Clopidogrel in non-ST-segment elevation acute coronary syndromes
Division of Cardiology, Population Health Research Institute, Hamilton Health Sciences, General Division, McMaster University, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2
Corresponding author. Tel: +1 905 521 2631; fax: +1 905 527 4463. E-mail address: smehta{at}mcmaster.ca
 |
Abstract |
|---|
 Top Abstract Rationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
Platelets play a central role in the pathophysiology of arterial thrombosis in patients with acute coronary syndrome (ACS). Aspirin is superior to placebo in preventing mortality and ischemic events in patients with ACS. Clopidogrel, when added to aspirin and given daily for up to 1 year, reduces cardiovascular death, myocardial infarction and stroke by 20% in patients presenting with ACS. The benefits of long term therapy with clopidogrel are present in those patients treated medically, with percutaneous coronary intervention and with CABG surgery. There is a higher risk of bleeding with clopidogrel, but this risk may be lowered with use of lower doses of aspirin (<100 mg daily). The benefits of clopidogrel in those patients undergoing an early invasive strategy may be enhanced by increasing the loading dose to 600 mg, followed by 150 mg daily for one week, then 75 mg daily. This hypothesis is being tested in the CURRENT OASIS 7 trial involving 14000 patients with ACS undergoing an early invasive strategy with intent for PCI within 24 hours, who will be randomized to this higher dose regimen of clopidogrel versus the standard dose regimen of 300 mg loading dose followed by 75 mg daily.
Key Words: Coronary disease • Platelets • Clopidogrel • Aspirin
|
Rationale for antiplatelet therapy in patients with acute coronary syndromes |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
Platelets play a central role in the pathophysiology of arterial thrombosis. Following plaque disruption, erosion, or rupture, there are three essential steps involved in the formation of a platelet-rich thrombus: platelet adhesion, platelet activation, and platelet aggregation.
The first step, platelet adhesion, is mediated by adhesive proteins such as von Willebrand factor. These adhesive proteins interact with platelet receptors (such as the glycoprotein 1b complex), which allow platelets in flowing blood to adhere to the site of injured endothelium.1 The second step, platelet activation, is an important step involving several interrelated processes. Initially, platelet activation involves a change in the three-dimensional shape of the platelet, from a smooth discoid contour, into a spiculated form.2 This shape change greatly increases the membrane surface area of the platelet, upon which thrombin generation occurs. Following this shape change, platelet activation involves degranulation or secretion of alpha and dense granules within the platelet, thereby releasing pro-thrombotic, inflammatory, and chemo-attractant mediators, which, propagate, amplify, and sustain the atherothrombotic process (‘release reaction’).3 Platelet activation then leads to a conformational change in the glycoprotein IIb/IIIa receptor, converting the receptor into a form that can bind fibrinogen and link with other platelets (platelet aggregation).4 The third final step in the formation of the platelet-rich thrombus is platelet aggregation or the actual cross-linking of platelets by fibrinogen.
|
Aspirin |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
There have been four key randomized trials evaluating the use of aspirin in unstable angina (Table 1).5–8 These early studies were performed in the 1970s and 1980s, prior to the routine use of currently used therapies including heparin, clopidogrel, and glycoprotein IIb/IIIa antagonists. They were also performed prior to the widespread use of invasive procedures such as percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery, which are now commonly performed in patients with unstable angina and NSTEMI. Nevertheless, these trials individually demonstrated benefits of aspirin over placebo or untreated control in reducing ischaemic events and have led to the universal recommendation of aspirin as standard therapy in acute coronary syndromes (ACS).
|
In the Antithrombotic Trialists' Collaboration overview,9 among all patients who were at high risk for vascular events, there was a 22% reduction in the composite of vascular death, myocardial infarction (MI), or stroke (13.2 vs. 10.7%, P<0.0001). Vascular death alone was reduced by 15% (P<0.0001). Among the subset of patients with unstable angina, there was a 46% reduction in vascular events (13.3 vs. 8.0%, P<0.0001) (Table 1).
