Journal of the American College of Cardiology Vol. 50, No. 19, by the American College of Cardiology Foundation ISSN /07/$32.

Transcription

1 Journal of the American College of Cardiology Vol. 50, No. 19, by the American College of Cardiology Foundation ISSN /07/$32.00 Published by Elsevier Inc. doi: /j.jacc Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y 12 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, Christopher P. Cannon, MD, FACC Sheffield, Nottingham, and Charnwood, United Kingdom; Århus and Copenhagen, Denmark; Durham, North Carolina; Wilmington, Delaware; Mölndal, Sweden; Baltimore, Maryland; and Boston, Massachusetts Objectives Background Methods Results Conclusions 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. 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 P2Y 12 receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study). Patients were randomized to receive either AZD mg twice a day, AZD 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. 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%], AZD mg 79% [ 22%], AZD mg 95% [ 8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel. 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. (J Am Coll Cardiol 2007;50:1852 6) 2007 by the American College of Cardiology Foundation 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 From the *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; and the TIMI Study Group, Cardiovascular Division, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts. 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. See accompanying online Cardiosource Slide Set. Manuscript received May 18, 2007; revised manuscript received July 19, 2007, accepted July 24, 2007.

2 JACC Vol. 50, No. 19, 2007 November 6, 2007: Storey et al. Effect of AZD6140 on Platelet Aggregation in ACS 1853 thromboxane A 2. 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 P2Y 12 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 P2Y 12 receptor antagonist that binds reversibly to the P2Y 12 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. using ADP 20 mol/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 A full description of the statistical methods is found in the Online Appendix. Abbreviations and Acronyms ACS acute coronary syndromes ADP adenosine diphosphate bid twice-daily administration qd once-daily administration Results Study population. Ninety-one patients were enrolled in this substudy (57 male, 34 female; mean age years), of whom 89 received study medication and had evaluable platelet aggregation data. Forty-five patients were clopi- Methods 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 AZD mg twice a day (bid), AZD 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 AZD 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 Figure 1 Randomization of Patients Randomization of (A) clopidogrel-naïve patients and (B) clopidogrel-pretreated patients. bid twice daily; qd once daily.

3 1854 Storey et al. JACC Vol. 50, No. 19, 2007 Effect of AZD6140 on Platelet Aggregation in ACS November 6, 2007: AZD6140 group (e.g., p 0.12, 0.04, and for clopidogrel vs. AZD mg at 4, 8, and 12 weeks, respectively, and p 0.004, 0.017, and for clopidogrel vs. AZD mg, respectively, 4 h post-dose, final response). 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 aggrega- 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 mol/l, for clopidogrel-naïve patients before and after clopidogrel 300 mg (n 14), AZD mg (n 9), AZD mg (n 7), or AZD 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. dogrel 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 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 AZD mg, and only a few individuals receiving clopidogrel had a similar response. Inhibition of platelet aggregation by AZD6140 remained stable at 4 weeks (Fig. 4), and the most consistent response was seen with AZD mg (Fig. 3B). Inhibition by clopidogrel remained lower than either 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 mol/l, for clopidogrel-naïve patients (A) after the first dose of either clopidogrel 300 mg, AZD mg, AZD mg, or AZD mg and (B) after 4 weeks of treatment and after next dose of either clopidogrel 75 mg, AZD mg, or AZD mg. Data are for the first 8hoftreatment 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.

4 JACC Vol. 50, No. 19, 2007 November 6, 2007: Storey et al. Effect of AZD6140 on Platelet Aggregation in ACS 1855 Discussion Figure 4 Steady-State and 24 h Postdose Inhibition of Platelet Aggregation by Clopidogrel and AZD6140 This substudy of DISPERSE-2 is the first study to assess the pharmacodynamic effects of a reversible oral P2Y 12 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 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 mol/l, before and after the next dose of either clopidogrel 75 mg (n 10), AZD mg (n 15), or AZD 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. tion 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%. 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. 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 mol/l, for clopidogrelpretreated patients before and after either clopidogrel 75 mg (n 12) or the first dose of AZD mg (n 9), AZD mg (n 7), or AZD 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.

5 1856 Storey et al. JACC Vol. 50, No. 19, 2007 Effect of AZD6140 on Platelet Aggregation in ACS November 6, 2007: 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 P2Y 12 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. Conclusions 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. 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. r.f.storey@sheffield.ac.uk. REFERENCES 1. Bertrand M, Simoons M, Fox K, et al., on behalf of the Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002;23: Storey RF. Biology and pharmacology of the platelet P2Y 12 receptor. Curr Pharm Des 2006;12: Antiplatelet Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: Savi P, Nurden P, Nurden A, Levy-Toledano S, Herbert JM. Clopidogrel: a review of its mechanism of action. Platelets 1998;9: Yusuf S, Zhao F, Mehta SR, et al., on behalf of the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345: Gurbel PA, Bliden KP, Hiatt BL, O Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107: Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109: Barragan P, Bouvier J-L, Roquebert P-O, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003;59: Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet REactivity in patients with Stent Thrombosis: results of the CREST study. J Am Coll Cardiol 2005;46: van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Haemost 2005;31: Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006;27: Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral ADP receptor antagonist, compared with clopidogrel, in patients with non STsegment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007;50: Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005;45: Muller I, Seyfarth M, Rudiger S, et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 2001;85:92 3. APPENDIX For supplementary materials and a list of participating substudy investigators, please see the online version of this article.