We conducted the “Egyptian Ticagrelor Study in patients who presented with Acute Coronary Syndrome (ETS in ACS)” on 830 patients from seven Egyptian governorates to determine the efficacy and safety of generic ticagrelor in patients who developed ACS during the 6 months prior to enrollment.
The primary end point (composite of CV death, myocardial infarction and stroke) occurred in 3.37% of patients at 6 months. The mean time to enrollment in our study was 2.1 (+ 1.57) months, with 45.8% of the patients enrolled during index hospitalization for the qualifying event. This is in contrast to the PLATO trial in which the primary endpoint occurred in 9.8% of patients in the ticagrelor group compared to 11.7% in those receiving clopidogrel. However, there were some differences between the two trials; in the latter all patients were included within 24 h of the diagnosis of ACS, the follow-up was for one year and the median age of the patients was higher .
In our study, the occurrence of the primary endpoint events was unevenly distributed during the follow-up period with 0.84% occurring in the first 3 months and 2.53% occurring in the second 3 months of the follow-up period. In the PLATO trial, death from vascular causes, MI and stroke in days 1–30 was 4.8%, with slightly more event rate during days 31–360 at 5.3% .
The secondary efficacy endpoints were relatively low in frequency in our study; the composite of the primary efficacy endpoints with the addition of hospitalization for unstable angina and urgent revascularization occurred in 15.3% of patients. CV death occurred in 1.2% in our 6-month study, compared to vascular death of 4.8% over one year in the PLATO trial, myocardial infarction in 0.8% compared to 5.8% in the PLATO trial. Hospitalization for unstable angina in our study occurred in 8.1%, while urgent revascularization occurred in 3.9% of patients. In the PLATO trial recurrent coronary ischemia occurred in 5.8% .
The rate of stroke was also relatively low during the study period (1.3% at 6 months of follow-up) compared to 1.5% during the one year PLATO study in the Ticagrelor arm .
The primary safety endpoint (TIMI major bleeding) occurred in 1.2% (n = 10) of our patients. Other safety endpoints including intracranial hemorrhage occurred in 0.2%. However, in the one year PLATO trial TIMI major bleeding occurred in 7.9% of the patients in the ticagrelor arm and 7.7% of the patients in the clopidogrel arm .On the other hand, in the PEGASUS TIMI 54 trial, the rates of fatal bleeding or non-fatal intracranial hemorrhage were less than 1% over a 3-year period in all three groups in this trial. The study, however, addressed a different population type and excluded patients who were at high bleeding risk .
As regards dyspnea, it occurred in 12.3% of our study population, which is in concordance with most of the published literature on dyspnea incidence in patients treated with ticagrelor [3, 8, 9]. Yet, most episodes were short-lived and discontinuation of the study drug was not reported in any of our patients. To the contrary, in the PEGASUS TIMI 54 trial, both the 60 mg and 90 mg ticagrelor doses also caused dyspnea, but the discontinuation rates of the study drug were significantly higher, as compared with placebo. The fact that the patients were recruited 1–3 years following the index event may have contributed to a higher discontinuation rate of the drug on the occurrence of any side effect.
Concerning bradycardia, it was reported in 3.1% of the study population with no syncopal events or need for pacemaker implantation. Seventy-seven percent of them were on beta-blockers which might have exaggerated the bradycardia effects of ticagrelor. In the PLATO trial, bradycardia occurred in 4.4% of the ticagrelor treated patients and 1.1% developed syncope. Holter monitoring detected more ventricular pauses during the first week in the ticagrelor group than in the clopidogrel group, but such episodes were infrequent at 30 days and were rarely associated with symptoms .
Comparing patients who underwent PCI at baseline and those who were treated conservatively, there was no statistically significant difference between the two groups regarding the primary or secondary efficacy endpoints. Similarly, in the PLATO trial, the benefits of ticagrelor were seen regardless of whether an invasive or a noninvasive management was planned .
Multiple logistic regression analyses showed that only previous CVA and previous PCI/CABG significantly predicted the occurrence of the composite primary endpoints, emphasizing the fact that higher risk patients are at a higher risk of developing complications.
In contrast to the PLATO trial, in which all patients were enrolled within 24 h from onset of ACS, the mean time of enrollment after ACS in our study was 2.1 months (1.57 SD) with 45.8% of the patients enrolled during index hospitalization for the qualifying event. However, there was no statistically significant difference between those enrolled from the onset of ACS with those who were enrolled later (from the second to the sixth month) for both the primary efficacy endpoints and safety endpoints. In the PLATO trial the treatment effects were the same in the short term (days 0–30) and in the longer term (days 31–360).
In our study, the overall rate of adherence to the study drug was 98.1% at visit one and 94.5% at the end of the follow-up period. In PLATO, premature discontinuation of the study drug was relatively high and occurred in 23.4% of patients in the ticagrelor group over one year .
In the PLATO trial, there was a difference in results between patients enrolled in North America and those enrolled elsewhere , and although no clear explanation was found, this put forward the question whether geographic differences or practice patterns influenced the effects of the randomized treatments. It also raised the importance of conducting trials on ticagrelor in our region where data on its efficacy and safety are quite scarce.
This study has the limitations of being a non-randomized trial, and lacking a comparative arm which could have better been brand ticagrelor. Nevertheless, the study gave us important insights on the type of ACS patients we may be seeing in our region, as well as a chance to compare our results with those reported in the literature. Another limitation was the intermediate term duration of the follow-up which was only 6 months and that it was allowed to enroll patients from day one of the diagnosis of ACS up to 6 months from index event. However, the design and duration of the study were preset in the protocol. The study included patients who recently underwent PCI and some of the investigators could have refrained from giving these patients a generic P2Y12 inhibitor newly introduced to the market, although it was approved by the national authorities to be marketed for such an indication. Also, as per protocol, any ACS patient whether he/she underwent PCI or not, would be eligible for 12 months of DAPT, so if a patient would be recruited at 6 months post-ACS he should continue for at least another 6 months (study duration) and still be within the guideline recommended DAPT duration.