In terms of safety, the Antithrombotic Trialists’ Collaboration meta-analysis demonstrated a 60% relative increase in major extracranial bleeding with antiplatelet therapy vs. control (1.13 vs. 0.71%, OR 1.6, 95% CI 1.4–1.8). With regard to fatal or non-fatal intracranial haemorrhage, there was a significant increase with antiplatelet therapy when compared with adjusted controls [217/48 571 (0.65%) vs. 162/48 681 (0.54%), relative increase 22%, 95% CI 3–44, P<0.01].9 However, this was balanced by a 30% reduction in fatal and non-fatal ischaemic stroke (24–35%, P<0.0001). Overall, there was a significant 22% reduction in total fatal or non-fatal stroke [2501/66 860 (3.74%) vs. 3146/67 021 (4.75%), RR 0.78, SE 0.03].9
|
Clopidogrel |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
The Clopidogrel in Unstable Angina to prevent Recurrent Events (CURE) trial established the beneficial effects of clopidogrel in addition to aspirin in patients with non-ST elevation ACS.10 CURE was a double blind, placebo-controlled, internationally randomized trial of acute and long-term therapy with clopidogrel vs. placebo in addition to aspirin and other standard therapies (including heparin, beta-blockers, ACE-inhibitors, lipid-lowering therapies) in patients with non-ST segment elevation ACS. Overall, 12 652 patients were recruited between December 1998 and September 2000 at 482 hospitals in 28 countries. Five thousand four hundred and ninety-one patients (44%) underwent angiography, 2072 (16.5%) underwent CABG, and 2658 (21.2%) underwent PCI.
The results demonstrated a 20% relative risk reduction in the first co-primary outcome of MI, stroke, or cardiovascular (CV) death in favour of clopidogrel over placebo (11.4 vs. 9.3%, RR 0.80, 95% CI 0.72–0.90, P=0.00009)10 (Table 1). Consistent reductions were observed in all components of the primary composite endpoint, with a 7% reduction in CV death (5.5 vs. 5.1%, RR 0.93), a 14% reduction in strokes (1.4 vs. 1.2%, RR 0.86), and a 23% reduction in MI (6.7 vs. 5.2%, RR 0.77). Of these MIs, the most pronounced reduction was in large MIs (with ST-elevation or Q-waves), which were reduced by 40% (3.1 vs. 1.9%, RR 0.60, 95% CI 0.48–0.76).
|
Early and late effects of clopidogrel |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
The effects of clopidogrel became apparent early after administration of the loading dose, with divergence in the Kaplan–Meier event curves occurring as early as 2 h after randomization, indicating that the 300 mg loading dose produced a rapid and clinically apparent effect.11 By 24 h after randomization, there was a significant 34% reduction in CV death, MI, stroke, or severe ischemia (RR 0.66, P=0.003). At 30 days, clopidogrel reduced the first primary endpoint by 21% (P<0.001)11 (Figure 1). These data strongly support giving the loading dose as soon as possible to obtain the greatest benefits in the largest number of patients.
|
In the CURE trial, patients were treated with study medication for a maximum of 1 year after randomization (mean follow-up 9 months). From day 31 up to 1 year, there was a highly significant reduction of 18% in the primary outcome with clopidogrel (RR 0.82, P<0.001)11 (Figure 1). This long-term benefit was in addition to the rapid early benefit observed (i.e. within the first 30 days). It is therefore recommended by both the ESC and the ACC/AHA guidelines for management of patients with UA/NSTEMI that clopidogrel be given for at least 9–12 months.
When the CURE results are stratified according to the TIMI risk score, there are significant benefits across all levels of risk. Low risk (4.1 vs. 5.7%, RR 0.71, ARR 1.6%, P<0.03), intermediate risk (9.8 vs. 11.4%, RR 0.71, ARR 1.6%, P<0.02), and high-risk patients (15.9 vs. 20.7%, RR 0.73, ARR 4.8%, P<0.003), all benefited but the greatest absolute benefit was observed in the high-risk patients.12
|
Patients with ACS treated medically (no revascularization procedure) |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
Patients who received medical therapy alone (i.e. no revascularization procedure) had a significant benefit with clopidogrel compared with placebo. In this group, there was a 10% rate of CV death, MI, or stroke in the placebo group and an 8.1% rate in the clopidogrel group which represents a 20% relative risk reduction (P<0.003) in favour of clopidogrel therapy13 (Figure 2). Therefore, clopidogrel is effective in reducing major CV events in patients with UA/NSTEMI who do not receive a revascularization procedure.
