GRAPHICAL ABSTRACT

Key Message

Limited studies have evaluated the long-term safety of combined azilsartan medoxomil and amlodipine therapy. This cohort study found the azilsartan and amlodipine combination therapy was not associated with increased risk of serious adverse events compared to other ARB-amlodipine combinations. These results support the real-world safety of azilsartan-amlodipine caombination therapy in patients with hypertension.

INTRODUCTION

Hypertension represents a significant global health burden, affecting an estimated 1.3 billion individuals worldwide [1,2]. It is an important risk factor for mortality, causing more than 8 million deaths annually worldwide due to cardiovascular complications such as coronary heart disease, heart failure, and stroke [1]. Guidelines recommend thiazide diuretics, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) as first-line primary agents for hypertension treatment [3]. Moreover, most patients, particularly those with stage 2 hypertension or comorbidities, are advised to initiate treatment with a combination of 2 medications to effectively manage their blood pressure [4].

ARBs and CCBs have independently demonstrated benefits in reducing blood pressure and lowering cardiovascular morbidity and mortality in hypertensive patients [5,6]. Additionally, recent evidence suggests that combining these medications exerts complementary effects on blood pressure control, as they target distinct signaling pathways crucial for vascular regulation [7,8]. Randomized clinical trials (RCTs) have demonstrated that combination therapy with amlodipine (a CCB) and valsartan (an ARB) substantially reduces blood pressure compared to high-dose monotherapy, with significantly more patients achieving blood pressure targets as early as 2 weeks after initiation [9]. Moreover, this combination regimen has exhibited good tolerability and safety, with only mild to moderate adverse events reported [10,11].

Azilsartan medoxomil is a novel, long-acting ARB approved by the U.S. Food and Drug Administration and the European Medicines Agency in 2011 [12,13]. Azilsartan medoxomil has been reported to exhibit more potent antihypertensive effects at the maximum approved dose compared to other commonly used ARBs, such as olmesartan and valsartan [14-16]. Furthermore, RCTs have demonstrated that combination therapy with azilsartan medoxomil and amlodipine is as effective as telmisartan with amlodipine and achieves greater blood pressure reductions compared to amlodipine monotherapy [17,18]. Animal studies suggest that azilsartan medoxomil binds more strongly to its receptor than other ARBs and may dissociate more slowly, resulting in a prolonged duration of action. However, limited studies have evaluated the long-term safety of combined azilsartan medoxomil and amlodipine therapy [19].

Therefore, this study aimed to evaluate the 6-month safety of azilsartan medoxomil combined with amlodipine compared to other ARBs combined with amlodipine among hypertensive patients, using administrative healthcare claims data from Korea and Taiwan.

MATERIALS AND METHODS

Data sources

We conducted a distributed study using a common study protocol approach involving 2 representative healthcare databases: Korea’s Health Insurance Review and Assessment Service (HIRA) database from July 1, 2018, to December 31, 2021, and Taiwan’s National Health Insurance Research Database (NHIRD) from January 1, 2013, to December 31, 2020 [20]. Researchers from each location independently implemented data analysis based on the common protocol, which included detailed descriptions of key design elements and analytic parameters.

The HIRA database covers approximately 98% of the Korean population, compiling all medical claims submitted by healthcare providers for reimbursement. This database provides comprehensive information about healthcare services delivered to beneficiaries, including diagnoses, treatments, procedures, surgical histories, and prescribed medications. Diagnoses were coded using the Korean Standard Classification of Diseases, 7th revision (KCD-7), adapted from the International Classification of Diseases, 10th revision (ICD-10). Prescription details included the generic drug names, prescription dates, durations, and administration routes. Prior validation studies compared diagnoses from claims data with hospital or clinic medical records, demonstrating an overall positive predictive value of 82% for diagnoses in the Korean healthcare database [21].

The NHIRD is an anonymized claims database covering approximately 99% of Taiwan’s population (over 23 million individuals). This database includes beneficiaries’ demographic information, ambulatory care claims, inpatient claims, pharmacy prescription records, and registry data on medical facilities and board-certified specialists.

