Antiplatelet Therapy with Prasugrel and Ticagrelor in the Treatment of Patients with Acute Coronary Syndrome

Introduction

Dual antiplatelet therapy (DAPT) forms the basis for the treatment of all patients undergoing percutaneous coronary intervention (PCI) and patients who suffered acute coronary syndrome (ACS) (1-3). Multiple clinical trials consistently show that one year of DAPT, consisting of aspirin and a P2Y₁₂ receptor inhibitor, lowers the risk of a future atherothrombotic event after ACS (4-7). Furthermore, therapy with more potent P2Y₁₂ inhibitors, prasugrel or ticagrelor, provides better protection from ischemic events but with a higher frequency of bleeding complications than with clopidogrel (5,6). This is why prasugrel and ticagrelor are the P2Y₁₂ inhibitors of choice when treating patients without a high risk of bleeding with acute ST elevation myocardial infarction (STEMI) and non-ST elevation ACS (2,3).

Prasugrel

Prasugrel is a thienopyridine P2Y₁₂ receptor inhibitor with a rapid onset of action (8,9). Just like clopidogrel, prasugrel requires conversion into active substance by intestinal esterase and by cytochrome P-450 before it can demonstrate its antiplatelet effect (10). Unlike with clopidogrel, this activation happens significantly sooner, already within 15 minutes. Moreover, prasugrel’s activation path through cytochrome P-450 is different from that of clopidogrel and is significantly less dependent on concomitant therapy and genetic variants of the cytochrome (9). Because of the above, prasugrel, when compared with clopidogrel, leads to more consistent and more reliable inhibition of platelet aggregation.

TRITON TIMI 38 was the first large, randomized, double-blind clinical study to compare prasugrel and clopidogrel (5). The study included patients with ACS, 99% of whom had undergone PCI. In the study, therapy with prasugrel led to a reduction in overall major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke (9.9% vs. 12.1%, hazard ratio (HR) 0.81, 95% CI 0.73-0.90, p < 0.001) (5). On the other hand, prasugrel treatment also caused a higher incidence of bleeding complications that were not associated with cardiac surgical revascularization (2.4% vs. 1.8%, HR 1.32, 95% CI 1.03-1.68, p = 0.03) (5). In subsequent subanalyses, three groups of patients with especially high risk of bleeding were identified: 1) patients with a history of stroke, 2) patients older than 75 years of age, 3) patients with body weight under 60 kg (5). In accordance with the above and under current clinical recommendations, prasugrel is contraindicated in patients with a history of stroke and transient ischemic attack, whereas in patients older than 75 and patients with body weight under 60 kg it is advisable to reduce the maintenance dose by half, from the standard 10 mg to 5 mg (1,3). It should be noted that the above-mentioned recommendations concerning dose reduction are the result of pharmacokinetic studies, i.e. that clinical efficacy has not been confirmed in a randomized clinical study (11,12). The ACCOAST clinical study, which included patients with non-ST elevation ACS, showed that using prasugrel before identifying coronary anatomy had no effect on the clinical or angiographic outcomes compared with the group of patients in whom the loading dose of prasugrel (60 mg) was administered after coronarography (13). On the other hand, patients in whom prasugrel was administered before coronarography (immediately after diagnosing ACS) had a significantly higher frequency of bleeding (HR, 1.90; 95% CI, 1.19 to 3.02; p = 0.006) (13). Based on this, prasugrel is indicated in patients with non-ST elevation ACS only after identifying coronary pathology or after deciding to perform PCI (3). Considering that the TRILOGY-ACS study, which included patients with ACS who had not undergone revascularization, found no significant reduction in MACE between clopidogrel and prasugrel, therapy with prasugrel is not indicated if PCI is not planned (14). Prasugrel therapy as a part of DAPT, can be continued even after one year, based on the results of the DAPT study (15). In it, out of almost 10.000 subjects in total, 32% had ACS, and after one year of DAPT (if they were able to tolerate it without significant adverse effects), they were randomized to continue treatment with either clopidogrel or prasugrel with aspirin or just aspirin with placebo (15). The results in the overall population confirmed statistically significantly lower incidence of stent thrombosis and myocardial infarction, but with a higher risk of bleeding and statistically borderline significantly higher overall mortality in the group receiving prolonged DAPT. After subgroup analysis, patients who had suffered ACS benefited more from the prolonged DAPT (15).

