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Blood Pressure–Lowering Effect of Fimasartan Versus Comparators: A Cross-Inference With a Systematic Review and Meta-Analysis Through a Quality Management System
Address correspondence to: Hojin Oh, PharmD, Oh Medicine and Methodology Research Institute, Building 105, Suite 702, 36 Seoryeong-ro, Seosan, Chungcheongnam-do, 31982, Republic of Korea.
Oh Medicine and Methodology Research Institute, Seoryeong-ro, Seosan, Chungcheongnam-do, Republic of KoreaChung-Ang Herb Dental Clinic, Seosan, Chungcheongnam-do, Republic of Korea
Fimasartan, one of the newest angiotensin receptor blockers (ARBs) available worldwide, has been investigated extensively since its initial development. Our study group conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating fimasartan and comparators for their blood pressure (BP)-lowering effect. Moreover, we employed a cross-inference (frequentist and Bayesian inference) system, which has never been used in the medical field, to confirm the results of our study. In addition, a quality management system was integrated throughout the study for data quality.
Methods
PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalKey, and ClinicalTrial.gov were searched for RCT studies from March 1998 to March 2022. In each study, the mean differences (MDs) and 95% CIs were identified for reductions in clinic sitting systolic and diastolic BP (SiSBP/SiDBP) or 24-hour mean systolic BP and diastolic BP by ambulatory BP monitoring (ASBP/ADBP) from baseline between the fimasartan and comparator groups, followed by meta-analysis. A subsequent meta-analysis was performed with frequentist and Bayesian inference as a tool in the cross-checking system.
Findings
Eleven RCTs with a total of 2459 subjects were included in the study. The clinic SiSBP/SiDBP–lowering effect of fimasartan was significantly greater relative to those of comparators (MD for clinic SiSBP, −2.58 mm Hg [95% CI, −4.35 to −0.81; P = 0.004]; MD for clinic SiDBP, −2.13 mm Hg [95% CI, −2.96 to −1.30; P = 0.00001]). The ASBP/ADBP–lowering effect of fimasartan was also significantly greater relative to those of comparators (MD for ASBP, −3.58 mm Hg [95% CI, −5.74 to −1.43; P = 0.001]; MD for ADBP, −1.99 mm Hg [95% CI, −3.34 to −0.63; P = 0.004]).
Implications
Fimasartan seems to be more effective in lowering BP than its comparators, including other ARBs. Although there is a limited amount of data and a minuscule number of study subjects available, the results of cross-inference (frequentist + Bayesian) were fairly consistent with the meta-analysis results through our quality management system.
In 2010, the Republic of Korea licensed a new antihypertensive drug called fimasartan, which became available on the market in 2011. It is one of the newest angiotensin receptor blockers (ARBs) available worldwide. In fimasartan, a pyrimidine ring replaces the existing losartan imidazole ring, and its AT1-selective binding is superior to that of other ARB preparations.
Synthesis and antihypertensive activity of pyrimidin-4(3H)-one derivatives as losartan analogue for new angiotensin II receptor type 1 (AT1) antagonists.
Safety, tolerability, pharmacokinetics, and pharmacodynamics of fimasartan following single and repeated oral administration in the fasted and fed states in healthy subjects.
Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension.
Since the late 2000s, several randomized controlled trials (RCTs) have compared BP-lowering effects between fimasartan and other related compounds. The RCTs were based on the change in clinic sitting systolic BP/diastolic BP (SiSBP/SiDBP) as well as 24-hour mean BP by ambulatory BP monitoring. For in-clinic SiSBP/SiDBP evaluation, fimasartan (at a concentration of 60 mg/120 mg) and losartan (at a concentration of 50 mg/100 mg) were administered at an optional dose escalation, and the outcomes were measured at 4, 8, and 12 weeks. The results for fimasartan were comparable to those of losartan at 12 weeks. In the post hoc comparison, the 2 groups had significantly different SiDBP, in favor of fimasartan.
Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, phase III, multicenter, prospective, randomized, double-blind, parallel-group, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension.
In another trial, 30 mg of low-dose fimasartan and 80 mg of valsartan were compared. At 4 and 8 weeks, fimasartan was superior to valsartan in lowering SiSBP/SiDBP.
Safety, tolerability, pharmacokinetics, and pharmacodynamics of fimasartan following single and repeated oral administration in the fasted and fed states in healthy subjects.
Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension.
Efficacy and safety of 30-mg fimasartan for the treatment of patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, Phase III clinical study.
A randomized, double-blind, candesartan-controlled, parallel group comparison clinical trial to evaluate the antihypertensive efficacy and safety of fimasartan in patients with mild to moderate essential hypertension.
Regarding ambulatory BP monitoring, 60 and 120 mg of fimasartan and 80 mg of valsartan were compared at a 1:1:1 ratio, wherein fimasartan was slightly better than or comparable to valsartan.
Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension.
Meanwhile, a 2020 study compared 120 mg of high-dose fimasartan and 160 mg of valsartan; in both SiSBP/SiDBP and 24-hour ambulatory systolic BP and diastolic BP (ASBP/ADBP), fimasartan was superior. However, a comparison of fimasartan with 20 mg of the reference drug olmesartan indicated that they were comparable.