Study population

We included patients aged between 18 years and 75 years who first received a hypertension diagnosis (ICD-10: I10-I15; ICD-9: 401-405) as a primary diagnosis (e.g., principal diagnosis) between January 1, 2019, and June 30, 2020, in the HIRA database, and between January 1, 2014, and June 30, 2019, in the NHIRD. Patients prescribed both ARBs and amlodipine within 6 months of their initial hypertension diagnosis were included. The cohort entry date was defined as the date of the first prescription for ARB and/or amlodipine. To identify new users of the study medications, patients prescribed ARBs, ACE inhibitors, or CCBs within the 6 months preceding the cohort entry date were excluded.

Patients were then classified into 2 groups based on ARB types prescribed within a 30-day window after cohort entry (i.e., the treatment group assessment window): (1) azilsartan medoxomil+amlodipine group: patients prescribed both azilsartan medoxomil and amlodipine on the cohort entry date or those who added on amlodipine to azilsartan medoxomil that was prescribed at cohort entry within the treatment group assessment window, or vice versa; (2) other ARB+amlodipine group: patients prescribed both ARB (except azilsartan medoxomil) and amlodipine on the cohort entry date or those who added on amlodipine to ARB that was prescribed at cohort entry within the treatment group assessment window, or vice versa. Other ARBs included candesartan, irbesartan, losartan, valsartan, telmisartan, eprosartan, Olmesartan, and fimasartan.

The index date was defined as the end of the 30-day treatment group assessment window after cohort entry. To ensure incident events, we excluded patients diagnosed with any of the specified safety outcomes within 6 months prior to the index date. Additionally, to maintain consistency across sites, patients prescribed azilsartan medoxomil at 20 mg/day were excluded, since only 40 mg and 80 mg tablets are approved in Korea [22]. Lastly, patients initiating treatment with both azilsartan medoxomil and other ARBs within the assessment window were also excluded. The study design and patient flowchart are illustrated in Figures 1 and 2, respectively.

Study outcomes and follow-up

We assessed 9 safety outcomes of interest: hypotension, angioedema, acute pancreatitis, hyperkalemia, hypokalemia, toxic liver disease, hepatic failure, nausea and vomiting, and fall-related injury. These outcomes were selected because they represent known or suspected clinically significant adverse events associated with antihypertensive medications [18,23]. To enhance accuracy, outcomes were restricted to primary or secondary diagnoses. Detailed outcome definitions are provided in Supplementary Material 1.

Patients were followed from the index date until the occurrence of a study outcome, switching to another treatment group, discontinuation of either ARB or amlodipine, death, or 180 days after the index date—whichever occurred first—using an as-treated follow-up approach. Continuous exposure was defined as having less than a 30-day gap between the end date of 1 prescription and the start date of the subsequent prescription.

Potential confounders

Socio-demographic covariates, including age, sex, and health insurance type, were assessed at cohort entry. We also recorded the hospital level where azilsartan medoxomil or another ARB was first prescribed. Hospital levels were categorized into 2 groups: (1) medical centers or regional hospitals, and (2) other institutions such as district hospitals and clinics. The Charlson comorbidity index (CCI) was calculated as an indicator of overall comorbidity burden. Comorbidities diagnosed during the 6 months preceding cohort entry were considered. These comorbidities included acute respiratory illness, chronic liver disease, chronic obstructive pulmonary disease, diabetes, gastrointestinal bleeding, gastroesophageal reflux disease, hyperlipidemia, malignancies, obesity, pneumonia, osteoarthritis, psoriasis, kidney disease, rheumatoid arthritis, urinary tract infections, ulcerative colitis, visual system disorders, atrial fibrillation, coronary artery sclerosis, cerebrovascular disease, peripheral vascular disease, pulmonary embolism, and venous thromboembolism [23]. Additionally, co-medications prescribed within the 6 months before cohort entry were evaluated, including systemic antibacterials, antidepressants, antiepileptics, anti-inflammatory and antirheumatic drugs, antineoplastic agents, antithrombotic drugs, beta-blockers, medications for airway obstruction, medications for acid-related diseases, antidiabetic drugs, immunosuppressants, lipid-lowering drugs, opioids, psychostimulants, and psycholeptics [23]. Specific definitions of comorbidities and co-medications are listed in Supplementary Material 1.

Statistical analysis

Results are presented as frequencies for categorical variables and as means (standard deviations) or medians (interquartile ranges) for continuous variables. Selected baseline characteristics were compared between the 2 treatment groups, and covariate balance was assessed using the absolute standardized mean difference, where a value greater than 0.1 indicates imbalance.