Ticagrelor

Ticagrelor is a non-thienopyridine, direct, reversible P2Y₁₂ receptor inhibitor with a rapid onset of action of 30 minutes (8,16). Unlike prasugrel, ticagrelor does not require conversion to active substance. In the PLATO registration study, there was a significant reduction in MACE (9.8% vs. 11.7%; HR 0.84; 95% CI 0.77-0.92, p < 0.001) and overall mortality as a separate outcome (HR 0.78; 95% CI 0.69-0.91, p < 0.001) with ticagrelor compared with clopidogrel (6). The group of patients treated with ticagrelor had a higher frequency of bleeding not associated with cardiac surgical revascularization (4.5% vs. 3.8%, p = 0.03), but there was no statistically significant difference in major hemorrhages (6). The study included patients regardless of which ACS treatment method was used (invasive or conservative), which is why ticagrelor is also indicated in cases where only medication therapy is used (1,6). PEGASUS-TIMI 54 was another ticagrelor study with a significant influence on clinical practice, where over 21,000 patients with a history of myocardial infarction were randomized to receive: 1) ticagrelor at full dosage (2 × 90 mg), 2) ticagrelor at reduced dosage (2 × 60 mg) or 3) placebo (17). All patients were receiving ongoing therapy with aspirin. After three years of follow-up, a significant reduction in MACE was reported in both groups treated with ticagrelor (7.85% vs. 7.77% vs. 9.04%; HR 0.85, 95% CI 0.75-0.96 and 0.84, 95% CI 0.74-0.95) (17). Moreover, major hemorrhage incidence was significantly higher in the ticagrelor groups, without any differences in fatal or intracranial hemorrhage (17). Based on this study, current guidelines state that ticagrelor at 2 × 60 mg can potentially be continued in selected patients post ACS after one year of “classic” DAPT (3).

It should be noted that patients who were considered to have high risk of bleeding were excluded in advance from all of the above-mentioned studies for both agents.

Prasugrel vs. ticagrelor

ISAR REACT 5 is the largest (over 4.000 patients) randomized study to date to directly compare prasugrel and ticagrelor in patients with ACS scheduled for intervention treatment (18). Subjects presenting with STEMI were immediately treated with the saturation dose for both agents (ticagrelor 180 mg, prasugrel 60 mg). If their initial diagnosis was non-ST elevation ACS, they were immediately treated with a saturation dose of ticagrelor, while prasugrel was administered only after coronarography (in line with the recommendations for administering these medications) (18). This generated the hypothesis that ticagrelor (due to its earlier administration) would be superior to prasugrel in MACE after one year. Contrary to the hypothesis, the results showed a clear reduction in MACE in the prasugrel group (6.9% vs. 9.3%, HR 1.36, 95% CI 1.09-1.70, p = 0.006) without any significant differences in bleeding complications (18). Patients with a history of stroke were excluded from the study (since prasugrel is contraindicated in these patients), while patients above the age of 75 (approximately 24% in both groups) and those with body weight below 60 kg (approximately 5% in both groups) were given a low dose of prasugrel of 5 mg (18). A subanalysis of these subgroups suggested the superiority of prasugrel (which is in line with the main results), but without statistical significance (18). A recently published meta-analysis of over 145,000 patients from a total of 14 randomized studies or large prospective registries compared prasugrel, ticagrelor, and clopidogrel in ACS (7). The results of this meta-analysis indicated that prasugrel was superior to ticagrelor and clopidogrel in reducing MACE and overall mortality after 30 days, while ticagrelor reduced overall mortality in comparison with clopidogrel (7). In addition, prasugrel significantly reduced the incidence of stent thrombosis, but without a significant difference in the incidence of myocardial infarction in comparison with ticagrelor. There were no statistically significant differences in bleeding after 30 days of follow-up. However, after one year there were no differences in MACE among the three studied P2Y₁₂ inhibitors (7). On the other hand, ticagrelor and prasugrel lead to a significant reduction in overall mortality compared with clopidogrel. In terms of numbers, prasugrel had fewer fatal outcomes than ticagrelor, but without statistical significance (7). Even after one year of follow-up, no statistically significant difference was reported in bleeding complications (7).

