The use of an oral P2Y12 inhibitor in adjunct to aspirin, known as dual antiplatelet therapy (DAPT), is the cornerstone of antithrombotic therapy in patients with acute coronary syndrome (ACS).[1] Ticagrelor has emerged as one of the most commonly utilized oral P2Y12 inhibitors in light of its established efficacy and favorable safety profile.[1] [2] However, the efficacy of ticagrelor-based DAPT is limited by treatment modifications that are common in clinical practice, with approximately 25% of patients discontinuing ticagrelor prematurely.[3] The reasons for these modifications can be diverse and include changes based on physician or patient decisions due to bleeding, drug-related side effects, need for oral anticoagulation, need for surgery, costs, and poor adherence.[4] [5] Dyspnea can occur in approximately 20% of patients taking ticagrelor, leading to treatment cessation in about one-third of cases.[3] Together, these factors explain the higher incidence of nonadherence to ticagrelor compared with clopidogrel.[3] Modifications in ticagrelor therapy after ACS may have relevant impact on ischemic and bleeding events, which depends on the reason, type, and timing of such modifications.[3] [4] The perspective from which this topic is approached is according to the traditional concept of DAPT, which considers ticagrelor as an adjunctive, temporary therapy on a background of chronic aspirin.[3] However, it is important to note that a strategy of ticagrelor monotherapy after 1 to 3 months of DAPT has recently been shown to be safe and effective after ACS.[6] [7] [8] [9] [10] Overall, understanding the patterns and implications of ticagrelor modifications after ACS in contemporary practice is of considerable interest.

In a new study published in Thrombosis and Haemostasis, van der Sangen and colleagues[11] evaluated the incidence and clinical implications of treatment modifications in 4,278 patients with ACS who were discharged on ticagrelor 90 mg twice daily (combined with aspirin in 98% of cases) using data from the FORCE-ACS registry. The FORCE-ACS is a prospective registry of nine Dutch hospitals, including consecutive patients with ACS since 2015. The mean age of the study population was 63 years old, 26% were female, and around 20% of patients were at high bleeding risk.[11] Patients were treated according to guideline recommendations, with nearly all undergoing coronary angiography and 80.1% undergoing percutaneous coronary intervention (PCI). In FORCE-ACS,[11] the most common reason for ticagrelor modification (26.7% of patients) was physician-recommended discontinuation after completion of the intended treatment period, at a median time of 357 days (interquartile range [IQR]: 298–365). Another common reason for ticagrelor modification (20.1% of patients) was treatment alteration, defined as a switch from ticagrelor to another P2Y12 inhibitor. This was most often a switch to clopidogrel within 6 months after ACS (median time, 73 days [IQR 38–149]), usually because of dyspnea (47.2%), new indication for oral anticoagulation (8.3%), bleeding (7.6%), or other side effects (15.8%). Less frequent reasons for ticagrelor modification were interruption (e.g., temporary cessation with planned resumption within 14 days), which occurred in 2.8% of patients, mostly due to surgery, and disruption (e.g., cessation due to bleeding or noncompliance), which occurred in 3.1% of cases, mostly due to bleeding or dyspnea. Both ticagrelor interruption and disruption generally occurred between 6 and 12 months after ACS.

In FORCE-ACS, modalities of ticagrelor modification affected outcomes differently.[11] At 12 months, the incidence of ischemic events (e.g., death, myocardial infarction, or stroke) was 6.6% in the overall population, with 20.1% of these events occurring in patients with ticagrelor modification. After adjustment for measured confounders, physician-recommended discontinuation and alteration were not associated with an increased risk of ischemic events compared with ticagrelor continuation.[11] These results are reassuring and suggest that treatment modulation based on the clinical considerations of the treating physician and de-escalation to clopidogrel early after ACS are safe, consistent with the evidence from observational studies[12] [13] and randomized trials.[14] [15] Conversely, ticagrelor interruption and disruption were associated with a more than 2-fold increased risk of ischemic events.[11] These situations appear less controllable, especially when poor patient compliance is the underlying cause. In these cases, the lack of oversight by the treating physician likely explains the observed increased risk of ischemic events.

The present analysis from the FORCE-ACS[11] and previous reports[3] address the important issue of ticagrelor therapy modifications in patients treated with DAPT after ACS, discussing current barriers and potential solutions. Noteworthy, treatment modification may become even more problematic in patients on ticagrelor monotherapy, for whom there are no standardized recommendations (e.g., in the case of surgery) and data are limited to randomized trials. In the GLOBAL LEADERS trial,[16] [17] which compared ticagrelor monotherapy from 1 month with standard of care after PCI, 18% of patients in the experimental arm and 15% of patients on ticagrelor in the control arm did not adhere to ticagrelor at 1 year. Dyspnea was the most common reason for nonadherence, but its occurrence did not affect the efficacy or safety of ticagrelor monotherapy compared with standard therapy.[18] The trial protocol provided specific guidance in case of ticagrelor discontinuation due to side effects, recommending prasugrel, if indicated, or clopidogrel, in case of elective PCI or contraindications to prasugrel.[16] In the case of surgery while on ticagrelor monotherapy, the protocol also recommended an algorithm of restarting aspirin (75–100 mg once daily), stopping ticagrelor at least 72 hours before surgery, and resuming ticagrelor monotherapy as soon as possible in the postoperative period.[16] In the TWILIGHT trial,[19] which compared ticagrelor plus placebo with ticagrelor plus aspirin from 3 months after PCI, nonadherence to ticagrelor at 1 year after randomization was similar in the experimental and control groups (12.9 and 14.1%, respectively). In a trial subanalysis,[20] dyspnea led to permanent discontinuation of ticagrelor in approximately 1 in 10 patients enrolled (9.1%) and was more common within 3 months (6.4%) than between 3 and 15 months after PCI (2.8%). Among randomized patients who discontinued ticagrelor due to dyspnea (in most cases switching to clopidogrel), ticagrelor monotherapy was not associated with a higher risk of ischemic events compared with ticagrelor plus aspirin (5.0 vs. 7.1%; p = 0.56).[20] Of note, in TWILIGHT, a standardized algorithm to manage ticagrelor-related dyspnea was provided, including patient counselling, concomitant caffeine intake, and a brief “drug-holiday” from ticagrelor switching to another P2Y12 inhibitor.[19]

Data from randomized trials of ticagrelor monotherapy suggest that (1) side effects requiring ticagrelor discontinuation (e.g., dyspnea)[21] occur more often early after PCI, when aspirin is concomitantly administered, (2) patient counselling and standardized algorithms can be useful to minimize ticagrelor discontinuation and to provide guidance when it occurs, and (3) withdrawing aspirin and continuing ticagrelor alone after 1 to 3 months of DAPT is safe, despite a non-negligible proportion of patients may experience adverse events leading to subsequent ticagrelor discontinuation.[16] [17] [18] [19] [20] However, the safety and efficacy of ticagrelor treatment modifications when used as monotherapy in real-world practice, outside the more rigorous oversight that occurs in randomized trials, remains unknown.

In the evolving field of ticagrelor-based regimens after ACS, the FORCE-ACS registry not only provides important real-world evidence on patterns of ticagrelor therapy modifications in the context of standard DAPT, but also highlights the need for more evidence to clarify the clinical implications and optimal management of ticagrelor modifications when this agent is used as monotherapy ([Fig. 1]). Appropriate patient selection and education, regular follow-up visits, and careful implementation of bleeding avoidance strategies should be targeted as key aspects to reduce nonadherence and maximize the benefits of ticagrelor after ACS (with or without aspirin) in current clinical practice.