Received: 6 February 2022 Revised: 14 March 2022 Accepted: 19 March 2022

DOI: 10.1111/jch.14478

ORIGINAL ARTICLE

Comparative effectiveness of generic nifedipine versus Adalat

long-acting nifedipine for hypertension treatment: A
multi-institutional cohort study

Ying-Chang Tung MD1 Chia-Pin Lin MD1 Fu-Chih Hsiao MD1

Chien-Te Ho MD1 Hsu Tzyy-Jer MD1 You-Chia Chu MS2 Wen-Jone Chen MD3,4,5
Pao-Hsien Chu MD1,6

1
Division of Cardiology, Department of
Internal Medicine, Chang Gung Memorial Abstract
Hospital, Chang Gung University College of
This retrospective multi-institutional database analysis aimed to evaluate the blood-
Medicine, Taipei, Taiwan
2 pressure-lowering efficacy and clinical outcomes of a generic versus brand-name
Department of Computer Science, National
Chiao-Tung University, Hsien-Chu, Taiwan nifedipine for hypertension management. A total of 12 693 patients who were pre-
3
Department of Emergency Medicine, scribed a generic or brand-name nifedipine between January 1, 2011, and Decem-
National Taiwan University Hospital, Taipei,
Taiwan
ber 31, 2018, were identified from the Chang Gung Research Database of Chang
4
Department of Emergency Medicine, College Gung Memorial Hospitals, Taiwan. Among them, 2112 (21.4%) were prescribed generic
of Medicine, National Taiwan University, nifedipine. After propensity score matching, both the generic and brand-name groups
Taipei, Taiwan
5
consisted of 2102 patients. At a mean follow-up of 3 years, the changes in office systolic
Division of Cardiology, Department of
Internal Medicine, National Taiwan University (p for interaction = .791) and diastolic blood pressure (p for interaction = .689) did not
Hospital and National Taiwan University differ significantly between the patients who received the generic and the brand-name
College of Medicine, Taipei, Taiwan
6
nifedipine. There was no significant difference between the two study groups regard-
Institute of Stem Cell and Translational
Cancer Research Chang Gung Memorial ing the composite of all-cause mortality, acute myocardial infarction, stroke, coronary
Hospital, Taiwan
revascularization, or hospitalization for heart failure (hazard ratio 0.98, 95% confi-
Correspondence dence interval 0.85–1.13; p = .774). In conclusion, the generic nifedipine was compa-
Pao-Hsien Chu, The Cardiology Division, rable to its brand-name counterpart regarding office blood pressure reduction and the
Department of Internal Medicine, Chang Gung
Memorial Hospital, College of Medicine, composite cardiovascular outcome for the treatment of patients with hypertension.
Chang Gung University, 199 Tun-Hwa North
Road, Taipei 105, Taiwan. KEYWORDS
Email: [email protected] blood pressure, generic drug, nifedipine, outcome

1 INTRODUCTION with hypertension had their systolic BP controlled below 140 mmHg.3
The 2017 American College of Cardiology/American Heart Associa-
Hypertension has long been considered a leading modifiable risk factor tion Guidelines has lowered the diagnostic threshold for hypertension
for cardiovascular disease.1,2 The global burden of hypertension was in adults to systolic BP ≥130 mmHg and/or diastolic BP ≥80 mmHg.4
1.4 billion people in 2010, and the number may substantially exceed 1.6 When this new definition was applied, the prevalence of hypertension
billion by 2025.3 In 2010, however, only approximately 14% of patients in the US general population increased from 32.0% to 45.4%,5 and

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.

