Abstract
Background:
Dual antiplatelet therapy is commonly used for patients with acute coronary syndrome (ACS). This study aimed to evaluate the safety and efficacy of aspirin and prasugrel at standard dosages in Korean patients using clinical outcome data.
Methods and Results:
For this prospective multicenter phase IV post-marketing surveillance (PMS) study, ACS patients from 29 July 2012 to 28 July 2016 were recruited. Patients received aspirin at a dose of 75–150 mg daily and a standard dose of prasugrel. Bleeding events were recorded and summarized to evaluate safety. Data on adverse events (AEs) and composite events such as cardiovascular (CV) death, myocardial infarction (MI), and stroke were recorded and summarized to assess efficacy. Of the 3,283 patients recruited, data from 3,110 and 3,044 patients were included in the safety and efficacy analyses, respectively (median treatment duration, 172 days). The most frequently reported AE was ecchymosis (2.8%). The number of patients with major bleeding was 29/3,110 (0.93%). The discontinuation rate for any reason was 12.6%. The number of cases that ended in CV death, MI, stroke, stent thrombosis, or unplanned coronary revascularization was 26/3,044 (0.85%).
Conclusions:
The present results are similar to those observed in clinical trials where administration of low-dose aspirin plus prasugrel was associated with a low rate of major bleeding and CV events.
The incidence of coronary artery disease (CAD) is steadily increasing in Korea and is accompanied by an increasing number of percutaneous coronary interventions (PCIs).1
After undergoing PCI, patients usually begin dual antiplatelet therapy (DAPT), such as a regimen of thienopyridine and aspirin, to prevent recurrent ischemia and stent thrombosis.2,3
DAPT is standard after PCI for patients with acute coronary syndrome (ACS), including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). Current American Heart Association guidelines recommend the use of adenosine diphosphate (ADP)-receptor inhibitors (e.g., prasugrel, clopidogrel, or ticagrelor) with aspirin for 12 months in patients with ACS who have undergone PCI (ACS-PCI).2,4
Previous studies have shown that genetic polymorphisms, especially those associated with reduced function of cytochrome P450 2C19 (CYP2C19), are associated with excess cardiovascular (CV) risk and death in patients with CAD treated with clopidogrel.5
Additionally, the
CYP2C19*2
genetic variant, which is more common in Korean patients than in Caucasians, may be associated with significant increases in cardiac death, MI, and stent thrombosis after drug-eluting stent (DES) placement and DAPT, including clopidogrel and aspirin.6
Prasugrel is a next-generation thienopyridine antiplatelet agent that provides more prompt, potent, and consistent platelet inhibition than clopidogrel. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) demonstrated that patients given prasugrel had significantly fewer ischemic events, but a higher incidence of bleeding compared with those given clopidogrel. Based on analyses of the TRITON-TIMI 38 data, age ≥75 years, body weight <60 kg, and a history of stroke or transient ischemic attack (TIA) were identified as risk factors for bleeding events.7
Even though results from previous studies show that prasugrel and ticagrelor are efficacious and safe for most patients, some physicians in Korea are concerned about the potential risk of bleeding because the previous studies included only a small proportion of Asian participants. The objective of this study, therefore, was to evaluate the safety and efficacy of a standard regimen of prasugrel in Korean patients with ACS in a clinical setting.
Methods
Study Design
This study was a prospective multicenter observational phase IV post-marketing surveillance (PMS) study conducted at 59 centers in South Korea between 29 July 2010 and 28 July 2016. The trial protocol was approved by the institutional review boards of all participating institutions and was performed in accordance with the Declaration of Helsinki and the ethical standards of the responsible committees on human experimentation.
