Translational Implications for Targeting Ischemia-Induced Cardiac Inflammation by Ticagrelor: One Fits All or Dose Matters?

Ticagrelor is a selective and stable nonphosphate P2Y12 receptor antagonist, which can decrease platelet aggregation and prohibit thrombus formation through preventing the binding of adenosine diphosphate to the P2Y12 receptor.1 Based on positive findings from controlled clinical trials, PDY12 receptor blocker drugs, such as clopidogrel, prasugrel, and ticagrelor, are frequently applied combined with acetylsalicylic acid in today's clinical practice primarily with the aim to enhance platelet inhibition in patients presenting with acute coronary syndrome (ACS), undergoing percutaneous coronary intervention, or in preventive treatment of patients who are at high risk of thromboembolism, myocardial infarction, or stroke.2 Several clinical trials investigated the pros and cons of the several PDY12 receptor blockers available, sometimes in direct comparison. The randomized multicenter, double-blind PLATO trial including 18,624 patients with ACS showed that incidence of the primary end point after 12 months defined as composite of death from vascular causes, myocardial infarction, or stroke was significantly lower in the ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) as compared to the clopidogrel treatment group (300- to 600-mg loading dose, 75 mg daily thereafter).3 In a recently published clinical report, Li et al4 also demonstrated better results in STEMI patients with diabetes as risk factor regarding angina, stent thrombosis, and all-cause mortality at 1-month post-therapy when treated with ticagrelor (n = 100) as compared to clopidogrel-treated patients. Current guidelines of the European Society of Cardiology as well as the American College of Cardiology therefore specifically advice use of ticagrelor in a rising number of indications (Fig. 1).5,6 However, pathophysiological mechanisms of action—including positive as well as negative effects observed clinically—still remain, at least in part, obscure.FIGURE 1.: Current accepted indications for ticagrelor on top of aspirin in coronary artery disease. CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy; MI, myocardial infarction; PCI, percutaneous coronary intervention.In a current study, Ye et al gave some further insights how ticagrelor, administered immediately before reperfusion by intraperitoneal injection, might protect against reperfusion injury: Both acute or chronic ticagrelor treatment (oral administration 300 mg/kg per day for 4 weeks starting 1 day after reperfusion), or their combination, improved myocardial function, attenuated fibrosis, and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor also attenuated the increase in proinflammatory tumor necrosis factor-α, interleukin-1β, and interleukin-18 and increased anti-inflammatory 15-epi-lipoxin-A4 levels.7 Specific cardioprotective effects of ticagrelor administration including reduced necrotic injury and edema formation were also evidenced in a myocardial infarction swine model.8 In this issue of the Journal of Cardiovascular Pharmacology, Liu et al9 further extend our knowledge on previously predescribed anti-inflammatory effects when reporting that ticagrelor, applied through gavage post-LAD ligation, reduces ischemia-reperfusion injury through an NF-κB–dependent pathway in rats. Their present as well as previous findings10 are generally in line with experimental results reported by other groups in the field, not only describing positive net effects on ischemia reperfusion injury—ultimately resulting in smaller infarct size—after administration of ticagrelor, but also specifically on inflammatory response. Positive effects on inflammatory markers have not only been evidenced in coronary artery disease, but recently also described in other pathologies such as pneumonia.11 The current study further extends our pathophysiological understanding in this regard, bringing more light into the complex mechanism of action of ticagrelor, suggesting a direct positive effect on inflammatory response in myocardial healing. However, while the anti-inflammatory mode of action described on the one hand apparently seems to add to the understanding of positive effects of ticagrelor, which have been described in addition to positive clopidogrel and also prasugrel effects, a closer look at the subject matter raises new questions, among others regarding ideal drug dosage. Notably, the dual antiplatelet and anti-ischemic/inflammatory effects of ticagrelor without doubt seem to contribute to the generally favorable clinical results in patients with ACS. Nanhwan et al12 found