Effect of fimasartan versus valsartan and olmesartan on office and ambulatory blood pressure in Korean patients with mild-to-moderate essential hypertension: a randomized, double-blind, active control, three-parallel group, forced titration, multicenter, phase IV study (Fimasartan Achieving Systolic Blood Pressure Target (FAST) Study).
As mentioned, numerous RCTs have reported the BP-lowering effect of fimasartan and its comparability or superiority to other antihypertensive drugs. However, network or extended meta-analyses have only analyzed fimasartan and comparators indirectly.
Systematic review with network meta-analysis: comparative efficacy and safety of combination therapy with angiotensin II receptor blockers and amlodipine in Asian hypertensive patients.
A direct comparison through systematic review and meta-analysis of RCTs assessing fimasartan and comparators regarding efficacy has not yet been reported. Thus, the goal of the present study was to collect RCTs of fimasartan and comparators, examine their BP-lowering effects, perform a systematic review and meta-analysis, and report the differences in efficacy.
Efficacy and safety of 30-mg fimasartan for the treatment of patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, Phase III clinical study.
Moreover, these results were verified through novel cross-inference (frequentist + Bayesian inference) for the first time, and our quality management system to maintain data quality was introduced.
Materials and Methods
This study conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.
Also, this study was analyzed for New Drug Application level clinical trials submitted to the Ministry of Food and Drug Safety or clinical trials registered in ClinicalTrials.gov. The 2000 Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram of the present study is depicted in Fig. 2.
Figure 1Diagram of study selection flow. PK/PD = pharmacokinetic/pharmacodynamic; RCTs = randomized controlled trials.
The careful design of the protocol development, database search, data extraction, individual RCT quality assessment, data management, and statistical analysis processes was critical for minimizing bias and maintaining the quality of the present systematic review and meta-analysis. The functional responsibilities for the confirmation of each step and the entire study procedure of the quality management system model are depicted in Figure 2.
The protocol development stage of our quality management system for systematic review was divided into 2 main stages. The first was the concept protocol phase, followed by the formal protocol development phase. The first step in designing a clinical trial is the development of a concept protocol to describe the basic details of our research; a concept protocol mainly contains an overall outline that includes the study design, disease state, potential subjects, and inclusion/exclusion criteria. The concept protocol was required to be initially reviewed by the responsible personnel such as the project leader and independent reviewer 1. Following the concept protocol's review, we determined that the concept is possible. Afterward, we gathered more research personnel, such as independent reviewers 2 and 3. Following the review of the concept protocol, the writing of the formal protocol began, and the formal protocol was analyzed in a final approval process. The formal protocol development phase was conducted based on the protocol criteria and Cochrane RCT data collection form, and the person in charge participated. Plans that were based on the protocol, such as the data management plan and statistical analysis plan, were also created in the formal protocol development phase.
From the formal protocol to the final stage of the protocol development phase, the 3 independent reviewers and project leader continued to discuss and change the protocol amendments as needed. Each study plan within the protocol was also concomitantly discussed and changed until the final protocol was approved. If the major plans needed to be changed after the protocol/plans were created and the analyses commenced, they were changed according to the criteria of the mitigation/deviation plan prepared during the protocol development stage. However, there was no major change or deviation after the analyses commenced in our research.
Database Search
We searched for data from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalKey, and ClinicalTrials.gov, retrieving all fimasartan RCTs published between March 1998 and March 2022. A literature search was initiated by 2 independent reviewers, and the results were finalized and approved by the project leader. The primary search strategy was discussed at the initiation meeting. Also discussed were any intermediate changes and minor deviations at interim meetings according to the guidelines within the mitigation plan; these were approved at the final meeting.
The main key words used were “Hypertension” and “fimasartan” or “Kanarb” or “BR-A-657” or “fimasartan and randomized” or “fimasartan and randomization” or “fimasartan and placebo” or “fimasartan and angiotensin receptor blocker” or “fimasartan and comparator” or “fimasartan and SiSBP/SiDBP” or “fimasartan and ASBP/ADBP” or “efficacy of fimasartan” or “BP-lowering effect of fimasartan.” We used “clinical trial” or “controlled clinical trial” or “randomized control trial” to limit or filter the search. The Cochrane RCT data collection form was then completed by our research team according to the search strategy and inclusion/exclusion criteria set forth in the study protocol. Next, full-text, reference, and detailed reviews of the selected RCTs were conducted. In case of a disagreement between the 2 independent reviewers during the search and review process, the final decision was made via consultation with the project leader.
Data Extraction
The information for data extraction and study classification was as follows: (1) the general characteristics of the study (design, country, sample size, publication year, funding, and conflict of interest); (2) the target population and setting; (3) the study method; (4) the outcomes measured; (5) the results and findings; (6) the limitations and mitigation plan; and (7) the conclusion from the Cochrane RCT data collection form.
The inclusion criteria were as follows: (1) the study was an RCT; (2) the study included patients with essential hypertension or explored a cardiovascular event focusing on patients with hypertension or a history of hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg)
2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
; (3) the study compared fimasartan versus antihypertensive comparator monotherapy; (4) the study duration was at least >4 weeks; (5) the study had clinic SiSBP/SiDBP or ASBP/ADBP as outcomes; and (6) the study results were publicly available as outcomes.
