Tailoring Antiplatelet Therapy in Acute Coronary Syndromes: The Thin Red Line

Despite advances in the diagnosis and management of acute coronary syndromes (ACS), ∼10% survivors of a first myocardial infarction (MI) will experience a recurrence, even with the new antiplatelet drugs with faster onset of action and more consistent platelet inhibition [1,2].A dual antiplatelet therapy (APT) strategy, combining low-dose aspirin and clopidogrel adenosine diphosphate P2Y12 receptor blockade, has been the cornerstone of ACS treatment and validated across the full spectrum of disease, despite only indirect evidence in ST elevation MI treated with percutaneous coronary intervention. Nevertheless, the variability in response to one or both agents has been one of the Achilles heels of this strategy which prompted the search for new drugs.Dual APT with the new P2Y12 receptor antagonists prasugrel and ticagrelor managed an impressive ∼20% relative reduction in major cardiovascular adverse events. The trade-off was an increased risk of bleeding, with both drugs showing a significant 0.6% absolute excess of TIMI major bleeding not related to coronary artery bypass graft surgery, which might even be higher in a ‘real-world' setting [1,2].Triple oral antithrombotic therapy, combining a ‘standard' regimen of aspirin/clopidogrel with novel anticoagulants, either oral low-dose Xa inhibition or oral platelet thrombin receptor blockade, has recently been investigated in ACS [3,4]. Ischemic events where reduced by ∼13% but the risk of significant bleeding almost tripled and uncertainty remains about their reversal in case of life-threatening hemorrhage [5]. Interestingly, a reduction in stent thrombosis and an intriguing mortality benefit (1.5% absolute decrease in the death rate) was seen with the 2.5 mg rivaroxaban dose in the ATLAS 2 ACS-TIMI 51 trial, one quarter of the full anticoagulation dose, supporting a role of the coagulation cascade and sustained activation of thrombin in these events.Although the one-size-fits-all strategy is far from being ideal, tailored APT remains challenging and to be proved. So, in the context of the delicate balance of ischemia and bleeding, is there space for a different APT? In this issue of Cardiology, Niazi et al. [6] present an extensive review of the available data regarding the use of a triple antiplatelet regimen with aspirin, clopidogrel plus cilostazol in patients with ACS. Platelet inhibition can be attained by either blockade of membrane receptors or interaction with intracellular signaling pathways. Inhibition of signal transduction pathways may produce broader suppression of platelet activation, regardless of the initial stimulus.Cilostazol is an old player in the APT field with direct arterial vasodilator properties, although mainly used in the pharmacological treatment of stable intermittent claudication. It is a potent and selective inhibitor of phosphodiesterase type 3A, the phosphodiesterase isoform that is highly expressed in the cardiovascular system. It suppresses cAMP (3′-5′ cyclic adenosine monophosphate) degradation, leading to an increase in its levels in platelets and vascular smooth muscle cells. cAMP is a key second messenger involved in intracellular signal transduction of physiological endothelium-derived platelet antagonists, such as nitric oxide, thus acting as a negative regulator of all platelet functions. Cyclic nucleotide-dependent signaling is one of the main pathways for platelet activation, and its inhibition is the most important physiological way to limit thrombus formation [7]. Cilostazol also suppresses the proliferation of vascular smooth muscle cells, key effectors of restenosis after coronary stenting, thus preventing neointimal hyperplasia. Several recent trials evaluating adjunctive cilostazol treatment on top of the ‘standard' dual APT in patients undergoing coronary artery stenting with either bare metal or drug-eluting stents, in different clinical scenarios, have highlighted its possible role in preventing restenosis following percutaneous coronary intervention. Furthermore, both OPTIMUS-2 [8] and ACCEL-AMI [9] have confirmed that the clinical benefit of the synergistic action of cilostazol with clopidogrel probably derived from blocking of the P2Y12 signaling pathway. Nevertheless, if retrospective and prospective data are excluded, the overall efficacy seen in the randomized clinical trials is limited to patients at high risk for in-stent restenosis, such as those with diabetes, small vessels or long lesions [10]. Primary endpoints were mainly angiographic and not hard clinical outcomes. This probably accounts for the discrepancy with the results of the recent large multicenter CILON-T trial, which did not preselect patients with high risk of in-stent restenosis and looked for clinical outcomes [11]. Although it was not powered to assess hard clinical endpoints, it did not show the superiority of triple APT with cilostazol in reducing the primary composite endpoint. Notably, in all available data, cilostazol did not increase major bleeding events when added to the ‘standard' dual APT.In summary, a growing body of evidence suggests that triple APT with cilostazol might be a viable option for a specific subset of patients at high risk for in-stent restenosis, namely those with diabetes, small vessels, long lesions or those treated with bare metal stents.Its pleiotropic effects, the absence of prolongation of the bleeding time and the relatively short recovery time of platelet function are clearly a favorable aspect thus opening a niche for patients with a high bleeding risk, in whom there is concern/contraindication for new antithrombotic drugs (elderly, women, or patients with a low body mass index, previous hemorrhagic stroke or chronic renal failure).However, the rate of side effects is not negligible, accounting for a high discontinuation rate (∼15% in some trials) [10]. Metabolism by CYP3A5 and CYP2C19 (whose polymorphisms account for significant variability in its biotransformation) entails potential clinically relevant drug interactions. Its half-life requires a twice-a-day regimen, also hampering patient compliance. Moreover, it is contraindicated in patients with NYHA class ≥3, who represent almost 20% of ACS patients, because inhibition of phosphodiesterase 3 can result in inadvertent inotropic and chronotropic effects. Further data from multicenter randomized clinical trials, powered to assess hard clinical endpoints, comparing cilostazol adjunctive therapy with dual APT including new antithrombotic drugs/triple oral antithrombotic therapy (and with new stent platforms) are needed to draw more definitive conclusions and to picture the place of cilostazol in modern ACS therapy. In Einstein's words, everything should be made as simple as possible, but not simpler.