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INTRODUCTION
Coronary Artery Disease (CAD) remains a leading cause of global morbidity and mortality, with an estimated 200 million affected individuals and 10 million annual deaths worldwide (Jourdi et al., 2022). Antiplatelet therapy forms the cornerstone of secondary prevention in CAD, reducing thrombotic complications through inhibition of platelet aggregation. Aspirin, a cyclooxygenase-1 inhibitor, has served as the foundational monotherapy for decades due to its cost-effectiveness and proven cardiovascular risk reduction (Watanabe et al., 2024). The evolution of antiplatelet regimens introduced DAPT combining aspirin with P2Y12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor), demonstrating superior efficacy in Acute Coronary Syndrome (ACS) and Percutaneous Coronary Intervention (PCI) settings compared to aspirin alone (Virk et al., 2023) While these therapies significantly reduce Major Adverse Cardiovascular Events (MACE), their benefits are counterbalanced by dose-dependent bleeding risks and non-hemorrhagic adverse effects that complicate long-term management (Floyd, 2020).
The therapeutic benefits of antiplatelet agents are tempered by their adverse effect profiles, which exhibit substantial prevalence across populations. GI complications affect 15-20% of aspirin users, ranging from dyspepsia to life-threatening ulcers and bleeding (Sorrentino et al., 2020). Ticagrelor induces dyspnea in 10-15% of patients through unclear pulmonary mechanisms, while prasugrel carries elevated bleeding risks in elderly patients and those with prior stroke (Zou et al., 2023; Guthrie, 2011). Bleeding events themselves demonstrate a 3-5-fold mortality increase, with intracranial hemorrhage proving particularly catastrophic. Recent registry data indicates 60.1% of elderly CAD patients experience antiplatelet therapy cessation within 5 years, frequently due to adverse effects or bleeding complications (Guthrie, 2011; Kang et al., 2022). This high discontinuation rate underscores the imperative for rigorous Adverse Drug Reaction (ADR) assessment, as unplanned therapy interruption elevates thrombotic risk by two to three-fold (Passacquale et al., 2022).
Comprehensive ADR evaluation requires structured causality, severity, and preventability analysis. The Naranjo scale and WHO-UMC criteria facilitate causality assessment by temporal relationship, rechallenge phenomena, and alternative etiology exclusion (Manjhi et al., 2024; Abubakar et al., 2023). Severity stratification plays a vital role in guiding clinical management while minor ecchymosis may only require observation, gastrointestinal bleeding often demands prompt intervention with proton pump inhibitors, endoscopic therapy, and temporary discontinuation of antiplatelet agents. Preventability analysis suggests that nearly 38% of antiplatelet-associated bleeding events could be avoided through proactive PPI use in high-risk patients and individualized regimen selection based on bleeding risk scores. Although mono- and dual-antiplatelet therapies have transformed coronary artery disease management by markedly reducing thrombotic events, their use is frequently complicated by bleeding and gastrointestinal adverse effects that may necessitate treatment interruption and heighten cardiovascular risk. Comparative data evaluating inpatient ADR patterns between MAPT and DAPT in Indian CAD patients are limited. Therefore, the objective of this study was to compare the causality, severity, and preventability of adverse drug reactions associated with MAPT and DAPT among hospitalized CAD patients.
MATERIALS AND METHODS
Study Design
A prospective observational study was conducted over a period of six months from April 2025 to September 2025 in the Cardiology and General Medicine Departments of a tertiary care teaching hospital.
Study Population
The study included male and female patients aged ≥18 years diagnosed with coronary artery disease and receiving antiplatelet therapy, either mono-antiplatelet or dual antiplatelet therapy, during their hospital stay. Patients were excluded if they were receiving antiplatelet therapy for conditions other than CAD (such as stroke or peripheral artery disease), outpatients, declined to provide written informed consent, or were pregnant or lactating.
Data Collection Procedure
Data was collected through patient interviews, review of medical records, and direct observation during inpatient care. The information recorded included demographic details such as age, sex, weight, and comorbidities. Drug-related data covered the antiplatelet regimen, including type, dose, frequency, and duration of use. Additionally, details of concurrent medications and relevant laboratory results were documented. For each suspected Adverse Drug Reaction (ADR), information regarding the onset time, clinical features, duration, and management was also systematically recorded.
