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Real-world efficacy of fimasartan vs. other angiotensin receptor blockers in combination with calcium channel blockers: a nationwide cohort study

Clinical Hypertension volume 30, Article number: 28 (2024) Cite this article

Abstract

Background

The antihypertensive efficacy of fimasartan was assessed based on the transition rate from a combination of calcium channel blockers (CCB) and angiotensin receptor blockers (ARB) to three-drug combination therapy, as compared to other ARBs.

Methods

This nationwide cohort study used data obtained from the Korean National Health Insurance Service database. Patients who had received national health checkups within 2 years prior to January 1, 2017, and were concurrently prescribed ARBs and CCBs for > 30 days during the 6 months from January 1, 2017, to June 30, 2017 were included in the study. Patients were categorized into the ‘fimasartan group’ (those prescribed fimasartan) and the ‘non-fimasartan group’ (those prescribed ARBs other than fimasartan). The index date was set as the last day of a 30-day prescription period for ARBs and CCBs, with a subsequent 2.5-year follow-up to observe the potential addition of a third drug, such as beta-blockers or diuretics.

Results

The study included 34,422 patients with a mean age of 60.3 years and 58.3% being male. The fimasartan group constituted 2.7% (n = 928) of the total, and the non-fimasartan group, 97.3% (n = 33,494). During the follow-up period, 38 patients in the fimasartan group (14.3 per 1,000 person-years) and 3,557 patients in the non-fimasartan group (42.8 per 1,000 person-years) required additional antihypertensive medications. After multivariate adjustment for age, sex, diabetes mellitus, dyslipidemia, cancer, heart failure, systolic blood pressure, and diastolic blood pressure, the fimasartan group showed a significantly lower rate of adding a third medication (hazard ratio 2.68, 95% confidence interval 1.95–3.69) compared to that of the non-fimasartan group.

Conclusions

Fimasartan is associated with a lower need for additional antihypertensive drugs compared to other ARBs. This implies its greater effectiveness in hypertension management, potentially enhancing cardiovascular outcomes, and minimizing polypharmacy.

Background

Hypertension has a substantial prevalence affecting approximately 1 billion patients worldwide and the prevalence is increasing [1, 2]. More importantly, hypertension is a well-known risk factor for cardiovascular events [3]. Effective treatment of hypertension significantly reduces cardiovascular disease (CVD)-related events, including a decreased risk of stroke (by 35–40%), myocardial infarction (by 15–25%), and congestive heart failure (by as much as 64%) [4,5,6].

Despite the availability of more than 100 different medications across various pharmacological categories and large financial investments in hypertension treatment, global blood pressure (BP) control rates remain suboptimal, even in developed countries [7]. Among various factors suggested as reasons for unsatisfactory hypertension control, an expanded medication regimen has been reported to be a significant factor associated with non-compliance [8, 9]. This non-compliance could, in turn, lead to poor BP control.

Angiotensin receptor blockers (ARBs) are renowned for their efficacy and excellent tolerability [10]. Based on these qualities, ARBs stand as the preferred initial therapeutic choice for hypertension management [11,12,13]. Fimasartan, created by substituting the imidazole ring in losartan with a pyrimidine ring, is one of the most recent additions to the global ARB armamentarium. It has several strengths compared with other ARBs. First, it shows superior angiotensin II receptor type 1 (AT1) -selective binding when compared to other ARBs [14]. Second, it has an antihypertensive effect over 24 h due to its extended half-life, ranging from 10 to 18 h, ranking it among the most prolonged half-lives within the ARB class [15, 16]. A recent report showed that fimasartan has a more pronounced BP-lowering effect relative to other ARBs [17, 18].

In real-world clinical practice, approximately 60% of patients with hypertension are prescribed two or more antihypertensive medications. Among those, about half use combinations of ARBs and calcium channel blockers (CCBs) [19]. Considering the distinct BP-lowering effects of ARBs, it is reasonable to hypothesize that transition rates from two-drug to three-drug combination therapy may vary across ARBs; fimasartan might have a lower transition rate owing to its high potency in controlling BP.

Based on this background, we aimed to explore the efficacy of fimasartan and other ARBs in patients with hypertension who are already undergoing treatment with CCBs and ARBs by analyzing the transition rates to a three-drug combination therapy.