The exclusion criteria were as follows: (1) observational studies, review, animal studies, in vitro, cell level, and molecular studies of fimasartan; (2) pharmacokinetic (PK) and pharmacodynamic studies of fimasartan; (3) the study compared fimasartan versus placebo; (4) the study compared fimasartan versus dual antihypertensive medication; (5) the study compared fimasartan versus an antihypertensive/statin combination; and (6) the study result was not reported or was an ongoing study.
A discussion was held among the 3 independent reviewers, 2 independent statisticians, and the project leader to review the study protocol and search strategy prepared during the study initiation meeting. Subsequently, the 2 independent reviewers were assigned the task of selecting studies from the corresponding medical search engines, performing the data extraction and study classification, and completing the Cochrane RCT data collection form according to the inclusion/exclusion criteria. The primary search was performed to select studies, and a subsequent decision was made by the 2 independent reviewers, 2 independent statisticians, and the project leader during the final meeting. After this meeting, the full text and references of the selected studies were reviewed, details were extracted, and a quality assessment (Cochrane Collaboration risk of bias tool + modified Jadad score) of the final selected studies was performed. Any alterations were managed during on-demand meetings.
Quality Assessment
For the RCTs that were ultimately selected during the data extraction process, 2 independent reviewers performed a quality assessment. The risk of bias for each RCT was evaluated according to the Cochrane Collaboration risk of bias tool.
The tool evaluates random sequence generation, allocation concealment, the blinding of participants and personnel, the blinding of outcome assessments, the analysis of incomplete outcome data, selective reporting, and other biases. Two independent reviewers evaluated each item as “yes” or “no” for a low risk of bias or high risk of bias, respectively. If the 2 reviewers’ opinions differed and disputes remained unresolved in terms of the information found, the item in question was rated as “unclear.” The rating was finalized after a discussion with the project leader. The modified Jadad score was used to determine the intrarater validity between the studies.
Regarding the quality assessment process, after an initial assessment was made by each independent reviewer, any discrepancy was resolved through consultation with the project leader in an on-demand meeting.
Data Management
The first step of data management was writing the data management plan, which involved the overall study aspects, including the study structure, data validation process, data entry, database import/export, and database locking/unlocking. The study structure was created in Excel (Microsoft Corporation, Redmond, WA, USA) based on the Cochrane RCT data collection form. The structure consisted of information on the study characteristics, participant demographic characteristics, ethnicity, withdrawals, intervention/control groups, and outcomes of the included RCTs. Subsequently, data validation was performed to ensure data completeness, consistency, and accuracy within the structure of the Cochrane RCT data collection form. The validation test was performed by independent reviewer 1 to ensure that if the validation results were out of the data range in the structure, it would be possible to correct the query once the dummy data were input manually. Next, double entry was manually performed by 2 independent reviewers. The first and second reviewers independently entered the data into the Excel spreadsheet software from the Cochrane RCT data collection form. The data set was then checked for any discrepancies using the Excel function. The database was locked once all expected data were accounted for and all data management activities were completed. If any data change was required, the data were modified with the approval of the project leader; approval was also obtained from each reviewer to unlock the data set, and the data set was again locked. The final data lock confirmation was performed by the project leader, following which the data were read only. Following this, a second independent reviewer performed quality checks to ensure the correctness and completeness of the data according to the transfer specification. Finally, the same data set was transferred to 2 independent statisticians for statistical analysis.
Statistical Analysis
Two independent statisticians performed the meta-analysis and cross-inference of the summary statistics of the RCTs that were finally selected. One statistician performed the analysis using Review Manager software version 5.4 (Nordic Cochrane Center, Copenhagen, Denmark) + Meta package in R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria); the other statistician performed the analysis using Comprehensive Meta-Analysis software version 3.3 (Biostat, Englewood, NJ, USA) + Meta package in R version 3.6.1. Any discrepancies or deviations were discussed during the interim data meeting regarding the progress of the research that was held with the project leader and the statisticians. Subsequently, the results of the meta-analysis were confirmed at a final data meeting. Quality checks were continually implemented for minor changes and deviations by 2 independent statisticians and were confirmed by the project leader.
To compare the BP-lowering effect of fimasartan and the comparator in each RCT study, the mean differences (MDs) Table I and 95% CIs of the final SBP/DBP were calculated relative to baseline. The missing SD was imputed via the method specified in the Cochrane Handbook for Systematic Reviews of Interventions. The effect of fimasartan on the pooled estimate was assessed by comparing 30, 60, and 120 mg of fimasartan with individual comparators. Statistical significance was set at P < 0.05. Cochran's Q and I2 statistics were calculated and used to evaluate the statistical heterogeneity of each selected study. The heterogeneity of studies according to the I2 statistics was categorized as follows: low (0%–40%), moderate (30%–60%), substantial (50%–90%), and considerable (75%–100%). Clinical heterogeneity (methodologic and clinical diversity) was also evaluated based on each trial's characteristics, such as study design, study duration, study population, the risk of bias, interventions, and outcome assessments.
