Comparative efficacy of generic nifedipine versus brand‐name amlodipine for hypertension management in Taiwan

Abstract The control rate of hypertension remains concerning, indicating the requirement for better management strategies. The calcium channel blockers brand‐name amlodipine and nifedipine with extended‐release formulations demonstrate similar clinical efficacy. However, the efficacy of generic nifedipine remains obscure. We compared the efficacy of generic nifedipine and brand‐name amlodipine in terms of cardiovascular (CV) outcomes. Patients prescribed generic nifedipine (SRFC CYH) or brand‐name amlodipine besylate (Norvasc, Pfizer) between August 1, 2017, and July 31, 2018, were enrolled; patients with CV events within 3 months were excluded. CV outcomes included CV death, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, hospitalization for heart failure, and composite endpoints of 3P‐ and 4P‐major adverse cardiac events (MACE). A total of 1625 patients treated with nifedipine (SRFC CYH) and 16 587 patients treated with Norvasc were included. After propensity score matching, there were 995 and 4975 patients in the nifedipine CYH and Norvasc groups, respectively. At a mean follow‐up period of 30.3 ± 6.4 months, nifedipine CYH was comparable to Norvasc in terms of CV death (P = .107), nonfatal MI (P = .121), nonfatal ischemic stroke (P = .453), hospitalization for heart failure (P = .330), 3P‐MACE (P = .584), and 4P‐MACE (P = .274). Cox regression analysis revealed that nifedipine CYH and Norvasc had similar efficacy in terms of 3P‐MACE (hazard ratio, 0.970; 95% confidence interval, 0.601–1.565, P = .900) and 4P‐MACE (hazard ratio, 0.880; 95% confidence interval, 0.628–1.233, P = .459). In conclusion, Nifedipine SRFC CYH and Norvasc have comparable clinical efficacy for hypertension management.


INTRODUCTION
Hypertension is one of the most predominant risk factors for cardiovascular (CV) diseases and is a global public health challenge. 1,2 Despite improvements in the awareness, treatment, and control of hypertension in the past few years, the control rate of hypertension is concerning, 3,4 implying that more efficient antihypertensive strategies are required.
Both nifedipine and amlodipine are widely used dihydropyridine calcium-channel blockers (CCBs) for hypertension management. [5][6][7][8] The development of extended-release formulations improved the safety profile of the original short-acting nifedipine. 9,10 Fiscal outcomes compared with both the gastrointestinal therapeutic system (GITS) and the osmotic-controlled release oral delivery system (OROS) of nifedipine use osmotic pressure as the driving force to deliver drugs through laser-drilled holes, providing stable drug concentrations, uniform drug effect, and reduced dosing frequency. 11,12 Furthermore, with regard to clinical efficacy, application of extended-release formulations of nifedipine demonstrated similar blood pressure (BP)lowering effects as long-acting amlodipine. 13,14 In contrast, because of their lower costs compared to their brandname counterparts, generic drugs are commonly used in the health care system globally. Over the past decade, about 90% of prescribed medications in the United States were generics, which only accounted for 26% of drug expenditure, saving approximately $1.7 trillion dollars. 15 Generic drugs have the same active chemical ingredients as brand-name products; however, whether the pharmaceutical equivalence and bioequivalence between both of them translate to evenly matched clinical outcomes remain unclear.
In 2018, owing to the decrease in the drug production capacity of the parent manufacturing company, the import of the brand-name nifedipine (Adalat OROS, Bayer) to Taiwan was greatly impacted, and the supply chain was not completely restored until 2021. Owing to the shortage of Adalat, generic nifedipine was used as an alternative. However, the clinical efficacy of generic nifedipine remains unknown. Recently, a nationwide study in Taiwan revealed comparable clinical outcomes between generic nifedipine and its brand-name counterpart. 16 In this study, we aimed to compare the efficacy of a generic nifedipine with brand-name amlodipine in terms of CV outcomes.

Study participants
The study was conducted in the outpatient clinics of Taipei

Study design
The flowchart of the study is presented in Figure 1. This was a retrospective study. All the data were collected from the Taipei Veter-

Clinical outcomes
The index date was defined as the date of any event or the date of last follow up.

Statistical analyses
The characteristics of the participants were summarized using descrip- in the nifedipine CYH group were then matched with those in the control group at a 1:5 ratio using the propensity-matching algorithm.
Parametric continuous data between hypertensive patients in the nifedipine CYH and control groups were compared using the unpaired Student's t-test, and nonparametric data were compared using the Mann-Whitney test.
Survival analysis was performed using the Kaplan-Meier curve, with significance based on the log-rank test. Cox proportional hazards regression analysis was performed. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated after adjusting for the potential confounding factors.

Demographic data of the participants
After propensity matching, 995 hypertensive patients receiving nifedipine CYH and 4975 hypertensive patients receiving Norvasc were selected for the study. A total of 57 patients in the Nifedipine CYH group (5.7%) had ever used Norvasc in the follow-up period, while they did not change the groups. Most of the characteristics were similar between the two groups, while the patients in the nifedipine CYH group used more concomitant antihypertensive agents (P < .001), including ACEI/ARB (P < .001), β-blocker (P < .001), and thiazide diuretics (P < .001) ( Table 2).  (Table 3).

