AZD6140 and bleeding: towards safer antiplatelet therapy?

Antiplatelet therapy has become a cornerstone of the modern management of coronary artery disease, with combination of aspirin and clopidogrel being progressively more often recommended (1,2). Indeed, this dual antiplatelet therapy combination has been proven to be effective in patients with acute coronary syndromes (ACS) and those after percutaneous interventions (PCI). However, bleeding complications are not uncommon in both aspirin and clopidogrel being used separately and can become somewhat alarming when the drugs are prescribed together. Not surprisingly, the developers of new antiplatelet drugs put at least as much attention to their safety as to their efficacy. For example, prasugrel, a novel oral thienopyridine selective inhibitor of the platelet P2Y12 ADP receptor, had efficacy superior to clopidogrel in patients with ACS, but bleeding events were greater with prasugrel (3). In the phase III TRITON-TIMI 38 clinical trial, which randomized 13608 patients with ACS undergoing PCI to either prasugrel 60 mg followed by 10 mg daily or clopidogrel 300 mg followed by 75 mg daily for 6–15 months, the treatment with prasugrel was associated with a significant reduction in the combined rate of cardiovascular death, myocardial infarction (MI) or stroke to 9.9% vs. 12.1% for clopidogrel treatment (3). However, major bleeding episodes, the key primary safety end-point of the TRITON TIMI 38 trial, were more significant in the prasugrel group (2.4% vs. 1.8% in clopidogrel group). Additionally, the rate of life-threatening bleedings was increased in patients treated with prasugrel. Whilst an analysis of ‘net clinical benefit’ in terms of rates of efficacy plus bleeding end-points showed that prasugrel caused a greater reduction in all cause mortality, non-fatal MI, non-fatal stroke or non-fatal major bleed (12.2% in prasugrel group vs. 13.9% in clopidogrel group); it was also emphasised at the same time that 3 specific subgroups of patients did not benefit from prasugrel treatment and were at an increased risk of bleeding: patients with a history of stroke or transient ischemic attack, patients aged 75 years or older and patients weighing less than 60 kg (4). Similar to clopidogrel and ticlopidine, prasugrel is a reversible P2Y12 ADP receptor inhibitor, undergoing transformation to its active metabolite through cytochrome P-450 oxidation (4). The safety concerns that arose from prasugrel clinical trials might reflect pharmacological limitations shared with other thienopyridines. The discovery of AZD6140 has been a welcome development in view of the above-mentioned problems with clopidogrel and other thienopyridines. AZD6140 is the first member in a new class of oral ADP receptor antagonists called cyclopentyltriazolo-pyrimidines (5). This drug has been shown to inhibit potently ADP-induced platelet aggregation, but in contrast to other thienopyridines, which cause irreversible P2Y12 receptor blockade, the effect of AZD6140 is reversible. This is of potentially important benefit in patients awaiting coronary artery bypass graft (CABG) surgery, where rapid recovery of platelet function is required. Also, AZD6140 does not require metabolic transformation to an active metabolite to express its antiplatelet effects (6). This is a further advantage over clopidogrel as it has been shown that the variable pharmacodynamic response to clopidogrel could be because of decreased exposure to its active metabolite, giving a background to a not uncommon phenomenon of ‘clopidogrel resistance’ (7–9). Do these theoretical advantages result in better safety profile of AZD6140? In the current issue of International Journal of Clinical Practice, Husted et al. have analysed the bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE (Dose confirmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogrel in non-ST-segment Elevation myocardial infarction)-2 study (10). With AZD6140 90 (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26), respectively, they show a reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%) and life-threatening bleeding (22% and 38% vs. 54%). These results imply that AZD6140 may be the antiplatelet drug of choice in ACS patients undergoing CABG. In the overall DISPERSE-2 study cohort, however, AZD6140 was not safer than clopidogrel from the bleeding perspective (11). In this phase II trial, patients with NSTE-ACS were randomised in a double-blind fashion to receive twice-daily AZD6140 90 mg, AZD6140 180 mg or clopidogrel 300-mg loading dose plus 75 mg once daily for up to 12 weeks. Both doses of AZD6140 provided