The selection of random- or fixed-effect models was made based on the clinical and statistical heterogeneity. In other words, although the Cochran's Q and I2 statistics can be used to categorize statistical heterogeneity, our research is in the medical field. Therefore, variation in both the clinical heterogeneity and statistical heterogeneity among the analyzed studies in our research was considered in the choice of whether to use either a random- or fixed-effect model. We excluded individual trials that were heterogeneous in research design, method, and patient selection using sensitivity analyses. Then, the pooled MDs, including those of the remaining studies, were recalculated into the pooled estimate, and each study's contribution was reevaluated.
A funnel plot was used to graphically evaluate publication bias. For mathematical evaluation, we used a linear regression test according to the method suggested by Egger et al.
To validate our meta-analysis results, frequentist inference was used to predict the likelihood mean in SiSBP, SiDBP, ASBP, and ADBP of fimasartan. The mean was estimated by using the maximum likelihood estimator method, and the likelihoodAsy version 0.51 package in R was used to generate plot.
Bayesian inference was used to predict the posterior mean in SiSBP, SiDBP, ASBP, and ADBP of fimasartan. Prior information and existing data (likelihood) were defined in the data from previous studies and the last study, respectively. The Shiny and ggsci packages (BRMS or Bayesian Meta) in R version 3.4.1 were used to generate the plot.
Among the 4282 initially retrieved studies, 346 studies were screened after duplicates were removed; 220 underwent a full-text review, of which 209 were excluded because they did not meet the inclusion criteria. Ultimately, 11 RCTs were selected. Figure 1 depicts the study selection flow. From the 11 RCTs of fimasartan versus monotherapy comparator, 7, 1, and 3 studies were conducted in patients with essential hypertension, patients with arterial hypertension, and patients with cardiovascular events (1 with acute coronary syndrome [ACS] and 2 with stroke) as well as hypertension or history of hypertension, respectively. Antihypertensive drugs used as comparators of fimasartan were losartan, valsartan, amlodipine, candesartan, atenolol, and olmesartan. Among these, the amlodipine comparative study was a 3 × 3 factorial design RCT, and only fimasartan versus monotherapy data were extracted.
A randomized, multicenter, double-blind, placebo-controlled, 3 × 3 factorial design, Phase III study to evaluate the efficacy and safety of the combination of fimasartan/amlodipine in patients with essential hypertension.
R-Pharm. Efficacy and safety evaluating study to compare Knarb (fimasartan) and Cozaar (losartan) in adult patients with grade I-II arterial hypertension. 2020 [cited 2021 September 23]. ClinicalTrials.gov. U.S. National Library of Medicine [Internet]. Available from: http://clinicaltrials.gov/show/NCT02248961.
All 11 RCTs were conducted in 114 clinical research hospitals. Of the 2459 extracted subjects, 272 were excluded due to dropout and withdrawal. The mean age of the included subjects was 56.4 years, and 72.4% of them were male. Table I summarizes the study characteristics with a Population, Intervention, Comparison, Outcomes, and Study design, and Table II presents the subject demographic characteristics of each RCT.
Table IStudy characteristics for 11 selected randomized controlled trials (RCTs) with Population, Intervention, Comparison, Outcomes, and Study design.
Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, phase III, multicenter, prospective, randomized, double-blind, parallel-group, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension.
Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension.
Efficacy and safety of 30-mg fimasartan for the treatment of patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, Phase III clinical study.
A randomized, multicenter, double-blind, placebo-controlled, 3 × 3 factorial design, Phase III study to evaluate the efficacy and safety of the combination of fimasartan/amlodipine in patients with essential hypertension.
A randomized, double-blind, candesartan-controlled, parallel group comparison clinical trial to evaluate the antihypertensive efficacy and safety of fimasartan in patients with mild to moderate essential hypertension.
R-Pharm. Efficacy and safety evaluating study to compare Knarb (fimasartan) and Cozaar (losartan) in adult patients with grade I-II arterial hypertension. 2020 [cited 2021 September 23]. ClinicalTrials.gov. U.S. National Library of Medicine [Internet]. Available from: http://clinicaltrials.gov/show/NCT02248961.
Effect of fimasartan versus valsartan and olmesartan on office and ambulatory blood pressure in Korean patients with mild-to-moderate essential hypertension: a randomized, double-blind, active control, three-parallel group, forced titration, multicenter, phase IV study (Fimasartan Achieving Systolic Blood Pressure Target (FAST) Study).
Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, phase III, multicenter, prospective, randomized, double-blind, parallel-group, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension.
Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension.
Efficacy and safety of 30-mg fimasartan for the treatment of patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, Phase III clinical study.
A randomized, multicenter, double-blind, placebo-controlled, 3 × 3 factorial design, Phase III study to evaluate the efficacy and safety of the combination of fimasartan/amlodipine in patients with essential hypertension.
A randomized, double-blind, candesartan-controlled, parallel group comparison clinical trial to evaluate the antihypertensive efficacy and safety of fimasartan in patients with mild to moderate essential hypertension.
R-Pharm. Efficacy and safety evaluating study to compare Knarb (fimasartan) and Cozaar (losartan) in adult patients with grade I-II arterial hypertension. 2020 [cited 2021 September 23]. ClinicalTrials.gov. U.S. National Library of Medicine [Internet]. Available from: http://clinicaltrials.gov/show/NCT02248961.
