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Comparison of the Efficacy and Safety of Fixed-dose S-Amlodipine/Telmisartan and Telmisartan in Hypertensive Patients Inadequately Controlled with Telmisartan: A Randomized, Double-blind, Multicenter Study
Address correspondence to: Chang Gyu Park, MD, PhD, Cardiovascular Center, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 08308, Korea.
The objective of this study was to evaluate the efficacy and safety of the fixed-dose combination S-amlodipine plus telmisartan (S-AM/TEL) compared with TEL monotherapy in patients with hypertension inadequately controlled by TEL monotherapy.
Methods
this study was a randomized, multicenter, double-blind, parallel group, Phase III, 8-week clinical trial to compare the superiority of the S-AM/TEL 2.5/40-mg and S-AM/TEL 5/40-mg combinations with TEL 80-mg mono-therapy. The primary end point was the change in the mean sitting diastolic blood pressure from baseline (week 0) after 8 weeks of therapy between treatment groups.
Findings
Of 325 patients screened, 183 were randomly assigned to 3 groups (61 in the S-AM/TEL 2.5/40-mg group, 60 in the S-AM/TEL 5/40-mg group, and 62 in the TEL 80-mg group). Mean (SD) age was 53.9 (7.5) years, and male patients comprised 87%. No significant differences were found among the 3 groups in baseline characteristics. The primary end points, the changes of mean (SD) diastolic blood pressure at week 8 from the baseline were −10.56 (7.23) mm Hg in the S-AM/TEL 2.5/40-mg group, −12.32 (9.23) mm Hg in the S-AM/TEL 5/40-mg group, and −2.44 (7.92) mm Hg in the TEL 80-mg group. Both the S-AM/TEL 2.5/40-mg group and the S-AM/TEL 5/40-mg group had a statistically superior hypotensive effect compared with the TEL 80-mg group (P < 0.0001 for both). For evaluation of the safety profile, the frequencies of adverse events (AEs) among the groups were also not significantly different (S-AM/TEL 2.5/40-mg group, 18.6%; S-AM/TEL 5/40-mg group, 20%; and TEL 80-mg group, 22.6%), and the incidences of AEs were not different among the groups. The most common AEs were respiratory disorders, followed by headache, dizziness, and peripheral edema.
Implications
Treatment with S-AM/TEL 2.5/40 mg and S-AM/TEL 5/40 mg was superior to increasing the TEL dose in terms of hypotensive effect in patients with hypertension inadequately controlled by TEL monotherapy. S-AM/TEL fixed-dose combinations are an effective and tolerable option for patients inadequately responding to TEL monotherapy and also a good option for improving patients’ medication adherence. ClinicalTrials.gov identifier: NCT011426100.
Hypertension is a chronic disease caused by the interactions among genetic factors, obesity, drinking, smoking, stress, aging, lack of physical activity, and high salt intake that leads to serious complications, such as cerebrovascular diseases, heart diseases, renal failure, and arteriosclerosis. Hypertension accounts for 35% of cerebrovascular diseases and 21% of ischemic heart diseases, suggesting the importance of hypertension management because it means that 35% of cerebrovascular diseases and 21% of ischemic heart diseases are preventable if normal blood pressure (BP) could be maintained in the population.
Ministry of Health, Korea Centers for Disease Control and Prevention, Yonsei University Office of Research Affairs & University – Industry Foundation, In-depth Analysis Report The 3rd Korea National Health and Nutrition Examination Survey: Examinations.
Korea Centers for Disease Control and Prevention,
Seoul, Korea2007
In the hypertension guidelines of various countries, including Korea, the recommended target BP for the treatment of hypertension is below 140/90 mm Hg for all hypertensive patients without other risk factors or below 130/80 mm Hg for high-risk patients with cerebrovascular diseases, myocardial infarction, albuminuria, or other risk factors.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report National High Blood Pressure Education Program Coordination Committee.
2007 ESH-ESC Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension: World Health Organization, International Society of Hypertension Writing Group.
