Medicina, Vol. 59, Pages 84: The Effectiveness of Antiplatelet Therapy and the Factors Influencing It in Patients with Acute Coronary Syndrome before and during the COVID-19 Pandemic

In daily clinical practice, aspirin resistance was more common than that described in controlled studies with a selected population, most likely due to the use of low doses and modified absorption formulas. This has been favored due to numerous clinical factors (men, young age, and overweight) as well as other factors, such as a high number of leukocytes and platelets. On the other hand, aggregation studies have revealed a much lower resistance to clopidogrel than that seen in other studies, with most patients being within the optimal antiplatelet treatment window. In patients treated with ticagrelor, it was found that almost half had an exaggerated antiplatelet response, exposing them to a significant risk of bleeding.

4.1. Aspirin TreatmentHTPR in patients treated with aspirin is a biomarker associated with poor prognosis due to the high risk of ischemic recurrences, especially due to increased mortality and intrastent thrombosis [24]. Aspirin is considered the cornerstone of ACS treatment. However, multiple studies have shown an extremely variable response, which is closely related to the method used, the selected population, and the time of blood collection. The literature lists more than 40 factors that may interact with the efficacy of aspirin, the most common of which are patient noncompliance, pharmacokinetics (underdose; limited absorption), and inefficient drug metabolism [25]. Most studies of this type have been carried out on patients on DAPT with clopidogrel, but the current standard treatment for stented patients with ACS implies a combination with more potent P2Y12 receptor inhibitors. In this context, two aspects need to be considered. First, the hemorrhagic risk for patients increases, and there is a tendency for clinicians to minimize the dose of aspirin to the limit of antiplatelet efficacy in order to counteract the risk. Next, there is evidence that the new antiplatelet agents interfere with the production of thromboxane A2 and with the action of aspirin [26]. In our study, almost 80% of the patients were treated with ticagrelor, and over 97% were treated with aspirin. Thus, we intended to evaluate, in addition to the effectiveness of the antiplatelet therapy in ACS patients stented in our hospital, certain factors that influence the response to these drugs based on aggregation analyses.On examination of the ASPI test using arachidonic acid as an agonist, 43.46% of the patients had an inadequate response to aspirin, one of the highest rates reported in the literature. This may be primarily due to the dose administered, which was the minimum recommended by European guidelines (75 mg/day); however, the ACC/AHA guidelines recommend a dose of at least 82 mg/day to sufficiently reduce ischemic recurrence, compared to higher doses of up to 325 mg daily [27,28]. Moreover, in our cohort, gastro-resistant tablets have been administered in the case of both loading and maintenance doses, which have been shown to reduce intestinal absorption and to produce “pseudo-resistance” to aspirin [29,30].Among the interaction factors analyzed, significant associations between age, gender, weight, and certain parameters of the blood count were observed (Table 2, Figure 2). Although there is an increase in platelet activity and a higher rate of ischemic events with age, and prothrombotic status is assigned to the elderly, a recent study showed that young people have higher ASPI test values, which was also confirmed in our study [13,31]. This may be due to some confounding factors, since the young patients in our study were predominantly overweight men who presented with STEMI. A meta-analysis published in 2018 of 10 randomized primary prevention trials showed that low doses of aspirin (75–100 mg) were only clinically effective in patients weighing less than 70 kg, and showed no benefit in the case of 80% of men and about 50% of women weighing over 70 kg [32]. Our results confirm the fact that increased body weight reduces the efficacy of aspirin. This can be explained by the increase in platelet activation and turnover, but also by the reduction in the bioavailability of aspirin due to the higher body mass distribution. The same mechanism of accelerating platelet turnover, as well as other mechanisms, such as inflammation, hyperglycemia, and insulin resistance, have been incriminated in diabetic patients exhibiting increased resistance to aspirin. Numerous studies have obtained contradictory results with regard to the link between diabetes and aspirin resistance [33,34]. One of the studies mentioned previously identified hypercholesterolemia as a predictor of aspirin resistance [34]. We found no association between aspirin resistance and diabetes or changes in the lipid profile.An elevated leucocyte count has been associated in the case of patients with ACS with an increased ischemic risk. This can either be because it is a marker of a higher inflammatory status, a consequence of a larger infarction, or due to a prothrombotic status induced by the modulation of platelet activity, the formation of tissue factors, direct endothelial injury, or the activation of the extrinsic pathway [35,36]. In our cohort, leukocytosis was found in half of the patients, and was observed to be a risk factor for aspirin resistance (OR: 2.51; 95% CI: 1.37–4.57). In the specified pandemic context, we cannot exclude the association of leukocytosis with COVID-19 infection. The latter predisposes patients to thrombotic events due to excessive inflammation, endothelial activation and injury, platelet