Effect of fimasartan versus valsartan and olmesartan on office and ambulatory blood pressure in Korean patients with mild-to-moderate essential hypertension: a randomized, double-blind, active control, three-parallel group, forced titration, multicenter, phase IV study (Fimasartan Achieving Systolic Blood Pressure Target (FAST) Study).
All 11 clinical trials were RCTs. The randomization procedure was performed by using an Interactive Voice/Web Response System or sealed envelope. Of 11 trials, 2 studies (NCT0224896124 and Oh et al
) were open-label, and the other studies were double-blind. Each trial was depicted appropriately for the subjects’ dropout or withdrawal rates. Each clinical study report or final result was properly reported to the authority (Ministry of Food and Drug Safety) or the Institutional Review Board, including the outcome measurement. Other uncertain biases were rated as question marks. Figure 3 presents the risk of bias using the Cochrane Collaboration tool + the modified Jadad scores.
Figure 3Quality assessment of the risk of bias of 11 randomized controlled trials (Cochrane +Jadad score).
These 11 prospective RCT studies comparing fimasartan and comparators underwent meta-analysis. Figures 4 and 5 illustrate the forest plots for the meta-analysis with cross-inference of clinic SiSBP and clinic SiDBP, respectively. Figures 6 and 7 illustrate the forest plots for the meta-analysis with cross-inference of ASBP and ADBP.
Figure 4Forest plot of fimasartan and comparators with cross-inference for clinic sitting systolic blood pressure. AMD = Amlodipine; ATL = Atenolol; CAN = candesartan; LOS = losartan; OLM = olmesartan; VAL = valsartan.
Figure 5Forest plot of fimasartan and comparators with cross-inference for clinic sitting diastolic blood pressure. CAN = candesartan; LOS = losartan; OLM = olmesartan; VAL = valsartan.
Figure 6Forest plot of fimasartan and comparators with cross-inference for 24-hour mean ambulatory systolic blood pressure. OLM = olmesartan; VAL = valsartan.
Figure 7Forest plot of fimasartan and comparators with cross-inference for 24-hour mean ambulatory diastolic blood pressure. OLM = olmesartan; VAL = valsartan.
In the clinic SiSBP, the effect size overall was −2.58 mm Hg (95% CI, −4.35 to −0.81; heterogeneity, Q = 33.93; I2 = 55.7%), with a statistically significant improvement in the effect of fimasartan. According to the dose, the effect size was −0.49 mm Hg at 30 mg (95% CI, −9.56 to 8.57), −2.61 mm Hg at 60 mg (95% CI, −4.53 to −0.68), and −3.79 mm Hg at 120 mg (95% CI, −5.88 to −1.71); thus, there was significantly improved effectiveness at 60 and 120 mg. Regarding frequentist inference, the likelihood mean (SD) was −0.45 (3.57) mm Hg at 30 mg, −2.43 (0.87) mm Hg at 60 mg, and −3.89 (1.41) mm Hg at 120 mg. Regarding Bayesian inference, the posterior mean was −1.55 mm Hg at 30 mg (95% CI, −3.66 to 0.55), −2.74 mm Hg at 60 mg (95% CI, −3.79 to −1.69), and −4.99 mm Hg at 120 mg (95% CI, −6.52 to −3.47). Thus, the mean of cross-inferences was fairly consistent with the meta-analysis results and suggest that fimasartan seemed to be more effective than comparators, especially at 60 and 120 mg.
In the clinic SiDBP, the effect size overall was −2.13 mm Hg (95% CI, −2.96 to −1.30; heterogeneity, Q = 18.47; I2 = 24.2%), with statistically significant improvement in the effect of fimasartan. According to the dose, the effect size was −2.38 mm Hg at 30 mg (95% CI, −5.78 to 1.01), −2.03 mm Hg at 60 mg (95% CI, −3.08 to −0.98), and −2.03 mm Hg at 120 mg (95% CI, −3.39 to −0.67); thus, there was significantly improved effectiveness at 60 and 120 mg. Regarding frequentist inference, the likelihood mean (SD) was −2.39 (1.28) mm Hg at 30 mg, −1.59 (0.50) mm Hg at 60 mg, and −1.92 (0.11) mm Hg at 120 mg. Regarding Bayesian inference, the posterior mean was −2.60 mm Hg at 30 mg (95% CI, −3.79 to −1.41), −2.13 mm Hg at 60 mg (95% CI, −2.76 to −1.50), and −1.97 mm Hg at 120 mg (95% CI, −2.95 to −0.99). Thus, the mean of cross-inferences was fairly consistent with the meta-analysis results and suggest that fimasartan seemed to be more effective than comparators at 30, 60, and 120 mg.