There are roughly 2 types of hypertension management: lifestyle modification and pharmacotherapy. Lifestyle modification is the foundation of hypertension treatment because it is effective for strengthening the effect of hypotensive agents and preventing cardiovascular diseases or other complications from risk factors and lowering BP. However, lifestyle modification alone is often not enough to reach a target BP, which is the reason that pharmacotherapy is required in most cases, and pharmacotherapy should be determined based on the severity of hypertension, risk factors, target organ damage, and underlying clinical conditions.
Proper BP control at an early stage is essential for high-risk patients with hypertension. Hypertension is not easily controlled with only a single agent unless it is mild, and dual combination therapy is recommended from the first for patients with stage 2 or higher hypertension or for high-risk patients.
2007 ESH-ESC Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
The synergistic effect of dual combination therapy provides not only the hypotensive activity but also a better prevention of complications of hypertension. In addition, concomitant use of drugs with different mechanisms of action can offset the potential adverse effects (AEs) of each drug. In this context, various types of fixed-dose combinations have recently been developed and used, revealing improved patient adherence with their convenient regimen.
Currently, diuretics, calcium channel blockers (CCBs), β-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) are widely used as antihypertensive drugs. The 2007 European Society of Hypertension/European Society of Cardiology guidelines for the management of hypertension introduced combination therapies with ACEIs and ARBs, such as ACEI/diuretic, ARB/diuretic, CCB/ARB, and CCB/ACEI, which are superior to other combination therapies. The ARB/CCB combination is particularly recommended as an effective hypotensive combination because ARB relieves the cause of peripheral edema, the major AE of CCB, reducing CCB-related peripheral edema.
2007 ESH-ESC Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
S-AM besylate is one of CCBs that contains active isomer of amlodipine besylate, which was approved for hypertension, fixed coronary artery stenosis (stable angina), or myocardial ischemia caused by coronary vasospasm and vasoconstriction (variant angina). S-AM besylate produces the hypotensive effect at least equivalent to half the dose of previous amlodipine besylate, and the reduced dose is also beneficial for decreasing the rate of AEs, such as edema. With its additional natriuretic activity, S-AM besylate is also effective for hypertension caused by fluid retention (non–renin-dependent hypertension).
Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Telmisartan is an ARB approved for essential hypertension, selectively acting on the receptor of angiotensin II, which is a potent vasoconstrictor in the renin-angiotensin-aldosterone system, and especially on the AT1 receptor, which is involved in important physiologic functions, such as vasoconstriction. The hypotensive effect lasts for >24 hours, even until the next morning, when BP suddenly rises. With its renal excretion rate of <2%, it does not require dosage adjustment in patients with mild or moderate renal impairment and is particularly effective for patients with renin-dependent hypertension.
MICARDIS® MICARDISPLUS® Product monograph Third Edition. Ingleheim am Rhein, Germany: Boehringer Ingelheim.
The objective of this 8-week, double-blind, multicenter, randomized phase III study was to compare the BP-lowering efficacy and safety of switching to fixed-dose combination S-AM plus telmisartan (S-AM/TEL) or TEL monotherapy in Korean patients with hypertension inadequately controlled by TEL monotherapy.
Patients and Methods
Study Population
This was an 8-week randomized, double-blind, multicenter, phase III clinical trial conducted at 9 sites in Korea between January 2012 and November 2012. The Korean Food and Drug Administration and the local ethics review boards of each hospital approved the study protocol.
The study was conducted in accordance with the ethical principles of the current Declaration of Helsinki, and participants signed informed consent forms before any relevant laboratory tests were conducted.
Study participants were ≥18 years old with essential hypertension. Drug-treated patients with diastolic BP (DBP) ≥90 mm Hg and drug-I patients with DBP ≥100 mm Hg were eligible to receive run-in treatment with TEL 40-mg daily or 4 weeks of placebo in a single-blind manner. At randomization (visit 2, day 0), patients with still DBP ≥90 mm Hg were reevaluated to determine whether they still met clause 3 of the inclusion criteria and clause 1 of the exclusion criteria.
