To avoid complications after percutaneous coronary intervention (PCI), such as acute and late thrombosis at the site of stenting and recurrent ischemic cardiovascular events, anti-platelet therapy is crucial [1]. Several studies [2‐4] have shown that dual anti-platelet therapy with aspirin and a thienopyridine ADP-receptor blocker is effective in preventing such acute and late complications. Clopidogrel is an ADP-receptor blocker that is used regularly in Japan. It has a better safety profile than ticlopidine, a previous-generation ADP-receptor blocker, but its main disadvantage is the wide interindividual variations of its anti-platelet effect [5]. Hoshino et al. evaluated the anti-platelet effect of clopidogrel in Japanese patients and found wide interindividual variation as well as a proportion (approximately 14%) of clopidogrel non-responders [6].

Prasugrel is a next-generation thienopyridine anti-platelet agent that has been approved in over 80 countries for patients with acute coronary syndrome (ACS) undergoing PCI. Prasugrel provides more prompt, potent, and consistent platelet inhibition than clopidogrel, and the effects of prasugrel are not influenced by the presence of CYP2C19 polymorphisms [7]. The efficacy and safety of prasugrel were confirmed in Japanese patients in two phase III studies [8, 9]. Based on these results, prasugrel was approved in Japan in March 2014 for ACS [including unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI)], stable angina, and old myocardial infarction that requires PCI. The approved doses of prasugrel, which are exclusive for Japanese patients, are 20 mg as the initial loading dose (LD) and 3.75 mg/day as the maintenance dose (MD), which are lower than those used in Western countries (LD/MD: 60/10 mg/day). Given the higher average age and lower body weight of Japanese patients compared with Western patients, we considered that lower doses of prasugrel may effectively lower the risk of bleeding during dual anti-platelet therapy in Japanese patients while maintaining more consistent platelet inhibition than clopidogrel.

At present, data on the safety and efficacy of prasugrel in Japanese patients are limited to the populations of the phase II/III clinical trials, in which patients were selected based on strict inclusion criteria. In addition, because bleeding adverse events (AEs) have been reported as the most common adverse drug reactions (ADRs) in clinical trials, safety information should be made available in clinical settings as soon as possible by determining the incidence and severity of bleeding AEs under actual conditions of use. Therefore, this early postmarketing observational study (PRASFIT-Practice I) aimed to evaluate the safety and efficacy of the short-term use of prasugrel in patients with ACS in real-world clinical practice settings in Japan.

This postmarketing observational study assessed the safety and efficacy of short-term treatment with prasugrel in patients with ACS in real-world clinical practice settings in Japan. We consider that this study provides relevant information in terms of the efficacy and safety of prasugrel as we included patients with severe cardiac disease (Killip IV) (6.7% of patients), history of ischemic stroke (5.1%), and severe renal impairment (on dialysis) (2.0%), as well as those concomitantly taking drugs that increase the tendency of bleeding AEs, such as warfarin/DOACs (2.6%) or NSAIDs (1.5%). Patients having these baseline demographics and/or taking these concomitant drugs (approximately one-sixth of the patients) were excluded from clinical studies in Japan, such as PRASFIT-ACS [8].

In approximately 99% of patients, the initial prasugrel LD and MD were 20 and 3.75 mg, respectively; 95.1% of patients received an initial LD. Prasugrel was administered as described in the package insert [10], and aspirin was used concomitantly in most patients. Nearly 70% of prasugrel treatment completions or discontinuations occurred as patients switched to other anti-platelet agents. Because prasugrel was only allowed to be prescribed for a period of 2 weeks during the first year after its launch, these patients were prescribed other anti-platelet agents for subsequent long-term treatment.

The incidence of ADRs was 8.6%, and the incidence of serious ADRs was 3.4%. The highest incidence of ADRs was for gastrointestinal disorders (3.3%). Most of the ADRs and serious ADRs were bleeding AEs. A total of 12 patients experienced major bleeding AEs. Approximately 60% (seven patients) of all major bleeding AEs were gastrointestinal disorders. This finding was consistent with the observation in a survey of clopidogrel (J-PLACE) in NSTEMI/unstable angina pectoris patients scheduled to undergo PCI [12], which suggests that gastrointestinal disorders are the main bleeding AEs in ACS patients. Therefore, preventive measures for gastrointestinal disorders might be required. Aspirin is highly likely to be a contributor to the development of these gastrointestinal disorders [13] and the prevention of low-dose aspirin-associated upper gastrointestinal injuries by proton pump inhibitors (PPIs) has been reported [14]. However, in this study, the proportion of patients receiving PPIs was less than half (47.4%) of the total population assessed. Although no significant difference was noted in the incidence of bleeding AEs between patients treated with or without concomitant PPIs in this study, concomitant use of PPIs from the start of dual anti-platelet therapy seems essential for preventing gastrointestinal disorders, especially in high-risk patients.

