,
similar to the benefit seen with aspirin in unstable
angina.47 However, there was no placebo arm, and the
study was performed on an open-label basis. In the CAPRIE trial, the
patients who were enrolled with myocardial infarction as their incident
event did not have a significant reduction in the primary end point of
death, myocardial infarction, or vascular death compared with
aspirin-treated patients. A post hoc analysis of all patients
(n=8446) with a history of myocardial infarction, including those
enrolled initially with a stroke or peripheral vascular
disease, revealed a nonsignificant risk reduction of 7.4% (95% CI
-5.2% to 18.6%).1 The ongoing CURE study (Clopidogrel
in Unstable angina to prevent Recurrent ischemic Events) in
patients with unstable angina and nonQ-wave myocardial infarction is
designed specifically to examine the effect of the combination of
clopidogrel and aspirin in coronary thrombosis.
Coronary Artery Stenting
A number of randomized trials have examined the combination of
aspirin and ticlopidine in patients after coronary artery
stenting (Table 2
). The STARS study
(STent Anticoagulation Restenosis Study) randomized
low-risk patients after successful stent implantation,48
the FANTASTIC (Full Anticoagulation versus ASpirin and TIClopidine
after stent implantation) and ISAR (Intracoronary Stenting and
Antithrombotic Regimen) studies evaluated intermediate- or mixed-risk
patients, and the MATTIS study (Multicenter Aspirin and Ticlopidine
Trial after Intracoronary Stenting) randomized high-risk
patients.49 50 51 The ISAR study demonstrated a significant
reduction in major cardiac events with aspirin-ticlopidine therapy
compared with aspirin-anticoagulant therapy. Similar trends were seen
in the MATTIS trial at 30 days (5.6% versus 11%, P=0.07)
and at 6 weeks in the FANTASTIC trial (5.7% versus 8.3%,
P=0.37). The STARS study compared 3 antithrombotic regimens
after successful coronary stent insertion: aspirin alone
(n=557), aspirin and warfarin (n=550), and the combination of aspirin
and ticlopidine (n=546). The combined primary end point of death,
myocardial infarction, angiographically evident thrombosis, or
revascularization of the target lesion within
30 days occurred in 3.6% of patients randomized to aspirin
monotherapy, 2.7% assigned to aspirin-warfarin therapy, and 0.5%
assigned to aspirin-ticlopidine therapy (P<0.001),
demonstrating the superiority of combined aspirin-ticlopidine therapy
over aspirin-anticoagulant and aspirin monotherapy. In the ISAR,
FANTASTIC, and MATTIS trials, hemorrhagic and peripheral
vascular complications were less frequent with antiplatelet
therapy. In the STARS study, the rate of these complications was
equivalent in the aspirin-ticlopidine group and the
aspirin-anticoagulant group, although these rates were higher than in
the aspirin monotherapy group. The combination of antiplatelet
therapies resulted in shorter hospital stays, and the early clinical
benefit of antiplatelet therapy persisted for up to 12
months,52 although no reduction in restenosis
was seen.53 The benefit of antiplatelet therapy was
also apparent in high-risk patients and was independent of stent design
(although the majority of trials used the Palmaz-Schatz
stent).54 55
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One issue raised by the trials was the timing of drug administration. In the FANTASTIC study, the acute (<24 hour) occlusion rate was higher for the antiplatelet-treated group (2.4% versus 0.4%, P=0.06). Furthermore, in the ISAR study, the benefit of combined antiplatelet therapy did not appear until 3 days after the procedure.51 Ticlopidine was delayed until after stent insertion in these trials. Ex vivo studies of platelet function indicate that ticlopidine administered after stent placement may not provide maximum periprocedural and early postprocedural protection. Platelet activation peaks at 48 to 72 hours after stent implantation,56 whereas the antiplatelet effects of ticlopidine peak at 3 to 5 days. Ticlopidine administration >24 hours before intervention results in significant inhibition of platelet aggregation at the time of the procedure.57 Furthermore, the duration of ticlopidine therapy before intervention correlates with a reduction in procedure-related nonQ-wave myocardial infarctions.58 Thus, earlier administration of ticlopidine may provide greater benefit.
In a porcine model of stent thrombosis, clopidogrel produced rapid (within 30 minutes) and dose-dependent inhibition of stent thrombosis.59 Its combination with aspirin was synergistic and produced 95% to 98% inhibition of thrombosis. The efficacy of clopidogrel in combination with aspirin is being studied in the CLopidogrel ASpirin Stent International Cooperative Study (CLASSICS). Whether clopidogrel can replace ticlopidine is as yet unclear. However, the lower rate of serious side effects reported with clopidogrel would make it an attractive alternative in this setting.
Peripheral Vascular Disease
Ticlopidine has been reported to improve pain-free and maximum
walking distance in patients with peripheral
arterial disease60 and to reduce the need for
vascular surgery.61 It has also been shown to reduce
reocclusion after thromboendarterectomy and to
significantly improve long-term patency of peripheral
saphenous vein grafts.62 63 Ticlopidine and clopidogrel
also reduce the high cardiac morbidity (60% over 10
years64 ) in patients with a history of
peripheral arterial disease.65 66
In the CAPRIE trial, clopidogrel was slightly superior to aspirin in
the prevention of stroke, myocardial infarction, and vascular death in
the patients enrolled with peripheral arterial
disease, with an average annual event rate in the clopidogrel-treated
group of 3.71% versus 4.86% in the aspirin-treated group
(P=0.0028). The combination of clopidogrel with aspirin
therapy may prove more effective, but this issue has not been addressed
in clinical trials.
Conclusions
Ticlopidine and clopidogrel are effective antiplatelet agents
and are useful in the prevention of stroke, myocardial infarction, and
vascular death in patients with vascular disease. Serious, sometimes
fatal blood dyscrasias are seen with ticlopidine use. In contrast,
clopidogrel has proved to be safe in long-term trials and to be at
least as effective as aspirin. Although clopidogrel would be an
attractive alternative to ticlopidine, it remains to be seen whether it
can prevent the thrombotic complications of coronary stent
placement. Perhaps the most important issue for antithrombotic therapy,
however, is whether clopidogrel adds to the benefit seen with aspirin.
If so, clopidogrel will have a major effect on the management of
cardiovascular disease.
| Acknowledgments |
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