J Clin Hypertens. 2022;24:621–629. wileyonlinelibrary.com/journal/jch 621

622 TUNG ET AL .

the increase was even greater in the Chinese general population, from 2.2 Study population
23.2% to 46.4%.6
Generic drugs, containing the same active chemical ingredients as A new user design was adopted to compare the generic nifedipine with
brand-name products, provide an opportunity to offer similar treat- the brand-name nifedipine. We first identified 23 921 patients who
ments at a lower cost to patients and payers and thus have a huge were diagnosed with hypertension and treated with the OROS for-
impact on health policy and economics. Generic drugs have been mulations of generic (Nifedipine S.RFC, Chunghwa Yuming Healthcare
increasingly used in daily practice worldwide and account for more Co., Taiwan) or brand-name nifedipine (Adalat OROS, Bayer) at a dose
than 80% of all prescriptions in the US.7 To apply for regulatory of 30 mg daily between January 1, 2011, and December 31, 2018,
approval, generic drug manufacturers are required to scientifically from the CGRD. We then excluded patients who were younger than
document pharmaceutical equivalence and bioequivalence with inno- 20 years old and had previously been prescribed any dihydropyridine
vator drugs. However, a bioequivalence study typically requires only CCBs (including the two study drugs). The date of the first prescrip-
24–36 healthy persons to qualify for “abbreviated” approval by the tion of the study drugs was defined as the index date, and the first 90
US Food and Drug Administration.8 Since preclinical or clinical data days after the index date was defined as the exposure time window. The
to establish safety and efficacy are not mandatory for generic drug use of the study drugs was ascertained by at least two outpatient pre-
approval, whether pharmaceutical equivalence and bioequivalence scriptions or one refilled prescription for treating chronic illness dur-
with brand-name drugs could translate to equivalent clinical outcomes ing the first 90-day window after the index date. We further excluded
remains uncertain. the patients who were concomitantly prescribed other dihydropyri-
Long-acting nifedipine is one of the commonly prescribed dihy- dine CCBs, switched between the generic and brand-name nifedipine,
dropyridine calcium-channel blockers (CCBs) for BP control. The had died or developed cardiovascular events during the first 90 days
osmotic-controlled release oral delivery system (OROS) uses osmotic after the index date, or had a follow-up period of less than 90 days,
pressure as the driving force to push the active drugs through the or whose baseline BP data were missing. Among the 12 693 patients
laser-drilled openings and thus ensures a more predictable pharma- who were eligible for further analysis, 2112 (16.6%) were prescribed
cokinetic profile.9,10 In Taiwan, a postmarketing surveillance study has generic nifedipine. Figure 1 illustrates the details of patient inclusion
examined the efficacy of BP control and the tolerability of nifedip- and exclusion.
ine OROS among hypertensive patients,11 but clinical outcomes were
not reported. The lack of long-term outcome data may raise concerns
about the “clinical equivalence” of generic and brand-name drugs. In 2.3 Office BP
this study, we aimed to compare the BP-lowering effect and clinical out-
comes of the generic and branded nifedipine OROS formulations for Information on office BP at follow-up clinic visits was extracted from
hypertension treatment. the nursing records of the CGRD. At CGMH, BP measurement was per-
formed by trained nurses with standardized techniques. Patients were
required to rest for at least 5 minutes in a seated position before BP
2 METHODS was measured. With the patient’s arm resting on a desk, BP was mea-
sured with automated upper-arm cuff BP measurement devices (GE
2.1 Data source Dinamap Carescape V100, Florida, USA), which had been validated14
and checked periodically for proper functioning.
We used the Chang Gung Research Database (CGRD) to conduct this
retrospective multi-institutional cohort study. The CGRD is derived
from the electronic medical records of seven Chang Gung Memorial 2.4 Clinical outcomes and follow-up
Hospitals (CGMH), including two medical centers, two regional hospi-
tals, and three district hospitals, together covering 1.3 million patients, The primary outcome was major adverse cardiovascular events, which
accounting for 6% of the population of Taiwan.12,13 The CGRD con- were defined as the composite of all-cause death, acute myocardial
tains standardized patient-level information since 2001, including dis- infarction (AMI), stroke, coronary revascularization (ie, percuta-
ease category data, laboratory test results, imaging and procedural neous coronary intervention and coronary bypass graft surgery),
reports, prescription drugs, and the use of medical facilities. Disease and hospitalization for heart failure (HF). All of the abovementioned
diagnoses were coded using the International Classification of Dis- outcomes were detected using the inpatient claims data. AMI was
eases, 9th Revision, Clinical Modification (ICD-9-CM) codes before identified with discharge diagnosis and ascertained with elevated
2016, and the ICD-9-CM and ICD-10-CM codes thereafter. To protect cardiac troponin-I levels above the 99th percentile of upper reference
patient privacy and to ensure anonymity, the CGRD has encrypted all limit. The diagnosis of stroke was further confirmed by brain imaging
patients’ personal identifiable information. Therefore, the requirement studies (computed tomography or magnetic resonance imaging).
for informed consent was waived. This study was approved by the Insti- Coronary revascularization was identified by the Taiwan National
tutional Review Board at Linkou Chang Gung Memorial Hospital, Tai- Health Insurance reimbursement code. The diagnosis of HF required
wan (IRB No.201901524B0). HF symptoms (eg, dyspnea) and elevated natriuretic peptide levels
TUNG ET AL . 623

