Abstract
Data from four clinical trials compared reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) among patients treated with amlodipine/losartan 5/50 mg vs 5/100 mg and amlodipine/losartan 5/50 mg vs amlodipine 5 mg and 10 mg. Response rate was assessed as reduction in SBP or DBP (>20/10 mm Hg) and proportion of patients achieving SBP <140 mm Hg or DBP <90 mm Hg. Patients were grouped into quartiles based on baseline SBP and DBP. Mean SBP and DBP were reduced in amlodipine/losartan 5/50 mg (n=182) and amlodipine/losartan 5/100 mg (n=95) users across all baseline quartiles. Patients using amlodipine/losartan 5/50 mg had significantly greater SBP and DBP reductions vs amlodipine 5 mg (P=.001 and P=.02, respectively). Amlodipine/losartan 5/50 mg users had significantly greater SBP reduction vs amlodipine 10 mg (SBP P=.02; DBP P=not significant). The odds of responding to therapy were significantly greater with amlodipine/losartan 5/50 mg vs amlodipine 5 mg (odds ratio, 5.33; 95% confidence interval, 1.42–25.5) and were similar vs amlodipine 10 mg (odds ratio, 0.67; 95% confidence interval, 0.017–9.51). These results support the use of combination therapy early in the treatment of hypertension.
Hypertension is an important modifiable risk factor for cardiovascular disease.1 Hypertension accounts for the greatest mortality burden, accounting for more than 7 million deaths worldwide, more than any other known risk factor.2 Moreover, mortality from stroke and ischemic heart disease doubles for every 20 mm Hg increase in systolic blood pressure (SBP) and every 10 mm Hg increase in diastolic blood pressure (DBP).3 It is estimated that if hypertension control were optimized, cardiac mortality would decline by 49% and cerebrovascular mortality by 62%.4
Hypertension contributes to a high global disease burden and is as prevalent in developing countries as in developed countries.5 Approximately one third of the world's burden of hypertension‐attributable cardiovascular disease is estimated to occur in East Asia, Pacific, Latin American, and Caribbean countries.6 Despite an increasing prevalence and awareness of hypertension and significant advances in effective treatment options, blood pressure (BP) control remains suboptimal.7 Moreover, compared with Western countries, BP control in Asian countries is still far from optimum.8
It is now recognized that treatment with a single antihypertensive agent, regardless of class, achieves the recommended BP target of 140/90 mm Hg in less than half of all patients.9, 10 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines state that more than two thirds of hypertensive individuals will require more than one antihypertensive agent from different drug classes to achieve their BP targets (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease).11 Treatment guidelines recommend that a combination of agents or fixed‐dose combinations (FDCs) be used to initiate therapy in patients with SBP/DBP >20/10 mm Hg above their goal or in those at high risk for cardiovascular complications or as an escalation for patients not controlled on monotherapy.
FDC therapy offers beneficial BP‐lowering effects while minimizing the adverse effects potentially related to the titration of each agent administered individually as monotherapy.12 By improving medication adherence, FDCs improve BP goal attainment, which, in turn, translates to better clinical outcomes.13 In addition, combination therapy has other advantages in terms of renoprotective effects other than controlling hypertension and reducing side effects caused by their synergistic actions.14, 15, 16
COZAAR XQ (Merck & Co., Inc. Whitehouse Station, NJ) is an FDC therapy of amlodipine (5 mg, 10 mg) and losartan (50 mg, 100 mg) for the treatment of essential hypertension. Clinical trials have consistently shown that this FDC has resulted in significantly greater BP reduction compared with amlodipine or losartan monotherapy among patients with both essential hypertension and stage 2 hypertension.17, 18, 19 Losartan and amlodipine are frequently used as first‐line therapies in hypertensive patients,20, 21 and other studies have also outlined the benefits of combining these two drugs.22
To further examine the antihypertensive efficacy and to understand the factors associated with BP target response, we conducted this secondary analysis of pooled amlodipine/losartan clinical trial data. The objectives of this study were (1) to examine the relationship between BP reduction among amlodipine/losartan 5/50 mg and 5/100 mg users and their baseline SBP and DBP status, (2) to examine the differences in patient response rate to therapy between starting dose of amlodipine/losartan (5/50 mg) and trial comparator (amlodipine 5 mg, 10 mg), and (3) to examine the differences in 8‐week mean BP change from baseline in patients treated with amlodipine/losartan (5/50 mg) in comparison with trial comparators.