Considering all of the above, both P2Y₁₂ receptor inhibitors, prasugrel and ticagrelor, are appropriate options for treating patients with ACS without high risk of bleeding. Nevertheless, considering the ISAR REACT 5 study and the meta-analysis, prasugrel is preferred to ticagrelor. This has also been recognized in the current guidelines for the treatment of non-ST elevation ACS, and similar recommendations can be expected in the future guidelines for STEMI (3). In addition, prasugrel is the treatment of choice for patients (undergoing PCI) who were initially treated with ticagrelor or who developed non-exertional dyspnea. Specifically, this adverse effect persists in approximately 4% of patients on ticagrelor after 7 days of therapy (8,19). On the other hand, the advantages of prasugrel are not as clear in certain patient populations and clinical scenarios. This primarily refers to patients who suffered a stroke, in whom prasugrel is contraindicated, i.e. in whom ticagrelor is the only right option (if the estimated total bleeding risk is not high). Similarly, in patients with ACS in whom medication treatment is intended and who do not have high bleeding risk, ticagrelor is a better option than clopidogrel. In addition, ticagrelor is also preferred in clinical scenarios when delayed invasive diagnostics or treatment is planned. Namely, guidelines for non-ST elevation ACS no longer recommend using P2Y₁₂ inhibitors without being familiar with coronary anatomy if early invasive treatment is planned, defined as occurring within 24 hours of diagnosis (3). It should be noted that the average time to PCI was 4.3 hours in ACCOAST (13). Nevertheless, the guidelines themselves include the option of using P2Y₁₂ inhibitors in situations when the risk of bleeding is not high and early invasive treatment is not planned (3). In such situations, according to the results of these studies, ticagrelor is preferred to clopidogrel. Finally, the question remains what to do with the group of patients who are candidates for a lower dose of prasugrel of 5 mg (older than 75 and below 60 kg). As stated previously, although the efficacy of this dose has been described in pharmacokinetic investigations, there is no clear clinical evidence of the superiority of prasugrel over ticagrelor in these patient groups. In case of prolonged DAPT (after one year), guidelines for treating non-ST elevation ACS recommend prolonged DAPT with a relatively strong level IIa recommendation (evidence level A) in patients with an estimated high risk of ischemic incidents and low risk of bleeding and provide a level IIb (evidence level A) recommendation for patients with moderate risk of ischemic events and low risk of bleeding (3). In such clinical cases, the recommended first treatment option is ticagrelor at a reduced dose (2 × 60 mg) based on the previously described PEGASUS-TIMI 54 study, while prasugrel (or clopidogrel) are second-choice agents based on the DAPT study (3,17).

Prasugrel and ticagrelor as monotherapy

Thanks to advancements in stent design and with the goal of reducing primarily bleeding complications of DAPT after PCI, studies have been conducted with earlier discontinuation of P2Y₁₂ inhibitors and continued monotherapy with aspirin (20,21). A similar approach has been in development in recent years, but it involves discontinuing therapy with aspirin after the initial 1-3 months of DAPT and continuing therapy with a P2Y₁₂ inhibitor (22). The premise behind this approach is that, besides inhibiting platelet aggregation, aspirin has a harmful effect on the gastrointestinal mucosa as a cyclooxygenase 1 inhibitor; gastrointestinal bleeding being the most common cause of bleeding complications (20). Furthermore, pharmacodynamics studies demonstrated limited influence of the anti-aggregation effect of aspirin if the patient was on a potent P2Y₁₂ inhibitor (20,23,24). Finally, the risk of stent thrombosis with a modern DES is highest during the first month (25-29).

Five randomized studies have been published to date in which DAPT was discontinued after 1-3 months post PCI, which involved discontinuing therapy with aspirin and continuing therapy with a P2Y₁₂ inhibitor (three studies involved ticagrelor and two involved various P2Y₁₂ inhibitors, primarily clopidogrel) (30-34). Most of these studies, as well as two meta-analyses, identified a reduction in serious bleeding complications from 31 to 71% in the “short” DAPT group (25,30-35). No study found statistically significant differences in ischemic complications, MACE, or mortality. The results were consistent regardless of the clinical circumstances of the PCI – acute or chronic coronary syndrome, high-risk patients, or complex PCI (26,36-38). Based on these results, guidelines for treating non-ST elevation ACS already allow using DAPT (aspirin and ticagrelor) for 3 months, after which monotherapy with ticagrelor is continued at a full dose in patients with low risk of bleeding (3).

The results of the ASET pilot study were recently published (39). ASET was a multicentric, observational study involving 201 subjects undergoing non-complicated elective PCI (39). On the day of their PCI, the subjects were given their last dose of standard therapy with DAPT (clopidogrel and aspirin) which was then discontinued and replaced by prasugrel monotherapy for the next 3 months of the follow-up period. During this time, one case (0.5%) of a combined ischemic and bleeding outcome was reported (39). Based on these results, plans are being made for a prospective study in which all the patients will exclusively receive prasugrel monotherapy during the study and the one-year follow-up.

Conclusion

Potent P2Y₁₂ inhibitors, prasugrel or ticagrelor, are an integral part of DAPT in patients with ACS who underwent PCI and who do not have a high risk of bleeding complications. According to present studies, the protection provided by prasugrel therapy compared with ticagrelor is greater than the potential ischemic outcomes in selected groups of patients, without increased risk of bleeding, and is therefore the first treatment of choice. On the other hand, ticagrelor is the treatment of choice in patients with ACS treated with medication. In spite of the promising results of the studies involving reduced 3-month DAPT followed by continued therapy with a P2Y₁₂ inhibitor, additional studies are required, primarily in patients with ACS, before introducing any changes to the current clinical practice.