The incidence of major bleeding AEs in patients treated with prasugrel was 1.9% in PRASFIT-ACS [8], and was slightly lower in this study (1.6%). Furthermore, the incidences of minor bleeding AEs, clinically relevant bleeding AEs, other bleeding AEs, and all bleeding AEs were all lower in this study in comparison with PRASFIT-ACS [8]. One possible explanation for these differences is that, in this study, intraoperative bleeding of the expected amount associated with invasive procedures, such as PCI, was not reported as an AE. Another possible explanation is that the observation period in this study differed from that in PRASFIT-ACS [8].

Notably, the incidence of bleeding AEs in this study was significantly higher in female patients and patients with severe cardiovascular disease (Killip Class III or IV), in addition to patients aged 75 years or older, patients with low body weight (50 kg or less), and patients with severe renal impairment. For the elderly, patients with low body weight, and patients with severe renal impairment, prasugrel treatment should be administered with caution as specified in the “Careful Administration” section of the package insert. Women generally have lower body weight than men, and there are differences in skin tissue structure between the sexes. Therefore, the fact that a higher proportion of female patients reported subcutaneous hemorrhage is likely to be related to these observed sex differences. In fact, the second most common bleeding AE was general disorders and administration site conditions (e.g., puncture site hemorrhage) (1.0%); thus, measures to prevent puncture site bleeding might also be required. Results of the MATRIX Access study [15], a clinical trial conducted in European ACS patients who were about to undergo CAG and PCI, suggested that radial access compared with femoral access decreased the net AEs through a reduction in major bleeding AEs and death. Furthermore, in PRASFIT-ACS, the incidence of puncture site bleeding during PCI was lower in the radial access route group than in the femoral access route group [11]. In this study, there was no difference in the number of patients with puncture site bleeding AEs between groups undergoing PCI via different puncture sites, which was likely because the incidence of patients with puncture site bleeding AEs was low [1.0% (7/732)], even though it was the second most common bleeding AE. The reason for the low incidence of puncture site bleeding AEs may be that—in contrast with PRASFIT-ACS—the proportion of patients undergoing PCI via femoral access was lower (43.0%) than that undergoing PCI via radial access (51.1%). Therefore, radial access seems more appropriate for preventing puncture site bleeding. In this study, the timing of the LD did not appear to significantly affect the incidence of bleeding AEs.

Though the overall incidences of bleeding AEs were lower in this study in comparison with PRASFIT-ACS [8], after calculating the total risk score in association with the incidence of bleeding AEs, we found that the risk of bleeding increased if patients had four or all five risk factors: “female sex”, “age of 75 years or older”, “body weight of 50 kg or less”, “severe cardiovascular disease”, and “severe renal impairment”. Another study assessed the risk of bleeding in patients with ACS undergoing PCI abroad; these investigators concluded that patients with ACS have marked variability in the risk of bleeding according to sex, age, and serum creatinine, among other factors [16]. A study by Saito et al. [11], which examined periprocedural bleeding in relation to the access route for PCI in a Japanese sample, found that sex, body weight, and age were risk factors, observations that are in line with our findings. There is a possibility that the risk of bleeding will increase in the above-mentioned patients. However, an analysis adjusting for confounding effects on each risk factor was not performed. Furthermore, as a limited number of patients with severe cardiac dysfunction were evaluated in clinical trials (these patients were generally excluded), these patients will be evaluated in the ongoing PRASFIT-Practice II study, a long-term observational study in patients with ischemic heart disease.

The incidence of MACE was lower in the current study (3.1%) than in PRASFIT-ACS [8] (9.4%). Conversely, the incidences of cardiovascular death (1.8%), all-cause death (2.2%), and non-fatal ischemic stroke (0.7%) were slightly higher in the current study than those in PRASFIT-ACS [8] (1.3, 1.8, and 0.4%, respectively). The explanation for these differences may involve: (1) the difference in the duration of the observation period in each study, and (2) that PRASFIT-Practice I was an observational study reflecting the clinical use of prasugrel in a real-world setting. Thus, patients with severe conditions were included, whereas in the PRASFIT-ACS [8], such cases were excluded. The incidence of non-fatal MI was low in this study, which may also explain the low incidence of MACE compared with PRASFIT-ACS [8]. A possible reason for this may be that naturally occurring MI as well as events judged according to CAG findings and markers of myocardial injury, including creatine kinase-MB, were evaluated in PRASFIT-ACS [8]; however, only cases of MI reported by investigators under the actual conditions of use were evaluated as events in this study.

This study had several limitations. Because the study was designed as a postmarketing observational study, only patients treated with prasugrel were evaluated. As this study aimed to assess the real clinical situation in Japan, patients were not subjected to strict exclusion criteria. The observation and follow-up periods varied for each patient. As this was a short-term study, the results are only applicable to patients treated during a short period. The length of the observational period was insufficient to collect an adequate number of cardiovascular events to thoroughly evaluate safety, especially in terms of risk factors. However, the long-term observational study “PRASFIT-Practice II” will address these issues.

Based on the results of this short-term clinical study in patients with ACS in a real-world acute setting, prasugrel administration at an LD of 20 mg and MD of 3.75 mg/day was considered to be acceptable for Japanese patients in terms of safety and efficacy.