Ticagrelor recommended over clopidogrel in STEMI patients

KEYWORDS:

• STEMI
• ticagrelor
• clopidogrel
• platelet inhibition

Patients with ST segment elevation myocardial infarction (STEMI) pose a special challenge for the clinician, as the optimal reperfusion therapy consisting of primary percutaneous coronary intervention (PCI), should be offered urgently, as soon as possible after first medical contact. As platelet activation has a central role in thrombus formation, particularly in the very early hours of STEMI [1], reaching adequate platelet inhibition at the time of primary PCI is considered a therapeutic strategy of utmost importance. Clopidogrel is a thienopyridine, which on top of aspirin, has been extensively used for almost two decades in patients undergoing a PCI, including those with STEMI. However, an impaired bioavailability following a 600 mg of this P2Y₁₂ receptor antagonist loading dose (LD) has been described in STEMI patients. Plasma concentrations (Cmax) of unchanged clopidogrel, its inactive carboxyl metabolite and its active thiol metabolite have been found to be significantly lower in STEMI patients as compared to controls [2]. Time-to-maximum concentrations (Tmax in minutes) for unchanged clopidogrel, its inactive carboxyl metabolite and the active thiol metabolite were prolonged in STEMI patients as compared to controls:156 ± 110, 171 ± 108, 137 ± 100 vs. 84 ± 40, 93 ± 55, 55 ± 32, with p = .067, p = .023 and p = .05, respectively. The pharmacodynamic response to clopidogrel was also diminished in the STEMI group, with Δaggregation being 7 ± 8% for 5 μmol/L ADP and 6 ± 7% for 20 μmol/L ADP (at 4 h) and 25 ± 6% for 5 μmol/L ADP and 23 ± 9% for 20 μmol/L ADP (at 24 h). In contrast, in healthy volunteers at 6 h post LD Δaggregation was 56 ± 13% for 5 μmol/L ADP and 45 ± 25% for 20 μmol/L ADP. In another pharmacodynamic study 2-h post clopidogrel 600 mg loading, almost 2/3 of STEMI patients presented with increased platelet reactivity, defined as PRU ≥ 235 P2Y12 reaction units by the VerifyNow assay [3].

Compared to clopidogrel, ticagrelor – a cyclotriazolopyrimidine is a P2Y₁₂ receptor antagonist, which provides stronger, faster and more consistent platelet inhibition [4,5]. Unlike clopidogrel, ticagrelor is not a prodrug and does not require metabolic activation to pursue its antiplatelet activity. In healthy subjects, it is rapidly absorbed, with a median time to peak concentration of 2–3 h. Ticagrelor and its active metabolite, AR-C124910XX, exhibit predictable linear pharmacokinetics in patients with stable coronary artery disease (CAD) and acute coronary syndrome (ACS) but this is not reflective of the physiological state of STEMI in which drug handling is invariably altered. In the STEMI cohort of the PLATelet inhibition and patient Outcomes (PLATO) trial, the reduction of the composite primary end point (death from vascular causes, myocardial infarction, or stroke) with ticagrelor versus clopidogrel [9.4% vs. 10.8%, with hazard ratio (HR) 0.87, 95% confidence interval (CI), 0.75–1.01, and p = .07] was consistent with the overall trial results. The favorable effects of ticagrelor over clopidogrel, were consistent regardless of gender (p for interaction = .98), age group (younger or older than 65 years, p for interaction = .84) or the presence of diabetes (p for interaction = .91) [6]. Furthermore, ticagrelor reduced several secondary end points, including myocardial infarction alone (HR 0.80, 95% CI 0.65–0.98) and total mortality (HR 0.82, 95% CI 0.71–0.96). No increase in the risk of major bleeding (HR 0.98, 95% CI 0.79–1.22) in the ticagrelor treated patients reported, compared with clopidogrel. Following the above results, European Society of Cardiology STEMI guidelines suggest the use of ticagrelor as early as possible with a class I (level of evidence B) recommendation, and the use of clopidogrel with a class I (level of evidence C) recommendation, preferably when prasugrel or ticagrelor are either not available or contraindicated [7]. In contrast, in the American College of Cardiology/American Heart Association STEMI guidelines both ticagrelor and clopidogrel are recommended as early as possible or at time of PCI with a class I (level of evidence B) recommendation [8].

A clinician deciding over the use of ticagrelor or clopidogrel should carefully consider contraindications and special warning and precaution for its drug. Ticagrelor is contraindicated in the presence of prior intracranial hemorrhage or moderate/severe hepatic impairment, while there is a warning and precaution for its use if there is a history of asthma/chronic obstructive pulmonary disease, hyperuricemia or gouty arthritis, an increased risk of bradycardiac events or cotreatment with strong CYP3A4 inducers. End-stage renal failure requiring hemodialysis needs special attention for both ticagrelor and clopidogrel. Conditions and comedication related to increased bleeding risk are also common for ticagrelor and clopidogrel, although in ‘real life’, in their presence, the less potent clopidogrel is preferred [9]. Cotreatment with moderate/strong CYP2C19 inhibitors requires special attention for clopidogrel administration.

