Association of Clopidogrel with Interstitial Lung Disease: Gaining Insight Through the Japanese Pharmacovigilance Database

Introduction

Atherosclerotic arterial disease is one of the most frequent causes of death globally. Antithrombotic treatment with aspirin plus a P2Y12 receptor inhibitor is an integral part of management of patients with atherosclerotic cardiovascular and cerebrovascular disease and those with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Clopidogrel has been a traditional choice for P2Y12 inhibition; however, it shows significant interindividual variability in therapeutic outcomes.¹ Clopidogrel is a prodrug that requires bioactivation into its active metabolite via cytochrome P450 (CYP) 2C19.² The polymorphism driven by the metabolic activity of CYP2C19 significantly affects the pharmacokinetics of clopidogrel by altering its metabolic conversion, which in turn indirectly affects its therapeutic effects.³ The prevalence of individuals with CYP2C19 loss-of-function variants is more common in Asian patients. In contrast, prasugrel, a newer thienopyridine P2Y12 inhibitor, offers more consistent antiplatelet effects⁴ and is less dependent on CYP enzymes for activation.⁵ Considering these pharmacokinetic differences between clopidogrel and prasugrel, concerns have been raised regarding the adverse events (AEs) of these drugs, but little is known about them.

There is widespread acceptance that pharmacovigilance activities, which can detect unexpected post-marketing issues, are important for guaranteeing the safe use of drugs.^6,7 Notably, the analysis of pharmacovigilance data offers updated AE information to healthcare professionals and their patients, thereby reducing the overall risks of drugs. Certainly, drugs are approved for clinical use based on evidence of a satisfactory balance between potential benefits and risks. However, the safety profiles of drugs can change over time as their use expands, with changes in patients’ characteristics, and with an increase in the number of patients exposed. In Japan, AEs are spontaneously reported by doctors, medical staff, patients, and pharmaceutical companies to the Pharmaceuticals and Medical Devices Agency (PMDA), which publicly releases them as the Japanese Adverse Drug Event Report (JADER) database.

The objective of this study was to compare the AE profiles of clopidogrel and prasugrel based on the JADER database.

Methods

AE reports in the JADER database can be freely downloaded from the PMDA website (http://www.pmda.go.jp/safety/info-services/drugs/adr-info/suspected-adr/0003.html) since April 1, 2004. This database includes only de-identified data; therefore, this study was deemed exempt from institutional review by the ethics committee of Osaka Medical and Pharmaceutical University. A total of 378,533 cases of data from the JADER database between April 2004 and January 2017 were examined.

Details of this database have been described previously.^8–15 In this study, only cases that were classified as “suspected medicine”, because the drug itself could have been associated with the AEs, were extracted. For the AEs, the PT Names coded in MedDRA (version 23.0) were used. A cross-tabulation table was compiled based on two classifications: the presence or absence of a particular AE, and the presence or absence of the suspected medicine. Then, the reporting odds ratio (ROR), which is the number of reports of a specific AE caused by a drug divided by that of all other drugs in the database, was calculated. A signal is considered to be present when the lower limit of the 95% confidence interval (CI) of the ROR is greater than one.

All analyses were performed with SPSS for Windows software (ver. 19.0; SPSS Inc., Tokyo, Japan).

Results

During the study period, a total of 1,904,433 AE reports with both age and sex information were obtained. Of them, 5869 AE reports were associated with clopidogrel and 513 with prasugrel. Table 1 shows the patients’ demographic information. AEs were frequently reported in men (clopidogrel, 69.6%; prasugrel, 74.1%) and in patients in their 70s (clopidogrel, 42.0%; prasugrel, 33.5%). Of note, the rate of recovery from AEs (clopidogrel, 39.2%; prasugrel, 41.9%) was high, followed by remission (clopidogrel, 24.6%; prasugrel, 27.7%).

Table 1 Characteristics of Study Patients

In the analysis, 703 and 135 different AEs identified the “suspected medicine” as clopidogrel and prasugrel, respectively. Of them, the 10 most frequently reported drugs are listed in Tables 2 and 3. As shown in Table 2, the most frequently reported AEs were cerebral hemorrhage (234 reports), interstitial lung disease (227 reports), and subcutaneous hemorrhage (157 reports). Focusing on RORs, 9 AEs in Table 2 yielded a positive signal, with a lower CI of the ROR greater than 1. Of note, there were noteworthy associations of clopidogrel with hepatocellular injury (ROR, 105.73; 95% CI, 82.8–135.0) and subcutaneous hemorrhage (ROR, 26.6; 95% CI, 22.5–31.4) after adjustment for age and sex.

Table 2 The Top 10 Adverse Drug Events Associated with Clopidogrel

Table 3 The Top 10 Adverse Drug Events Associated with Prasugrel

Table 3 shows that the most frequently reported AEs for prasugrel were cerebral hemorrhage (ROR, 24.2; 95% CI, 18.0–32.4), followed by gastrointestinal hemorrhage (ROR, 23.6; 95% CI, 17.3–32.3) and anemia (ROR, 1.62; 95% CI, 1.02–2.56). There were noteworthy associations of prasugrel with melena (ROR, 165.7; 95% CI, 95.6–287.3), cardiac tamponade (ROR, 93.3; 95% CI, 49.2–176.8), and retroperitoneal hematoma (ROR, 61.9; 95% CI, 36.1–106.2). With prasugrel, AEs ranked relatively highly with clopidogrel, interstitial lung disease and liver injury (abnormal hepatic function and hepatocellular injury), were not ranked highly.