ADR Identification and Documentation
Suspected ADRs were identified based on clinical presentation, physician diagnosis, laboratory investigations, and patient reports. Each ADR was documented in a Suspected Adverse Drug Reaction reporting form version 1.4 which includes suspected drug, dose, reaction details, and outcome.
Data analysis
All collected data were entered into Microsoft Excel and analyzed using IBM SPSS Statistics version 26.0. Categorical variables such as age groups, gender distribution, comorbidities, and antiplatelet therapy patterns were summarized using frequencies and percentages.
Adverse drug reactions were analyzed by calculating their incidence, severity, predictability, seriousness, and causality using standard tool such as WHO-UMC criteria, and Hartwig-Siegel severity scale. The distribution of System Organ Classes (SOC) and Preferred Terms (PT) was also presented in percentages.
RESULTS
A total of 252 hospitalized CAD patients receiving antiplatelet therapy were evaluated. Of these, majority of the patients were receiving DAPT [180 (71.4%)]. Among the study population, 179 ADRs were analyzed, of which 54 ADRs occurred in the MAPT group and 125 ADRs in the DAPT group. Age distribution differed markedly between the two groups. Younger patients (18-45 years) were more frequently managed with MAPT (62.5%) compared with DAPT (26.7%). In contrast, patients aged >75 years constituted the largest proportion of the DAPT cohort (32.2%) versus 9.7% in the MAPT group. Males predominated in the DAPT group (74.4%), whereas females were more common in the MAPT group (58.3%). Comorbidities were more prevalent among DAPT patients, particularly hypertension (62.2%), diabetes mellitus (42.2%), and dyslipidemia (54.4%), compared with MAPT (52.8%, 27.8%, and 44.4%, respectively). Only 6.7% of DAPT patients had no comorbidity, compared with 8.3% in MAPT (Refer Table 1).
| Variable | MAPT group (n=72) | DAPT group (n=180) |
|---|---|---|
| Age Group (years) | ||
| 18-30 | 19 (26.4%) | 25 (13.9%) |
| 31-45 | 26 (36.1%) | 23 (12.8%) |
| 46-60 | 12 (16.7%) | 31 (17.2%) |
| 61-75 | 8 (11.1%) | 43 (23.9%) |
| >75 | 7 (9.7%) | 58 (32.2%) |
| Gender | ||
| Male | 30 (41.7%) | 134 (74.4%) |
| Female | 42 (58.3%) | 46 (25.6%) |
| Comorbidities | ||
| Hypertension | 38 (52.8%) | 112 (62.2%) |
| Diabetes Mellitus | 20 (27.8%) | 76 (42.2%) |
| Dyslipidemia | 32 (44.4%) | 98 (54.4%) |
| Chronic Kidney Disease (CKD) | 10 (13.9%) | 29 (16.1%) |
| Heart Failure | 8 (11.1%) | 28 (15.6%) |
| COPD | 4 (5.6%) | 14 (7.8%) |
| Anemia | 18 (25.0%) | 64 (35.6%) |
| Hypothyroidism | 6 (8.3%) | 15 (8.3%) |
| Liver Disease | 2 (2.8%) | 6 (3.3%) |
| No Comorbidity | 6 (8.3%) | 12 (6.7%) |
Causality assessment using the WHO-UMC scale showed that the possible category represented the highest proportion of ADRs in the DAPT group (42.4%), whereas the unlikely category accounted for the lowest (4.0%). For preventability, probably preventable ADRs were most frequent (42.4%), while definitely preventable events were least common (18.4%). Regarding severity, moderate reactions formed the largest proportion (47.2%), whereas severe reactions constituted the smallest share (9.6%). These exact extremes emphasize the greater overall ADR burden observed with dual antiplatelet therapy (Refer Table 2).