We estimated the propensity score (PS) for receiving azilsartan medoxomil and amlodipine combination therapy using multivariate logistic regression that included all measured covariates in the model. A 1:1 greedy nearest-neighbor PS matching approach was applied to establish comparability between the 2 groups. Matched pairs were formed using an 8-to-1-digit greedy nearest-neighbor matching algorithm without replacement (i.e., each patient receiving azilsartan medoxomil and amlodipine was matched to the patient receiving another ARB and amlodipine who had the closest PS, with each patient included in matching pairs only once) [24]. Within the PS-matched cohort, we calculated the number of events, person-years, and incidence rate per 1,000 person-years for all outcomes in each treatment group. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). We then conducted a random-effects meta-analysis to calculate summary HRs, pooling effect estimates across the 2 databases. Statistical analyses were performed using SAS Enterprise Guide version 7.1 (SAS Institute Inc., Cary, NC, USA).

Subgroup and sensitivity analyses

We conducted subgroup analyses according to the initial azilsartan medoxomil dose: standard dose (40 mg, as recommended by the Ministry of Food and Drug Safety, Korea) and high-dose (80 mg). The PS was re-estimated, and matching was performed separately within the high-dose and standard-dose groups. Additionally, we evaluated the risk of adverse outcomes specifically among patients who received a combination of high-dose azilsartan medoxomil (80 mg) and high-dose amlodipine (10 mg). Furthermore, we conducted a sensitivity analysis by selecting olmesartan as an alternative active comparator instead of other ARBs, given that azilsartan medoxomil and olmesartan both exhibit stronger antihypertensive effects compared to other ARBs [25]. We also performed sensitivity analysis using PS fine stratification rather than matching, aiming to estimate the average treatment effect. After trimming observations from non-overlapping regions of the PS distribution, patients receiving the study medications were stratified into 50 equal-sized strata based on their PS distributions. In each stratum, patients receiving azilsartan medoxomil and amlodipine were assigned a weight of 1, whereas patients receiving other ARBs and amlodipine were re-weighted according to the proportion of exposed patients within the corresponding stratum. Finally, we conducted an intention-to-treat analysis, in which patients were followed from the index date until the earliest occurrence of a study outcome, death, or the end of a 180-day follow-up period. This approach was intended to minimize concerns regarding informative censoring.

Ethics statement

This study was approved by the institutional review board of each site (Korea: SKKU 2022-07-018; Taiwan: HREC No. 111-715), and the requirements for informed consent were waived because the data analyses were performed retrospectively using anonymized data. Authors received permission to access the database from the database owners.

RESULTS

Study population and baseline characteristics

We identified a total of 673,940 eligible patients: 314,432 from the HIRA database, of whom 1,521 received azilsartan medoxomil and amlodipine and 312,911 received other ARBs combined with amlodipine; and 359,508 from the NHIRD database, of whom 951 received azilsartan medoxomil and amlodipine and 358,557 received other ARBs combined with amlodipine (Figure 2). Before PS matching, although many baseline characteristics were well balanced, patients initiating azilsartan medoxomil and amlodipine were more likely to have prescriptions issued by medical centers or regional hospitals at both study sites (azilsartan medoxomil group: 51.1% vs. other ARB group: 24.6%) (Table 1, Supplementary Materrial 2). After PS matching, all baseline characteristics became well balanced between the treatment groups (Table 1, Supplementary Materrial 3). Among matched patients, 68.7% were aged 40-64 years, and 62.6% were male.