Discussion

In this study, the JADER database was used to clarify the characteristics of patients treated with clopidogrel and prasugrel. AEs of clopidogrel and prasugrel tended to show a peak age of onset in patients in their 70s and 70s-80s, respectively. Adverse drug reactions of clopidogrel and prasugrel occurred more often in men. Bleeding complications were commonly detected for both clopidogrel and prasugrel, whereas interstitial lung disease, abnormal hepatic function, and hepatocellular injury ranked higher with clopidogrel than with prasugrel. To the best of our knowledge, this is the first study to show differences in the adverse event profiles of clopidogrel and prasugrel in real-world practice based on the JADER pharmacovigilance database.

According to the 2019 ACC/AHA Guidelines on the Primary Prevention of Cardiovascular Disease, a double-therapy regimen (oral anticoagulant plus single antiplatelet therapy with a P2Y12 inhibitor) is recommended for patients with atrial fibrillation (AF) and coronary heart disease.¹⁶ This anticoagulation therapy causes an increased risk of hemorrhagic events. In the present study, report frequency differed between the two groups (clopidogrel, 5869 AE reports; prasugrel, 513 AE reports); however, the patients’ characteristics in these groups were similar. Furthermore, bleeding complications were often reported with both clopidogrel and prasugrel in the JADER database.

However, the results showed some differences in AEs between clopidogrel and prasugrel. First, clopidogrel was significantly associated with interstitial lung disease, whereas prasugrel was not. This is consistent with a case report showing subacute interstitial pneumonia caused by clopidogrel using a lung biopsy specimen.¹⁷ In addition, clopidogrel-induced lung injury has been reported, including bleeding events such as alveolar hemorrhage, as well as interstitial lung diseases such as eosinophilic pneumonia or organizing pneumonia.^18,19 Furthermore, a retrospective, cohort study showed that the incidence of community-acquired pneumonia was significantly greater in patients receiving clopidogrel (OR, 3.39; 95% CI 3.27–3.51, P < 0.0001), which remained after adjustment (OR, 1.48; 95% CI 1.41–1.55, P < 0.0001).²⁰ Conversely, clinical studies suggest that antiplatelet agents may be associated with better outcomes in patients with pneumonia.^21,22 The mechanism underlying the conflicting effects of antiplatelet agents on pulmonary tissue is that platelets contribute to the host defense against bacterial infectious agents by limiting vascular lesions and inducing injury repair,²³ whereas unbalanced platelet activation may have pathological consequences. Indeed, platelet activation may exacerbate acute lung injury by promoting the recruitment of neutrophils and release of pro-inflammatory mediators.²⁴ Second, clopidogrel was significantly associated with liver injury. This is consistent with experimental studies.^25,26 Metabolites of clopidogrel produced by CYP3A4 have toxicity for hepatocytes via mitochondrial damage and cytochrome C release, eventually promoting apoptosis and/or necrosis.²⁶ However, clopidogrel shows decreased hepatic necroinflammation by inhibition of platelet aggregation.²⁷ There are several reports that platelets have harmful effects on the liver. Platelets bind to the endothelium, causing the endothelium to upregulate and secrete chemokine (C-C motif) ligand 2 (CCL-2) and chemokine (C-X-C motif) ligand 8 (CXCL-8), which recruit T cells and neutrophils to the endothelium. Clopidogrel inhibits dense granule release. Platelets also drive fibrosis and produce transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF)-β, and CXCL4 to aid conversion of hepatic stellate cells into collagen-producing myofibroblasts.^28,29 Indeed, clopidogrel has been shown to have an anti-fibrotic effect against carbon tetrachloride (CCl4)-induced liver fibrosis in rats by reduction of TGF-β1.³⁰

As with any pharmacovigilance study, the present study has several limitations, including reporting bias, signal strength, and lack of detailed clinical data. The JADER database is subject to under-reporting and over-reporting biases. These reporting biases can affect the accuracy and completeness of the data, potentially influencing the observed AE profiles. The ROR provides an estimate of the association between a drug and an AE, but does not measure the absolute risk or the strength of the signal. It reflects the likelihood of a drug being reported in association with an AE compared to all other drugs, rather than the actual incidence of the AE. Finally, the JADER database lacks detailed clinical information, such as patients’ medical histories, family histories, and the etiology of underlying diseases. This limits our ability to fully understand the context and causality of the reported AEs.

Conclusion

In conclusion, the present study showed three main findings. First, the study showed the rank-order of AEs associated with clopidogrel and prasugrel using a nationwide pharmacovigilance database (JADER). Second, common AEs were identified. Bleeding complications were found to be common AEs for both drugs in the present study. This finding is well-supported by the study’s analysis and is consistent with known side effects of antithrombotic therapy. Finally, differences in AEs between clopidogrel and prasugrel, specifically interstitial lung disease, hepatic function abnormalities, and hepatocellular injury with clopidogrel, were found. This differentiation is a key finding of this study.