that oral ticagrelor (0, 75, 150, or 300 mg/kg/d) administered for 7 days before 30-minute coronary artery ligation and 24-hour reperfusion reduced myocardial infarct size in a dose-dependent manner. However, ticagrelor was also found associated with a significantly higher rate of non–procedure-related major bleedings, including higher numbers of fatal intracranial bleeding as compared to clopidogrel.3 The clinical net benefit achieved by the use of P2Y12 receptor antagonists, either as monotherapy, dual, or even triple antiplatelet therapy, therefore is often obtained at the price of augmented bleedings, which are known to be strong predictors of adverse outcome in patients with ACS. In this context, it is important to note that—despite the clear superiority of ticagrelor over clopidogrel when looking at the primary end points in clinical practice only in recent trials—it was also revealed that clopidogrel was generally safer than ticagrelor with regard to bleedings.13 In this line, the PEGASUS-TIMI 54 trial randomly assigned 21,162 patients to 2 different doses of ticagrelor or placebo, revealing favorable net effects of 60-mg ticagrelor twice daily in direct comparison with 90-mg ticagrelor twice daily in patients who suffered from myocardial infarction 1–3 years before therapy. These findings led to the current guideline recommendations, supporting a reduced dosage of 60-mg ticagrelor twice daily for long-term use in stable coronary artery disease.14 Of note, in contrast to ticagrelor application, several clinical trials investigating clopidogrel treatment at a dose of 75 mg per day were not able to show positive net effects for an extended intake in various clinical scenarios in the past.15,16 This has been explained related to certain specific nondrug class but substance-related drug effects uniquely inherent to ticagrelor by several groups in the field. At the same time, although the various cardioprotective effects of ticagrelor observed in experimental studies have been confirmed in clinical trials, the incremental bleeding risk seen in patients treated with ticagrelor as compared to clopidogrel needs to be considered carefully during the therapeutic decision-making in clinical practice. This represents one of the major factors explaining why current guidelines still advise the use of clopidogrel as the P2Y12 receptor antagonist of choice after percutaneous coronary intervention in patients with non-ACS.5,6 However, interestingly, several very recent clinical trials for the first time were able to show positive effects of extended nonticagrelor P2Y12 receptor antagonist intake for longer than 1 year after an index event in specific, carefully selected subsets of patients also when treated with clopidogrel or prasugrel.17–19 Carefully weighting the increasing evidence proving incremental effects of ticagrelor on top of direct platelet inhibition-which are mostly positive but in certain cases can also be contrary regarding clinical outcome-one is forced to conclude that there is still a long way to go until drug-specific as well as dose-dependent effects of the several P2Y12 receptor antagonists, and their clinical implications in various clinical scenarios, are fully understood. Because both the cardioprotective and hemorrhagic effects were found to be a dose-dependent phenomenon, further randomized clinical trials designed to test not only the net clinical benefit of the several P2Y12 receptor antagonists but also respective ideal drug doses in various clinical scenarios and patient groups might provide important clinical information for revealing the maximal tolerable effective drug dosage with the minimal (bleeding) risk not only in ACS, but also other patient collectives. From the clinical perspective, P2Y12 receptor antagonists share several aspects with direct anticoagulants such as rivaroxaban. However, in contrast to P2Y12 receptor antagonists, rivaroxaban is used in a rising number of at least 4 different dosing schemes in many countries routinely today, proven to fit different indications and patient collectives by meeting the respective ideal risk-benefit ratio for each scenario.20 One might speculate whether certain specific mechanisms of action of ticagrelor, such as the impact on the NF-κB pathway described in the current study by Liu et al, also require a dosing of 90 (or even 60) mg twice daily or might require higher or lower drug doses, therefore, ie, potentially proving beneficial in patients with non-ACS or patients at high risk for bleedings. Despite their availability for many years, the race is still on regarding optimal P2Y12 receptor antagonist treatment in clinical practice.