In the ASBP, the effect size overall was −3.58 (95% CI, −5.74 to −1.43; heterogeneity, Q = 3.25; I2 = 0.0%), with a statistically significant improvement in the effect of fimasartan. According to the dose, the effect size was −5.00 mm Hg at 30 mg (95% CI, −11.10 to 1.10), −3.53 mm Hg at 60 mg (95% CI, −8.38 to 1.32), and −3.10 mm Hg at 120 mg (95% CI, −6.36 to −0.16); hence, there was significantly improved effectiveness at 120 mg. Regarding frequentist inference, the likelihood mean (SD) was −3.45 (0.10) mm Hg at 60 mg and −3.45 (0.04) mm Hg at 120 mg. Regarding Bayesian inference, the posterior mean was −3.56 mm Hg at 60 mg (95% CI, −6.86 to −0.26) and −1.82 mm Hg at 120 mg (95% CI, −3.44 to −0.19). Thus, the mean of cross-inferences was fairly consistent with the meta-analysis results and suggest that fimasartan seemed to be more effective than comparators at 60 and 120 mg.
In the ADBP, the effect size overall was −1.99 (95% CI, −3.34 to −0.63; heterogeneity, Q = 2.05; I2 = 0.0%), with a significantly improved effect of fimasartan. According to the dose, the effect size was −0.90 at 30 mg (95% CI, −4.41 to 2.61), −2.69 at 60 mg (95% CI, −5.89 to 0.50), and −2.04 at 120 mg (95% CI, −3.70 to −0.39); hence, the effectiveness was significantly improved at 120 mg. Regarding frequentist inference, the likelihood mean (SD) was −2.45 (0.10) mm Hg at 60 mg and −1.84 (0.23) mm Hg at 120 mg; thus, there was significantly improved effectiveness at 60 and 120 mg. Regarding Bayesian inference, the posterior mean was −2.86 mm Hg at 60 mg (95% CI, −5.05 to −0.67) and −1.22 mm Hg at 120 mg (95% CI, −2.41 to −0.03). Thus, the mean of cross-inferences was fairly consistent with the meta-analysis results and suggest that fimasartan seemed to be more effective than comparators at 60 and 120 mg.
Sensitivity Analysis
The sensitivity analysis was conducted on the effect size for SiSBP, SiDBP, ASBP, and ADBP by removing one study at a time. The results were analyzed by using the MDs of the pooled estimate with Comprehensive Meta-Analysis software version 3.3, and they are shown in Figure 8. The results still indicated statistically significant differences in favor of fimasartan for SiSBP, SiDBP, ASBP, and ADBP.
Figure 8Sensitivity analysis of the studies examined for clinic sitting systolic blood pressure (SiSBP), clinic sitting diastolic blood pressure (SiDBP), 24-hour mean ambulatory systolic blood pressure (24-h ASBP), and 24-hour mean ambulatory diastolic blood pressure (24-h ADBP).
Publication bias was determined by using the funnel plot and Egger's linear regression test for the effect size and SE for each study. Such bias was not significant with clinic mean SiSBP (t = 0.661; P = 0.519), clinic mean SiDBP (t = 0.949; P = 0.360), ASBP (t = 0.951; P = 0.395), or ADBP (t = 1.037; P = 0.358). Figure 9 depicts the funnel plots for publication bias.
Figure 9Funnel plots for clinic sitting systolic blood pressure (SiSBP)/clinic sitting diastolic blood pressure (SiDBP)and 24-hour mean ambulatory systolic blood pressure (24-h ASBP)/24-hour mean ambulatory diastolic blood pressure (24-h ADBP).
BP homeostasis is regulated by the renin-angiotensin-aldosterone system, which is the main target pathway for the development of antihypertensive drugs. Since the development of ARBs, these agents have played a major role in the treatment of hypertension, with proven mortality and morbidity effects in chronic heart and renal failure, and secondary stroke prevention.
In line with the importance of ARBs, our meta-analysis revealed that one of the newest leading ARBs, fimasartan, is more effective in terms of antihypertensive effect than the other ARBs. Using a meta-analysis of 11 RCTs, the fimasartan group had a more favorable BP-lowering effect in the entire SiSBP/SiDBP and ASBP/ADBP than the comparator group, showing a statistically significant difference. When evaluated according to dose, significant differences were observed at 60 and 120 mg in clinic SiSBP and at 30, 60, and 120 mg in clinic SiDBP. The 120-mg group was significantly different in ASBP and ADBP.
We emphasize that our systematic review is different from other reviews. During our study, a cross-inference method was applied for the first time to confirm the results with meta-analysis. Inferential statistics were introduced to confirm the results obtained from descriptive statistics. This was done so that during our systematic review, the cross-inference including Bayesian and frequentist inference could be used to predict the prior probability from the results of the conventional descriptive method. There are philosophical distinctions between the 2 inferences in the parametric framework. Regarding frequentist inference, given fixed parameters, what is the probability of observing the sample data, and does repeated sampling find that the estimate makes the data most probable? On the other hand, regarding the Bayesian inference and given the observed data, what are the probability parameters and how do we find the most probable population parameters? Therefore, through cross-inferences, it is possible to increase the certainty of the meta-analysis results, and then minimize the possible misinterpretation of P values produced by descriptive statistics through 2 different inferences of crossing.
Efficacy and tolerability of evogliptin in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with Bayesian inference through a quality-management system.
Antidiabetic effect of gemigliptin: a systematic review and meta-analysis of randomized controlled trials with Bayesian inference through a quality management system.