Participants and methods

Study design and study population

This nationwide cohort study used data from the Korean NHIS database. Detailed information regarding this database has been published earlier [20,21,22]. In essence, the NHIS is a single public insurer that covers the entire Korean population and encourages eligible Korean adults to receive general health checkups on a regular basis. Demographic information, general health checkup results, and medical history coded according to the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) were collected and recorded in the NHIS database.

A flowchart of the study is shown in Fig. 1. Initially, we screened 137,089 patients who were prescribed CCBs for > 30 days between January 1, 2017, and June 30, 2017. Among them, 81,722 patients who were prescribed ARBs for > 30 days during the same period were identified. Patients who underwent a health checkup within 2 years prior to receiving CCB and ARB prescriptions were included. After excluding patients taking additional antihypertensive drugs, those aged < 20 years, and those with missing health data, 34,422 patients remained. Prescription of ARBs were defined as that of Fimasartan, Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, and Valsartan.

Fig. 1
figure 1

Flow chart detailing the study enrollment process. Abbreviations: CCB - calcium channel blocker; ARB - angiotensin receptor blocker

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Covariates

Patients with hypertension were identified based on one of the following criteria: (1) at least one annual claim for an antihypertensive prescription associated with ICD-10-CM codes I10-I13 and I15, derived from insurance claims data, or (2) a recorded systolic BP of ≥ 140 mmHg and/or a diastolic BP of ≥ 90 mmHg alongside the aforementioned ICD-10-CM codes [23,24,25]. Patients’ demographic data, comorbidities, medications, and results from general health checkups were collected and analyzed as covariates. The comorbidity definitions are summarized in Supplemental Table 1 [23].

Study outcome and follow-up

The index date was defined as the last day of the 30-day ARBs and CCBs prescription period. Patients were followed up for a period of 2.5 years from the index date. The transition to three-drug combination therapy was defined as the addition of beta-blockers or diuretics during the follow-up period. Transition rates were analyzed between patients receiving fimasartan and those receiving all other ARBs (non-fimasartan), as well as between those receiving fimasartan and each individual ARB.

Statistical analysis

Data were presented as the mean ± standard deviation for continuous variables and as counts and percentages for categorical variables. Chi-squared or Fisher’s exact tests were used for categorical variables, as appropriate. Continuous variables were analyzed using unpaired Student’s t-test, and one-way analysis of variance was used for comparisons between more than two groups. The annualized incidence rate (IR) of transitioning to three-drug combination therapy was calculated by dividing the number of new cases by the total follow-up period, and was expressed as a rate per 1,000 person-years. For the category ‘transition to three-drug combination therapy,’ we established two definitions: Definition 1 required prescriptions of CCBs, ARBs, and either beta-blockers or diuretics, within the timeframe of July 1, 2017, to December 31, 2020. Definition 2 mirrored these criteria but additionally necessitated the consistent use of the initially prescribed ARB, which was sustained until the issuance of a third antihypertensive prescription (either a beta-blocker or diuretic). Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated using Cox proportional hazard regression models. The multivariate models were adjusted for a variety of covariates, including age, sex, systolic and diastolic BP, and comorbidities such as diabetes mellitus, dyslipidemia, atrial fibrillation, and cancer. The HRs were reported using the fimasartan group as a reference. Considering the time required to initiate antihypertensive medication, assess its efficacy, and introduce additional medications, we conducted a sensitivity analysis incorporating a 6-month lag period. To exclude biases from other cardiovascular events, we further analyzed the differences in the incidence of myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF) during follow-up between the fimasartan group and the non-fimasartan group. Additionally, we analyzed the transition rate to three-drug combination therapy in patients without a prior medical history of AF, MI, HF, and chronic kidney disease (CKD) as sensitivity analyses. Statistical significance was defined as a two-sided P-value < 0.05. All the statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Baseline characteristics

We analyzed 34,422 patients with a mean age of 60.3 ± 11.5 years, and 20,071 patients (58.3%) were men. Among the total study population, 928 patients (2.7%) were classified into the fimasartan group and 33,494 patients (97.3%) were classified into the non-fimasartan group. The non-fimasartan group comprised patients who were prescribed candesartan, esprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan (n = 1,541, 92, 590, 7,390, 5,293, 7,319, and 11,269, respectively). Baseline characteristics according to ARBs use are presented in Table 1. There were no significant differences in age, sex, or body mass index between the fimasartan and non-fimasartan groups. Regarding comorbid conditions, the fimasartan group showed unfavorable baseline characteristics, including dyslipidemia, atrial fibrillation, stroke, cancer, and heart failure, compared to the non-fimasartan group. Additionally, significant differences were observed in the systolic BP and diastolic BP between the two groups.