Patients were excluded if they had a mean sitting DBP ≥115 mm Hg or a mean sitting systolic BP (SBP) ≥200 mm Hg measured at screening and randomization, a minimum-maximum difference of ≥20 mm Hg in seated SBP or ≥10 mm Hg in seated DBP in the chosen arm at screening, or a difference of ≥20 mm Hg in seated SBP and ≥10 mm Hg a seated DBP in both arms at screening. Patients were also excluded if they had known or suspected secondary hypertension; clinically significant renal, metabolic, hepatic, or psychiatric disorders; clinically relevant or unstable cardiovascular diseases; or poorly controlled diabetes mellitus. In addition, pregnant or nursing women and women of childbearing potential not using medically approved contraception were excluded from study participation. Any antihypertensive or concomitant medications known to affect BP were not permitted during the study.
For each participant, BP of both arms was measured 3 times from each arm, and the arm with the higher mean DBP was selected.
Study Design and Procedures
Participants who received TEL 40-mg monotherapy for the 4-week run-in period but who did not meet their BP goals (mean sitting SBP/DBP of 140/90 mm Hg) and met eligibility at randomization were randomly assigned to receive S-AM/TEL 2.5/40 mg, S-AM/TEL 5/40 mg, or TEL 80 mg and entered the 8-week, double-blind treatment period. SAS software, version 9.2 (SAS Institute, Cary, North Carolina), was used to generate random numbers with the uniform distribution, and participants were randomly assigned to each treatment group in the 1:1:1 ratio. Dose was not adjusted during the 8-week treatment period, and participants in all groups received 4 tablets (the real medicine and a matched placebo of 3 other drugs; CKD Pharma Co, Seoul, Korea) every day once a day in the morning to maintain double-blinding.
Participants should have a medication adherence of at least 80% throughout the trial, and those with medication adherence <80% were considered as having poor adherence and were excluded from the per-protocol (PP) set.
Clinical Evaluation
The primary objective of this study was to evaluate the efficacy of the S-AM/TEL fixed-dose combination by comparing the mean change from baseline in DBP after 8 weeks of treatment among the treatment groups. The secondary objectives of this study were to compare (1) the mean change from baseline in DBP after 4 weeks of treatment, (2) the mean change in SBP from baseline after 4 weeks and 8 weeks of treatment, and (3) the BP response rate, which was defined as the percentage of patients who achieved the target BP (SBP <140 mm Hg or DBP <90 mm Hg) or achieved a decrease of SBP >20 mm Hg or DBP >10 mm Hg.
Safety assessments included monitoring and recording all laboratory tests, adverse events, serious adverse events, and possible association with the study. All laboratory tests, including blood tests, urinalysis, serum biochemistry, and pregnancy tests, were analyzed in the laboratory of each participating center.
Safety Assessment
Safety end points were treatment-emergent AEs, which are defined as any untoward event not present before the administration of the study drug or already present but worsened in either intensity or frequency during treatment. Treatment-emergent AEs included abnormalities found in clinical laboratory tests, physical examinations, and ECG readings.
Statistical Analyses
Frequency and percentage were presented for categorical data, such as sex, whereas descriptive statistics, such as mean, SD, median, minimum, and maximum, were presented for continuous data, such as age. Frequency and percentage in each group were presented for medical history and present illness. Same disease was described only once in the same patient. Concomitant medications taken before administration of the investigational product (IP) were categorized by the Korean Index of Medical Specialties (KIMS) medicinal index. All parameters were assumed as follows: the superiority margin for the difference in the mean sitting DBP between treatments (ε), −3.5 mm Hg; significance level (α), 0.05; power, 0.80 (β = 0.2); and SD (σ), 10.55 mm Hg. An estimated sample size of 168 patients per treatment group would be required, and 325 patients were needed for screening, considering a dropout rate of 20%.
Study patients were allocated in a 1:1:1 ratio by the randomization codes and sufficient size were generated from programming by a specialized statistician using SAS software, version 9.2, in consideration of the prespecified block size. Randomization for this study was conducted by each investigation site in accordance with the Interactive Web Response System. Efficacy data were evaluated in the intent-to-treat population.
Frequency and percentage of participants who have taken each category of concomitant medications were obtained and compared using the χ2 test to investigate whether there was a statistical significance among the groups. To investigate the superiority of the study drug to the comparator, an independent-samples t test was performed for mean difference in BP reductions between the groups. A significant result would indicate that the fixed-dose combination was superior to the monotherapy.