Methods
Study Design
Data were pooled from four randomized, double‐blind, clinical trials (three phase III and one phase II) that included essential hypertensive patients treated with amlodipine/losartan (HM‐ALOS‐201 [clinicaltrials.gov: NCT00942344]; HM‐ALOS‐301 [ClinicalTrials.gov: NCT00940667; HM‐ALOS‐302 [ClinicalTrials.gov: NCT00940680], HM‐ALOS‐303 [ClinicalTrials.gov: NCT01127217]).17, 18, 19, 23 In all studies, patients provided written informed consent, and study protocols were approved by the appropriate local ethical review boards of each study site.
To assess the overall mean change from baseline in DBP and SBP after 8 weeks among patients treated with amlodipine/losartan 5/50 mg and 5/100 mg, data from all four trials were combined. To compare the response rate and change from baseline in BP after 8 weeks of treatment with amlodipine/losartan 5/50 mg vs amlodipine 5 or 10 mg, data were pooled from two trials (HM‐ALOS‐201 and HM‐ALOS‐303).19, 23 Two trials (HM‐ALOS‐301 and HM‐ALOS‐302) were excluded from the analysis because one (HM‐ALOS‐301) was an amlodipine 5 mg nonresponder study and the other (HM‐ALOS‐302) did not include amlodipine/losartan (5/50 mg) and amlodipine (5, 10 mg).
Patients
The analysis population included patients 18 years or older with essential hypertension (HM‐ALOS‐303 limited to stage II hypertension patients). The baseline demographics were generally similar between the study populations included in the four trials. Mean age was 50 to 55 years, the majority of participants were men (72–81%), and body weight ranged from 68 kg to 72 kg. Mean baseline SBP ranged from 144 mm Hg to 170 mm Hg and mean DBP ranged from 97 mm Hg to 103 mm Hg. All four studies were randomized, double‐blind, multicenter trials conducted in Korea. Three of the four studies were 8‐week phase III trials with 1:1 randomization of two treatment groups (HM‐ALOS‐301, conducted from May to September 2008; HM‐ALOS‐302, conducted from April to November 2008; and HM‐ALOS‐303 conducted May 2009 to March 2010). One study was an 8‐week, phase II trial (HM‐ALOS‐201, conducted from May through December of 2007) with a block randomization code for eight treatment groups (1:1:1:1:1:1:1:1). Before randomization, any prior treatments with antihypertensive drugs were discontinued in all participants. Patients were excluded if the dose was titrated from amlodipine 5 mg to amlodipine 10 mg by week 2 or week 6 of the study HM‐ALOS‐303. Other exclusion criteria were applied according to the exclusion criteria of the individual trials. Patients included in these analyses were maintained on the same dose regimen (amlodipine/losartan 5/50 mg, 5/100 mg, amlodipine 5 mg, or amlodipine 10 mg) for 8 weeks after any run‐in during the trials.
Measures
Throughout the trials, all patients had their BP measured three times at each visit using a mercury sphygmomanometer and the mean value was used. The mean change from baseline in SBP and DBP and response rate were measured and compared between amlodipine users and combination therapy users. Responders were defined as patients with >20 mm Hg reduction from baseline in SBP or >10 mm Hg reduction from baseline in DBP at 8 weeks or having achieved a BP goal of SBP <140 mm Hg or DBP <90 mm Hg at 8 weeks.
