Author + information
- Dimitrios Alexopoulos, MD†∗ (, )
- Vassilios Gkizas, MD†,
- Sotirios Patsilinakos, MD‡,
- Ioanna Xanthopoulou, MD†,
- Christos Angelidis, MD§,
- Prodromos Anthopoulos, MD‖,
- George Makris, MD†,
- Angelos Perperis, MD†,
- Stavros Karanikas, MD‡,
- Nikolaos Koutsogiannis, MD†,
- Periklis Davlouros, MD†,
- Spyridon Deftereos, MD§,
- John Chiladakis, MD† and
- George Hahalis, MD†
- †Department of Cardiology, Patras University Hospital, Rion, Patras, Greece
- ‡Department of Cardiology, Konstantopoulio General Hospital, Athens, Greece
- §Department of Cardiology, Athens General Hospital “G. Gennimatas”, Athens, Greece
- ‖Catheterization Laboratory, Evangelismos Hospital, Athens, Greece
- ↵∗Department of Cardiology, Patras University Hospital, Rion 26500, Patras, Greece
To the Editor:
Early and strong platelet inhibition is highly desirable in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Ticagrelor, which has direct action on the P2Y12 receptor and no need for previous metabolic activation, provides faster platelet inhibition than clopidogrel (1,2). In patients with stable coronary artery disease or acute coronary syndrome, ticagrelor has been administered as a 180-mg loading dose (LD), leading to marked inhibition of platelet reactivity within 1 h, with almost all patients below the predefined cutoff points of high platelet reactivity (HPR) (1,3). However, in the acute phase of STEMI, we recently reported a delayed onset of antiplatelet action, with more than one-half of patients exhibiting HPR at 1 h post-treatment with a 180-mg LD of ticagrelor (4). Because the mean maximum concentration and area under the curve for ticagrelor and its main metabolite AR-C124910XX increased approximately dose-proportionately in healthy volunteers treated with 50 to 600 mg of ticagrelor once daily (5), we hypothesized that doubling the standard 180-mg LD of ticagrelor might lead to a faster onset of its antiplatelet action.
We performed a prospective, 4-center, nonrandomized, controlled study in 2 sequential groups of P2Y12 inhibitor-naive consecutive patients with STEMI undergoing primary PCI. After a 325-mg LD of aspirin, patients were treated with 360 mg or 180 mg ofticagrelor. We excluded patients with a history of stroke/transient ischemic attack, oral anticoagulation, hemodynamic instability, platelet count <100,000/μl, hematocrit <30%, creatinine clearance <30 ml/min, severe hepatic dysfunction, increased risk of bradycardia, severe chronic obstructive pulmonary disease, or periprocedural administration of IIb/IIIa inhibitors. Platelet reactivity (PR) was assessed at hour 0 (before administration of ticagrelor immediately before PCI) and at hours 0.5, 1, 2, and 4 thereafter. Platelet function testing (in platelet reaction units [PRU]) was performed with the VerifyNow (Accumetrics Inc., San Diego, California) P2Y12 function assay. The propensity score of exposure to a double LD was estimated with a logistic regression model fit with sex, diabetes mellitus, smoking, use of bivalirudin, creatinine clearance <60 ml/min, and age ≥75 years as categorical variables and hematocrit, platelet count, pain-to-balloon time, body mass index, and PR at baseline as continuous variables (C-statistic: 0.725; 95% confidence interval [CI]: 0.612 to 0.838). Differences in PR between groups were analyzed via a mixed-effect model with treatment as a fixed effect, patient as a random intercept, and PR at baseline and propensity score as covariates. Least squares estimates of the mean difference with 95% CI are presented for the treatment effect. HPR rates (thresholds ≥230 PRU and ≥208 PRU) were calculated. All tests were 2-tailed, and statistical significance was considered for p values <0.05. Statistical analyses were performed using SPSS for Windows (version 16.0; SPSS Inc., Chicago, Illinois). The study protocol was approved by the ethics committee of each participating hospital. All patients provided written informed consent before participation in the study.
PR was assessed in 45 and 38 patients treated with a double and standard LD, respectively. In total, 86.7% were men, with a median (quartile 1 to quartile 3) age of 54 (48.0 to 65.0) years and pain-to-balloon time of 3.5 (2.0 to 5.3) h. No significant differences in demographic and clinical characteristics were observed between groups (Online Table 1). Individual PR values are shown in Figure 1. PR least squares mean difference (95% CI) between groups at 0.5, 1, 2, and 4 h post-loading was −11.9 (−34.1 to 10.2), 6.3 (−29.1 to 41.7), 11.4 (−37.6 to 60.3), and 19.5 (−9.7 to 48.8) with p = 0.3, p = 0.7, p = 0.6, and p = 0.2, respectively (Online Table 2). HPR rates did not differ significantly between groups at any time post-LD (Online Tables 3 and 4). During in-hospital observation, minor bleeding events (bruising) were observed in 3 patients treated with a double LD patients and one patient treated with a standard LD.
Because the magnitude of platelet inhibition has been associated with plasma ticagrelor concentrations (5), we speculated that doubling of the LD might achieve a high drug concentration earlier than the standard dose, which would provide faster onset of antiplatelet activity. This hypothesis was not confirmed in our study. Intravenous antiplatelet agents such as IIb/IIIa inhibitors or cangrelor may offer a bridge for this initial delay of antiplatelet action of ticagrelor administered as either a standard or double LD. Alternatively, earlier (i.e., pre-hospital) administration of ticagrelor may lead to better platelet inhibition during primary PCI. The clinical utility of this strategy is being tested by the ongoing ATLANTIC study (NCT01347580).
Our study was not randomized; however, demographic and clinical characteristics were balanced between patients treated with a double and a standard LD. Furthermore, a propensity score was used to adjust for potential biases. The study was purely pharmacodynamic, not allowing any conclusions on clinical outcome. We used only 1 method for platelet function testing; however, VerifyNow is the most validated method and correlates well with light transmittance aggregometry. The lack of pharmacokinetic data does not allow elucidation of the exact mechanisms responsible for the double LD delayed onset of action of ticagrelor. In this small study, a double LD was well tolerated, which is consistent with a previous report (5).
In patients with STEMI undergoing primary PCI, doubling the LD of ticagrelor is not accompanied by a faster than standard dose onset of antiplatelet action.
For supplementary tables, please see the online version of this article.
Please note: This study was supported by the Research Committee of the Patras University Medical School. Dr. Alexopoulos has received speaker fees from AstraZeneca. All other authors have reported that they have no relationships relevant to the content of this paper to disclose.
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