Abstract
Skepticism exists among healthcare workers and patients regarding the efficacy and safety of generic medication, despite its potential to lower healthcare costs. This study aimed to compare the outcomes of a generic clopidogrel and its brand‐name counterpart for secondary prevention in patients with acute myocardial infarction (AMI). Using the Taiwan National Health Insurance Research Database, we identified 49,325 patients who were hospitalized for AMI between January 1, 2008 and December 31, 2013 and prescribed either generic or brand‐name clopidogrel. Among them, 2419 (4.9%) were prescribed the generic clopidogrel. After propensity score matching, both the generic and brand‐name groups consisted of 2382 patients. The primary efficacy outcome was a composite of myocardial infarction, coronary revascularization, ischemic stroke, and all‐cause death. The primary safety outcome was major bleeding requiring hospitalization. At a mean follow‐up of 2.5 years, the generic and brand‐name clopidogrel groups had comparable risks of primary efficacy outcome (41.9% vs. 42%; hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.88–1.04), and the risks of the individual components were also similar. There were no significant differences between the two groups in major bleeding (7.9% vs. 7.9%; HR 0.99; 95% CI 0.81–1.21). Subgroup analyses also revealed no statistically significant interactions between the treatment effect and various subgroups. In this retrospective database analysis, the generic clopidogrel was comparable to its brand‐name counterpart regarding cardiovascular and bleeding outcomes for the treatment of patients with AMI.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
The popularity of affordable generic drugs is on the rise.
WHAT QUESTION DID THIS STUDY ADDRESS?
Comparing outcomes of generic clopidogrel versus its brand‐name counterpart for secondary prevention in acute myocardial infarction patients.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The cardiovascular and bleeding outcomes were comparable between generic clopidogrel and its brand‐name counterpart.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
Analyzing real‐world databases can confirm the efficacy and safety of generic drugs.
INTRODUCTION
The Global Burden of Disease study estimated that 244.1 million people were living with ischemic heart disease (IHD) in 2020. 1 The World Health Organization reported that IHD is the leading cause of death worldwide, responsible for 16% of all cases of mortality. Moreover, the incidence of IHD is expected to increase due to the rising prevalence of diabetes, hypertension, obesity, and metabolic syndrome, and also to the aging population. 2 Globalization and rapid urbanization in lower‐ and middle‐income countries have also affected the rates of disease‐related deaths and disabilities from infectious diseases and non‐communicable diseases such as IHD. 3 One potentially life‐threatening manifestation of IHD is acute myocardial infarction (AMI). Besides substantial morbidity and mortality, AMI also resulted in a significant financial burden on healthcare systems, from hospitalizations and revascularization procedures to prescribed drug treatments. 4 , 5 , 6 , 7 It was reported that hospitalization contributed to the major cost of AMI in the first year, but medication dominated in the long term. 8
The increasing burden of various chronic diseases and their economic consequences has led to a gradual rise in the use of generic drugs worldwide. Generic drugs must be approved by regulators based on evidence of pharmaceutical equivalence and bioequivalence with the brand‐name product, even though they may contain different inactive ingredients. Bioequivalence refers to the equivalent release of the same drug substance from two or more drug products or formulations. In order to be approved for use, a generic medicine must be bioequivalent to the originator product and must be the same in terms of strength, safety, and quality. 9 Generic medicines provide a chance to offer a similar medication to patients at a lower cost, and they have had a huge impact on economic and health policy. 10 , 11 Generic medicines are frequently used in daily practice globally, and account for more than 80% of all prescriptions in the United States. 12 Generic drugs cost less mostly because they do not have to repeat various studies that were required by their brand‐name counterparts to prove their effectiveness and safety. 10 Even though replacing brand‐name medicines with less expensive generic equivalents is practiced globally and many studies have demonstrated no difference in outcomes between cardiovascular (CV) generics and their brand‐name counterparts, 13 , 14 , 15 , 16 many professionals and the general public have negative opinions on the effectiveness and/or safety of generic medications. 17
Therefore, this study aimed to examine the efficacy and safety of patients receiving a generic clopidogrel versus brand‐name clopidogrel after AMI.
METHODS
Data source
This nationwide retrospective cohort study was conducted using data from the Taiwan National Health Insurance Research Database (NHIRD). In Taiwan, it is mandatory to join the National Health Insurance (NHI) program. The Taiwan government is the single‐payer, and the co‐payments are very low. The NHIRD contains comprehensive information from the claims data submitted by medical institutions, including demographic information, diagnoses, dates of admission and discharge, prescription drugs, and the use of medical facilities. Diseases are recorded according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD‐9‐CM) diagnosis codes. Details about the NHIRD have been reported elsewhere. 18 , 19 , 20 In Taiwan, all anti‐antiplatelet drugs are available only through physician prescriptions, all of which are recorded in the NHIRD. Both brand‐name and generic clopidogrel are reimbursed by the Taiwan NHI. This study was approved by the Institutional Review Board at Linkou Chang Gung Memorial Hospital, Taiwan (IRB number: 104‐2932B).