Over the 180-day follow-up period, most outcomes did not occur even once in either treatment group, making the calculation of HRs impossible for these outcomes. The risk of acute pancreatitis was not significantly different between patients receiving azilsartan medoxomil and amlodipine and those receiving other ARBs and amlodipine (summary HR, 0.86; 95% CI, 0.14 to 5.37). Specifically, in the HIRA database, during the 180-day follow-up period (mean duration: 98.0 days), there was 1 event of hypotension, 1 event of acute pancreatitis, 1 event of toxic liver disease, 6 events of nausea and vomiting, and no occurrences of other outcomes among patients receiving azilsartan medoxomil and amlodipine (Supplementary Material 4). After matching, the other ARB and amlodipine group experienced 2 events of hypotension, 1 angioedema event, 2 events of acute pancreatitis, 1 hyperkalemia event, 6 events of toxic liver disease, twelve events of nausea and vomiting, and 1 event of fall-related injury. The risks of hypotension, acute pancreatitis, toxic liver disease, and nausea and vomiting did not significantly differ between the azilsartan medoxomil and amlodipine and other ARB and amlodipine groups (HR, 1.00; 95% CI, 0.09 to 11.50; HR, 0.77; 95% CI, 0.07 to 8.88; HR, 0.50; 95% CI, 0.06 to 4.32; and HR, 1.01; 95% CI, 0.38 to 2.71, respectively). In the NHIRD database, risks of acute pancreatitis, hypokalemia, and fall-related injury were not significantly different between the 2 groups (HR, 1.00; 95% CI, 0.06 to 15.99; HR, 1.33; 95% CI, 0.30 to 5.96; and HR, 1.50; 95% CI, 0.53 to 4.21, respectively). HRs for other outcomes could not be calculated because no events occurred in the azilsartan treatment group (Table 2).

In both HIRA and NHIRD, risks of all outcomes did not differ when stratified by the initial dose of azilsartan medoxomil (Supplementary Material 5). These findings remained consistent when we applied PS fine stratification methods to adjust for confounders and when using the intention-to-treat analysis (Supplementary Materials 6 and 7). Due to limited sample sizes at both study sites, HRs for outcomes among patients who initiated concomitant high-dose azilsartan medoxomil (80 mg) and high-dose amlodipine (10 mg) could not be calculated (Supplementary Material 8). Our primary findings were also consistent in sensitivity analyses using olmesartan as an alternative active comparator rather than other ARBs (Supplementary Material 9).

DISCUSSION

In this study, utilizing healthcare databases from Korea and Taiwan, we found no evidence suggesting an association between combined azilsartan medoxomil and amlodipine therapy and safety outcomes, including hypotension, angioedema, acute pancreatitis, hyperkalemia, hypokalemia, toxic liver disease, hepatic failure, nausea and vomiting, or fall-related injury. The incidence rates of all evaluated safety outcomes following initiation of azilsartan medoxomil and amlodipine were low at both study sites.

Several previous studies have examined the short-term safety profile of combined azilsartan medoxomil and amlodipine therapy. Weber et al. [18] conducted a 6-week RCT evaluating the safety of different doses of azilsartan medoxomil combined with amlodipine. The adverse event rates were comparable between the placebo with amlodipine (5 mg) group (47%) and the azilsartan medoxomil (40 mg) with amlodipine (5 mg) group (48%), and were even lower in the azilsartan medoxomil (80 mg) with amlodipine (5 mg) group (40%). Additionally, 4 participants experienced serious adverse events, 1 of which was syncope related to treatment with azilsartan medoxomil (40 mg) combined with amlodipine (5 mg), leading to study withdrawal. Another non-inferiority trial comparing azilsartan medoxomil and amlodipine combination therapy with telmisartan and amlodipine over 12 weeks found headaches were the most frequently reported side effect in both treatment groups, with no serious adverse events reported in either group [17].

Concerns about falls are common among patients with hypertension, particularly elderly individuals, and these concerns may influence decisions regarding antihypertensive treatment selection [26,27]. Previous studies examining the impact of various antihypertensive medications on fall risk indicated that ARBs generally do not increase this risk [27,28]. However, it remains uncertain whether the newer and more potent ARB, azilsartan medoxomil, could increase fall risk, especially given the possibility of increased risk associated with intensified antihypertensive therapy [27]. Our findings contribute to the existing literature by demonstrating that combination therapy with azilsartan medoxomil and amlodipine did not increase the risk of fall-related injuries compared to other ARBs combined with amlodipine.

The combination of azilsartan medoxomil and amlodipine has previously demonstrated potent antihypertensive effects [17,18]. One RCT showed blood pressure reductions of approximately 25/15 mmHg after 6 weeks with both 40 mg and 80 mg once-daily azilsartan medoxomil combined with amlodipine, significantly greater than the 14/8 mmHg reduction observed with placebo and amlodipine (p≤0.001) [18]. Another RCT demonstrated that after 12 weeks of treatment, the response rate with azilsartan medoxomil and amlodipine was non-inferior to that of telmisartan and amlodipine (88 vs. 96%, respectively; p=0.61) [17]. Although previous studies have documented the safety of combining other renin-angiotensin-aldosterone system inhibitors with amlodipine [29,30], direct head-to-head comparisons assessing the safety of combining the high-potency ARB azilsartan medoxomil with amlodipine remain lacking [14,15]. Thus, our study provides valuable real-world evidence supporting the safety of this combination, potentially informing future regulatory approval decisions.