Study Population
The study involved Korean patients with ACS, including UA, NSTEMI, or STEMI, who underwent or were waiting to undergo PCI. All patients enrolled in the PMS took 5 or 10 mg of prasugrel with 75–150 mg of aspirin daily unless they could not tolerate the drugs. Patients were included according to the Korean approval label for prasugrel, which recommends use in patients with (1) no history of TIA or stroke, (2) body weight ≥60 kg, and (3) age <75 years. Prasugrel was administered to patients according to these criteria. All dosages and duration of treatment were left to the discretion of each investigator. The investigator provided appropriate information regarding the study to patients. Potential participants were required to complete informed consent forms and agreed not to participate in other interventional studies while enrolled in this study.
Safety Evaluation
Investigators had to report all serious AEs in participants who underwent PCI during the investigation period, regardless of their prasugrel regimen. The participants’ medical records were reviewed, and bleeding events were defined according to the PLATO study.8
Major life-threatening bleeding was defined as fatal bleeding, intracranial bleeding, intrapericardial bleeding with cardiac tamponade, hypovolemic shock, severe hypotension due to bleeding and requiring pressors or surgery, a decline in the hemoglobin (Hb) level of ≥5.0 g/dL, or the need for transfusion of at least 4 units of red cells. Other major bleeding was defined as bleeding that led to a clinically significant disability (e.g., intraocular bleeding with permanent vision loss) or bleeding associated with a drop in the Hb level of at least 3.0 g/dL but less than 5.0 g/dL or requiring transfusion of 2–3 units of red blood cells. We defined minor bleeding as any bleeding requiring medical intervention.
Efficacy Evaluation
Efficacy was measured by composite events of CV death, MI and stroke, stent thrombosis (ST) or unplanned coronary revascularization. Events of all-cause death, MI, stroke, ST or unplanned coronary revascularization, and coronary artery bypass graft (CABG) surgery were collected from the initiation of prasugrel to the end of the last follow-up visit and entered as a binary variable (yes/no).
Statistical Analysis
Continuous variables are summarized as mean±standard deviation (SD), and categorical variables are summarized as absolute numbers and percentages (%). Efficacy and safety endpoints are presented as absolute numbers and percentages.
Results
Patients’ Characteristics
The flow chart of the study is shown in the
Figure. A total of 3,283 ACS patients who underwent successful PCI were enrolled in this PMS. We excluded data from 173 patients because of: enrollment before informed consent (7/173), violation of inclusion criteria (25/173), and violation of administrative protocol (141/173). Finally, data from 3,110 ACS patients were included in the safety analysis and 3,044 of them were included in the efficacy analysis.
The mean weight, height, and age of participants were 71.1±9.95 kg, 167.69±7.04 cm, and 56.80±9.43 years, respectively. Although prasugrel is not be recommend for ACS-PCI patients aged over 75 years, age >5 years is not considered an absolute contraindication. Therefore, prasugrel was administered to patients aged >75 years with great caution under the discretion of the attending physician. Thus, 41 (1.32%) patients who were >75 years of age were enrolled in this study. Of the 3,110 ACS patients, 2,744 (88.23%) were men. In total, 1,173 patients were diagnosed with UA and 1,937 were diagnosed with MI. The majority of patients were treated with a DES (Table 1).
Table 1.
Baseline Characteristics of Study Participants
| |
(n=3,110) |
| Age (mean±standard deviation), years |
56.80±9.43 |
| Age group |
| <75 years |
3,069 (98.68%) |
| ≥75 years |
41 (1.32%) |
| Sex |
| Male |
2,744 (88.23%) |
| Female |
366 (11.77%) |
| Weight (mean±SD), kg |
71.10±9.95 |
| Height (mean±SD), cm |
167.69±7.04 |
| Medical history |
| Hypertension |
1,642 (67.82%) |
| Diabetes |
891 (36.80%) |
| Dyslipidemia |
1,153 (47.62%) |
| Chronic kidney disease |
39 (1.61%) |
| Final diagnosis of index event |
| Unstable angina pectoris |
1,173 (37.72%) |
| ST-elevation myocardial infarction |
1,124 (36.14%) |
| Non-ST-elevation myocardial infarction |
813 (26.14%) |
In total, 1,533 ACS patients were administered 60 mg of prasugrel as a loading dose (LD). Of the total ACS patients, 3,097 were administrated 5–10 mg (5 mg 113 patients (3.65%), 5–10 mg 456 patients (14.72%), 10 mg 2,528 patients (81.63%), median, 9.31 mg) of prasugrel as an maintenance dose (MD) irrespective of the LD. The median treatment duration was 172 days, and 2,290 (73.9%) ACS patients undergoing PCI were treated with prasugrel for more than 6 months. The number of patients who discontinued treatment for any reason was 393, of which 176/393 were lost to follow-up, 93/393 due to an investigator’s decision, 65/393 due to AEs, and 59/393 for other reasons.