Study design
A total of 58,736 patients who were hospitalized for AMI and prescribed either generic (Thrombifree, Hygica Biotech Limited, Taipei, Taiwan) or brand‐name clopidogrel (Plavix®, Sanofi, Paris, France) at a dose of 75 mg per day were identified from the NHIRD between January 1, 2008, and December 31, 2013. We excluded patients with a follow‐up duration of less than 90 days (n = 5093) and those who were prescribed clopidogrel for less than 28 days (n = 3785) or switched between P2Y12 inhibitors (n = 529) within 90 days of follow‐up. The date on which clopidogrel was prescribed was defined as the index date. The use of clopidogrel was ascertained by the filling of at least two outpatient prescriptions or one refilled prescription for chronic illness during the first 90‐day window after the index date. Among the 49,325 patients who were eligible for further analysis, 2419 (4.9%) were prescribed generic clopidogrel (Figure 1).
FIGURE 1.
Flowchart to illustrate the inclusion and exclusion of the study patients. MI, myocardial infarction.
Outcomes
The primary efficacy outcome of this study was a composite of myocardial infarction, revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting), ischemic stroke, and all‐cause death. The primary safety outcome was major bleeding, defined as any bleeding requiring hospitalization. The secondary safety outcomes included intracranial hemorrhage, gastrointestinal bleeding, and fatal bleeding. Other outcomes, including heart failure hospitalization (HFH) and CV death, were also evaluated. The occurrence of myocardial infarction, stroke, bleed events, and heart failure required a principle inpatient diagnosis. The accuracy of most of these diagnoses has been validated in previous NHIRD studies. 21 , 22 , 23 Coronary revascularization was identified by NHI reimbursement codes. Information on dates and causes of death were obtained from the NHIRD. All patients were followed up until the occurrence of a clinical outcome, the date of switching between the two study drugs, or the end of the study period (December 31, 2013), whichever occurred first.
Covariates
The covariates included demographics (age, sex, urbanization level of the residence, and monthly income), comorbidities (hypertension, diabetes and 10 others shown in Table 1), Charlson Comorbidity Index (CCI) score, and previous CV or bleeding events, and baseline medications (aspirin, anticoagulants and 18 others shown in Table 1). Previous CV events included ischemic stroke, HFH, and venous thromboembolism. Previous bleeding included major bleeding, defined as any bleeding requiring hospitalization or emergency department visit, gastrointestinal bleeding, and intracranial hemorrhage. Comorbidities and previous events were identified by at least two outpatient diagnoses or one inpatient diagnosis during the year before the index date. Information on baseline medications was captured during the 90‐day window after the index date using the Taiwan NHI reimbursement codes. Clinical features during the index AMI admission were also extracted, including the time interval between the day of discharge for the AMI admission and prescription of clopidogrel (the index date), hospital level, coronary intervention, number of intervened vessels, details of PCI, and in‐hospital management/outcomes (intubation, shock, and seven others shown in Table 2).
TABLE 1.
Demographics and clinical characteristics of patients receiving one generic clopidogrel versus brand‐name clopidogrel.
| Variable | Total (n = 49,325) | Before matching | After matching | ||||
|---|---|---|---|---|---|---|---|