F I G U R E 1 Flowchart for patient inclusion and exclusion. Abbreviations: DCCB, dihydropyridine calcium-channel blocker; OROS,
osmotic-controlled release oral delivery system

(B-type natriuretic peptide > 100 pg/mL or N-terminal probrain natri- 2.6 Statistical analysis
uretic peptide > 300 pg/mL)15 in addition to the inpatient diagnosis.
All patients were followed from the index date until the occurrence of We used the propensity score matching method to reduce confounding
clinical outcomes, discontinuation of the initial study drug, any switch when comparing outcomes between generic and brand-name nifedip-
between the generic and brand-name nifedipine, the day of death, or ine. The propensity score, the predicted probability to be included in
the end of the database follow-up (September 30, 2019), whichever the generic nifedipine group, was derived from multivariable logistic
came first. regression using all the covariates listed in Table 1, except that the
follow-up year was replaced by the index date. The continuous vari-
ables (eg, age) were not converted to categorical variables in the cal-
2.5 Covariates culation of propensity score and the linearity between the continuous
variables and the predicted probability was assumed. Patients in the
The baseline covariates in this study included demographic data (age, generic nifedipine group and in the brand-name nifedipine group were
sex, body mass index, history of smoking), comorbidities, the Charl- matched at a 1:1 ratio. The matching was processed using a greedy,
son Comorbidity Index (CCI) score, the use of antihypertensive medi- nearest-neighbor algorithm, with a caliper of 0.2 times the standard
cations other than dihydropyridine CCBs, the use of other medications deviation of the logit of the propensity score, with random matching
(ie, antiplatelet agents and oral hypoglycemic agents), vital signs (office order and without replacement. The balance of baseline characteristics
systolic blood pressure [SBP], office diastolic blood pressure [DBP], between the two groups was assessed using the absolute value of the
and heart rate), and laboratory test results (ie, low-density lipoprotein standardized difference (STD), where a value of less than 0.1 was con-
cholesterol and serum creatinine). Other comorbidities were identified sidered a negligible difference. Some records of body mass index, heart
by any inpatient diagnosis or at least two outpatient diagnoses regis- rate, and laboratory tests were missing (the available numbers of each
tered before the index date with the use of the ICD-9-CM and ICD- covariate are listed in detail in Table 1). Therefore, the original data was
10-CM codes. Baseline medications were prescriptions during the 90- singly imputed using the Expectation–Maximization algorithm and the
day window after the index date extracted from the medical records of matching was conducted on the imputed cohort.
CGRD. Laboratory data at the index date were also extracted from the The changes in the two groups’ long-term office systolic and dias-
outpatients’ medical records of CGRD. tolic BP measurements from baseline over the course of follow-up
624 TUNG ET AL .

TA B L E 1 Baseline characteristics of patients who were prescribed the generic and the brand-name nifedipine