Recently, a post hoc subgroup analysis of PLATO, which included 4949 patients with STEMI undergoing primary PCI showed that the primary efficacy end point occurred in 7.9% of ticagrelor-treated and in 8.6% of clopidogrel-treated patients during a median follow-up of 286 days (HR 0.91, 95% CI 0.75–1.12, p = .38) [10]. No interactions were observed for the treatment effect of ticagrelor versus clopidogrel on the primary efficacy (p = .40) and primary safety end points (p = .15), in consistency with the overall PLATO population. Additionally, treatment with ticagrelor versus clopidogrel reduced the occurrence of definite stent thrombosis (HR 0.58, 95% CI 0.37–0.89, p = .013). However, a higher rate of acute (within 24 h) stent thrombosis was observed among ticagrelor than clopidogrel treated patients, 0.5% vs. 0.2%. Remarkably, the magnitude of risk reduction with ticagrelor vs. clopidogrel in the primary PCI cohort appears to be less marked compared with its use in the full ACS population. Several explanations have been offered for this findings, like different population (younger, healthier) undergoing primary PCI and difficulty in definition of periprocedural myocardial infarction in patients with ongoing STEMI, leading possibly to underestimation of the effects of the newer antiplatelet agents. Moreover, in STEMI the interval between drug administration and mechanical reperfusion is generally short and the efficacy of antiplatelet agents is highly affected by impaired pharmacokinetics. Indeed, in STEMI patients the onset of action of the fast-acting oral P2Y₁₂ receptor antagonist, ticagrelor and prasugrel, is delayed [11]. A significant proportion of patients exhibit high platelet reactivity at 2-h post-ticagrelor LD leading to the speculation that even after timely ticagrelor administration, the procedure is performed in most cases with platelet reactivity levels above the ischemic threshold, a scenario which may be related with adverse events. An additional compelling finding is the association of morphine use with high platelet reactivity early after P2Y₁₂ receptor antagonists LD, which has been attributed to the effect of morphine on intestinal motility and absorption [12,13].

Several strategies have been implemented to overcome the delay in achieving robust platelet inhibition, in patients intended for primary PCI. An early, high 600 mg clopidogrel LD in the prehospital phase did not increase pre-PCI patency of the infarct related vessel [14]. Likewise, in the Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation MI to Open the Coronary Artery (ATLANTIC) trial 1862 low-risk STEMI patients were randomized to either prehospital (in the ambulance or referring hospital) treatment with ticagrelor or same drug administration at the time of primary PCI [15]. There were no significant differences in the preangiographic TIMI flow or ST-segment resolution between groups. No differences in major bleeding were reported either. Of note, pharmacodynamic data from ATLANTIC study clearly demonstrated the performance of primary PCI prior to achieving strong platelet inhibition. Although routine prehospital pretreatment cannot be recommended for STEMI patients over the in-lab administration of the drug, whenever the diagnosis of STEMI is confirmed and primary PCI is planned ticagrelor LD may be used, especially if long transfer time to the PCI center are anticipated [16,17].

Moreover, several modifications of the ticagrelor LD have been tried in STEMI patients. In the Mashed Or Just Integral Tablets of ticagrelOr (MOJITO) study administration of ticagrelor LD in a crushed form instead of integral tablets did accomplish a more rapid onset of the pharmacodynamic effect [18]. A faster intestinal absorption for the crushed ticagrelor tablets was hypothesized as mainly responsible for the difference observed. These results were further confirmed by the OraL crushed and dIspersed ticagrelor 180 mg versus whole tablets of eQUal dose in STEMI patients unDergoing primary PCI (LIQUID) study, where at 1 h, ticagrelor and AR-C124910XX (active metabolite) plasma exposure was higher and time to maximum plasma concentration was shorter in the crushed versus integral tablets loaded patients [19].

In real-world practice patients with STEMI are commonly loaded with clopidogrel 600 mg in the ambulance or at the non-PCI hospital and afterwards reloaded with ticagrelor 180 mg LD. Of interest, among patients allocated to ticagrelor in the PCI cohort of PLATO trial, 40.7% of them had received prerandomization 600 mg of clopidogrel. It has been hypothesized that clopidogrel administration prior to ticagrelor may result in a positive pharmacodynamic synergy between the two agents. This hypothesis was not confirmed in a randomized study comparing ticagrelor LD alone versus a strategy of clopidogrel LD plus ticagrelor LD 2 h later [5]. The ticagrelor alone group was proved to be non-inferior to the combined (clopidogrel plus ticagrelor) LD group regarding platelet reactivity, as assessed at 24 h. Moreover, a clear pharmacodynamic superiority of ticagrelor over clopidogrel has been demonstrated in patients after cardiac arrest undergoing therapeutic hypothermia, a scenario where clopidogrel is especially ineffective [20]. There is no doubt that cangrelor, an intravenous P2Y₁₂ receptor antagonist, by providing almost immediate strong platelet inhibition may be attractive for STEMI cases when platelet inhibition is urgently needed. In the STEMI cohort (n = 1991) of the Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial, cangrelor compared to clopidogrel reduced the 48-h primary end point with odds ratio (95% CI) 0.75 (0.46–1.25), consistent with the overall trial results (p for interaction = .98), without any significant increase in the incidence of severe bleeding or transfusions [21].

In summary, STEMI is a common and high-risk condition for which clopidogrel presents with several drawbacks. The marginal precedence of ticagrelor over clopidogrel, has drag the balance toward the use of ticagrelor as a new standard of care for the management of patients with STEMI intended for primary PCI. Suboptimal inhibition of platelet reactivity during the procedure, and for the first few hours thereafter, even with the newer P2Y₁₂ receptor antagonists, remains, however, an obstacle to be overcome with novel strategies aimed at intensification of platelet inhibition and with the expectation of leading to a better clinical outcome.

Declaration of interest

D Alexopoulos reports receiving advisory board fees from Astrazeneca, Boehringer Ingelhein, Bayer and The Medicines Company and lecturing honoraria from Astrazeneca. J Lekakis reports receiving advisory board fees and lecturing honoraria from Astrazeneca, Actelion and MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.