| Generic (n = 2419) | Brand‐name (n = 46,906) | STD | Generic (n = 2382) | Brand‐name (n = 2382) | STD | ||
| Demographics | |||||||
| Age, years | 66.4 ± 13.2 | 68.3 ± 13.3 | 66.3 ± 13.2 | 0.15 | 68.3 ± 13.3 | 68.2 ± 12.8 | <0.01 |
| Male, sex | 36,909 (74.8) | 1756 (72.6) | 35,153 (74.9) | −0.05 | 1732 (72.7) | 1710 (71.8) | 0.02 |
| Urbanization level | |||||||
| 1, most urbanized | 12,683 (25.7) | 606 (25.1) | 12,077 (25.7) | −0.02 | 596 (25.0) | 588 (24.7) | 0.01 |
| 2 | 17,636 (35.8) | 809 (33.4) | 16,827 (35.9) | −0.05 | 797 (33.5) | 831 (34.9) | −0.03 |
| 3 | 13,986 (28.4) | 764 (31.6) | 13,222 (28.2) | 0.07 | 749 (31.4) | 710 (29.8) | 0.04 |
| 4, least urbanized | 5020 (10.2) | 240 (9.9) | 4780 (10.2) | −0.01 | 240 (10.1) | 253 (10.6) | −0.02 |
| Monthly income | |||||||
| Tertile 1 | 14,743 (29.9) | 850 (35.1) | 13,893 (29.6) | 0.12 | 828 (34.8) | 828 (34.8) | <0.01 |
| Tertile 2 | 16,658 (33.8) | 752 (31.1) | 15,906 (33.9) | −0.06 | 746 (31.3) | 736 (30.9) | 0.01 |
| Tertile 3 | 17,924 (36.3) | 817 (33.8) | 17,107 (36.5) | −0.06 | 808 (33.9) | 818 (34.3) | −0.01 |
| Comorbidity before the index date | |||||||
| Hypertension | 34,004 (68.9) | 1816 (75.1) | 32,188 (68.6) | 0.14 | 1785 (74.9) | 1793 (75.3) | −0.01 |
| Diabetes mellitus | 21,047 (42.7) | 1079 (44.6) | 19,968 (42.6) | 0.04 | 1063 (44.6) | 1097 (46.1) | −0.03 |
| Hyperlipidemia | 24,048 (48.8) | 1089 (45.0) | 22,959 (48.9) | −0.08 | 1074 (45.1) | 1016 (42.7) | 0.05 |
| Chronic obstructive pulmonary disease | 5302 (10.7) | 322 (13.3) | 4980 (10.6) | 0.08 | 315 (13.2) | 331 (13.9) | −0.02 |
| Chronic kidney disease | 10,563 (21.4) | 592 (24.5) | 9971 (21.3) | 0.08 | 585 (24.6) | 597 (25.1) | −0.01 |
| Peripheral artery disease | 2465 (5.0) | 152 (6.3) | 2313 (4.9) | 0.06 | 150 (6.3) | 155 (6.5) | −0.01 |
| Gout | 5851 (11.9) | 281 (11.6) | 5570 (11.9) | −0.01 | 278 (11.7) | 297 (12.5) | −0.02 |
| Peptic ulcer disease | 8759 (17.8) | 561 (23.2) | 8198 (17.5) | 0.14 | 546 (22.9) | 574 (24.1) | −0.03 |
| Atrial fibrillation | 3379 (6.9) | 177 (7.3) | 3202 (6.8) | 0.02 | 175 (7.3) | 170 (7.1) | 0.01 |
| Liver cirrhosis | 485 (1.0) | 22 (0.9) | 463 (1.0) | −0.01 | 22 (0.9) | 17 (0.7) | 0.02 |
| End‐stage renal disease | 2825 (5.7) | 177 (7.3) | 2648 (5.6) | 0.07 | 174 (7.3) | 187 (7.9) | −0.02 |
| Malignancy | 2596 (5.3) | 138 (5.7) | 2458 (5.2) | 0.02 | 135 (5.7) | 129 (5.4) | 0.01 |
| CCI score | 2.8 ± 1.8 | 3.0 ± 2.1 | 2.7 ± 1.8 | 0.13 | 3.0 ± 2.1 | 3.0 ± 2.0 | −0.02 |
| History of event | |||||||
| Venous thromboembolism | 446 (0.9) | 27 (1.1) | 419 (0.9) | 0.02 | 27 (1.1) | 23 (1.0) | 0.02 |
| Heart failure hospitalization | 13,549 (27.5) | 820 (33.9) | 12,729 (27.1) | 0.15 | 807 (33.9) | 793 (33.3) | 0.01 |
| Ischemic stroke | 8976 (18.2) | 558 (23.1) | 8418 (17.9) | 0.13 | 547 (23.0) | 551 (23.1) | <0.01 |
| Major bleeding | 13,861 (28.1) | 871 (36.0) | 12,990 (27.7) | 0.18 | 849 (35.6) | 893 (37.5) | −0.04 |
| Gastrointestinal bleeding | 12,285 (24.9) | 776 (32.1) | 11,509 (24.5) | 0.17 | 755 (31.7) | 791 (33.2) | −0.03 |
| Intracranial hemorrhage | 894 (1.8) | 52 (2.1) | 842 (1.8) | 0.03 | 52 (2.2) | 62 (2.6) | −0.03 |
| Medications at the index date | |||||||
| Aspirin | 38,874 (78.8) | 1593 (65.9) | 37,281 (79.5) | −0.31 | 1593 (66.9) | 1547 (64.9) | 0.04 |
| Anticoagulations | 1829 (3.7) | 134 (5.5) | 1695 (3.6) | 0.09 | 133 (5.6) | 149 (6.3) | −0.03 |
| ACE inhibitor | 17,671 (35.8) | 657 (27.2) | 17,014 (36.3) | −0.20 | 649 (27.2) | 665 (27.9) | −0.02 |
| ARB | 24,702 (50.1) | 1151 (47.6) | 23,551 (50.2) | −0.05 | 1139 (47.8) | 1077 (45.2) | 0.05 |
| Beta blocker | 24,618 (49.9) | 1126 (46.5) | 23,492 (50.1) | −0.07 | 1109 (46.6) | 1121 (47.1) | −0.01 |