In addition, sitting DBP changes at week 4 and sitting SBP changes at week 4 and week 8 were compared among the groups using independent-samples t test. As described above, control rate and response rate were calculated and compared between the groups using the χ2 test or Fisher exact test. The χ2 test or Fisher exact test was used for comparison for serious AEs (SAEs) and AEs among the groups.
Results
Patient Disposition and Baseline Characteristics
This clinical trial was conducted for 9 months from August 2011 to May 2012 at 18 general hospitals. A total of 325 patients provided written consent form to participate in the study, and 26 of them were screened out for not meeting the inclusion and exclusion criteria (n = 24), for withdrawal of consent (n = 1), and because of abnormal findings on chest radiography (n = 1), leaving 299 patients who entered the TEL monotherapy run-in period (first enrollment). There were 116 first-dropout patients, and the remaining 183 were finally randomly assigned to a group (second enrollment). After randomization, 26 patients were left out of the study for various reasons (second dropout), and the remaining 157 patients completed the study. Participants were randomly assigned to receive S-AM/TEL 2.5/40 mg (n = 61), S-AM/TEL 5/40 mg (n = 60), or TEL 80 mg (n = 62), and 52, 54, and 51 patients in each group completed the study, except for 9, 6, and 11 patients, respectively, who dropped out of the study (second dropout). Patient recruitment and flow are summarized in Figure 1. Mean (SD) age was 53.9 (7.5) years, and male patients comprised 87%. no significant differences among the 3 groups in baseline characteristics (Table I).
Figure 1Flow of patients through the study. Protocol violations included inclusion and exclusion criteria violations, medication nonadherence, contraindicated medications, and visit window violations. ITT = intent to treat; S-AM/TEL= S-amlodipine/telmisartan; TEL = telmisartan 100 mg.
After 8 weeks of double-blind treatment, the changes in mean sitting DBP at 8 weeks compared with baseline were −8.12 mm Hg and −9.88 mm Hg between the TEL 80-mg group and the S-AM/TEL 2.5/40-mg group or S-AM/TEL 5/40-mg group, both indicating a statistically superior hypotensive effect compared with the TEL 80-mg group (P < 0.0001 for both) (Table II). Mean sitting SBP change from baseline to week 8 was −10.56 (7.23) mm Hg in the S-AM/TEL 2.5/40-mg group, −12.32 (9.23) mm Hg in the S-AM/TEL 5/40-mg group, and −2.44 (7.92) mm Hg in the TEL 80-mg group, with both doses of S-AM/TEL having a statistically significant BP reduction at 8 weeks compared with baseline (P < 0.0001 for both) (Figure 2).
Table IIComparison of mean blood pressure change (95% CI) from baseline to each visit between the groups.
Figure 2Systolic blood pressure (SBP) and diastolic blood pressure (DBP) change from baseline to 8 weeks of treatment. The percentage of patients who achieved target blood pressure (SBP <140 mm Hg or DBP <90 mm Hg) or achieved a decrease of SBP of ±20 mm Hg or DBP of ±10 mm Hg at weeks 4 and 8. Asterisk indicates P <0.0001 for the comparison between telmisartan 80 mg and the 2 study drug dose groups.
As the secondary end point, mean sitting DBP change from baseline to week 4 was −9.44 (7.03) mm Hg in the S-AM/TEL 2.5/40-mg group, −12.64 (8.34) mm Hg in the S-AM/TEL 5/40-mg group, and −4.95 (7.78) mm Hg in the TEL 80-mg group, indicating the statistically significant hypotensive effect in all the groups. In terms of the change in mean sitting DBP at 4 weeks compared with baseline, there were difference of −4.49 mm Hg and −7.69 mm Hg between TEL 80-mg group and S-AM/TEL 2.5/40-mg group or S-AM/TEL 5/40-mg group, both indicating a statistically significant hypotensive effect (P < 0.0013 and P < 0.0001, respectively) (Figure 3).