Before matching After matching

Available Generic Brand-name Generic Brand-name
Variables number (no. = 2112) (no. = 10 581) STD (no. = 2102) (no. = 2102) STD
Age, years 12 693 63.7 ± 15.1 62.8 ± 14.4 0.07 63.8 ± 15.1 63.9 ± 14.5 <0.01
Male 12 693 1,106 (52.4) 5865 (55.4) −0.06 1,102 (52.4) 1106 (52.6) <0.01
Body mass index, kg/m 2
9588 26.3 ± 4.5 26.7 ± 4.6 −0.07 26.4 ± 4.1 26.3 ± 4.2 0.01
Smoker 12 693 372 (17.6) 1723 (16.3) 0.04 368 (17.5) 396 (18.8) −0.03
Cardiovascular disease
Coronary artery disease 12 693 350 (16.6) 2267 (21.4) −0.12 350 (16.7) 334 (15.9) 0.02
Peripheral artery disease 12 693 128 (6.1) 551 (5.2) 0.04 128 (6.1) 132 (6.3) −0.01
Acute coronary syndrome 12 693 45 (2.1) 289 (2.7) −0.04 45 (2.1) 45 (2.1) <0.01
Stroke 12 693 163 (7.7) 927 (8.8) −0.04 163 (7.8) 163 (7.8) <0.01
Any cardiovascular disease 12 693 566 (26.8) 3282 (31.0) −0.09 566 (26.9) 549 (26.1) 0.02
Comorbidity
Diabetes mellitus 12 693 803 (38.0) 3766 (35.6) 0.05 794 (37.8) 815 (38.8) −0.02
Chronic kidney disease 12 693 863 (40.9) 3535 (33.4) 0.15 853 (40.6) 906 (43.1) −0.05
Atrial fibrillation 12 693 105 (5.0) 467 (4.4) 0.03 105 (5.0) 108 (5.1) −0.01
Malignancy 12 693 548 (25.9) 2,290 (21.6) 0.10 544 (25.9) 545 (25.9) <0.01
Prior heart failure 12 693 83 (3.9) 351 (3.3) 0.03 81 (3.9) 84 (4.0) −0.01
Liver cirrhosis 12 693 76 (3.6) 296 (2.8) 0.05 75 (3.6) 85 (4.0) −0.02
Chronic obstructive pulmonary 12 693 183 (8.7) 875 (8.3) 0.01 182 (8.7) 178 (8.5) 0.01
disease
Charlson’s Comorbidity Index score 12 693 2.8 ± 2.6 2.4 ± 2.4 0.16 2.8 ± 2.6 2.9 ± 2.8 −0.05
Anti-hypertensive medications
ACE inhibitors/ARBs 12 693 1068 (50.6) 5400 (51.0) −0.01 1064 (50.6) 1093 (52.0) −0.03
Beta-blockers 12 693 953 (45.1) 4819 (45.5) −0.01 946 (45.0) 945 (45.0) <0.01
Diuretics 12 693 508 (24.1) 2294 (21.7) 0.06 504 (24.0) 519 (24.7) −0.02
Alpha blockers 12 693 30 (1.4) 277 (2.6) −0.09 30 (1.4) 46 (2.2) −0.06
Nitrates 12 693 107 (5.1) 621 (5.9) −0.04 106 (5.0) 107 (5.1) <0.01
Vasodilators 12 693 403 (19.1) 1905 (18.0) 0.03 400 (19.0) 408 (19.4) −0.01
Number of anti-hypertensive 12 693 1.45 ± 1.16 1.45 ± 1.13 <0.01 1.45 ± 1.16 1.48 ± 1.11 0.03
agents
Other medications
Antiplatelet agents 12 693 586 (27.7) 3470 (32.8) −0.11 585 (27.8) 589 (28.0) <0.01
Metformin 12 693 348 (16.5) 1923 (18.2) −0.04 347 (16.5) 350 (16.7) <0.01
GLP-1 receptor agonists 12 693 13 (0.6) 26 (0.2) 0.06 11 (0.5) 14 (0.7) −0.02
SGLT2 inhibitors 12 693 17 (0.8) 61 (0.6) 0.03 17 (0.8) 16 (0.8) 0.01
Other oral hypoglycemic agents 12 693 421 (19.9) 2126 (20.1) <0.01 420 (20.0) 437 (20.8) −0.02
Insulin 12 693 207 (9.8) 754 (7.1) 0.10 204 (9.7) 226 (10.8) −0.03
Statins 12 693 580 (27.5) 3277 (31.0) −0.08 579 (27.5) 572 (27.2) 0.01
Fibrates or gemfibrozil 12 693 59 (2.8) 398 (3.8) −0.05 59 (2.8) 64 (3.0) −0.01
Vital signs at baseline
Systolic blood pressure, mm Hg 12 693 155.3 ± 26.1 157.4 ± 24.8 −0.08 155.4 ± 26.1 155.1 ± 24.9 0.01
Diastolic blood pressure, mm Hg 12 693 84.8 ± 17.0 85.8 ± 16.0 −0.06 84.7 ± 16.4 84.6 ± 16.0 0.01
Heart rate, beats/min 12 613 80.5 ± 15.5 79.9 ± 14.9 0.04 80.5 ± 15.4 80.6 ± 15.2 −0.01
(Continues)
TUNG ET AL . 625

TA B L E 1 (Continued)