Table 1 Baseline characteristics
Full size table

Different transition rates to three-drug combination therapy

During a median follow-up of 2.1 years (interquartile range 2.05–2.35 years), 3,595 patients (10.5%) transitioned to three-drug combination therapy. Significant differences in the transition to three-drug combination therapy were observed between the fimasartan and non-fimasartan groups (P < 0.001), as well as across ARBs (P < 0.001) (Table 2). Notably, the patients taking fimasartan exhibited a remarkably lower rate of adding other antihypertensive medications; only 38 patients (4.1%) taking fimasartan required additional medication. In contrast, eprosartan (29.4%) and irbesartan (29.8%) exhibited the highest transition rates in three-drug combination therapy, followed by candesartan (21.5%) and losartan (20.4%). Olmesartan (5.8%), telmisartan (6.3%), and valsartan (6.6%) showed comparatively lower rates.

Table 2 Time to addition of third antihypertensive medication: comparison among angiotensin II receptor blockers
Full size table

The time taken to use additional antihypertensive medications was also significantly different across ARBs (Table 2). Indeed, patients taking fimasartan showed a longer duration of two-drug combination therapy before additional medication was required, with a median time of 213.5 days (interquartile range, 184–278 days), indicating a longer interval than that for most other ARBs. Irbesartan demonstrated the shortest duration (median: 193 days; interquartile range, 183–211 days).

The annualized IRs of each ARB were quite different. The fimasartan group showed an IRs of 14.26 per 1,000 PY, whereas the non-fimasartan group showed an IRs of 42.76 per 1,000 PY. As shown in the Kaplan-Meier curves (Fig. 2), the probability of taking additional antihypertensive medications was significantly lower in the fimasartan group than in the non-fimasartan group (log-rank P < 0.001). After multivariable adjustment, the non-fimasartan group consistently showed significantly higher transition rates to three-drug combination therapy (HR 2.68, 95% CI 1.95–3.69) compared to the fimasartan group (Fig. 3). These results highlight the potential clinical efficacy of fimasartan in minimizing the need for additional antihypertensive agents. When comparing the rate of transition in the three-drug combinations involving fimasartan and telmisartan (Supplemental Fig. 1A, p = 0.047) and fimasartan and olmesartan (Supplemental Fig. 1B, p = 0.027), the rate of transition in the three-drug combination was statistically significantly lower for fimasartan than for both telmisartan and olmesartan. The results of sensitivity analysis with the 6-month landmark analysis were consistent with the main results (Supplemental Fig. 2).

Fig. 2
figure 2

Survival analysis contrasting the transition rate to a three-drug combination therapy regimen between the fimasartan and non-fimasartan cohorts

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Fig. 3
figure 3

Multivariate Cox-proportional hazard regression analysis assessing the transition rate to three-drug combination therapy across fimasartan and non-fimasartan groups, and the aggregate of all angiotensin receptor blockers. The fimasartan group is utilized as a reference. Incidence rate is expressed per 1,000 person-years. Abbreviations: CI = confidence interval; HR = hazard ratio; IR = incidence rate

Full size image

We further compared the transition rate to three-drug combination therapy for each ARB, with patients taking fimasartan as the reference group. Supplemental Fig. 3 illustrates the trend of adding antihypertensive medications to each ARB. In multivariate analysis, all other ARBs showed significantly higher risks of additional antihypertensive medications than that of fimasartan. Specifically, candesartan (HR 5.78, 95% CI 4.13–8.09), eprosartan (HR 7.68, 95% CI 4.69–12.58), and irbesartan (HR 8.33, 95% CI 5.86–11.82) demonstrated remarkably higher transition rates to three-drug combination therapy compared to fimasartan. Regarding olmesartan, telmisartan, and valsartan, the relative magnitude of increased risks for adding additional antihypertensive medications was comparatively small compared to that of candesartan, eprosartan and irbesartan, but these also showed significantly higher risks compared to fimasartan (HR 1.45, 95 CI 1.03–2.03; HR 1.58, 95% CI 1.14–2.20; and HR 1.64, 95% CI 1.19–2.27, respectively) (Fig. 3). This result was consistently observed in the sensitivity analysis with a 6-month lag period. (Supplemental Fig. 3) and in the analysis excluding patients with a past medical history of MI, HF, AF, and CKD (Supplemental Tables 2 and Supplemental Fig. 4).