Safety Outcomes
In this study, 3,110 ACS patients were included in the group to evaluate safety. A total of 403 bleeding events were reported, and ecchymosis was the most frequent. Of the 403 events, 29 were classified as major bleeding. Intracerebral hemorrhage (ICH), major gastrointestinal (GI) bleeding, hematoma needing transfusion, and bleeding needing surgical treatment were reported in 5, 11, 2, and 6 patients, respectively (Table 2).
Table 2.
Safety of Prasugrel Use in Korean Patients With Acute Coronary Syndrome
| Bleeding event |
n (%) |
| Non-fatal intracerebral hemorrhage |
5/3,110 (0.16%) |
| Major gastrointestinal bleeding |
11/3,110 (0.35%) |
| Needing surgical treatment |
6/3,110 (0.19%) |
| Hematoma needing transfusion |
2/3,110 (0.06%) |
| Other |
5/3,110 (0.16%) |
| Total |
29/3,110 (0.93%) |
A total of 66 patients were excluded from the safety analysis because of missing data of efficacy outcomes due to early discontinuation of study medication, so 3,044 ACS patients were included in the efficacy analysis. The composite endpoints of CV death, MI and stroke, ST, or unplanned coronary revascularization were reported in 26 cases among the 3,044 ACS patients who underwent successful PCI. Of these, the number of cases of death, MI, stroke, ST, and unplanned coronary revascularization was 3, 7, 5, 2, and 13, respectively (Table 3). A Kaplan-Meier estimate was not calculated because the number of events was too low to meet the criteria for statistical analysis.
Table 3.
Efficacy of Prasugrel Use in Korean Patients With Acute Coronary Syndrome
| Composite endpoints |
n (%) |
| Cardiovascular-related death |
3/3,044 (0.10%) |
| Myocardial infarction |
7/3,044 (0.23%) |
| Stroke |
5/3,044 (0.16%) |
| Stent thrombosis |
2/3,044 (0.07%) |
| Unplanned coronary revascularization |
13/3,044 (0.43%) |
| Total |
26/3,044 (0.85%) |
Discussion
This study aimed to assess the efficacy and safety of standardized prasugrel use in Korean patients with ACS who undergo PCI. The main finding was a low incidence of major bleeding events in Korean ACS patients who underwent stenting and then more than 6 months of DAPT with prasugrel. Therefore, if physicians manage eligible ACS patients with a standard regimen of prasugrel and aspirin according to the label criteria, CV events (such as death, MI, stroke, ST, or unplanned coronary revascularization) in Korean patients may decrease without an increased risk of major bleeding.
Even though the standard LD regimen of prasugrel was 60 mg with a MD of 10 mg, the Japanese government approved a different regimen of prasugrel based on a study conducted in Japan. In PRASFIT-ACS, an LD/MD of 20 mg/3.75 mg of prasugrel was associated with a low incidence of ischemic events and with a low risk of clinically serious bleeding in Japanese ACS patients, similar to the results of the TRITON-TIMI 38 study.9
However, this did not establish a global standard dose of prasugrel, and the efficacy of prasugrel at a LD/MD of 20/3.75 mg was not statistically different to clopidogrel in the PRASFIT-ACS study. Because results may differ between races, clinical results need to be analyzed from patients on standard doses of prasugrel in the Korean population.