Before matching After matching

Available Generic Brand-name Generic Brand-name
Variables number (no. = 2112) (no. = 10 581) STD (no. = 2102) (no. = 2102) STD
Laboratory data at baseline
LDL-C, mg/dL 9744 74.2 ± 58.7 73.9 ± 59.3 0.01 74.2 ± 50.5 73.7 ± 48.2 0.01
HDL-C, mg/dL 9182 45.9 ± 14.3 46.6 ± 13.2 −0.05 46.3 ± 12.0 46.2 ± 11.4 0.01
Non-HDL-C, mg/dL 7485 137.3 ± 41.6 138.3 ± 40.3 −0.02 137.5 ± 35.1 136.5 ± 34.9 0.03
Total cholesterol, mg/dL 9969 183.2 ± 43.6 185.2 ± 41.9 −0.05 184.0 ± 37.8 182.6 ± 37.1 0.04
Triglyceride, mg/dL 9794 154.8 ± 104.2 152.1 ± 99.1 0.03 154.2 ± 89.5 150.3 ± 83.7 0.04
HbA1C, % 7959 6.7 ± 1.5 6.8 ± 1.5 −0.02 6.62 ± 1.23 6.61 ± 1.20 0.01
Fasting glucose, mg/dL 8234 118.8 ± 42.8 118.8 ± 42.6 <0.01 118.9 ± 35.1 119.1 ± 37.6 <0.01
Creatinine, mg/dL 12 006 2.3 ± 2.9 1.9 ± 2.5 0.14 2.2 ± 2.8 2.4 ± 3.0 −0.07
eGFR, mL/min/1.73m2 12 006 60.4 ± 36.3 65.4 ± 34.6 −0.14 61.2 ± 35.5 59.2 ± 35.8 0.06
Uric acid, mg/dL 8413 6.7 ± 1.9 6.7 ± 1.9 −0.01 6.6 ± 1.6 6.6 ± 1.7 −0.01
ALT, U/L 10 711 27.8 ± 22.1 27.6 ± 20.9 0.01 27.8 ± 20.5 28.1 ± 21.0 −0.02
AST, U/L 7038 30.4 ± 19.6 29.8 ± 18.1 0.03 29.5 ± 16.0 29.8 ± 16.4 −0.02
Follow-up, years 12 693 3.0 ± 2.3 3.8 ± 2.3 −0.38 3.0 ± 2.3 3.2 ± 2.1 −0.11

Data were presented as frequency (percentage) or mean ± standard deviation.

Abbreviations: ACE, angiotensin-converting enzyme; ALT, alanine aminotransferase; ARBs, angiotensin receptor blockers; AST, aspartate transaminase;
eGFR, estimated Glomerular filtration rate; GLP-1, glucagon-like peptide-1; HbA1C, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-
C, low-density lipoprotein cholesterol; non-HDL-C, non-high-density lipoprotein cholesterol; SGLT2, sodium-glucose co-transporter 2; STD, standardized
difference.

were compared using a linear mixed model. Two random effects were 3 RESULTS
set in the linear mixed model: the intercept (the baseline value) and the
slope (the effect of time). Cox proportional hazards model was used to 3.1 Patient characteristics
compare the risks of fatal time-to-event outcomes (ie, all-cause death
and the composite outcome) between the generic and brand-name A total of 12 693 patients were eligible for this study. Among them,
nifedipine groups. The Fine and Gray subdistribution hazards model there were 2112 incident users of the generic nifedipine and 10 581
was used to account for the competing risk of death in the compar- were incident users of the brand-name nifedipine. The patient char-
ison of the two groups’ risks of nonfatal time-to-event outcomes (ie, acteristics are shown in Table 1. Before propensity score matching,
MI, stroke, HF, or coronary revascularization). The study group was the the mean ages were 63.7 ± 15.1 and 62.8 ± 14.4 years (STD = 0.07)
only explanatory variable in the survival models. The within-pair clus- and male patients constituted 52.4% and 55.4% (STD = 0.06) of the
tering of outcomes after matching was accounted for by using a robust generic group and the brand-name group, respectively. Atherosclerotic
standard error.16 cardiovascular disease was common in both groups (26.8% vs 31.0%;
Furthermore, we performed subgroup analysis on the primary STD = 0.09), with coronary artery disease more prevalent in the brand-
composite outcome stratifying by several prespecified variables at name group (16.6% vs 21.4%; STD = 0.12). The generic group had a
baseline, including age (< 65 and ≥65 years), sex, body mass index markedly higher CCI score (2.8 ± 2.6 vs 2.4 ± 2.4; STD = 0.16) due
(< 27 and ≥27 kg/m2 [the World Health Organization definition to their higher prevalence of chronic kidney disease (40.9% vs 33.4%;
of obesity for Asian populations]),17 SBP (< 140, 140–160, and STD = 0.15) and malignancy (25.9% vs 21.6%; STD = 0.1). Concomi-
≥160 mmHg), DBP (< 90, 90–100, and ≥100 mmHg), history of any tant use of other antihypertensive drugs was common and the num-
cardiovascular disease, diabetes, estimated glomerular filtration bers in the two groups were comparable (1.45 vs 1.45, STD < 0.01).
rate (eGFR; < 30, 30–60, and ≥60 mL/min/1.73 m2 ), CCI score (< 3 Approximately half of the patients received angiotensin-converting
and ≥3), alanine aminotransferase (ALT; < 35 U/L [1× upper limit of enzyme inhibitors or angiotensin II receptor blockers, 45% received
normal] and ≥35 U/L), and use of statins. A two-sided p-value < .05 beta-blockers, and 22% received diuretics. There was no significant dif-
was considered to be statistically significant. All statistical anal- ference in baseline systolic (155.3 vs 157.4 mmHg; STD = 0.08) and
yses were performed using SAS version 9.4 (SAS Institute, Cary, diastolic BP (84.8 vs 85.8 mmHg; STD = 0.06) and heart rates (80.5 vs
NC, USA). 79.9 beats per minute; STD = 0.04) between the two groups.
626 TUNG ET AL .