To exclude the biases from the newly developed cardiovascular events except hypertension, we further analyzed the differences in the incidence of MI, HF, and AF during follow-up between the two groups. Supplemental Fig. 5 illustrates the multivariate analysis of these four outcomes, showing similar risks in the non-fimasartan group for MI (HR: 0.79, 95 CI: 0.35–1.79), HF (HR: 0.74, 95 CI: 0.44–1.24), AF (HR: 0.87, 95 CI: 0.48–1.59), and the composite outcome (HR: 0.77, 95 CI: 0.53–1.13).

Discussion

We evaluated the efficacy of ARBs by examining the rate at which patients transitioned from a combination of CCBs and ARBs to a triple-drug regimen. The key findings are as follows: First, fimasartan was associated with a lower frequency of introducing a third antihypertensive agent compared to other ARBs. Second, patients on fimasartan had a longer median duration (778 days) before the addition of a third antihypertensive agent than those on other ARBs (median 764 days). This trend persisted even after adjusting for covariates, with fimasartan showing a decreased likelihood of requiring a third antihypertensive medication. It is important to note that despite unfavorable baseline characteristics in the fimasartan group, there was less need for an additional antihypertensive agent. These results suggest that fimasartan may offer superior antihypertensive efficacy, as evidenced by both a lower incidence of, and delayed requirement for, additional antihypertensive medication.

Because of the unacceptably high global disease burden of hypertension, numerous efforts have been made to improve clinical outcomes, demanding lifelong compliance with treatment [26, 27]. However, most patients with hypertension remain asymptomatic despite the increased risk of cardiovascular events. Consequently, adherence to antihypertensive medications, which may not provide immediate benefits, is crucial for these patients. The documented correlation between complex medication schedules, involving multiple drugs and daily doses, and reduced compliance underscores the challenge [28,29,30]. This complexity is further compounded when considering comorbidities, leading to intricate drug regimens involving multiple medications and doses [31]. In consideration of this, it is essential for physicians to simplify the antihypertensive medication regimen while preserving equivalent medical and antihypertensive benefits to enhance outcomes.

ARBs have a shared molecular structure that contributes to their class effect [32], yet variations exist, leading to different clinical benefits. The number of hydrogen bonds, which affect binding affinity, varies among ARBs and influences their antihypertensive effects [33]. Fimasartan is distinct in the replacement of losartan’s imidazole ring with a pyrimidine ring, resulting in enhanced AT1-selective binding compared to other ARBs [14]. It also has an extended half-life and potent BP-lowering effect [15, 16, 18]. Considering that fimasartan belongs to the later generation of ARBs, comparisons are made with with earlier ARBs to establish its antihypertensive efficacy. The antihypertensive efficacy of fimasartan has been investigated compared to losartan [34], valsartan [16, 35, 36], and candesartan [37] and it is clear that fimasartan has comparable or superior BP-lowering effects. A previous head-to-head study clearly demonstrated that fimasartan has superior efficacy in BP reduction compared with valsartan [38]. As expected from its novel molecular characterization, fimasartan has consistently demonstrated a more pronounced BP-lowering effect than other ARBs in clinical studies [15, 16, 18].

The use of the conversion rate to the three-drug combination therapy as a surrogate measure in our study offers a novel approach for evaluating the effectiveness of antihypertensive medications, bypassing the traditional method of direct BP measurement. Additionally, the potential of this conversion rate as an indicator of patient compliance with antihypertensive medications is noteworthy. Our cohort of > 30,000 participants is a strength, although the implications and broader applications of these findings warrant further exploration.