activation, and hypercoagulability [37]. The aggregation studies performed on COVID-19 patients have shown contradictory results. A study involving 41 patients who were not receiving antiaggregant treatment showed an increased aggregability in COVID-19 patients in response to different agonists [38]. Another study that used impedance-based aggregometry with Multiplate did not show significant differences in platelet aggregation in COVID-19 patients on ventilation support compared to healthy volunteers. The aggregability samples from our study, which were collected during the pandemic from patients treated with aspirin, showed an increase in the incidence of aspiring resistance, although it was statistically insignificant, likely due to the inclusion of COVID-19-infected patients. This can, most likely, be explained by the increased synthesis of thromboxane in infected patients, which is why aspirin was initially used in the treatment of these patients to reduce thrombotic complications. However, the most recent Recovery trial did not demonstrate a reduction in mortality or the progression of respiratory failure to mechanical ventilation in patients with COVID-19 who were treated with 150 mg of aspirin daily [39].There are few and contradictory data in the literature regarding the influence of platelet parameters on aspirin efficiency. Platelets are the target of antiplatelet drugs, so their number and characteristics play an important role in therapeutic efficacy, especially due to the different amounts of platelet cytoplasm, which is known to contain many pro-aggregating substances. In one study, the platelet count was not correlated with the ASPI test value, but only with the ADP test, in patients treated with clopidogrel and aspirin. In another, which used light transmission aggregometry (LTA), it influenced the efficacy of aspirin [40,41]. To restore clinical utility, we analyzed the platelet counts below and above the mean normal range. This way, a high platelet count predisposed patients to aspirin resistance (OR: 2.47; 95% CI: 1.23–4.97). As for the other indices, only the PCT with a value above 0.26/fL was noted as another resistance factor, as evidenced by another study [40]. However, in contrast to these studies, we did not find a significant association with MPV. 4.2. Treatment with P2Y12 InhibitorsIn line with current recommendations and guidelines, most patients with ACS were treated with more potent P2Y12 inhibitors: in this case, ticagrelor [4,7]. Nevertheless, in the case of certain conditions associated with an increased risk of bleeding (old age, low weight, renal dysfunction, associated drugs, or a history of bleeding), the patient was prescribed clopidogrel, the decision being made by the attending physician. This explains the difference between the characteristics of the two groups of patients, those under clopidogrel and under ticagrelor (Table 1). In our cohort, the results of the aggregation test showed, as expected, that the ADP test values of the patients being treated with clopidogrel were well above the values of patients on ticagrelor, but only two patients (5%) had HTPR (Figure 1). The incidence was very low in our study compared to the last large trial (TROPICAL-ACS), which used impedance-based aggregation, and where the incidence was about 40% [42]. In our case, this is more likely due to the selection criteria of patients receiving clopidogrel in “real life”, as mentioned above. Most patients being treated with clopidogrel were within the “therapeutic window” of antiplatelet therapy, which was also recommended by the last consensus reached [12]. On the other hand, approximately half of the patients being administered ticagrelor had decreased platelet reactivity, which is consistent with recent data from the TOPIC-VASP study [43]. It has been shown that patients with LTPR have an increased risk of bleeding, which is clearly correlated with the unfavorable prognosis and analysis of the ADEPT-DES study [44]. Thus, the patients treated with more potent antiplatelet agents are at an increased risk of bleeding throughout the treatment. This may offset their beneficial anti-ischemic effect, which is more pronounced during the acute period. Hence, the principle of the “de-escalation” of antiplatelet therapy from a more potent drug (ticagrelor; prasugrel) to clopidogrel, after the acute phase of ACS, may be applied with or without monitoring platelet function [42,43]. The first studies showed favorable results in this regard, with a reduction in the frequency of hemorrhagic events and without significantly increasing the incidence of ischemic events. This had a clearly favorable clinical benefit and low economic cost, which was confirmed by the last meta-analysis that was recently published [45,46].In our study, due to the high percentage of LTPR patients being treated with ticagrelor, we attempted to identify the factors that influence this exaggerated antiplatelet response to aggregation tests. These factors could also be used as a clinical practice tool to individualize the antiplatelet treatment and to avoid an exaggerated response to it. Other studies have shown a direct link between age and the rate of bleeding, but it is not known to what extent this depends strictly on the degree of antiplatelet or other intricate factors (low weight, vascular fragility, other drugs, or associated co-morbidities) [47]. We have shown that old age is a factor that predisposes patients to an exaggerated response to ticagrelor, and furthermore, we have shown that being under the age of 50 can be considered a protective factor for its occurrence. The other clinical factors investigated (i.e., weight, gender, cardiovascular risk factors or diagnosis