(STD = 0.38). After propensity score matching, all covariates were bal-
anced between the two groups (Table 1).

3.2 Office BP

As shown in Figure 2, there was no significant difference between

the generic and the brand-name nifedipine regarding the changes in
office BP measurements throughout clinical follow-up (p for inter-
action = .791 for SBP and .689 for DBP). At a mean follow-up of
3 years, the mean SBP was 140.9 mmHg in the generic group and
141.4 mmHg in the brand-name group (p = .748), and the mean DBP
was 85.3 mmHg in the generic group and 85.0 mmHg in the brand-
name group (p = .939). The mean reduction in SBP from baseline
was 12.5 mmHg in the generic group and 14.8 mmHg in the brand-
name group (p = .281); the mean reduction in DBP from baseline was
7.5 mmHg in the generic group and 7.1 mmHg in the brand-name
group (p = .734). The mean number of additional antihypertensive
drugs administered per patient was comparable at the end of follow-up
(1.33 vs 1.33; p = .938). The percentages of patients who achieved the
conventional target BP of < 140/90 mmHg were 45.2% and 48.4% in
the generic and the brand-name groups, respectively (p = .349), while
the numbers decreased to 23.6% and 27.7%, respectively, when the
intensive target BP of < 130/80 mmHg was applied (p = .169).

F I G U R E 2 Changes in the office systolic (A) and diastolic (B)

blood pressure measurements at the long-term follow-up visits 3.3 Clinical outcomes

Table 2 shows the results of the primary outcome and its compo-
In addition, the generic group was more frequently prescribed
nents after propensity score matching. At a mean follow-up of 3 years,
insulin (9.8% vs 7.1%; STD = 0.1), and the brand-name group was more
the primary outcome occurred in 15.6% of the generic group and in
frequently prescribed antiplatelet agents (27.7% vs 32.8%, STD = 0.11)
17.1% of the brand-name group (hazard ratio [HR] 0.98; 95% confi-
due to a higher prevalence of CAD. No significant difference between
dence interval [CI] 0.85–1.13). The cumulative event rates for the pri-
the two groups was observed in terms of the use of other antidiabetic
mary outcome are shown in Figure 3. There was no significant differ-
drugs, statins or other lipid-lowering agents, vital signs, or laboratory
ence between the two groups with respect to all-cause death (6.9% vs
data, except that eGFR was markedly lower in the generic group (60.4 ±
6.2%; HR 1.22; 95% CI 0.97–1.54), MI (1.9% vs 2.3%; subdistribution
36.3 vs 65.4 ± 34.6 mL/min/1.73 m2 ; STD = 0.14) due to a higher preva-
HR [SHR] 0.87; 95% CI 0.58–1.32), stroke (4.4% vs 4.8%; SHR 0.97;
lence of chronic kidney disease. The follow-up period was 3.0 ± 2.3
95% CI 0.73–1.28), HF hospitalization (4.5% vs 5.9%; SHR 0.81; 95%
years in the generic group and 3.8 ± 2.3 years in the brand-name group

TA B L E 2 Clinical outcomes of the patients prescribed with the generic and the brand-name nifedipine in the propensity-score-matched cohort

Generic Brand-name HR/SHR (95% CI)

Outcome (no. = 2102) (no. = 2102) for Generic p
Coronary intervention 67 (3.2) 75 (3.6) 0.96 (0.69–1.33) .785
Acute myocardial infarction 40 (1.9) 49 (2.3) 0.87 (0.58–1.32) .523
Stroke 92 (4.4) 101 (4.8) 0.97 (0.73–1.28) .828
All-cause death 146 (6.9) 130 (6.2) 1.22 (0.97–1.54) .090
Heart failure hospitalization 94 (4.5) 124 (5.9) 0.81 (0.62–1.05) .112
Composite cardiovascular 328 (15.6) 360 (17.1) 0.98 (0.85–1.13) .774
outcome*

Data were presented as frequency (percentage).