Figure 3Mean change from treated baseline in sitting systolic blood pressure (SBP) and sitting diastolic blood pressure (DBP) at weeks 4 and 8. Asterisk indicates paired t test for change from baseline (week 0). Dagger indicates result of independent-samples t test for comparison between s-amlodipine/telmisartan 9S-AM/Tel) 2.5/40 mg or S-AM/Tel 5/40 mg and TEL 80 mg (P <0.0001). Results of ANOVA for comparison among S-AM/Tel 2.5/40-mg, S-AM/Tel 5/40-mg, and telmisartan 80-mg groups. error bars show SDs.
Mean sitting SBP change from baseline to week 4 was −11.78 (11.80) mm Hg in the S-AM/TEL 2.5/40-mg group, −17.42 (14.94) mm Hg in the S-AM/TEL 5/40-mg group, and −5.36 (11.49) mm Hg in the TEL 80-mg group, with a statistically significant hypotensive effect in all groups. In terms of the change in mean sitting SBP at 4 weeks compared with baseline, there were differences of −6.42 mm Hg and −12.07 mm Hg between the TEL 80-mg group and the S-AM/TEL 2.5/40-mg group or S-AM/TEL 5/40-mg group, both indicating a statistically significant hypotensive effect (P = 0.003 and P < 0.0001, respectively) (Figure 3).
The number of participants who achieved target BP at week 8 (ie, control rate) was 21 patients (35.59%) in the S-AM/TEL 2.5/40-mg group, 24 (40.68%) in the S-AM/TEL 5/40-mg group, and 7 (11.86%) in the TEL 80-mg group, and the response rates were 25.42% (n = 15), 37.29% (n = 22), and 8.47% (n = 5), respectively. Both S-AM/TEL groups had a statistically significant difference compared with the TEL 80-mg group.
Mean (SD) adherence was 97.13% (5.86%) overall, 96.62% (5.37%) in the S-AM/TEL 2.5/40-mg group, 98.36% (4.9%) in the S-AM/TEL 5/40-mg group, and 96.42% (7.01%) in the TEL 80-mg group, with no statistically significant differences among the groups (P = 0.1416).
Safety Evaluation
Among the 181 patients in the safety profile set, 37 (20.44%, 42 cases) experienced at least 1 AE after randomization. There were no significant differences in the incidence of overall AEs, adverse drug reactions (ADRs), and SAEs among the groups (Table III). The most common AE was respiratory disorders, followed by general disorders, central nervous system and peripheral nervous system disorders, skin and appendages disorders, and hepatobiliary disorders.
Table IIINumber (percentage) of AEs in all randomized patients who received at least 1 dose of investigational drug.
There were 2 cases of SAEs reported by 2 patients (1.10%; tonsillitis and hospitalization for tonsillectomy in the S-AM/TEL 2.5/40-mg group and hospitalization for left foot fracture in the S-AM/TEL 5/40-mg group), but none of them were related to the IP. No significant differences were found among the groups in terms of the incidence of overall AEs, ADRs, and SAEs or in weight, vital signs (pulse, body temperature), and laboratory findings after the IP administration.
Discussion
Proper control of BP is essential in patients with hypertension. Therefore, patients without proper BP control despite monotherapy are recommended to use a dual combination, where 2 types of drugs are used to benefit from their synergistic effect on hypotensive activity and to offset adverse effects from monotherapy of each drug. Various types of fixed-dose combinations have been developed recently to improve patient adherence with a more comfortable dosage. A combination of ARB and CCB is particularly effective for decreasing BP and is also recommended because ARB reduces peripheral edema, the main AE of CCB.
This was a confirmatory clinical trial to evaluate the efficacy and safety of S-AM/TEL in patients with hypertension inadequately controlled by TEL monotherapy 40-mg/d. In this study, we found that Korean patients with moderate hypertension who did not achieve their BP goals with initial low-dose TEL monotherapy had significant improvement in BP control after switching to a fixed-dose combination of S-AM/TEL compared with high-dose TEL monotherapy without increasing overall AEs.
The primary efficacy end point was mean sitting DBP change at 8 weeks of treatment compared with baseline to validate the superiority of S-AM 5/TEL 2.5/40 mg or S-AM /TEL 5/40 mg compared with TEL monotherapy 80 mg in decreasing BP. The result indicated that mean sitting DBP reduction was greater in the S-AM /TEL groups compared with the TEL monotherapy group at a 2-sided significance level of ≤0.05, supporting the superiority of S-AM /TEL.