This study has several notable strengths. First, by using 2 representative healthcare databases and employing a distributed network approach with a standardized protocol, the reliability and generalizability of our findings are enhanced. Second, our active comparator user study design minimizes susceptibility to confounding by indication and depletion of susceptibles bias [31,32].

Nevertheless, this study also has limitations. First, residual confounding may still exist, although we minimized potential bias by extensively adjusting for 43 baseline characteristics through PS matching. Second, limited sample sizes prevented the calculation of HRs for certain safety outcomes. While the low absolute numbers suggest that these outcomes were likely unrelated to azilsartan medoxomil and amlodipine therapy, further studies with larger populations are necessary to confirm these findings. Third, potential outcome misclassification might have influenced results. However, our focus on severe adverse events, which are typically distinct and more easily identified, makes such misclassification unlikely. Fourth, we assessed safety outcomes over a 6-month period, as ARB-related side effects typically manifest during the initial treatment months [14,33]. However, the 180-day follow-up may be insufficient for capturing longer-term safety issues; thus, these findings should be interpreted cautiously and require further investigation. Lastly, underestimation of some outcomes was possible. For example, nausea and vomiting often resolve spontaneously, and only severe cases usually result in medical encounters, meaning mild-to-moderate episodes might not have been captured. Similarly, hypotension frequently occurs asymptomatically, usually leading only to dose adjustments rather than medical encounters. Hence, captured events may represent particularly severe or incidental cases, and true incidence could be higher. Nonetheless, given comparable overall safety among ARBs, the risks likely remain non-differential between the compared groups.

In conclusion, this population-based cohort study found no evidence of an association between combined azilsartan medoxomil and amlodipine therapy and adverse safety outcomes—such as hypotension, angioedema, acute pancreatitis, hyperkalemia, hypokalemia, toxic liver disease, hepatic failure, nausea and vomiting, or fall-related injury—compared to therapy with other ARBs combined with amlodipine. Additionally, high-dose azilsartan medoxomil appeared safe in combination with regular or high-dose amlodipine. Our findings offer important real-world safety evidence for this therapeutic combination.

Supplementary materials

NOTES

Data availability

The data used for this study are available from the Health Insurance Review and Assessment Service of Korea, but restrictions apply to the availability of these data due to domestic laws and regulations that prohibit the distribution or release of individuals’ data to the public, and so are not publicly available. However, the data are available from the authors upon reasonable request and with permission from the Health Insurance Review and Assessment Service of Korea.

Conflict of interest

The authors have no conflicts of interest to declare for this study.

Funding

This study was funded by Celltrion, Inc. (Incheon, Republic of Korea).

Acknowledgements

None.

Author contributions

Conceptualization: Lee H, Hong B, Su CTT, Bea S, Jeong HE, Jung K, Cheng MCY, Chang ZCJ, Lai ECC, Lee J. Data curation: Lee H. Formal analysis: Hong B. Funding acquisition: Lee H. Methodology: Lee H, Hong B, Su CTT, Bea S, Jeong HE, Jung K, Cheng MCY, Chang ZCJ, Lai ECC, Lee J. Project administration: Lee H. Visualization: Hong B. Writing – original draft: Lee H, Hong B. Writing – review & editing: Lee H, Hong B, Su CTT, Bea S, Jeong HE, Jung K, Cheng MCY, Chang ZCJ, Lai ECC, Lee J.

Figure 1.

Study diagram. ¹First prescription date indicates the first prescription date for angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs). ²Outcomes of interest include hypotension, angioedema, acute pancreatitis, hyperkalemia, hypokalemia, toxic liver disease, hepatic failure, nausea and vomiting, and fall-related injury. ³Antihypertensive medications include any type of angiotensinconverting enzyme inhibitor, ARB, and CCB. ⁴Censored at earliest occurrence of the study outcome, switching to another group, discontinuation (either ARB or amlodipine), death, or end of the study period.

Figure 2.