*Anyone having a coronary intervention, acute myocardial infarction, stroke, all-cause death, or heart failure hospitalization.
Abbreviations: CI, confidence interval; HR, hazard ratio; SHR, subdistribution hazard ratio.
TUNG ET AL . 627

4 DISCUSSION

This multi-institutional cohort study compared BP-lowering efficacy

and clinical outcomes of hypertensive patients who were treated with
the OROS formulations of either generic or brand-name nifedipine.
The generic nifedipine was comparable to its brand-name counterpart
regarding the reduction in SBP and DBP from baseline, BP control
rates, and the composite outcome of all-cause death, nonfatal MI, non-
fatal stroke, coronary revascularization, and hospitalization for HF.
In this study, comparable BP reduction and control rates associ-
ated with the generic and the brand-name nifedipine suggest “ther-
apeutical equivalence” between these two drugs. This finding is con-
sistent with the results of prior meta-analyses of RCTs comparing
F I G U R E 3 Cumulative event rates of the primary composite
outcome for patients who were prescribed the generic and the generic and brand-name drugs in the treatment of hypertension or
brand-name nifedipine in the propensity-score-matched cohort other cardiovascular diseases.18,19 In the meta-analysis conducted by
Kesselheim and associates, nine subclasses of cardiovascular medica-
tions were analyzed and no evidence of brand-name drug superiority
was observed in a wide spectrum of cardiovascular diseases as com-
pared with their generic counterparts. However, more than half of the
editorials analyzed in their systematic review argued against generic
interchangeability.18 Similarly, the meta-analysis performed by Man-
zoli and associates revealed no significant differences between the
generic and brand-name drugs regarding the combined estimate of effi-
cacy or possible serious adverse events.19 However, more than half
of the trials included in these meta-analyses are bioequivalence stud-
ies, which were conducted in predominantly young and healthy per-
sons with small samples sizes and short duration of follow-up, limit-
ing their generalizability to the real-world management of hyperten-
sion or other cardiovascular diseases. Furthermore, the clinical efficacy
examined in these comparative studies were usually surrogate mark-
ers or soft endpoints and may not be translated to long-term clini-
cal outcomes. In a more recent meta-analysis, Leclerc and associates
revealed that 60% of studies on generic vs. brand-name cardiovascu-
lar drugs revealed no difference between drug types regarding clinical
measures or all-cause hospital visits, while 26% concluded the brand-
name drug to be more effective or safe, 13% were inconclusive, and
only 1% showed that generics did better.20 In this study, generic drugs
were associated with a moderate increase in the crude risk ratio (RR)
for all-cause hospital visits (RR 1.14; 95% CI 1.06–1.23) but a compara-
ble risk for cardiovascular hospital visits (RR 1.05; 95% CI 0.98–1.14).
F I G U R E 4 Subgroup analyses of the primary composite outcome However, the enrolled studies were too heterogeneous to draw firm
in the propensity-score-matched cohort. Abbreviations: ALT, alanine
conclusions from the results and a comparison of “hard” endpoints was
aminotransferase; BMI, body mass index; CCI, the Charlson
not available in this study.
Comorbidity Index; CI, confidence interval; DBP, diastolic blood
pressure; eGFR, estimated glomerular filtration rate; HR, hazard ratio; In the present study, the rates of composite clinical outcomes were
SBP, systolic blood pressure comparable between the generic and the brand-name nifedipine at a
mean follow-up of 3 years. Although there was a tendency toward
a higher risk of death in the generic group, this finding could be
CI 0.62–1.05), or coronary revascularization (3.2% vs 3.6%; SHR 0.96; play of chance, since the absolute risk difference was small (0.7%)
95% CI 0.69–1.33). Figure 4 illustrates the results of subgroup analysis and the BP-lowering efficacy and the risks of other cardiovascular
for the primary composite outcome. Consistent with the main analysis, events were comparable between the two groups. In our prior study
the generic and brand-name nifedipine had comparable effects on the using the National Health Insurance Research Database (NHIRD) of
primary outcome across all subgroups stratified by the baseline char- Taiwan, the risk of major adverse cardiovascular events, a compos-
acteristics. ite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary
628 TUNG ET AL .