| Loops diuretics | 15,792 (32.0) | 796 (32.9) | 14,996 (32.0) | 0.02 | 787 (33.0) | 795 (33.4) | −0.01 |
| Thiazide | 5964 (12.1) | 304 (12.6) | 5660 (12.1) | 0.02 | 297 (12.5) | 301 (12.6) | −0.01 |
| MRAs | 6668 (13.5) | 342 (14.1) | 6326 (13.5) | 0.02 | 333 (14.0) | 316 (13.3) | 0.02 |
| Alpha blocker | 9445 (19.1) | 550 (22.7) | 8895 (19.0) | 0.09 | 541 (22.7) | 557 (23.4) | −0.02 |
| Nitrate | 34,518 (70.0) | 1674 (69.2) | 32,844 (70.0) | −0.02 | 1654 (69.4) | 1653 (69.4) | <0.01 |
| Vasodilator | 1433 (2.9) | 61 (2.5) | 1372 (2.9) | −0.02 | 59 (2.5) | 68 (2.9) | −0.02 |
| Dihyropyridine calcium channel blocker | 22,617 (45.9) | 1114 (46.1) | 21,503 (45.8) | 0.00 | 1103 (46.3) | 1157 (48.6) | −0.05 |
| Digoxin | 3577 (7.3) | 215 (8.9) | 3362 (7.2) | 0.06 | 210 (8.8) | 205 (8.6) | 0.01 |
| Oral hypoglycemic agent | 20,049 (40.6) | 1015 (42.0) | 19,034 (40.6) | 0.03 | 999 (41.9) | 1035 (43.5) | −0.03 |
| Insulin | 5078 (10.3) | 301 (12.4) | 4777 (10.2) | 0.07 | 295 (12.4) | 328 (13.8) | −0.04 |
| Statin | 30,827 (62.5) | 1385 (57.3) | 29,442 (62.8) | −0.11 | 1366 (57.3) | 1332 (55.9) | 0.03 |
| Proton pump inhibitor | 9327 (18.9) | 502 (20.8) | 8825 (18.8) | 0.05 | 496 (20.8) | 554 (23.3) | −0.06 |
| H‐2 blocker | 13,451 (27.3) | 797 (32.9) | 12,654 (27.0) | 0.13 | 779 (32.7) | 764 (32.1) | 0.01 |
| NSAIDs | 3810 (7.7) | 222 (9.2) | 3588 (7.6) | 0.06 | 217 (9.1) | 232 (9.7) | −0.02 |
| Cox‐2 inhibitor | 2939 (6.0) | 146 (6.0) | 2793 (6.0) | 0.00 | 143 (6.0) | 151 (6.3) | −0.01 |
| Follow‐up years | 3.22 ± 1.91 | 2.59 ± 1.49 | 3.25 ± 1.92 | −0.38 | 2.59 ± 1.49 | 2.54 ± 1.53 | 0.04 |
Abbreviations: ACE inhibitor, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCI, Charlson Comorbidity Index; Cox‐2 inhibitor, cyclo‐oxygenase‐2 inhibitor; H‐2 blocker, histamine‐2 blocker; MRA, mineralocorticoid receptor antagonist; NSAID, nonsteroidal anti‐inflammatory drug; STD, standardized difference.
TABLE 2.
Clinical features during the index acute myocardial infarction admission of patients receiving one generic clopidogrel versus brand‐name clopidogrel.
| Variable | Total (n = 49,325) | Before matching | After matching | ||||
|---|---|---|---|---|---|---|---|
| Generic (n = 2419) | Brand‐name (n = 46,906) | STD | Generic (n = 2382) | Brand‐name (n = 2382) | STD | ||
| Duration between the discharge day and prescription of clopidogrel, months | |||||||
| <1 | 26,026 (52.8) | 490 (20.3) | 25,536 (54.4) | −0.76 | 490 (20.6) | 490 (20.6) | 0.00 |
| 1–12 | 6275 (12.7) | 702 (29.0) | 5573 (11.9) | 0.43 | 688 (28.9) | 688 (28.9) | 0.00 |
| >12 | 17,024 (34.5) | 1227 (50.7) | 15,797 (33.7) | 0.35 | 1204 (50.5) | 1204 (50.5) | 0.00 |
| Hospital level | |||||||
| Medical centers | 17,594 (35.7) | 1284 (53.1) | 16,310 (34.8) | 0.38 | 1248 (52.4) | 1207 (50.7) | 0.03 |
| Regional or district hospitals | 31,731 (64.3) | 1135 (46.9) | 30,596 (65.2) | −0.38 | 1134 (47.6) | 1175 (49.3) | −0.03 |
| Coronary intervention | |||||||
| None | 13,619 (27.6) | 774 (32.0) | 12,845 (27.4) | 0.10 | 767 (32.2) | 857 (36.0) | −0.08 |
| PCI | 33,445 (67.8) | 1453 (60.1) | 31,992 (68.2) | −0.17 | 1429 (60.0) | 1339 (56.2) | 0.08 |
| CABG | 1954 (4.0) | 165 (6.8) | 1789 (3.8) | 0.13 | 160 (6.7) | 159 (6.7) | <0.01 |
| Both PCI and CABG | 307 (0.6) | 27 (1.1) | 280 (0.6) | 0.06 | 26 (1.1) | 27 (1.1) | <0.01 |
| Number of intervened vessels | |||||||
| 0 | 13,619 (27.6) | 774 (32.0) | 12,845 (27.4) | 0.10 | 767 (32.2) | 857 (36.0) | −0.08 |
| 1 | 26,534 (53.8) | 1144 (47.3) | 25,390 (54.1) | −0.14 | 1126 (47.3) | 1056 (44.3) | 0.06 |
| 2 | 6712 (13.6) | 322 (13.3) | 6390 (13.6) | −0.01 | 315 (13.2) | 299 (12.6) | 0.02 |