The secondary efficacy end points, sitting DBP at 4 weeks compared with baseline and sitting SBP change from baseline to week 4 and week 8, also supported the superiority of S-AM/TEL compared with TEL monotherapy. Superiority tests for other secondary efficacy end points (control rate and response rate) also indicated statistically significant effect with S-AM/TEL compared with TEL monotherapy.
In addition, the hypotensive effect was compared between the 2 S-AM/TEL groups. The S-AM/TEL 5/40-mg group had a statistically significant additional BP decrease at 4 weeks compared with the S-AM/TEL 2.5/40-mg group. the difference was not statistically significant at 8 weeks, but there was still an increasing trend in the hypotensive effect.
Overall, 42 AEs were reported by 37 patients (20.44%) among the 181 participants in the safety profile set, including 12 cases by 11 participants (18.64%) in the S-AM/TEL 2.5/40-mg group, 15 cases by 12 participants (20.00%) in the S-AM/TEL 5/40-mg group, and 15 cases by 14 participants (22.58%) in the TEL 80-mg monotherapy group, with no statistically significant difference among the groups.
In a clinical trial that compared racemic amlodipine plus TEL combination versus TEL monotherapy, the overall incidence rate of AEs was 22.2% to 34.5% in the TEL monotherapy group compared with 30.1% to 37.5% in the racemic amlodipine plus TEL combination group, but the difference was not significant between the groups.
Telmiartan and amlodipine single-pill combinations vs amlodipine monotherapy for superior blood pressure lowering and improved tolerability in patients with uncontrolled hypertension: results of the TEAMSTA-5 study.
Telmisartan plus amlodipine in patients with moderate or severe hypertension: results from a subgroup analysis of a randomized, placebo-controlled, parallel-group, 4 x 4 factorial study.
In the present study, the overall incidence rate of AEs in the TEL 80-mg group was similar to those in the previous study, but the rates (approximately 20%) in the S-AM/TEL groups were relatively lower than the incidence rate in the previous study.
There were 9 cases of ADRs reported by 8 patients (4.42%) that have a causal relationship with the medication that cannot be ruled out. These ADRs were all mild or moderate and had been reported previously with combinations and monotherapy of each drug on the market. The ADRs were reported by 2 patients (3.39%, 2 cases) in the S-AM/TEL 2.5/40-mg group, 2 patients (3.33%, 2 cases) in the S-AM/TEL 5/40-mg group, and 4 patients (6.45%, 5 cases) in the TEL 80-mg monotherapy group. There were no statistically significant differences among the groups.
Among the ADRs reported in the present study, edema is one of the major AEs of amlodipine, and TEL, when used in combination with amlodipine, is known to reduce the occurrence rate of edema by relieving the cause of edema. In previous studies, the occurrence rate of edema was 1.0% to 8.6% with racemic amlodipine 5 mg and 17% to 27.2% with 10 mg, revealing a greater occurrence rate with increasing dose of amlodipine.
Telmiartan and amlodipine single-pill combinations vs amlodipine monotherapy for superior blood pressure lowering and improved tolerability in patients with uncontrolled hypertension: results of the TEAMSTA-5 study.
Telmisartan plus amlodipine in patients with moderate or severe hypertension: results from a subgroup analysis of a randomized, placebo-controlled, parallel-group, 4 x 4 factorial study.
However, the rate was 1.4% to 5.1% and 3.6% to 7.0% with racemic amlodipine/TEL 5/40 mg and 10/40 mg, respectively, indicating that increasing the dose of amlodipine did not result in a great increase in the occurrence rate of edema as was with the monotherapy.
Telmiartan and amlodipine single-pill combinations vs amlodipine monotherapy for superior blood pressure lowering and improved tolerability in patients with uncontrolled hypertension: results of the TEAMSTA-5 study.
Telmisartan plus amlodipine in patients with moderate or severe hypertension: results from a subgroup analysis of a randomized, placebo-controlled, parallel-group, 4 x 4 factorial study.