Study flowchart. ACE, angiotensin converting enzyme; ARB, angiotensin receptor blockers; CCB, calcium channel blocker; ICD-10, International Classification of Diseases, 10th revision, Clinical Modification. 1Antihypertensive medications include any type of ACE inhibitor, ARB, and CCB. 2Outcomes included hypotension, angioedema, acute pancreatitis, hyperkalemia, hypokalemia, toxic liver disease, hepatic failure, nausea and vomiting, and fall-related injury.

REFERENCES

• 1. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet 2021;398:957-980. https://doi.org/10.1016/S0140-6736(21)01330-1ArticlePubMedPMC
• 2. World Health Organization. Hypertension; 2019 [cited 2023 Dec 12]. Available from: https://www.who.int/news-room/fact-sheets/detail/hypertension
• 3. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018;71:e13-e115. https://doi.org/10.1161/HYP.0000000000000065ArticlePubMed
• 4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206-1252. https://doi.org/10.1161/01.HYP.0000107251.49515.c2ArticlePubMed
• 5. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003. https://doi.org/10.1016/S0140-6736(02)08089-3ArticlePubMed
• 6. Schrader J, Lüders S, Kulschewski A, Hammersen F, Plate K, Berger J, et al. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 2005;36:1218-1226. https://doi.org/10.1161/01.STR.0000166048.35740.a9ArticlePubMed
• 7. Dagenais NJ, Jamali F. Protective effects of angiotensin II interruption: evidence for antiinflammatory actions. Pharmacotherapy 2005;25:1213-1229. https://doi.org/10.1592/phco.2005.25.9.1213ArticlePubMed
• 8. Schulman IH, Zachariah M, Raij L. Calcium channel blockers, endothelial dysfunction, and combination therapy. Aging Clin Exp Res 2005;17(4 Suppl):40-45.PubMed
• 9. Philipp T, Smith TR, Glazer R, Wernsing M, Yen J, Jin J, et al. Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension. Clin Ther 2007;29:563-580. https://doi.org/10.1016/j.clinthera.2007.03.018ArticlePubMed
• 10. Smith TR, Philipp T, Vaisse B, Bakris GL, Wernsing M, Yen J, et al. Amlodipine and valsartan combined and as monotherapy in stage 2, elderly, and black hypertensive patients: subgroup analyses of 2 randomized, placebo-controlled studies. J Clin Hypertens (Greenwich) 2007;9:355-364. https://doi.org/10.1111/j.1524-6175.2007.06689.xArticlePubMedPMC
• 11. Stroppa C, Hunjan I, Umulisa A, Irebe B, Parati G, Bianchetti MG, et al. Single-pill, triple antihypertensive therapy in rural sub-Saharan Africa: preliminary experience. Cardiol Ther 2024;13:431-442. https://doi.org/10.1007/s40119-024-00358-5ArticlePubMedPMC
• 12. U.S. Food and Drug Administration. Drug approval package: Edarbi (azilsartan medoxomil). [cited 2023 Dec 12]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200796sOrig1s000_Edarbi_TOC.cfm
• 13. European Medicines Agency. Edarbi: azilsartan medoxomil. [cited 2023 Dec 12]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/edarbi
• 14. White WB, Weber MA, Sica D, Bakris GL, Perez A, Cao C, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension 2011;57:413-420. https://doi.org/10.1161/HYPERTENSIONAHA.110.163402ArticlePubMed
• 15. Bakris GL, Sica D, Weber M, White WB, Roberts A, Perez A, et al. The comparative effects of azilsartan medoxomil and olmesartan on ambulatory and clinic blood pressure. J Clin Hypertens (Greenwich) 2011;13:81-88. https://doi.org/10.1111/j.1751-7176.2010.00425.xArticlePubMedPMC
• 16. Katsi V, Michalakeas C, Soulaidopoulos S, Antonopoulos AS, Vlachopoulos C, Tousoulis D, et al. Evaluating the safety and tolerability of azilsartan medoxomil alone or in combination with chlorthalidone in the management of hypertension: a systematic review. Curr Hypertens Rev 2021;17:217-227. https://doi.org/10.2174/1573402117666210112144505ArticlePubMed
