CLINICAL RESEARCH
Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12 Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes
Robert F. Storey, MD*,*,
Steen Husted, MD ,
Robert A. Harrington, MD, FACC ,
Stanley Heptinstall, PhD ,
Robert G. Wilcox, MD,
Gary Peters, MD||,
Mark Wickens, BSc¶,
Håkan Emanuelsson, MD, PhD#,
Paul Gurbel, MD, FACC**,
Peer Grande, MD and
Christopher P. Cannon, MD, FACC
* Cardiovascular Research Unit, University of Sheffield, Sheffield, United Kingdom
Department of Medicine and Cardiology, Århus University Hospital, Århus, Denmark
Division of Cardiovascular Medicine, Duke Clinical Research Institute, Durham, North Carolina
Cardiovascular Medicine, University of Nottingham, Nottingham, United Kingdom
|| AstraZeneca R&D, Wilmington, Delaware
¶ AstraZeneca R&D, Charnwood, United Kingdom
# AstraZeneca R&D, Mölndal, Sweden
** Sinai Center for Thrombosis Research, Baltimore, Maryland
Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Manuscript received May 18, 2007;
revised manuscript received July 19, 2007,
accepted July 24, 2007.
* Reprint requests and correspondence: Dr. Robert F. Storey, Cardiovascular Research Unit, School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, United Kingdom. (Email: r.f.storey{at}sheffield.ac.uk).
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Abstract
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Objectives: In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non–ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients.
Background: Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y12 receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study).
Methods: Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals.
Results: AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (±SD)]: clopidogrel 64% [±22%], AZD6140 90 mg 79% [±22%], AZD6140 180 mg 95% [±8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel.
Conclusions: AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients. (Substudy of DISPERSE-2; http://www.clinicaltrials.gov/ct/show/NCT00391872
[ClinicalTrials.gov]
; NCT00391872)
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Abbreviations and Acronyms
| | ACS = acute coronary syndromes | | ADP = adenosine diphosphate | | bid = twice-daily administration | | qd = once-daily administration |
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Most cases of acute coronary syndromes (ACS) are caused by the formation of a platelet-rich arterial thrombus at the site of atherosclerotic plaque rupture or erosion, and antiplatelet therapy is a standard part of their management (1). Aspirin irreversibly inactivates platelet cyclooxygenase-1, preventing the formation and release of the platelet agonist thromboxane A2. However, this positive feedback loop plays a limited role in platelet reactivity to soluble platelet agonists (2), so that, although aspirin is effective in reducing the incidence of thromboembolic complications of ACS, a substantial risk of arterial thromboembolism remains (3).
Clopidogrel is a thienopyridine antiplatelet agent that is inactive until absorbed and converted to its active metabolite by hepatic cytochrome P450 enzymes (4). This active metabolite binds irreversibly to platelet P2Y12 receptors, which play a major role in amplifying the platelet responses that underlie arterial thrombosis and associated inflammation (2). The addition of clopidogrel to aspirin in the management of ACS yields greater protection against arterial thromboembolic events than aspirin alone (5). However, some patients have little detectable response to clopidogrel therapy and appear to have a higher risk of major adverse cardiac events (6–9).
AZD6140 is a novel oral P2Y12 receptor antagonist that binds reversibly to the P2Y12 receptor, antagonizing the binding of adenosine diphosphate (ADP) (10). AZD6140 does not require metabolic activation, although the major metabolite, AR-C124910XX, is also active (data on file, AstraZeneca). A phase IIa study in patients with stable atherosclerotic disease showed that AZD6140 yielded greater mean levels of inhibition of platelet aggregation than clopidogrel, and the highest doses of AZD6140 yielded consistently high levels of inhibition (11). The DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non–ST-segment Elevation myocardial infarction)-2 study compared different dose regimens of AZD6140 with clopidogrel in patients with non–ST-segment elevation ACS (12). We report here a substudy of DISPERSE-2 assessing the pharmacodynamics and pharmacokinetics of AZD6140 in comparison with clopidogrel.
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Methods
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Study design.
Full description of the methods may be found in the Online Appendix. In brief, this substudy of DISPERSE-2 was performed in selected centers. Patients who had not received clopidogrel before randomization ("clopidogrel-naïve") were studied separately from those who were currently receiving clopidogrel ("clopidogrel-pretreated").