Clinical outcomes of the participants
Kaplan-Meier survival curves and log-rank tests were used to compare the number of patients who did not exhibit any clinical CV event during the follow-up period. The incidences of 3P-MACE (P = .477, Figure 2A) and 4P-MACE (P = .193, Figure 2B)

DISCUSSION
This retrospective study compared the clinical outcomes of hypertensive patients treated with SRFC CYH and those treated with Norvasc.
We found that the efficacy of SRFC CYH was similar to that of Norvasc in terms of CV death, nonfatal MI, nonfatal ischemic stroke, heart failure hospitalization, and composite CV outcomes.

Generic CCB versus brand-name CCB
Earlier studies have suggested that generic antihypertensive medications may be as effective as brand-name drugs for managing BP.
In a systematic review and meta-analysis comprising 47 studies, seven randomized controlled trials (RCTs) focusing on generic and brand-name CCBs used to manage CV diseases were evaluated. The results showed that the BP-lowering effect of generic CCBs was similar to that of brand-name CCBs. 18 Another meta-analysis of 74

Short-acting CCBs with extended-release formulations versus long-acting CCBs
Short-acting CCBs with extended-release formulations have been developed to maintain BP control, as patients using short-acting CCBs may commonly experience uncontrolled hypertension due to suboptimal compliance, especially during the initial stage of treatment. 11,12 Short-acting CCBs with extended-release formulations displayed more uniform and lasting drug effects than the prototype. An RCT using an arterial line for BP monitoring demonstrated that extended-release nifedipine (nifedipine GITS; n = 15) provided a more constant drug concentration than short-acting nifedipine (n = 16; P < .001) and placebo (n = 9). Moreover, extended release of nifedipine led to a persistent decrease in BP over 360 minutes (P = .0028), whereas the BP-lowering effect of short-acting nifedipine only remained significant through the

Short-acting nifedipine with extended-release formulations versus amlodipine
Comparisons were made between the BP-lowering effects of shortacting nifedipine with an extended-release formulation and long-acting CCB, namely, amlodipine. Nonetheless, previous studies evaluated a relatively small number of patients and were conducted solely in clinics and did not conduct ambulatory BP monitoring. 20   or nighttime administration (−9.9 vs −9.9 mmHg, P > .05). 14,25 Thus, short-acting nifedipine with extended-release formulation appeared to demonstrate a BP-lowering effect similar to that of long-acting CCB (amlodipine), despite the fact that when a dose of medication was missed, the latter seemed to be more efficacious. [21][22][23] Given the similar efficacies of the generic and the brand-name antihypertensive medications, and of the extended-release formulations of short-acting CCB and long-acting CCB, we further compared the clinical outcomes of the generic nifedipine SRFC CYH and of the brand-name amlodipine Norvasc, and observed no significant differences.

Study limitations
The present study has some limitations. First, the sample size is relatively small. Further studies with large sample size and longer follow-up period are indicated in the future. Second, the study was conducted at a single medical center in Taiwan. Patients in the medical center might receive better medical care. Due to potential differences between the setting of the institute and that of other institutes and between the health insurance cover of the patients at this institute and those at other institutes and hospitals, further studies are needed to confirm whether the results could be applied on a global scale. Third, we do not have the information about the duration of hypertension in each participant, which might be a possible confounding factor. Fourth, the data on the comorbidities and clinical outcomes of the patients were extracted from the Taipei Veterans General Hospital database. However, there may be a potential risk of ascertainment bias. However, the same methodologies have been applied using the National Health Insurance Research Database in Taiwan, which has been verified in numerous studies. [26][27][28][29][30] Fifth, this study may have been subject to selection bias since the patients who were prescribed nifedipine generally had more comorbidities. Although rigorous propensity score matching was conducted to balance potential differences between the treatment groups, potential selection bias and unmeasured confounding factors may have affected the results. Finally, given the retrospective design of the present study, our results can lay sufficient grounds for the development of a hypothesis, which should then be validated by conducting well-powered RCTs with sufficient follow-up.

CONCLUSION
The generic nifedipine SRFC CYH was comparable to the brand name Norvasc in terms of CV death, nonfatal MI, nonfatal ischemic stroke, heart failure hospitalization, and composite outcomes.

ACKNOWLEDGMENTS
This work was supported by a research grant from Chunghwa Yuming Healthcare Co., Taiwan. The funder had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

CONFLICT OF INTEREST
None.

AUTHOR CONTRIBUTIONS
HWL contributed to conception and design, interpretation of data, and drafted the manuscript. CCH contributed to conception, data acquisition, analysis and interpretation of data, drafted and critically revised the manuscript. HBL contributed to conception and design, data acquisition, and drafted the manuscript. YJL contributed to conception and design, data acquisition, and drafted the manuscript. All authors gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.