Our study had several limitations. First, as this was an observational study, unmeasured confounders may have influenced our results. Second, the study, which was based on the NHIS database, encountered limitations in accessing data on the degree of BP change from the index date to the prescription of a third antihypertensive medication. However, it is important to note that our findings align with a previous study that reported the effectiveness of fimasartan in lowering BP compared to other ARBs. Additionally, this study was conducted only in South Korea, and thus, generalizing the findings to global populations with diverse genetic and environmental backgrounds should be approached with caution. Another limitation is the absence of data regarding the discontinuation of ARB prescriptions. While we included individuals who were prescribed ARBs for 30 days or more within the inclusion period, we were unable to ascertain the subsequent discontinuation status of these prescriptions. In the future, research on more specific topics, such as cost-effectiveness, will be necessary.

Conclusions

The use of fimasartan is associated with a significantly lower transition rate to three-drug combination therapy and extends the time to the incorporation of a third drug into the treatment regimen. The antihypertensive efficacy of fimasartan in the management of hypertension minimizes the need for additional medications.

Data availability

All raw data were accessible from designated terminals approved by the National Health Insurance Service (NHIS). On reasonable request from the corresponding author, the data will be available under approval and oversight by the NHIS.

Abbreviations

CVD:

Cardiovascular disease

BP:

Blood pressure

ARBs:

Angiotensin receptor blockers

AT1:

Angiotensin II receptor type 1

CCBs:

Calcium channel blockers

NHIS:

National Health Insurance Service

ICD-10-CM:

International Classification of Diseases, Tenth Revision, Clinical Modification

IR:

Incidence rate

HRs:

Hazard ratios

CIs:

Confidence intervals

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Acknowledgements

Not applicable.

Funding

This project was an investigator-initiated trial. This research was funded by a grant from Boryung Pharmaceutical Co., Ltd. (Seoul, Korea). The funder had no role in the study design, data collection and analysis, preparation of the manuscript, or decision to submit the manuscript.

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Author notes

  1. Huijin Lee and Chan Soon Park contributed equally to this work.

Authors and Affiliations

  1. Department of Critical Care Medicine, Seoul National University Hospital, Seoul, Republic of Korea

    Huijin Lee

  2. Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea

    Chan Soon Park, Yong-Jin Kim & Hyung-Kwan Kim

  3. Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea

    Bongseong Kim & Kyungdo Han

  4. Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center, 152, Teheran-ro, Gangnam-gu, Seoul, Republic of Korea

    Tae-Min Rhee & Heesun Lee

  5. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

    Yong-Jin Kim & Hyung-Kwan Kim

Authors
  1. Huijin Lee
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  2. Chan Soon Park
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  3. Bongseong Kim
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  4. Tae-Min Rhee
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  5. Heesun Lee
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  6. Yong-Jin Kim
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  8. Hyung-Kwan Kim
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Contributions

Conception: Hyung-Kwan Kim, Kyung-Do Han; Design: Hyung-Kwan Kim, Kyung-Do Han; Supervision: Yong-Jin Kim, Hyung-Kwan Kim, Kyung-Do Han; Fundings: Hyung-Kwan Kim; Materials: Tae-Min Rhee, Heesun Lee; Data collection and processing: Bongseong Kim, Kyung-Do Han; Analysis and interpretation: Bongseong Kim, Kyung-Do Han, Huijin Lee, Chan Soon Park. Hyung-Kwan Kim; Writer: Huijin Lee, Chan Soon Park. Critical review: Chan Soon Park. Hyung-Kwan Kim.

Corresponding author

Correspondence to Hyung-Kwan Kim.

Ethics declarations

Ethics approval and consent to participate

This study adhered to the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Seoul National University Hospital (E-2103-004-120), which waived the need for informed consent due to the use of de-identified data.

Consent for publication

Not applicable.

Competing interests

Hyung-Kwan Kim has received research grants from HK Inno. N, Johnson and Johnson, GSK, Samjin Pharm, ChongKunDang Pharm, Boryung Pharm, and JW Pharm. The authors declare no conflict of interest.

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Lee, H., Park, C., Kim, B. et al. Real-world efficacy of fimasartan vs. other angiotensin receptor blockers in combination with calcium channel blockers: a nationwide cohort study. Clin Hypertens 30, 28 (2024). https://doi.org/10.1186/s40885-024-00287-4

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Keywords

Clinical Hypertension

ISSN: 2056-5909

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