Statistical Analysis
Patients who had no protocol violations, received at least one dose of study medication (including the control medication), and had valid 8‐week BP measures were included in the analysis. Descriptive and univariate statistics were used to analyze patient profiles and treatment effect on patient responder rates and BP reduction across treatment arms. The patients were classified into quartiles based on baseline SBP and DBP separately for both doses of amlodipine/losartan use to assess change in BP across each of the arms. The quartile ranges corresponded to Q1: below 25th percentile; Q2: 25th to 50th percentile; Q3: 50th to 75th percentile; and Q4: above 75th percentile of the corresponding baseline SBP and DBP values for each of the amlodipine/losartan. Chi‐square tests were used for categorical data and t tests and analysis of variance were used for continuous variables. Data are reported as mean and standard deviation (SD) for continuous variables and percentage for categorical variables. Two‐sided P values <.05 were considered significant. Multivariate logistic regression, adjusted for covariates including age, sex, height, weight, baseline SBP, baseline DBP, smoking status, drinking status, history of cardiovascular comorbidities, and history of antihypertensive medications was performed to compare treatment effect on patient responder rates across treatment arms, reported as odds ratios and P values. All analyses were performed using SAS version 9.2 (SAS Institute Inc, Cary, NC).
Results
Across the four studies, a total of 182 patients were treated with amlodipine/losartan 5/50 mg and 95 patients were treated with amlodipine/losartan 5/100 mg (Table). The mean age of patients treated with amlodipine/losartan 5/50 mg was 55 years (SD=9.51) and were predominantly men (74.7%). This was similar in the amlodipine/losartan 5/100 group (mean age, 53 years; 70.5% men). Mean BMI was similar for both amlodipine/losartan 5/50 mg (25.8; SD=3.16) and 5/100 mg (25.8; SD=3.24) users. Amlodipine/losartan 5/50 users had an average baseline SBP of 155 (SD=16.9) mm Hg and DBP of 100 (SD=7.4) mm Hg. Amlodipine/losartan 5/100 users had a slightly lower baseline SBP of 146 mm Hg (SD=15.2) and DBP of 98 mm Hg (SD=6.7). Compared with the amlodipine/losartan 5/100 mg users, patients in the amlodipine/losartan 5/50 mg group had a higher proportion of current smokers (5/50 mg: 24.24%, 5/100 mg: 18.9%) and patients with alcohol consumption (5/50 mg: 70.3%, 5/100 mg: 62.1%).
Table 1.
Baseline Patient Characteristics
| Variable, Mean (SD) or No. (%) | Amlodipine 5 mg and Losartan 50 mg (n=182) | Amlodipine 5 mg and Losartan 100 mg (n=95) | Amlodipine 5 mg (n=57) | Amlodipine 10 mg (n=32) |
|---|---|---|---|---|
| Age | 54.98 (9.51) | 52.63 (9.13) | 54.84 (9.03) | 55.53 (9.66) |
| Male | 136 (74.73) | 67 (70.53) | 37 (64.91) | 21 (65.63) |
| BMI | 25.79 (3.16) | 25.81 (3.24) | 24.91 (2.34) | 26.13 (2.77) |
| Baseline SBP | 155.00 (16.89) | 146.05 (15.02) | 157.03 (14.76) | 153.04 (12.9) |
| Baseline DBP | 99.93 (7.40) | 98.29 (6.68) | 100.67 (5.99) | 100.40 (4.55) |
| Current smoking status | 45 (24.73) | 18 (18.95) | 8 (14.04) | 4 (12.5) |
| History of smoking | 84 (46.15) | 47 (49.47) | 23 (40.35) | 15 (46.88) |
| Current alcohol consumption | 128 (70.33) | 59 (62.11) | 34 (59.65) | 22 (68.75) |
| History of alcohol consumption | 137 (75.27) | 64 (67.37) | 37 (64.91) | 25 (78.13) |
| Medical historya | 40 (21.98) | 24 (25.26) | 19 (33.33) | 5 (15.63) |
| Cardiovascular | 8 (4.40) | 3 (3.16) | 2 (3.51) | 0 |
| Cerebrovascular | 1 (0.55) | 2 (2.11) | 1 (1.75) | 0 |
| Diabetes | 7 (3.85) | 2 (2.11) | 3 (5.26) | 2 (6.25) |
| Dyslipidimia | 14 (7.69) | 16 (16.84) | 10 (17.54) | 2 (6.25) |
| Renal | 13 (7.14) | 3 (3.16) | 6 (10.53) | 2 (6.25) |
| History of medication | 116 (63.74) | 64 (67.37) | 34 (59.56) | 18 (56.25) |
| Antidiabetics | 3 (1.65) | 1 (1.05) | 1 (1.75) | 2 (6.25) |
| Concurrent comorbiditya | 33 (18.13) | 21 (22.11) | 18 (31.58) | 4 (12.5) |
| History of hypertension treatment | 109 (59.89) | 59 (62.11) | 32 (56.14) | 18 (56.25) |
Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation.