|
|
Patients with ACS undergoing PCI |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
In the PCI CURE substudy, there was a 31% reduction in CV death or MI with clopidogrel pre-treatment and long-term therapy (up to 1 year) after PCI (12.6 vs. 8.8%, RR 0.69, 95% CI 0.54–0.87, P=0.002) (Figure 2). There was a 30% reduction in the primary endpoint of CV death, MI, or urgent revascularization from the time of PCI to 30 days (6.4 vs. 4.5%, RR 0.70, P=0.03) indicating that pre-treatment with clopidogrel is beneficial. When only patients receiving an intracoronary stent were examined (100% of whom received open-label thienopyridine after PCI), there was a 44% relative risk reduction in CV death, MI, or urgent target revascularization with clopidogrel pretreatment over placebo. (P=0.017), again supporting the benefit of clopidogrel pre-treatment.14
In the long term, there was a benefit of clopidogrel over placebo from >30 days after PCI to end of follow-up, during which there was a significant reduction in CV death, MI, or rehospitalization (RR 0.86, P<0.05). There was also a reduction in CV death or MI (RR 0.79, 95% CI 0.53–1.20) during this time period, which is consistent with the highly significant overall risk reduction in PCI CURE and the late (>30 days) benefit in the overall CURE trial (Figure 1). Further, in patients who had early PCI (within 72 h of admission, n=544), there was a consistent 38% risk reduction in CV death or MI (95% CI 0.37–1.05, P=0.076) compared with patients who had delayed intervention (risk reduction 29%, 95% CI 0.54–0.92, P=0.01). The benefit of clopidogrel was identical, regardless of whether patients underwent an intervention during the initial hospitalization (12.0 vs. 8.3%, RR 0.68, 95% CI 0.50–0.92, P=0.01) or more electively, after discharge (13.8 vs. 9.8%, RR 0.70, 95% CI 0.48–1.02, P=0.06).15
|
Patients with ACS undergoing CABG |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
In CURE, 2072 patients underwent CABG. The effects of clopidogrel were consistent in CABG patients with the overall results of the CURE study on the primary outcome of CV death, MI, or stroke (14.5% clopidogrel vs. 16.2% placebo, RR 0.89, 95% CI 0.71–1.11).13 Similar benefits were observed among the 1013 patients who underwent CABG during the initial hospitalization (RR 0.78, 95% CI 0.57–1.08) (Figure 2). Overall, there was no significant increase in bleeding in patients undergoing CABG in the CURE trial. However, most patients had stopped clopidogrel for various time periods prior to CABG. When clopidogrel was stopped greater than 5 days prior to CABG, there was no excess in bleeding. When clopidogrel was continued to within 5 days of CABG, there was an increased bleeding risk (RR 1.55, P=0.06).13 There was no increase in Thrombolysis in Myocardial Infarction (TIMI) major bleeding, regardless of whether clopidogrel was continued to within 5 days of surgery. Therefore, in the minority of patients who require CABG surgery after ACS, it is recommended to hold clopidogrel for several days if possible. Alternatively, if urgent CABG is necessary, platelet transfusion may help to avoid bleeding or to treat bleeding complications should they arise. The rationale is that the half-life of clopidogrel is <24 h and new platelets transfused should not be inhibited if given after this period of time. There is also evidence that administration of aprotonin will reduce bleeding complications in patients undergoing CABG surgery who recently received dual antiplatelet therapy, even though aprotinin was not shown to reverse the pharmacological effect of clopidogrel.16
|
Safety |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
In the CURE trial, there was no significant increase in life-threatening bleeding with clopidogrel compared with placebo (2.2 vs. 1.8%, RR 1.21, 95% CI 0.95–1.56, P=0.13).10 There were similar rates of fatal bleeding (0.2 vs. 0.2%), intracranial bleeding (0.1 vs. 0.1%), bleeding requiring surgical intervention (0.7 vs. 0.7%), and bleeding resulting in a large (>5 g/dL) drop in haemoglobin (0.9 vs. 0.9%) between the clopidogrel and placebo groups.10 There was a modest increase in major bleeding with clopidogrel as defined by the CURE criteria (3.7 vs. 2.7%, RR 1.38, 95% CI 1.13–1.67, P=0.001), but no increase in TIMI major bleeding (1.08 vs. 1.15%, RR 0.94, 95% CI 0.68–1.30, P=0.70).10 Bleeding in CURE was lower in the aspirin alone group and in the aspirin plus clopidogrel group when low dose aspirin (<100 mg) was used, with no apparent compromise in efficacy, compared with higher doses of aspirin.17