at hospital admission) did not influence the occurrence of this exaggerated response (LTPR).On the other hand, the investigated laboratory parameters showed multiple associations in this sense. A recent study showed that platelet count influences ADP test results in patients being treated with ticagrelor [13]. Additionally, we have also demonstrated that their high number is protective against the appearance of an exaggerated antiplatelet response (LTPR). We have demonstrated that the same is true of patients with high MPV, even though the most recent studies published in the literature have not found a correlation between this index and resistance to clopidogrel or ticagrelor (HTPR) [13,48]. PCT is the index that includes the two previously mentioned ones, and its impact on aggregability has not been reported so far. It can be used as a global platelet marker to assess the risk of developing LTPR, where a high value can be considered a protective factor.A recent study demonstrated that ADP is the main target in the development of microvascular obstruction in COVID-19 patients. Therefore, ADP receptor inhibitors could be used as therapeutic agents against thrombotic complications in these patients [49]. Nevertheless, a study published recently did not demonstrate any additional benefit of adding P2Y12 inhibitors to heparin for reducing mortality or the need for respiratory or cardiovascular support at 21 days [50]. In the second enrollment period in our study, during the COVID-19 pandemic, a more frequent use of ticagrelor, and at the same time, a decrease in the number of patients with hemorrhagic risk, was observed. This is explained by the increased platelet aggregation of patients in this period (Table 1 and Table 3). A slight increase in ADP test values was observed in patients on ticagrelor, and a significant one in those on clopidogrel during the COVID-19 pandemic. Patients who were probably infected but undiagnosed were included in the study. Ticagrelor, being more potent than clopidogrel, retained an antiplatelet effect without significant changes.Unlike the medullary suppression effect of thienopyridines, ticagrelor has a neutral effect, according to the data published in a PLATO trial sub-study [51]. Therefore, the number of leucocytes reflects the inflammatory status of the patient, in direct connection with the type of ACS and the size of the endangered myocardium. In our study, patients with leukocytosis had a significantly lower LTPR rate, as indicated by the ADP tests, which was, possibly, also closely related to their higher inflammatory and pro-thrombotic status.Renal dysfunction is an important indicator of ischemic complications in patients with ACS due to advanced atherosclerosis, inflammation, oxidative stress, and hyperaggregability, but also due to the underuse of antithrombotic medication and revascularization interventions [52]. On the other hand, it increases the risk of bleeding due to an overdose of drugs that are eliminated mainly in this way [44]. Ticagrelor and its active metabolite are predominantly metabolized extrarenally, so renal impairment should have little impact on them; moreover, creatinine levels may increase during treatment with ticagrelor, the mechanism of which has not yet been elucidated [53]. In our cohort, the patients treated with ticagrelor showed lower serum creatinine values less often than those being treated with clopidogrel in the context of selection bias. Still, in these patients, renal dysfunction influenced the ADP test values, showing that a significantly higher percentage of patients presented with LTPR and an implicit risk of bleeding. This analysis suggests that renal dysfunction is a predisposing factor for additional bleeding risk, but this should not limit the use of potent antiplatelet agents in these patients, who also have a much higher ischemic risk. In the PLATO study, ticagrelor was shown to be much more effective than clopidogrel in reducing ischemic events in patients with ACS, especially those with impaired renal function, without a modification in dosage and without increasing the rate of major bleeding [54]. 4.3. Limitations of the Study

The results of the present study need to be interpreted while considering several limitations. This is an observational cohort study, and as such, it was influenced by the patient selection procedure. Thus, even though the patients were selected randomly for the study, a large percentage of patients were young, under the age of 50, which could have influenced the results. For this reason, the study should only be interpreted as a generator of hypotheses and as a clinical guidance tool. We note the small sample size and, especially, the small number of patients treated with clopidogrel, which did not allow us to carry out a statistical analysis of the factors that could have influenced its effectiveness. Some of the significant associations found may be due to confounding factors without adjusting for these using multivariable analysis.

Our study coincided with the beginning of the pandemic, which made the enrollment process difficult. Therefore, we wanted to analyze in which manner this influenced the results of the aggregometry analysis. Unfortunately, by the time the pandemic had begun, we could not screen the asymptomatic patients using molecular COVID-19 tests. That is why we could not specify in what aspect, per se, the infection could influence our results.

The lack of long-term follow-up to establish a correlation between the aggregation data and the bleeding, respectively, and ischemic events are another limitation of the study, but this should be the subject of future studies.

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