This study enrolled 3,283 ACS-PCI patients, making it the largest study of the standard regimen of prasugrel in Asian ACS patients. As a result, we found that 5–10 mg of prasugrel resulted in a low incidence of the composite endpoints (0.85%) and major bleeding (0.93%) when compared with a similar study population without a history of TIA/stroke, body weight ≥60 kg, and age <75 years reported in the TRITON-TIMI 38 study, which reported a composite endpoint rate of 8.3% and non-CABG related Thrombolysis in Myocardial Infarction major bleeding of 2.0%.7
Although it is widely held that Asian patients undergoing PCI have a higher bleeding risk because of their lower body mass index (BMI) compared with Caucasians, the 10 mg of prasugrel was appropriate, and the risk of bleeding was low in the Asian patients in the present study. Prasugrel 20/3.75 mg (LD/MD) was associated with a low incidence of ischemic events and a low risk of clinically serious bleeding in Japanese ACS patients and is the current indication for prasugrel administration in Japan based on a previous study.9
However, the results from PRASFIT-ACS did not show a significant difference in clopidogrel efficacy, and it is not a globally recognized standard prasugrel regimen. Despite differences in the prasugrel dosage, characteristics of the enrolled subjects, and study protocol between the present and previous studies, this study showed promising results of a standardized dose of prasugrel in the Korean population.
We speculate that incidences of the composite endpoint and bleeding were low because the 10 mg of prasugrel was administrated to more than 80% of ACS patients according to the product label (no history of TIA/stroke, body weight ≥60 kg, age <75 years). Thus, the antiplatelet effect was great enough without an increased risk of bleeding, as shown in TRION-TIMI 38. In addition, some subjects were excluded from the prasugrel regimen by the investigator because of bleeding risk factors such as old age, low BMI, presence of chronic kidney disease (CKD), female sex, and emergency PCI.7
In this study, the number of patients aged ≥75 years was small (1.32%) as was the number of patients with CKD (1.61 %), and the proportion of female patients with a low BMI was lower than that of females with a normal or high BMI. These patient characteristics may have contributed to the lower incidence of bleeding compared with other prasugrel studies. Finally, advancements in the strut design and drug coating of stents have been continual, and have been shown to improve composite endpoints.10
Study Limitations
The main limitation of this study was the lack of a control group. In addition, robust statistical analysis was not possible because of the PMS design and small number of recorded AEs. However, the recently published TICAKOREA study that compared the efficacy and safety of ticagrelor to that of clopidogrel in Korean patients showed that major bleeding and fatal bleeding, according to the PLATO study, occurred in 8.1% and 4.1% of patients, respectively, and 9.2% and 5.8% of patients, respectively, were reported to have a composite of CV death, MI, or stoke.11
There are limitations to comparing these results directly with our findings. However, our results are considered promising despite the difference in baseline characteristics and follow-up duration between our study and previous studies; 15.3% of patients aged over 75 years, 5.1% with a BMI <20 kg/m2, and 5% with a history of stroke were included with 12 months’ follow-up in the TICAKOREA study.
However, our study offers preliminary results on a standard dose of prasugrel, appropriate for an Asian population, which can be confirmed by a large-scale randomized controlled trial in the future.
Conclusions
In this study, a standard dose of prasugrel with a low dose of aspirin was associated with a low rate of major bleeding and CV events in a Korean population with ACS and no history of TIA/stroke, body weight ≥60 kg, and age <75 years. Results show that the safety and efficacy profiles at this dosage were similar to those observed in other clinical trials.
Acknowledgments
The authors greatly appreciate the contributions of all the investigators and other clinical/research staff involved in the present study. This work was supported for 2 years by a Pusan National University Research Grant. We also acknowledge the support of Daiichi Sankyo Co., Ltd.
Data Availability
Not available.
Conflict of Interest Statement
The authors declare no conflicts of interest.
IRB Information
Name of the ethics committee: Pusan National University Yangsan Hospital IRB. Approval number: PNUYH IRB No. 06-2012-010.
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