| Causality Category (WHO-UMC scale) | Number of ADRs seen in MAPT group | Number of ADRs seen in DAPT group |
|---|---|---|
| Certain | 6 | 24 |
| Probable/Likely | 21 | 43 |
| Possible | 24 | 53 |
| Unlikely | 3 | 5 |
| Preventability Category (Modified Schumock and Thornton criteria) | Number of ADRs seen in MAPT group | Number of ADRs seen in DAPT group |
| Definitely Preventable | 7 | 23 |
| Probably Preventable | 16 | 53 |
| Not Preventable | 31 | 49 |
| Severity Level (Modified Hartwig and Siegel Severity Assessment Scale) | Number of ADRs seen in MAPT group | Number of ADRs seen in DAPT group |
| Mild | 29 | 54 |
| Moderate | 18 | 59 |
| Severe | 7 | 12 |
Actions taken for ADR management varied between groups, with the MAPT group most commonly requiring no dose change (the highest action rate at 66.7%), while drug withdrawal was the least frequent intervention (14.8%). In contrast, among DAPT patients, drug withdrawal represented the most frequent action (29.6%), whereas maintaining the same dose was the least common (46.4%). These extremes indicate that ADRs in the DAPT group more often necessitated treatment modification or discontinuation compared to MAPT (Refer Table 3).
| Action Taken | MAPT group | DAPT group |
|---|---|---|
| Drug Withdrawn | 8 | 37 |
| Dose Reduced | 10 | 30 |
| Dose not Changed | 36 | 58 |
Across all MedDRA system organ classes, gastrointestinal disorders represented the highest contribution to ADRs, accounting for 25.1% of all events, while nervous system disorders and skin and subcutaneous tissue disorders showed the lowest individual contributions at 5.0% and 6.1%, respectively. At the preferred-term level, gastrointestinal bleeding was the most frequently reported ADR (25.1%), whereas petechiae constituted the least common reaction (1.1%). Notably, all intracranial hemorrhage cases (2.4% of DAPT ADRs) were reported exclusively in patients receiving dual therapy, underscoring the greater bleeding risk associated with DAPT compared with MAPT (Refer Table 4).
| System Organ Class | Preferred Term | MAPT (n=54) | DAPT (n=125) | Total (n=179) |
|---|---|---|---|---|
| Gastrointestinal disorders | Gastrointestinal bleeding | 12 | 33 | 45 |
| Gum bleeding | 5 | 13 | 18 | |
| Diarrhea | 2 | 4 | 6 | |
| Respiratory, thoracic and mediastinal disorders | Epistaxis | 7 | 14 | 21 |
| Dyspnea | 6 | 11 | 17 | |
| Skin and subcutaneous tissue disorders | Bruising | 12 | 20 | 32 |
| Petechiae | 1 | 1 | 2 | |
| Rash | 2 | 4 | 6 | |
| Blood and lymphatic system disorders | Thrombocytopenia | 2 | 6 | 8 |
| Renal and urinary disorders | Hematuria | 3 | 12 | 15 |
| Nervous system disorders | Intracranial hemorrhage | 0 | 3 | 3 |
| Headache | 2 | 4 | 6 | |
| Total | 54 | 125 | 179 |
Among individual antiplatelet agents, aspirin monotherapy contributed the highest proportion of ADRs (40.7%), whereas prasugrel showed the lowest (5.6%) among monotherapy-related reactions. Within dual therapy regimens, the aspirin + clopidogrel combination accounted for the greatest ADR burden (60.0%), while aspirin + prasugrel contributed the fewest (3.2%). Overall, patients receiving DAPT experienced a broader range and higher intensity of adverse events compared with those on monotherapy (Refer Table 5).
| Therapy Type | Drugs | Number of ADRs seen | ADRs Observed |
|---|---|---|---|
| Monotherapy | Aspirin | 22 | GI Bleeding, Epistaxis, Rash, Headache |
| Clopidogrel | 14 | Bruising, Gum Bleeding, Thrombocytopenia, Hematuria | |
| Ticagrelor | 15 | Dyspnea, Bleeding, Headache, Diarrhea | |
| Prasugrel | 3 | GI Bleeding, Petechiae, Rash | |
| Dual Therapy | Aspirin+Clopidogrel | 75 | GI Bleeding, Bruising, Epistaxis, Gum Bleeding, Hematuria |
| Aspirin+Ticagrelor | 46 | Dyspnea, Rash, Gum Bleeding, Intracranial Hemorrhage, Diarrhea | |
| Aspirin+Prasugrel | 4 | GI Bleeding, Petechiae, Thrombocytopenia, Bruising | |
| Total | - | 179 | - |
DISCUSSION
In the current study, Adverse Drug Reactions (ADRs) associated with antiplatelet therapy were commonly observed among middle-aged and elderly patients, particularly males with underlying comorbidities such as hypertension, diabetes, and dyslipidemia. This trend mirrors the demographic and clinical characteristics of typical coronary artery disease cohorts reported in earlier studies (Mahadevappa et al., 2022; Gozzo et al., 2017; Wei et al., 2024). The higher ADR occurrence in these groups may be attributed to increased disease burden, polypharmacy, and physiological changes related to aging, all of which can influence drug metabolism and response. These findings emphasize the need for individualized risk-benefit assessment when prescribing antiplatelet agents in complex, comorbid CAD populations.