• 17. Dash A, Meher BR, Padhy BM, Mohanty RR, Tripathy A. Comparison of efficacy and safety of azilsartan and amlodipine combination versus telmisartan and amlodipine combination in hypertensive patients: a non-inferiority trial. Cureus 2023;15:e35865. https://doi.org/10.7759/cureus.35865ArticlePubMedPMC
• 18. Weber MA, White WB, Sica D, Bakris GL, Cao C, Roberts A, et al. Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension. Blood Press Monit 2014;19:90-97. https://doi.org/10.1097/MBP.0000000000000027ArticlePubMedPMC
• 19. Ojima M, Igata H, Tanaka M, Sakamoto H, Kuroita T, Kohara Y, et al. In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies. J Pharmacol Exp Ther 2011;336:801-808. https://doi.org/10.1124/jpet.110.176636ArticlePubMed
• 20. Toh S, Pratt N, Klungel O, Gagne JJ, Platt RW. Distributed networks of databases analyzed using common protocols and/or common data models. In: Strom BL, Kimmel SE, Hennessy S, eds. Pharmacoepidemiology. Hoboken: John Wiley & Sons;; 2019. p 617-638. https://doi.org/10.1002/9781119413431
• 21. Park BJ, Sung JH, Park KD, Seo SW, Kim SW. Report of the evaluation for validity of discharged diagnoses in Korean Health Insurance Database. Seoul: Health Insurance Review & Assessment Service; 2003. (Korean).
• 22. Health Insurance Review & Assessment Service. Drug formulary. [cited 2023 Dec 12]. Available from: https://www.hira.or.kr/bbsDummy.do?pgmid=HIRAA030014050000 (Korean)
• 23. Suchard MA, Schuemie MJ, Krumholz HM, You SC, Chen R, Pratt N, et al. Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis. Lancet 2019;394:1816-1826. https://doi.org/10.1016/S0140-6736(19)32317-7ArticlePubMedPMC
• 24. Desai RJ, Franklin JM. Alternative approaches for confounding adjustment in observational studies using weighting based on the propensity score: a primer for practitioners. BMJ 2019;367:l5657. https://doi.org/10.1136/bmj.l5657ArticlePubMed
• 25. Satoh M, Haga T, Hosaka M, Obara T, Metoki H, Murakami T, et al. The velocity of antihypertensive effects of seven angiotensin II receptor blockers determined by home blood pressure measurements. J Hypertens 2016;34:1218-1223. https://doi.org/10.1097/HJH.0000000000000902ArticlePubMed
• 26. Berlowitz DR, Breaux-Shropshire T, Foy CG, Gren LH, Kazis L, Lerner AJ, et al. Hypertension treatment and concern about falling: baseline data from the systolic blood pressure intervention trial. J Am Geriatr Soc 2016;64:2302-2306. https://doi.org/10.1111/jgs.14441ArticlePubMedPMC
• 27. Tinetti ME, Han L, Lee DS, McAvay GJ, Peduzzi P, Gross CP, et al. Antihypertensive medications and serious fall injuries in a nationally representative sample of older adults. JAMA Intern Med 2014;174:588-595. https://doi.org/10.1001/jamainternmed.2013.14764ArticlePubMedPMC
• 28. Gribbin J, Hubbard R, Gladman J, Smith C, Lewis S. Risk of falls associated with antihypertensive medication: self-controlled case series. Pharmacoepidemiol Drug Saf 2011;20:879-884. https://doi.org/10.1002/pds.2176ArticlePubMed
• 29. Billecke SS, Marcovitz PA. Long-term safety and efficacy of telmisartan/amlodipine single pill combination in the treatment of hypertension. Vasc Health Risk Manag 2013;9:95-104. https://doi.org/10.2147/VHRM.S40963ArticlePubMedPMC
• 30. Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417-2428. https://doi.org/10.1056/NEJMoa0806182ArticlePubMed
• 31. Kyriacou DN, Lewis RJ. Confounding by indication in clinical research. JAMA 2016;316:1818-1819. https://doi.org/10.1001/jama.2016.16435ArticlePubMed
• 32. Suissa S, Dell’Aniello S. Time-related biases in pharmacoepidemiology. Pharmacoepidemiol Drug Saf 2020;29:1101-1110. https://doi.org/10.1002/pds.5083ArticlePubMed
• 33. Juhasz A, Wu J, Hisada M, Tsukada T, Jeong MH. Efficacy and safety of azilsartan medoxomil, an angiotensin receptor blocker, in Korean patients with essential hypertension. Clin Hypertens 2018;24:2. https://doi.org/10.1186/s40885-018-0086-4ArticlePubMedPMC

Figure & Data

References

Citations

Citations to this article as recorded by