|
Clopidogrel with an early invasive strategy |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
In recent years, management of ACS has shifted toward earlier angiography and revascularization, which are often performed within 24 h of hospital presentation.18 This contemporary shift in ACS management has brought with it new questions of how to optimize the benefits of antiplatelet therapy. One promising approach is to increase the loading dose of clopidogrel, thereby achieving a more rapid antiplatelet effect, potentially further improving clinical outcomes.
|
Rationale for a higher clopidogrel loading dose |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
Studies evaluating platelet aggregation parameters
Initiating therapy with clopidogrel 75 mg daily induces inhibition of ADP-induced platelet aggregation as early as 2 h after the first dose, but requires 3–7 days to achieve maximal inhibition of platelet aggregation.19 Adding a 300 mg loading dose to clopidogrel shortens the time to maximal platelet inhibition significantly.20 However, a 300 mg loading dose may not reach peak antiplatelet levels rapidly enough in patients undergoing early intervention.21,22 Recent data suggest that further increasing the loading dose to 600 mg provides an even shorter time to maximal platelet inhibition.20 A recent observational study involving 428 patients undergoing PCI demonstrated that after a clopidogrel loading dose of 600 mg, the full antiplatelet effect of the drug was achieved after 2 h.23 Two smaller studies have also suggested that a 600 mg loading dose provides a more rapid anti-platelet effect.22,23
The ALBION study (Assessment of the best Loading Dose of clopidogrel to Blunt platelet activation, Inflammation and Ongoing Necrosis) was a randomized comparison of three loading doses of clopidogrel (300, 600, and 900 mg) in high-risk coronary patients.24 Its main objective was to define the pharmocodynamic differences among these doses over 24 h, based on the inhibition of platelet activation. The results demonstrated that a loading dose of 600 mg of clopidogrel produced significantly greater inhibition of platelet aggregation by 30 min when measured using ADP 5 µM/L compared with the 300 mg loading dose. This greater inhibition became maximal by 3 h and the difference was maintained over 24 h. The rate of bleeding was similar in the 600 and 300 mg loading dose groups. The overall rate of major adverse cardiac event was higher in the 300 mg loading dose group [17.1% (6/35 included patients)] compared with the 600 mg loading dose group [5.9% (2/34 included patients]. These findings support the use of a 600 mg loading dose in ACS patients planned for PCI. ALBION also demonstrated an incremental reduction in platelet aggregation by 24 h after the loading dose, which supports the use of a higher dose (150 mg) of clopidogrel for a few days beyond the loading dose in these patients. Although promising and mechanistically important, the results of ALBION and the other platelet aggregation studies require confirmation in studies assessing clinical outcomes.
Studies evaluating clinical outcomes
Two randomized trials have assessed treatment with a 600 mg loading dose as background therapy in patients randomized to receive abciximab or placebo.22,23 In the ISAR REACT trial, 2159 patients undergoing elective PCI all received a 600 mg loading dose of clopidogrel and then were randomized to receive abciximab or placebo. There was no significant difference in the primary outcome of death, MI, or urgent target vessel revascularization between abciximab and placebo (4.2% abciximab vs. 4.0% placebo, P=NS).25 Despite the trial being underpowered, there was no trend in favour of abciximab, supporting the notion that pre-treatment with a 600 mg loading dose of clopidogrel may obviate the benefits of abciximab in lower risk elective PCI patients. A similar trial performed in diabetic patients undergoing PCI pre-treated with a 600 mg loading dose (ISAR-SWEET), also found no significant benefit of abciximab over placebo (death or MI 8.3% abciximab and 8.6% placebo, P=NS).26 These trials provide support for the efficacy of a clopidogrel 600 mg loading dose. However, because the clopidogrel dose was not randomized, definitive conclusions regarding this are not possible.