Abubakar et al. (2023) emphasized the efficacy of DAPT in reducing major adverse cardiovascular events, particularly with aspirin plus P2Y12 inhibitors, while their study focused on therapeutic outcomes, our work complemented this by highlighting ADRs, especially their preventability and severity in real-world CAD settings. Both identified bleeding, particularly gastrointestinal, as a key complication (Abubakar et al., 2023).
A study by Mahadevappa et al. (2022) similarly analyzed ADRs in ACS using Naranjo and WHO-UMC scales. Both studies found most ADRs predictable and preventable. However, while their common ADRs included headaches and heparin-related effects, our study identified GI bleeding, bruising, epistaxis and ticagrelor-induced dyspnea as predominant, reflecting a broader CAD population (Mahadevappa et al., 2022).
Gozzo et al. (2017) reported that clopidogrel accounted for the highest ADRs, while prasugrel and ticagrelor were linked with more serious reactions (Gozzo et al., 2017). Present findings uphold these safety concerns, particularly ticagrelor-associated dyspnea and prasugrel-related bleeding, adding clinical causality and preventability data lacking in pharmacovigilance reports. Together, these findings confirm the importance of closely monitoring newer antiplatelet agents and tailoring therapy to patient risk profiles.
Wei et al. (2024) described ticagrelor’s potent platelet inhibition but frequent ADRs, especially dyspnea and bleeding, attributed to ENT1 inhibition (Wei et al., 2024). Current findings paralleled this clinical pattern, reinforcing the need for patient-specific therapy and close monitoring. Patrono et al. (2017) highlighted efficacy-guided selection of aspirin and clopidogrel while recommending newer agents for select patients (Patrono et al., 2017). Our study supports these recommendations, showing more severe ADRs with newer DAPT agents, underscoring the need for individualized therapy.
Hirose et al. (2025) demonstrated regimen-dependent platelet aggregation reduction, with higher activity in ACS patients (Hirose et al., 2025). This aligns with our observation of higher ADR frequency and severity among DAPT users. Gangavarapu et al. (2024) concluded that newer antiplatelets reduce MACE but increase bleeding and dyspnea risks (Gangavarapu et al., 2024). Our study substantiates this at the clinical level, showing ticagrelor-based DAPT associated with distinct ADR patterns, reinforcing the importance of balancing efficacy with safety through vigilant monitoring.
LIMITATIONS
The present study was limited by its single-center design and modest sample size, which may restrict generalizability. Additionally, the observational nature precludes establishing definitive causal relationships. Nevertheless, it offers valuable real-world insight into the safety profile of mono- and dual-antiplatelet therapies among Indian CAD patients.
CONCLUSION
The present study highlights that adverse drug reactions are common among hospitalized CAD patients receiving antiplatelet therapy, with DAPT demonstrating a notably higher ADR burden than MAPT. DAPT was associated with increased frequency and severity of bleeding-related events such as gastrointestinal bleeding, epistaxis, bruising, hematuria, and intracranial hemorrhage along with distinct reactions like ticagrelor-induced dyspnea. Although most ADRs were classified as probable or possible, a significant proportion were both predictable and preventable, emphasizing missed opportunities for risk mitigation.
The findings reinforce the necessity for individualized antiplatelet selection, especially in elderly patients and those with multiple comorbidities. Routine monitoring, early identification of high-risk patients, and adoption of preventive strategies such as appropriate PPI co-prescription, dose adjustment, and close surveillance of newer P2Y12 inhibitors can substantially reduce clinically significant harm. Strengthening pharmacovigilance practices and ensuring vigilant ADR documentation can further enhance patient safety. Overall, optimizing antiplatelet therapy through personalized care and proactive monitoring is essential to balance therapeutic efficacy with safety in the management of CAD.