| 3 | 2460 (5.0) | 179 (7.4) | 2281 (4.9) | 0.11 | 174 (7.3) | 170 (7.1) | 0.01 |
| PCI details, n = 33,752 | |||||||
| POBA | 16,606 (49.2) | 785 (53.0) | 15,821 (49.0) | 0.08 | 771 (53.0) | 728 (53.3) | −0.01 |
| Bare metal stent | 10,192 (30.2) | 429 (29.0) | 9763 (30.3) | −0.03 | 423 (29.1) | 419 (30.7) | −0.03 |
| Drug‐eluting stent | 3218 (9.5) | 124 (8.4) | 3094 (9.6) | −0.04 | 121 (8.3) | 109 (8.0) | 0.01 |
| Both BMS and DES | 3736 (11.1) | 142 (9.6) | 3594 (11.1) | −0.05 | 140 (9.6) | 110 (8.1) | 0.06 |
| Use of inotropic agents | 11,586 (23.5) | 609 (25.2) | 10,977 (23.4) | 0.04 | 597 (25.1) | 602 (25.3) | <0.01 |
| Intubation | 3495 (7.1) | 159 (6.6) | 3336 (7.1) | −0.02 | 159 (6.7) | 161 (6.8) | <0.01 |
| Aspiration catheter used | 4156 (8.4) | 186 (7.7) | 3970 (8.5) | −0.03 | 183 (7.7) | 168 (7.1) | 0.02 |
| New‐onset dialysis | 2900 (5.9) | 157 (6.5) | 2743 (5.8) | 0.03 | 154 (6.5) | 165 (6.9) | −0.02 |
| Temporary pacemaker | 2621 (5.3) | 109 (4.5) | 2512 (5.4) | −0.04 | 109 (4.6) | 114 (4.8) | −0.01 |
| ICU duration, days | 4.5 ± 7.4 | 5.1 ± 8.9 | 4.5 ± 7.4 | 0.07 | 5.1 ± 9.0 | 5.2 ± 10.0 | −0.01 |
| Hospitalization duration, days | 10.3 ± 12.1 | 11.0 ± 20.9 | 10.3 ± 11.5 | 0.04 | 10.6 ± 12.2 | 11.3 ± 12.6 | −0.05 |
| Major bleeding | 3448 (7.0) | 160 (6.6) | 3288 (7.0) | −0.02 | 157 (6.6) | 164 (6.9) | −0.01 |
| Gastrointestinal bleeding | 3299 (6.7) | 154 (6.4) | 3145 (6.7) | −0.01 | 151 (6.3) | 158 (6.6) | −0.01 |
Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; DES, drug‐eluting stent; ICU, intensive care unit; PCI, percutaneous coronary intervention; POBA, plain old balloon angioplasty; STD, standardized difference.
Statistical analysis
We used propensity score matching to reduce confounding when comparing outcomes between the generic and brand‐name clopidogrel groups. The propensity score was the predicted probability to be in the generic clopidogrel group, and it was derived from multivariable logistic regression using all of the covariates listed in Table 1 (the follow‐up year was replaced with the index date) and Table 2. Each patient in the generic clopidogrel group was matched with one counterpart in the brand‐name clopidogrel group. We used the greedy nearest‐neighbor algorithm for matching with a caliper of 0.2, with random matching order and without replacement. The balance of baseline characteristics between the two groups was assessed using the absolute value of the standardized difference (STD), where a value of less than 0.1 was considered a negligible difference.
The risk of fatal outcomes (e.g., all‐cause death) between the two groups was compared using a Cox proportional hazard model. The incidence of other outcomes (e.g., myocardial infarction) between groups was compared using a Fine and Gray subdistribution hazard model which considered all‐cause death during follow‐up as a competing risk. The study group (generic vs. brand‐name) was the only explanatory variable in the above survival models. The outcome dependency within‐pair clustering after matching was accounted for by using a robust standard error. Subgroup analyses for the primary composite efficacy outcome were conducted using 10 prespecified subgroup variables, including sex, age (≤65 vs. >65 years), hypertension, diabetes, dyslipidemia, chronic kidney disease, CCI score (<3 vs. ≥3), history of HFH, history of ischemic stroke, and the duration from the day of discharge for the AMI admission to the index date (<1, 1–12, and ≥12 months). A two‐sided p‐value <0.05 was considered to be statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).