The only randomized evaluation of clopidogrel 600 vs. 300 mg loading dose assessing clinical outcomes was the ARMYDA II trial.27 In this trial, 255 patients undergoing mostly elective PCI (75% of patients) were randomized to receive either clopidogrel 600 mg or clopidogrel 300 mg 4–8 h before the procedure. There was a reduction in the primary composite outcome of death, MI, or urgent target vessel revasculization in favour of the clopidogrel 600 mg loading dose (4 vs. 12%, P=0.041), as well as in peak troponin, CK-MB, and myoglobin values.
Thus, the platelet function and clinical outcome studies performed to date have been promising for the use of a clopidogrel 600 mg loading dose. However, in order to reliably evaluate both the incremental benefit and the risk of this regimen, a large double-blind randomized trial is needed.
CURRENT-OASIS 7 trial
The CURRENT-OASIS 7 trial will evaluate the effects of a clopidogrel 600 mg loading dose, followed by 150 mg daily for 1 week followed by 75 mg daily vs. the standard regimen of 300 mg followed by 75 mg daily in patients with ACS undergoing an early invasive strategy with intent for PCI within 24 h of randomization. The primary outcome is 30-day CV death, MI, or recurrent ischaemia. In addition, the optimal dose of aspirin in patients undergoing an early invasive strategy will be studied. In a 2x2 factorial design, patients will also be randomized to high dose (
300 mg) of aspirin vs. low dose (
100 mg) of aspirin for 30 days. This trial will clarify the optimal dosing regimen of both clopidogrel and aspirin in patients with ACS undergoing an early invasive strategy.
Conflict of interest: Research grants via the Population Health Research Institute, Hamilton Health Sciences and McMaster University from Sanofi-Aventis, Bristol Myers Squibb and GlaxoSmithKline. Consultant for Sanofi-Aventis, Bristol Myers Squibb and GlaxoSmithKline.
|
References |
|---|
|
TopAbstractRationale for antiplatelet...AspirinClopidogrelEarly and late effects...Patients with ACS treated...Patients with ACS undergoing...Patients with ACS undergoing...SafetyClopidogrel with an early...Rationale for a higher...References |
|---|
- Sakariassen KS, Bolhuis PA, Sixma JJ. (1979) Human blood platelets adhesion to artery subendothelium is mediated by factor VIII-von Willebrand factor bound to the subendothelium. Nature 279:636–638.[CrossRef][Medline]
- Fox JE. (1993) The platelet cytoskeleton. Thromb Haemost 70:884–893.[Web of Science][Medline]
- Hoylaerts MF. (2002) Amplification loops: release reaction. In Gresele P, Page C, Fuster V, Vermylen J (Eds.). Platelets in Thrombotic and Non-thrombotic Disorders(Cambridge Univesity Press, Cambridge, UK).
- Calvete JJ, Mann K, Schafer W, et al. (1994) Proteolytic of the RGD-binding and non RGD-binding conformers of platelet integrin GP IIb/IIIa. Clues for identification of regions involved in receptor's activation. Biochem J 298:1–7.
- Lewis HD, Davis J, Archibald D, et al. (1983) Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med 309:396–403.[Abstract]
- Cairns J, Gent M, Singer J, et al. (1985) Aspirin, sulphinpyrazone, or both in unstable angina. N Engl J Med 313:1369–1375.[Abstract]
- Theroux P, Ouimet H, McCans J, et al. (1988) Aspirin, heparin or both to treat unstable angina. N Engl J Med 319:1105–1111.[Abstract]
- The RISC Group. (1990) Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 336:827–830.[CrossRef][Web of Science][Medline]
- Antithrombotic Trialists' Collaboration. (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324:71–86.