Patients were randomized to receive either AZD6140 90 mg twice a day (bid), AZD6140 180 mg bid, or clopidogrel for 4, 8, or 12 weeks depending on the enrollment phase. One-half the patients in each AZD6140 group were randomized to receive a loading dose of AZD6140 270 mg. Patients randomized to receive clopidogrel were given a loading dose of clopidogrel 300 mg if clopidogrel naïve or a maintenance dose of 75 mg once daily (qd) if clopidogrel pretreated.
At the time points shown in the Results section, venous blood samples were collected into lithium heparin for pharmacokinetic studies and into sodium citrate for platelet aggregation studies. Optical aggregometry was performed using ADP 20 µmol/l as agonist. Percentage aggregation was recorded as both the maximum aggregation response and the final aggregation response 6 min after the addition of ADP.
Statistical analysis.
Data are presented as mean and standard deviation. Statistical significance was assigned to p values <0.05. A full description of the statistical methods is found in the Online Appendix.
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Results
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Study population.
Ninety-one patients were enrolled in this substudy (57 male, 34 female; mean age 63 ± 11 years), of whom 89 received study medication and had evaluable platelet aggregation data. Forty-five patients were clopidogrel naïve and 44 patients were clopidogrel pretreated (Fig. 1).
Platelet aggregation in clopidogrel-naïve patients.
AZD6140 inhibited platelet aggregation in a dose-dependent manner (Fig. 2). Levels of inhibition seen with all AZD6140 doses were greater than the maximum level of inhibition seen after the clopidogrel loading dose (p < 0.001 for all AZD6140 groups vs. clopidogrel at 4 h, final aggregation response). In order to illustrate interindividual variability in responses, individual data are presented as area under the curve (Fig. 3). On day 1, a consistently high response was seen with AZD6140 270 mg, and only a few individuals receiving clopidogrel had a similar response.
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Figure 2 Inhibition of Platelet Aggregation After Initial Doses of Clopidogrel and AZD6140
Mean percentage inhibition of platelet aggregation derived from (A) maximum aggregation response and (B) final aggregation response at 6 min after addition of adenosine diphosphate 20 µmol/l, for clopidogrel-naïve patients before and after clopidogrel 300 mg (n = 14), AZD6140 90 mg (n = 9), AZD6140 180 mg (n = 7), or AZD6140 270 mg (n = 15). Error bars show standard deviation and points are nudged on the X axis only to reveal error bars. *p < 0.05 for AZD6140 versus clopidogrel.
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Figure 3 Individual Responses to Clopidogrel and AZD6140
Individual area-under-the-curve data for inhibition of platelet aggregation derived from final aggregation response at 6 min after addition of ADP 20 µmol/l, for clopidogrel-naïve patients (A) after the first dose of either clopidogrel 300 mg, AZD6140 90 mg, AZD6140 180 mg, or AZD6140 270 mg and (B) after 4 weeks of treatment and after next dose of either clopidogrel 75 mg, AZD6140 90 mg, or AZD6140 180 mg. Data are for the first 8 h of treatment but are representative of the smaller numbers for whom data were available for the full 12 h. The lines indicate mean values. *p < 0.05 for AZD6140 versus clopidogrel. ADP = adenosine diphosphate; IPA = inhibition of platelet aggregation; other abbreviations as in Figure 1.
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Inhibition of platelet aggregation by AZD6140 remained stable at 4 weeks (Fig. 4), and the most consistent response was seen with AZD6140 180 mg (Fig. 3B). Inhibition by clopidogrel remained lower than either AZD6140 group (e.g., p = 0.12, 0.04, and 0.002 for clopidogrel vs. AZD6140 90 mg at 4, 8, and 12 weeks, respectively, and p = 0.004, 0.017, and 0.004 for clopidogrel vs. AZD6140 180 mg, respectively, 4 h post-dose, final response).
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Figure 4 Steady-State and 24 h Postdose Inhibition of Platelet Aggregation by Clopidogrel and AZD6140
Mean percentage inhibition of platelet aggregation both after 4 weeks of study medication (clopidogrel-naïve patients) and 24 h after discontinuation of study medication derived from (A) maximum aggregation response and (B) final aggregation response at 6 min after addition of adenosine diphosphate 20 µmol/l, before and after the next dose of either clopidogrel 75 mg (n = 10), AZD6140 90 mg (n = 15), or AZD6140 180 mg (n = 10). Error bars show standard deviation and points are nudged on the X axis only to reveal error bars. *p < 0.05 for AZD6140 versus clopidogrel; p < 0.05 for clopidogrel predose versus 2 h postdose.
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Platelet aggregation in clopidogrel-pretreated patients..