Moreover, the 5 main steps of our quality management system (protocol development, data search and extraction, quality assessment, data management, and statistical analysis) were performed from the first to the final step of each stage. Particularly, in the system model structure, from the Cochrane RCT data collection form to the data management stage, 2 independent reviewers performed cross-checking for quality control of the data set. Notably, statistical analysis was performed by using Comprehensive Meta-Analysis, Review Manager, and R-pack, and the results were cross-checked by 2 independent statisticians.
Efficacy and tolerability of evogliptin in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with Bayesian inference through a quality-management system.
Antidiabetic effect of gemigliptin: a systematic review and meta-analysis of randomized controlled trials with Bayesian inference through a quality management system.
The results of the BP-lowering effect on fimasartan were consistent not only for 2 different statistical inferences but also through our quality management system.
Looking at the encouraging results of fimasartan's BP-lowering effect, the PK and pharmacodynamic benefits of fimasartan may yield better BP-lowering effects than those of the comparators. In fimasartan, the losartan imidazole ring was replaced with a pyrimidine-4(3H)-one. Therefore, the structure has 2 hydrogen bonds of losartan that can bind to the AT1 receptor, 3 of valsartan, and 4 of fimasartan, indicating that this drug has a high binding affinity with the AT1 receptor. As a result of comparing the AT1 binding affinity between ARB preparations, fimasartan had the highest association rate among other ARB preparations at 0.36 nM/min; losartan was 0.12 nM/min, and valsartan was 0.03 nM/min. Therefore, when valsartan binds to one receptor, fimasartan binds to 12 receptors. Conversely, the dissociation rate was the lowest in the ARB preparation of fimasartan at 0.01 nM/min, losartan at 0.18 nM/min, and valsartan at 0.06 nM/min; hence, the rate of separation from receptors is the slowest. These pharmacologic properties are highly potent in lowering BP, with fimasartan strongly binding to the AT1 receptor. Therefore, fimasartan can maintain the longest bound state (ie, long half-lives) and displays a rapid onset of antihypertensive effects.
Pharmacological profiles of a highly potent and long-acting angiotensin II receptor antagonist, fimasartan, in rats and dogs after oral administration.
The trough-to-peak ratio of fimasartan is also high, with a minimum of 0.75, and the blood concentration of the drug is relatively constant, thereby exhibiting a stable BP-lowering effect.
Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension.
The superior receptor affinity, association rate, dissociation rate, long half-lives, and the trough-to-peak ratio of fimasartan indicate that this drug has a better BP-lowering effect than other comparators, consistent with our study results.
Of the 11 studies analyzed, the 2018 study of Oh et al
reported differences in the extent of decrease in carotid atherosclerotic plaque inflammation and BP lowering between patients with ACS treated with amlodipine and those treated with fimasartan. They found that amlodipine and fimasartan are similarly effective in reducing carotid atherosclerotic plaque inflammation. In addition, the 2018 study of Choi et al
reported several hemodynamic changes in patients with ischemic stroke. They compared central BP, cerebral hemodynamic parameters, and N-terminal pro–B-type natriuretic peptide levels, including brachial BP, between fimasartan (60 mg), valsartan (80 mg), and atenolol (50 mg) groups in a 1:1:1 ratio. In the tested ARB groups, fimasartan (60 mg) and valsartan (80 mg) had a higher dampening effect on central pressure, cerebral pulsatility, and NT protein than atenolol (50 mg). Therefore, the ARB preparations yielded more favorable effects for patients with ischemic stroke. In the 2019 study by Shin et al,
BP variability with 24-hour AMBP was compared between patients with acute ischemic stroke administered fimasartan (60 mg) and those administered valsartan (80 mg). Compared with valsartan, fimasartan can prevent recurrent stroke, with beneficial cardiovascular effects in patients with stroke, with its greater effect on lowering measured BP variability according to 24-hour AMBP.
In our systematic review and meta-analysis, we included a previous study on cardiovascular events (ie, cardiovascular factors and results of BP-lowering effects) in patients with ACS and stroke.
Analysis of our selected studies (which comprised 7 RCTs targeting essential hypertension with fimasartan, 1 RCT targeting arterial hypertension, and 3 RCTs targeting cardiovascular events) revealed that the BP-lowering effect favored fimasartan. In other words, fimasartan may be a good choice for lowering the BP of hypertensive patients with cardiovascular events as well as those with essential hypertension. To determine the indicators of cardiovascular events for fimasartan, more RCT studies need to be conducted on the parameters of the cardiovascular effect as well as the BP-lowering effect.
Although not RCTs, several recent large-scale studies have been conducted. According to a prospective observational study called the Efficacy of Fimasartan for Cardiovascular Events and Metabolic Syndrome (K-MetS Study), a total of 6399 patients, including 2363 elderly patients, were treated with fimasartan 30 to 120 mg daily for 1 year.
The result was that fimasartan reduced SiSBP from 144.1 to 127.7 mm Hg and SiDBP from 85.1 to 76.8 mm Hg. Home BP values also decreased similarly. In particular, SBP and DBP findings in elderly patients fell to the same level as SBP and DBP in nonelderly patients. Further reduction to BP lasted for 1 year and was gradual. In addition, the home pulse pressure and clinic heart rate were significantly reduced. The study showed a gap of 7 to 8 mm Hg in SBP between clinic and home, but this difference disappeared in fimasartan therapy over 1 year. These optimal BP effects of fimasartan are encouraging facts for controlling BP in elderly patients in whom isolated hypertension is common. In another recent large-scale study, which was postmarketing surveillance, overall improvement in 3473 patients for efficacy assessment as outpatients or in a hospitalized setting was analyzed.