RESULTS
Patient characteristics
A total of 49,325 patients were included in this study, of whom 46,906 were prescribed brand‐name clopidogrel and 2419 the generic version. The patients' characteristics and use of medications are shown in Table 1. Before matching, the mean ages were 68.3 ± 13.3 and 66.3 ± 13.2 years in the generic and brand‐name groups, respectively. About 75% of the patients were male. The CCI score was higher in the generic group (3.0 ± 2.1 vs. 2.7 ± 1.8; STD = 0.13) due to the higher prevalence of hypertension (75.1% vs. 68.6%; STD = 0.14) and peptic ulcer disease (23.2% vs. 17.5%; STD = 0.13). There were more previous documented events of HFH, ischemic stroke, major bleeding, and gastrointestinal bleeding in the generic group. The brand‐name group was more often prescribed aspirin, angiotensin‐converting enzyme inhibitors and statins, whereas H2 blockers were more frequently prescribed in the generic group (absolute STD values >0.1). After matching, there were negligible differences in the baseline characteristics and the use of medications between the two groups.
Clinical features
Table 2 shows in‐hospital management and the timing of initiation of the generic or brand‐ name clopidogrel. The generic clopidogrel was more often prescribed after 12 months post‐discharge (50.7%), whereas the brand‐name clopidogrel was most commonly prescribed within 1 month of discharge. About 65% of the brand‐name clopidogrel prescriptions were made at regional or district hospitals, whereas 53.1% of the generic clopidogrel prescriptions were made at medical centers. Regarding in‐hospital management, most patients (67.8%) underwent PCI. The prevalence of not receiving a coronary intervention (32% vs. 27.4%; STD = 0.1) or coronary artery bypass graft (6.8% vs. 3.8%; STD = 0.13) was higher in the generic group than in the brand‐name group. There were no significant differences in the PCI details, use of inotropic agents, intubation, new‐onset dialysis, temporary pacemaker placement, length of stay in the intensive care unit, and duration of hospitalization between the two groups. The risks of major bleeding and gastrointestinal bleeding were comparable between the two groups. After matching, there were negligible differences in the details of in‐hospital management.
Efficacy outcomes
The efficacy and safety bleeding outcomes are shown in Table 3. At a mean follow‐up of 2.5 years, the generic and brand‐name groups had a comparable risk of the primary efficacy outcome (41.9% vs. 42%; hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.88–1.04) (Figure 2a). No significant differences were observed in the risks of the individual components of the composite efficacy outcome, including myocardial infarction (6.7% vs. 6.8%; subdistribution HR [SHR] 0.96; 95% CI 0.77–1.19), revascularization (18.7% vs. 18.3%; SHR 1.00; 95% CI 0.87–1.14), ischemic stroke (4.9% vs. 5.0%; SHR 0.96; 95% CI 0.75–1.24), and all‐cause death (24.1% vs. 23.5%; HR 1.01; 95% CI 0.90–1.13).
TABLE 3.
Follow‐up outcomes of patients receiving one generic clopidogrel versus brand‐name clopidogrel.
| Outcome | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| Generic (n = 2419) | Brand‐name (n = 46,906) | Generic (n = 2382) | Brand‐name (n = 2382) | HR/SHR for generic (95% CI) | P‐value | |
| Primary composite outcome a | 1010 (41.8) | 22,711 (48.4) | 998 (41.9) | 1003 (42.1) | 0.96 (0.88–1.04) | 0.320 |
| Component of primary outcome | ||||||
| Myocardial infarction | 160 (6.6) | 4206 (9.0) | 159 (6.7) | 162 (6.8) | 0.96 (0.77–1.19) | 0.705 |
| Revascularization | 449 (18.6) | 11,806 (25.2) | 446 (18.7) | 437 (18.3) | 1.00 (0.87–1.14) | 0.939 |
| PCI | 422 (17.4) | 10,878 (23.2) | 419 (17.6) | 395 (16.6) | 1.04 (0.91–1.20) | 0.562 |
| CABG | 38 (1.6) | 1264 (2.7) | 38 (1.6) | 50 (2.1) | 0.74 (0.49–1.14) | 0.170 |
| Ischemic stroke | 119 (4.9) | 2715 (5.8) | 116 (4.9) | 118 (5.0) | 0.96 (0.75–1.24) | 0.772 |
| All‐cause death | 582 (24.1) | 11,563 (24.7) | 574 (24.1) | 559 (23.5) | 1.01 (0.90–1.13) | 0.893 |
| Bleeding outcomes | ||||||
| Major bleeding | 193 (8.0) | 3859 (8.2) | 188 (7.9) | 187 (7.9) | 0.99 (0.81–1.21) | 0.916 |
| Intracranial hemorrhage | 14 (0.6) | 363 (0.8) | 14 (0.6) | 14 (0.6) | 0.98 (0.47–2.05) | 0.955 |
| Gastrointestinal bleeding | 157 (6.5) | 3007 (6.4) | 152 (6.4) | 143 (6.0) | 1.05 (0.83–1.32) | 0.687 |
| Fatal bleeding | 58 (2.4) | 1213 (2.6) | 57 (2.4) | 54 (2.3) | 1.03 (0.71–1.50) | 0.876 |
| Secondary outcomes | ||||||
| Heart failure hospitalization | 217 (9.0) | 4626 (9.9) | 213 (8.9) | 219 (9.2) | 0.95 (0.79–1.15) | 0.604 |
| CV death | 323 (13.4) | 6526 (13.9) | 317 (13.3) | 309 (13.0) | 1.00 (0.86–1.17) | 0.992 |
Abbreviations: CABG, coronary artery bypass graft; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; PCI, percutaneous coronary intervention; SHR, subdistribution hazard ratio.