In the present study, edema was observed in 1 person each (approximately 1.7%) in the S-AM/TEL 2.5/40-mg group and S-AM/TEL 5/40-mg group, supporting that increasing the dose of S-AM (2.5 to 5 mg) does not result in a higher incidence rate of edema. Furthermore, the rate of edema in the S-AM/TEL 5/40-mg group was relatively lower than the rate with racemic amlodipine 10-mg monotherapy (17% to 27.2%) and even lower than the rate with racemic amlodipine/TEL 10/40-mg combination therapy (3.6% to 7.0%).
Other common AEs of the amlodipine/TEL combination are headache and dizziness. In previous reports, the incidence rate of headache was approximately 4% to 6% with the amlodipine/TEL combination, and the rate of dizziness was 3%.
Telmisartan plus amlodipine in patients with moderate or severe hypertension: results from a subgroup analysis of a randomized, placebo-controlled, parallel-group, 4 x 4 factorial study.
The incidence rates of headache and dizziness were relatively low in the present study, with 1 patient (1.67%) in the S-AM/TEL 5/40-mg group reporting headache, and 1 patient (1.69%) in the S-AM/TEL 2.5/40-mg group reporting dizziness. the causal relationship of these events with the IP was unlikely. In the TEL 80-mg group, headache and dizziness were reported by 2 patients (3.23%) each; a causal relationship with both these ADRs and the IP could not be ruled out. One of the patients discontinued the study because of headache. No other AEs resulted in participant dropout, except for 1 patient (1.61%) in the TEL 80-mg group who discontinued participant in the study because of uncontrolled BP (sitting SBP ≥180 mm Hg) despite the IP administration.
There were 2 cases of SAEs in 2 patients (1.09%) (tonsillitis and hospitalization for tonsillectomy in the S-AM/TEL 2.5/40-mg group and hospitalization for left foot fracture in the S-AM/TEL 5/40-mg group), but none of the cases were related to the IP, and the difference between the groups was not significant. In addition, changes in weight and vital signs (pulse rate and body temperature), physical examination findings, and clinical laboratory findings after the IP administration were also not significantly different among the groups.
In conclusion, this is the first clinical study of S-AM/TEL fixed-dose combinations for the treatment of hypertension. Both S-AM/TEL 2.5/40 mg and S-AM/TEL 5/40 mg were superior to increasing TEL dose in terms of hypotensive effect in patients with hypertension inadequately controlled by TEL monotherapy. As for the tolerability, reported ADRs were all mild or moderate and were not different from the AEs previously reported with the combinations or monotherapies of each drug. The AEs in the combination groups were not significantly different from those reported in the TEL 80-mg group, and an increasing S-AM dose did not result in the occurrence of any unusual AE, suggesting a good tolerance of S-AM/TEL. Taken together, S-AM/TEL is an effective and tolerable option for patients inadequately responding to TEL monotherapy and also a good option for improving patients’ medication adherence.
Conflicts of Interest
The authors have indicated that they have no conflicts of interest regarding the content of this article.
Acknowledgments
This study was sponsored by CKD pharmaceutical company, Seoul, Korea. The sponsor supported the supply of the investigational products, laboratory tests, and clinical research coordinator expenses.
References
2013 Korean Society of Hypertension guidelines for the management of hypertension. Part II: treatments of hypertension.
Ministry of Health, Korea Centers for Disease Control and Prevention, Yonsei University Office of Research Affairs & University – Industry Foundation, In-depth Analysis Report
The 3rd Korea National Health and Nutrition Examination Survey: Examinations.
Korea Centers for Disease Control and Prevention,
Seoul, Korea2007
2007 ESH-ESC Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension: World Health Organization, International Society of Hypertension Writing Group.
Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Telmiartan and amlodipine single-pill combinations vs amlodipine monotherapy for superior blood pressure lowering and improved tolerability in patients with uncontrolled hypertension: results of the TEAMSTA-5 study.
Telmisartan plus amlodipine in patients with moderate or severe hypertension: results from a subgroup analysis of a randomized, placebo-controlled, parallel-group, 4 x 4 factorial study.
Difference 1 is the difference in change between the S-amlodipine/telmisartan 2.5/40-mg and telmisartan 80-mg groups.
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