greater levels of platelet inhibition than clopidogrel (73–79%, 87–95% and 52–64% of inhibition of platelet aggregation, respectively). During the 4 weeks of the study, total bleeding rates were 9.8% for 90 mg dose and 8.0% for 180 mg dose of AZD6140 and did not differ significantly compared with clopidogrel group (8.1%) (11). The DISPERSE-2 trial was preceded by the DISPERSE trial conducted on patients with known atherosclerotic disease who were randomised to receive one of the following dose regimens of AZD6140: 50 mg twice daily, 100 mg twice daily, 200 mg twice daily or 400 mg once daily to compare with combination of clopidogrel 75 mg daily and aspirin (12). Inhibition of platelet aggregation in patients receiving 400 mg of AZD6140 per day was significantly more pronounced and rapid than in patients on clopidogrel. In this study, the incidence of bleeding was also higher with the three higher doses of AZD6140 compared with clopidogrel. Episodes of dyspnoea were associated with AZD6140 treatment in a dose-dependant manner, although the extent of dyspnoea was not considered to be of a serious nature (12). In both these trials, the discontinuation of treatment by patients because of dyspnoea was no more frequent in the AZD6140-treated patients than in clopidogrel group. Another effect more often noted in the AZD6140 patient population was the occurrence of ECG pauses > 2.5 sec, although the patients remained asymptomatic during these periods (4). While the critics may argue that the increased bleeding risk with AZD6140 and prasugrel negates their clinical benefit, it has to be borne in mind that bleeding events as a result of anticoagulant therapy have a multifactorial origin and therefore must not be ascribed solely to the anticoagulant effect of any new treatment under investigation. Many different patient characteristics have been identified as having supporting evidence for being risk factors for anticoagulation-related bleeding complications including advanced age, uncontrolled hypertension, history of MI or ischaemic heart disease, cerebrovascular disease, anaemia or a history of bleeding and the concomitant use of other drugs such as antiplatelet agents (13). Similarly, it has been shown that in patients with CAD who are anticoagulated after coronary intervention procedures, factors other than anticoagulant therapy, such as glycoprotein IIb/IIIa inhibitor use, multivessel/left main artery disease and anaemia are also independent predictors of early and late major bleeding episodes (14). This is further complicated by the need for prolonged anticoagulation in case of implantation of drug-eluting stents. For these reasons, large phase III trials are required to establish finally the clinical utility and safety of the novel antiplatelet drugs. An ongoing head-to-head randomised, double-blind phase III PLATO trial compares AZD6140 vs. clopidogrel (both in combination with aspirin) in 18600 patients with ACS with the primary end-point of vascular death, non-fatal MI or non-fatal stroke (15). The patients in this trial are in the 12 month follow-up phase now. It is hoped that this trial will address not only the issue of bleeding but also the less significant side effect of dyspnoea reported by patients in both DISPERSE trials. Furthermore, it will also be interesting to see how a group of patients with ‘clopidogrel resistance’ respond to AZD6140, given that the phenomenon of clopidogrel resistance may be because of a pre-existent variability in platelet response to ADP, and this variability is not increased by clopidogrel administration (16, 17). The greater potency of the novel antiplatelet drugs, such as AZD6140, can also be described as its nemesis. While these agents have a more potent and predictable effect, it may also bring with it the risk of excessive bleeding compared with existing anti-platelet therapies. Furthermore, the superiority of certain agents may not necessarily apply to all clinical situations, given that real-life patients do not obey textbooks or follow clinical trial protocols. As it was demonstrated by Husted et al., a subanalysis of large clinical trials can help identify categories of patients who could benefit from AZD6140 administration (10). However, these data would still have to be confirmed by specifically designed studies to prove the efficacy and safety of these drugs. G.Y.H.L. has acted as consultant to various pharmaceutical companies involved in thrombosis and antithrombotic therapy research, including AstraZeneca, which manufacture AZD6140. In addition, G.Y.H.L. has been an investigator on the PLATO trial. A.S. and E.S. – none declared.