[Abstract/Free Full Text] - The CURE Investigators. (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST segment elevation. N Engl J Med 345:494–502.
[Abstract/Free Full Text] - Yusuf S, Mehta SR, Zhao F, et al. (2003) Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 107:966–972.
[Abstract/Free Full Text] - Budaj A, Yusuf S, Mehta SR, et al. for the CURE Investigators. (2002) Benefit of clopidogrel in patients with acute coronary syndromes without ST-segment elevation in various risk groups. Insights from the CURE trial. Circulation 106:1622–1626.
[Abstract/Free Full Text] - Fox KA, Mehta SR, Peters R, et al. (2004) Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-segment elevation acute coronary syndrome: The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial. Circulation 110:1202–1208.
[Abstract/Free Full Text] - Mehta SR, Yusuf S, Peters RJ, et al. (2001) Effects of pretreatment with clopidogrel and aspirin followed by long term therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358:527–533.[CrossRef][Web of Science][Medline]
- Lewis BS, Mehta SR, Fox KAA, et al. (2005) Benefit of clopidogrel according to timing of percutaneous coronary intervention in patients with acute coronary syndromes: further results from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Am Heart J 150:1177–1184.[CrossRef][Web of Science][Medline]
- Van der Liden J, Lindvall G, Sartipy U. (2005) Aprotinin decreases postoperative bleeding and number of transfusions in patients on clopidogrel undergoing coronary artery bypass graft surgery: a double blind, placebo-controlled, randomized clinical trial. Circulation 112:Suppl. 9, 1276–1280.
- Peters RJ, Mehta SR, Fox KA. (2003) Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the CURE study. Circulation 108:1682–1687.
[Abstract/Free Full Text] - Mehta SR, Cannon CP, Fox KAA, Wallentin L, Boden WE, Spacek R, Widimsky P, McCullough PA, Hunt D, Braunwald E, Yusuf S. (2005) Routine versus selective invasive strategiesin patiens with acute coronary syndromes: A collaborative meta-analysis of the randomized trials. JAMA 293:2908–2917.
[Abstract/Free Full Text] - Savcic M, Hauert J, Bachmann F, et al. (1999) Clopidogrel loading dose regimens: kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost 25:15–19.
- Bertrand ME, Rupprecht HJ, Urban P, et al. (2000) Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 102:624–629.
[Abstract/Free Full Text] - Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. (2004) Is a 300 mg clopidogrel loading dose sufficient to inhibit platelet function early after coronary stenting? A platelet function profile study. J Invasive Cardiol 16:325–329.[Medline]
- Lepantalo A, Virtanen KS, Heikkila J, et al. (2004) Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. Eur Heart J 25:476–483.
[Abstract/Free Full Text] - Hochholzer W, Trenk D, Fundi D, et al. (2005) Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 111:2560–2564.
[Abstract/Free Full Text] - Montalescot G, Sideris G, Meuleman G. (2006) A randomized comparison of high clopidogrel loading doses in patients with non-ST segment elevation acute coronary syndromes. The ALBION trial. J Am Coll Cardiol 48:931–938.
[Abstract/Free Full Text] - Kastrati A, Mehilli J, Schuhlen H, et al. (2004) A clinical trial of elective PCI after pretreatment with clopiodgrel. N Engl J Med 350:232–238.
[Abstract/Free Full Text] - Mehilli J, Kastrati A, Schuhlen H, et al. (2004) Randomized clinical trial of abciximab in diabetic patients undergoing elective PCI after treatment with a high clopidogrel loading dose. Circulation 110:3627–3635.
[Abstract/Free Full Text] - Patti G, Colonna G, Pasceri V, et al. (2005) Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) Study. Circulation 111:2099–2106.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Widimsky, Z. Motovska, S. Simek, P. Kala, R. Pudil, F. Holm, R. Petr, D. Bilkova, H. Skalicka, P. Kuchynka, et al. Clopidogrel pre-treatment in stable angina: for all patients >6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8 Eur. Heart J., June 2, 2008; 29(12): 1495 - 1503. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||