Anyone of myocardial infarction, revascularization, ischemic stroke, and all‐cause death.
FIGURE 2.
Cumulative event rate of primary composite efficacy outcome (a) and major bleeding (b) for patients receiving generic clopidogrel versus brand‐name clopidogrel in the propensity score matched cohort. CI, confidence interval.
Safety and other outcomes
In terms of safety outcomes, there was no significant difference between the generic and brand‐name groups in the risk of major bleeding (7.9% vs. 7.9%; SHR 0.99; 95% CI 0.81–1.21) (Figure 2b). In addition, no significant differences were observed in the risks of each bleeding event, including intracranial hemorrhage (0.6% vs. 0.6%; SHR 0.98; 95% CI 0.47–2.05), gastrointestinal bleeding (6.4% vs. 6.0%; SHR 1.05; 95% CI 0.83–1.32), and fatal bleeding (2.4% vs. 2.3%; HR 1.03; 95% CI 0.71–1.50). The results of other outcomes showed that the two groups did not significantly differ in the risks of HFH and CV death.
Subgroup analysis of composite efficacy outcome
Subgroup analyses were performed to investigate potential differences in the primary composite efficacy outcome between the generic and brand‐name groups among predefined subgroups based on age, sex, hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, CCI total score, previous heart failure and ischemic stroke, and timing of prescriptions. The results showed that there were no statistically significant interactions between the treatment effect and various subgroups (Figure 3).
FIGURE 3.
Subgroup analysis of the primary composite efficacy outcome in the propensity score matched cohort. CI, confidence interval; CCI, Charlson Comorbidity Index.
DISCUSSION
This nationwide cohort study analyzed the clinical outcomes of AMI patients who received a generic clopidogrel versus brand‐name clopidogrel. At a mean follow‐up of 2.5 years, the generic clopidogrel and brand‐name clopidogrel groups were comparable in terms of the primary composite outcome, which included myocardial infarction, ischemic stroke, and all‐cause death. The risks of major bleeding, intracranial, gastrointestinal bleeding, and fatal bleeding were also comparable between the two groups.
To the best of our knowledge, this is the largest retrospective study to compare the clinical outcomes of generic and brand‐name clopidogrel with the longest follow‐up period. Our results are consistent with prior studies showing comparable effectiveness and safety of generic and brand‐name clopidogrel. In a meta‐analysis comparing brand‐name and generic clopidogrel, no significant differences were observed between the two drugs in terms of CV events, adverse events, and withdrawal rates. However, only three studies were included in this meta‐analysis, with relatively small patient numbers and short follow‐up period. 24 Furthermore, previous meta‐analyses on studies comparing generic and brand‐name CV drugs found no significant differences in terms of various outcomes and adverse events, suggesting that using generic instead of brand‐name CV drugs does not mean compromising either efficacy or safety. 13 , 14 However, most of the studies in the meta‐analyses on clopidogrel were bioequivalence trials with a crossover design, a small sample size, or short follow‐up duration and soft endpoints, and some included young and healthy participants, thereby limiting their applicability to the real‐world setting in managing CV disease patients. A more recent meta‐analysis by Leclerc and colleagues demonstrated that the crude risk of all‐cause hospital visits was modestly but significantly increased in patients prescribed generic versus brand‐name CV drugs, but not for CV hospital visits. 25 Nevertheless, due to high heterogeneity among the enrolled studies, no firm conclusion could be drawn from this meta‐analysis. A large population‐based study in Ontario, Canada reported no significant difference in major adverse CV outcomes at 1 year between acute coronary syndrome patients prescribed either generic clopidogrel or the brand‐name counterpart. 26
Clopidogrel is a prodrug that is mainly metabolized and activated by the CYP2C19 enzyme. A high prevalence of CYP2C19 loss‐of‐function alleles in East Asian populations (50%–60%) compared with Western populations (30%) has raised concerns about the efficacy and safety of clopidogrel therapy in these patients. 27 , 28 In a study involving Taiwanese acute coronary syndrome patients, 56.9% of patients had at least one CYP2C19 loss‐of‐function allele, 29 and the prevalence is similar to other studies in Taiwan. 30 , 31 However, East Asians have a different risk–benefit profile for antithrombotic therapy compared to Western populations, with a higher incidence of bleeding complications and similar or lower rates of ischemic events at the same level of platelet reactivity compared with Caucasian patients. This is referred to as the “East Asian paradox”. 32 , 33 The clinical significance of clopidogrel resistance in East Asian populations is still uncertain, and current guidelines do not recommend routine platelet function tests in the decision‐making for personalized treatment approaches. 34 The recent TAILOR PCI (Tailored Antiplatelet Therapy Following PCI) trial, which included about 30% of East Asians, failed to show that a genotype‐guided strategy was superior at reducing adverse CV events compared with standard therapy after PCI. 35 The subgroup analysis of TAILOR PCI also did not show better clinical benefit in East Asian populations with genotyping. Besides, a number of bioequivalence studies, including studies from East Asia, 36 , 37 were conducted on various generic clopidogrel versus brand‐name clopidogrel to evaluate their efficacy in platelet aggregation inhibition and no significant difference was observed, suggesting generic clopidogrel and brand‐name clopidogrel have comparable antiplatelet effects. 38 , 39 , 40