revascularization, and heart failure hospitalization, had not differed Despite the standardized protocol for BP measurement, patients may
significantly between the two drugs at a mean follow-up of 4.1 years.21 not always take a 5-minute sitting rest in a busy hospital setting, and
The NHIRD study did not observe significant difference in the risk three consecutive BP readings may not be taken for averaging all
of all-cause death (7.2% vs 7.1%; p = .597). However, the NHIRD the measurements. Apart from the potential technical errors, office
does not contain BP records, laboratory test results, or clinically rel- BP is known to be subject to a random error influencing casual BP
evant demographic data, such as body mass index and smoking history, readings and a systematic error associated with the “white coat effect.
that may have an impact on cardiovascular outcomes. Complemen- 29 ” How these factors may have affected the comparative BP results
tary to our prior work, the present study took into account baseline is unknown. The clinical outcomes were simply extracted from the
BP, lipid profiles, and blood glucose levels as well as other important CGRD and were not validated independently. For a patient who had
demographic factors to mitigate potential confounders in the propen- a clinical event but had not received management at CGMH, the
sity score method. More importantly, the comparable BP reduction event rates could have been underestimated. The study results were
between generic and brand-name drugs supports our conclusion that derived from a single research database containing information from
the generic nifedipine was comparable to its brand-name counter- only 6% of the population in Taiwan and may not be representative
part for the prevention of cardiovascular events. It has recently been of hypertension management in Taiwan. We did not analyze common
shown that machine learning methods can potentially have better abil- side effects associated with CCBs or other antihypertensive treat-
ity than traditional statistics models to detect predictors of adverse ments, such as edema, constipation, or hypotension, since physicians
events associated with cardiovascular medications.22 Although our may not always register these side effects in their daily practice.
two database analyses may provide real-world evidence for “clinical Although the study results supported therapeutic and clinical equiv-
equivalence” between the generic and the brand-name nifedipine, fur- alence between the generic and the brand-name nifedipine OROS,
ther studies using machine learning may help investigate differences the results are hypothesis-generating and could not be generalized
between generic and brand-name medications in the future. to other formulations of nifedipine or different antihypertensive
BP control rates remained suboptimal in our study cohort. Less drugs.
than half of the study patients achieved the traditional target
of < 140/90 mmHg at the end of follow-up. When the 2017 American
College of Cardiology/American Heart Association BP guidelines were 6 CONCLUSIONS
applied, only approximately a quarter of them achieved the more strin-
gent BP target (below 130/80 mmHg).23 The reasons for inadequate In this multi-institutional cohort study, the generic nifedipine was com-
BP control are multifactorial. In a developed health care setting, ther- parable to its brand-name counterpart regarding BP-lowering efficacy
apeutic inertia and medication adherence have been considered major and clinical outcomes at long-term follow-up.
impediments to achieving BP goals.24,25 Although we were not able to
identify the reasons behind poor BP control in our cohort, the reluc- ACKNOWLEDGEMENTS
tance of physicians or patients to intensify their antihypertensive reg- The authors would like to thank Alfred Hsing-Fen Lin, MS, of Raising
imens may be attributable to a high comorbid burden, the numbers of Statistics Consultants Inc., for his statistical assistance. Mr. Lin received
antihypertensive and other concomitant medications, and closeness to compensation and declared no competing interests between the find-
the target BP of 140/90 mmHg at follow-up.26–28 Nevertheless, the ings of this study and his company.
BP-lowering efficacy of the generic and the brand-name nifedipine was
similar and was above that of a standard dose of a single antihyperten-
CONFLICT OF INTEREST
sive drug (10/5 mmHg) due to a relatively high BP level at baseline.
None.

ORCID
5 STUDY LIMITATIONS
Ying-Chang Tung MD https://orcid.org/0000-0002-8557-1472
Chia-Pin Lin MD https://orcid.org/0000-0001-7959-7804
The strength of this study is its long-term follow-up for office BP
Pao-Hsien Chu MD https://orcid.org/0000-0003-0361-6348
measurements and clinical outcomes, as well as the large sample size
for specific comparison between a generic antihypertensive drug and
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