The mean (standard deviation) baseline level of platelet aggregation in the group of patients allocated to receive further clopidogrel 75 mg qd was 38% (±15%, final response) and changed little at 4 h (36% [±17%], final response), whereas each of the AZD6140 doses produced substantial further inhibition of platelet aggregation in a dose-dependent fashion (Fig. 5). This substantial inhibition by AZD6140 occurred regardless of the baseline aggregation response; the 12 patients in the highest tertile of aggregation response at baseline (52.6% to 100%) that received any dose of AZD6140 had a mean reduction in platelet aggregation from 62.3% to 7.4%, compared with 10 patients in the lowest tertile of aggregation response at baseline (0% to 35.5%), who had a mean reduction in platelet aggregation from 19.3% to 2.2%.
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Figure 5 Suppression of Platelet Aggregation by AZD6140 in Clopidogrel-Pretreated Patients
Mean percentage platelet aggregation derived from final aggregation response at 6 min after addition of adenosine diphosphate 20 µmol/l, for clopidogrel-pretreated patients before and after either clopidogrel 75 mg (n = 12) or the first dose of AZD6140 90 mg (n = 9), AZD6140 180 mg (n = 7), or AZD6140 270 mg (n = 16). Error bars show standard deviation and points are nudged on the X axis only to reveal error bars. *p < 0.05 for AZD6140 versus clopidogrel.
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Pharmacokinetics of AZD6140 and its active major metabolite, AR-C124910XX.
Mean levels of AZD6140 were highest at the 2-h time point whereas mean levels of the active metabolite AR-C124910XX peaked at 2 to 4 h with levels 2- to 5-fold lower than those of AZD6140. Pharmacokinetic parameters are shown in the Online Appendix.
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Discussion
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This substudy of DISPERSE-2 is the first study to assess the pharmacodynamic effects of a reversible oral P2Y12 receptor antagonist in patients with ACS. All initial doses of AZD6140 achieved greater inhibition of platelet aggregation than a 300-mg loading dose of clopidogrel, providing a rationale for further studies assessing whether AZD6140 offers superior efficacy in protecting against thromboembolic events in patients with ACS.
Some patients respond poorly to clopidogrel, even when a higher loading dose of 600 mg is employed, although this higher dose does reduce the proportion of patients exhibiting a poor response in the early phase of treatment (13). Although we did not study a 600-mg loading dose of clopidogrel and would expect to have seen higher levels of inhibition in the first day of treatment with this higher loading dose, a previous study has suggested that levels of inhibition after 48 h are similar to those achieved with a 300-mg loading dose followed by maintenance therapy (14). We found in this study that the clopidogrel 75-mg daily maintenance dose achieves an increase in inhibition 4 h postdose at steady state, as seen at the 4-week time point. This may relate to the fact that clopidogrel is metabolized rapidly to its inactive carboxyl metabolite, and new platelets released into the circulation after clopidogrel is metabolized in this way will not be exposed to active metabolite of clopidogrel until the next dose is given. This is different from the dynamics of inhibition by AZD6140, which is constantly present in the plasma and so will continue to inhibit new platelets as they are released, to an extent determined by the steady-state plasma levels of AZD6140 and its active metabolite.
This study also demonstrates that treatment with AZD6140 leads to further inhibition of platelet aggregation in those patients who are already receiving treatment with clopidogrel, even in those patients who have the highest platelet aggregation response on clopidogrel alone. This is consistent with blockade of P2Y12 receptors by AZD6140 that are not blocked by clopidogrel therapy and supports the assumption that AZD6140 can address the problem of high platelet reactivity in patients treated with clopidogrel.
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Conclusions
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AZD6140 yields greater and more consistent inhibition of platelet aggregation, in a dose-dependent and reversible fashion, than a standard regimen of clopidogrel in patients with non–ST-segment elevation ACS and, furthermore, additionally suppresses platelet aggregation in patients currently receiving clopidogrel. These characteristics of AZD6140 may yield benefits in clinical practice; this will be explored in a large, ongoing outcomes trial in patients with ST-segment elevation and non–ST-segment elevation ACS.
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Appendix
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For supplementary materials and a list of participating substudy investigators, please see the online version of this article.
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Footnotes
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This work was funded by AstraZeneca LP, Wilmington, Delaware. Drs. Storey, Husted, Harrington, Heptinstall, Wilcox, Gurbel, and Cannon have received honoraria and/or research grant support from AstraZeneca. Drs. Peters, Emanuelsson, and Wickens are current or former employees of AstraZeneca.
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Abstract
Methods