Overall, the prescription rate of generic clopidogrel was relatively low in this study, and it was more often prescribed 12 months after the AMI episode, presumably when the physician considered the patient to be more stable and only requiring a single antiplatelet agent. The use of generic medications has increased rapidly over the past 20 years, however about one‐third of patients, physicians, and pharmacists are still skeptical about the safety, effectiveness, and quality of generic medications. 41 , 42 Kesselheim et al. reported that physician perceptions about generic drugs have shifted toward greater confidence in their quality and safety, but that skepticism remains, especially among physicians who learned about the generic drugs from pharmaceutical companies. 41 A recent study also showed that Chinese physicians were generally positive toward generic drugs, but that insufficient knowledge about generic drugs may reduce confidence in their safety and quality. 43 In Taiwan, the NHI program covers up to 89% of the cost of prescribed medications, and the patients only have to pay a small co‐payment per prescription to get brand‐name medication. 44 The high coverage rate thus provides a strong incentive for physicians to prescribe more expensive drugs for their patients. Another Taiwanese study also revealed that a larger price difference between brand‐name and generic drugs increased the number of generic prescriptions made by physicians, but that this effect decreased for physicians in large hospitals as the NHI program covered more of the cost. Larger hospitals have more power when negotiating the price of brand‐name medications than small hospitals or clinics, and thus pay less for brand‐name medication. 45 Patients also tend to choose brand‐name medications over generic medications as they do not consider generic medications to be equivalent to their brand‐name counterparts, and believe that brand‐name medications have fewer side effects. 46 , 47 , 48 A general perception that cheaper drugs means lower quality has also been reported among patients, 49 and that patients are more accepting of generics for the treatment of minor illnesses but prefer branded medicines for serious health problems. 47 , 50 , 51
LIMITATIONS
This retrospective study design has several inherent limitations. First, the prescription rate of generic clopidogrel was relatively low in this study, and it was more often prescribed 12 months after the AMI episode although the duration between the discharge day and prescription of clopidogrel had been matched. Second, there might be a selection bias between the two groups as we do not know the reason behind the prescription of brand‐ name or generic medication for patients. Third, the propensity score matching was used to balance potential differences between the two study groups, but unmeasured variables can still confound data analysis. Fourth, the study cohort was limited to the Taiwanese population and one generic clopidogrel, limiting the generalizability of the results. Fifth, although there is currently no comparative data on bioequivalence and pharmacodynamics of generic “Thrombifree, Hygica Biotech Limited” clopidogrel and its brand‐name counterpart on inhibiting platelet aggregation or other functional platelet tests, our study provides evidence supporting the comparable efficacy and safety of generic clopidogrel. However, further prospective studies are needed to validate and reinforce these findings. Finally, our study database did not include information on CYP2C19 alleles or genetic testing results as current guidelines do not support routine platelet function tests or genotype‐guided strategy in the decision‐making for treatment approaches. Therefore, we were unable to assess the power of our study to detect intersubject variability in response specifically driven by single nucleotide polymorphisms when administering generic clopidogrel. Furthermore, we could not directly compare the efficacy and safety outcomes between brand‐name and generic clopidogrel in relation to CYP2C19 polymorphisms. The assessment of genetic factors and their impact on drug response was beyond the scope of our study due to the lack of genetic data.
CONCLUSIONS
In this nationwide cohort study analyzing the clinical outcomes of AMI patients who received a generic clopidogrel versus brand‐name clopidogrel, the generic clopidogrel was comparable to the brand‐name clopidogrel regarding the CV and bleeding outcomes.
AUTHOR CONTRIBUTIONS
C.C.C and Y.C.T. wrote the manuscript. P.H.C. designed the research. C.C.C., K.T.L., and P.H.C. performed the research. Y.H.C. analyzed the data.
FUNDING INFORMATION
No funding was received for this work.
CONFLICT OF INTEREST STATEMENT
The authors declared no competing interests for this work.
Chan CC, Tung Y‐C, Lee K‐T, Chan Y‐H, Chu P‐H. Clinical outcomes of generic versus brand‐name clopidogrel for secondary prevention in patients with acute myocardial infarction: A nationwide cohort study. Clin Transl Sci. 2023;16:1594‐1605. doi: 10.1111/cts.13590
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