Safety and efficacy of fimasartan with essential hypertension patients in real world clinical practice: data from a post marketing surveillance in Korea.
These patients were administered fimasartan between 30 mg and 60 mg daily, and dose escalation of up to 120 mg daily was allowed when BP was not controlled. As a result, 87.1% of the patients had improvements, with decreased SBP differences >20 mm Hg or DBP differences >10 mm Hg. This improvement consistently confirmed the results of a Phase III trial comparing fimasartan, valsartan, and placebo.
Efficacy and safety of 30-mg fimasartan for the treatment of patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, Phase III clinical study.
These large-scale studies support the effectiveness of fimasartan‘s BP-lowering effect in real clinical practice as well as our study results.
The present study, however, has 2 major limitations. The first limitation is that there might be ethnic differences in efficacy. Among the 11 RCTs, 10 involved the Korean population. Therefore, the study results cannot determine differences between races. Nevertheless, our study included one Russian RCT (NT02248961) in subjects who were mostly White (177 European subjects and 2 Asian subjects). Considering a similar study design with Lee et al (fimasartan 60/120 mg vs losartan 50/100 mg, optional dose escalation), the result correlates well with the Korean data regarding clinic SiSBP/SiDBP.
Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, phase III, multicenter, prospective, randomized, double-blind, parallel-group, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension.
R-Pharm. Efficacy and safety evaluating study to compare Knarb (fimasartan) and Cozaar (losartan) in adult patients with grade I-II arterial hypertension. 2020 [cited 2021 September 23]. ClinicalTrials.gov. U.S. National Library of Medicine [Internet]. Available from: http://clinicaltrials.gov/show/NCT02248961.
This study reported that the PK parameters (ie, Tmax, Cmax, AUC0-∞, AUC0–tlast ratio) correlate well with the Korean data. Also, an RCT study involving a Mexican population, which was not a 1:1 monotherapy, compared fimasartan versus fimasartan with hydrochlorothiazide at 12.5 mg. This study noted that Mexican subjects had a reliable estimate of efficacy and safety according to the selection criteria in a Phase III clinical study, which was conducted on Korean subjects and concentrated on fimasartan's BP-lowering effect.
These studies are meaningful because they involve various ethnic groups other than Asian subjects, and the results are not significantly different from the Korean data.
The second limitation is the small subject number, with only 11 RCTs. In particular, 24-hour ASBP/ADBP was limited to 4 RCTs in the analysis results presented. Numerous RCTs and observational studies of various study designs related to fimasartan are available. According to the inclusion criteria of our research, studies on fimasartan versus monocomparator therapy should be selected; thus, only 11 RCTs were found. In addition, the results of publication bias are possibly affected by small subject numbers. According to the Cochrane Handbook for Systematic Reviews of Interventions regarding publication bias, small-study effects, which is the tendency to show more beneficial effects in smaller studies, can occur.
Hence, considering the small corresponding subject numbers, the results cannot be confirmed.
Conclusions
In this systematic review and meta-analysis of recent monotherapy RCTs between fimasartan and comparators, we found that fimasartan may have more robust efficacy than other antihypertensive drugs, including ARBs, in terms of its BP-lowering effect. Our finding represents fimasartan's optimal pharmacologic characteristics, such as rapidity, powerfulness, and duration. This research will be a cornerstone in a large-scale systematic review and meta-analysis to be conducted in the future regarding introduction of a new verification method called cross-inference for the meta-analysis as well as the data quality assurance method through our updated quality management system. However, although we suggest the new methods, more studies with the larger subject numbers are warranted for future analysis to confirm the result.
Declaration of Interest
The authors have no relevant financial or non-financial interests to disclose.
Acknowledgments
The authors thank Boryung Pharmaceutical Co Ltd for consultation on the randomization and blinding process of each clinical trial involved in our research. Except for the consultation, no funding body had a role in the study design; collection, analysis, and interpretation of the data; writing of the report; or decision to submit the article for publication. The authors also thank all scientists and researchers who performed previous studies on fimasartan.
Details regarding author contributions are as follows: conceptualization and supervision, Dr Oh; data curation, formal analysis, methodology, and writing–review and editing, all authors; investigation, project administration, and writing–original draft, Drs Oh and Yoon; and validation, Drs Kim and Yoo.
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Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, phase III, multicenter, prospective, randomized, double-blind, parallel-group, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension.
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Efficacy and tolerability of evogliptin in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with Bayesian inference through a quality-management system.
Antidiabetic effect of gemigliptin: a systematic review and meta-analysis of randomized controlled trials with Bayesian inference through a quality management system.
Pharmacological profiles of a highly potent and long-acting angiotensin II receptor antagonist, fimasartan, in rats and dogs after oral administration.
Safety and efficacy of fimasartan with essential hypertension patients in real world clinical practice: data from a post marketing surveillance in Korea.
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