Concurrent comorbidity included any one with one or more of the conditions such as cardiovascular and cerebrovascular comorbidity, diabetes, dyslipidemia, and renal conditions.
Within the amlodipine/losartan 5/50 mg group, with a baseline SBP range of 123 mm Hg to 199 mm Hg, the quartile limits corresponded to 140 mm Hg for 25th percentile, 159.65 mm Hg for 50th percentile, and 166 mm Hg for 75th percentile. The mean baseline SBP by quartile was 133.98 mm Hg in quartile 1 (Q1), 147.02 mm Hg in quartile 2 (Q2), 162.39 mm Hg in quartile 3 (Q3), and 175.2 mm Hg in quartile 4 (Q4). Similarly, the mean DBP at baseline by quartile was 91.38 mm Hg in Q1, 96.21 mm Hg in Q2, 100.45 mm Hg in Q3, and 109.85 mm Hg in Q4. In patients treated with amlodipine/losartan 5/100 mg, mean baseline SBP by quartile was 133.41 mm Hg in Q1, 142.85 mm Hg in Q2, 147.72 mm Hg mm Hg in Q3, and 156.74 mm Hg in Q4 and baseline mean DBP by quartile was 94.08 mm Hg in Q1, 95.9 mm Hg in Q2, 98.7 mm Hg in Q3, and 103.57 mm Hg in Q4.
At week 8, the mean change in BP among patients treated with amlodipine/losartan 5/50 mg based on quartiles is shown in Figure 1. Patients in Q4 experienced a mean change in DBP of 18.3 mm Hg, while patients in Q1 experienced a mean change in DBP of 8.28 mm Hg. The differences in the mean change in SBP between quartiles were Q4=−37.14, Q3=−32.46, Q2=−14.6, and Q1=−9.81 mm Hg.
Figure 1.
Blood pressure reduction with amlodipine/losartan 5/50 mg categorized based on baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) into quartiles.
Quartile limits for amlodipine/losartan 5/100 mg patients corresponded to a minimum value of 110 mm Hg, 25th percentile of 136.7 mm Hg, 50th percentile of 146 mm Hg, 75th percentile of 154 mm Hg, and a maximum value of 198.7 mm Hg. Similarly, quartile cutoffs for baseline DBP corresponded to a minimum value of 92.7 mm Hg, 25th percentile of 92.7 mm Hg, 50th percentile of 97.3 mm Hg, 75th percentile of 101.3 mm Hg, and a maximum value of 116.7 mm Hg. Figure 2 shows the change in BP among patients treated with amlodipine/losartan 5/100 mg for all quartiles. In patients treated with amlodipine/losartan 5/100 mg, mean changes by quartiles in SBP were −9.49 mm Hg in Q1, −10.82 mm Hg in Q2, −18.69 mm Hg in Q3, and −27.69 mm Hg in Q4, and mean changes by quartile in DBP were −10.33 mm Hg in Q1, −11.63 mm Hg in Q2, −12.67 mm Hg in Q3, and −15.80 mm Hg in Q4. The mean reduction in SBP and DBP was greater in patients in the higher quartile compared with those in the lower quartile.
Figure 2.
Blood pressure reduction with amlodipine/losartan 5/100 mg categorized based on baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) into quartiles.
A total of 155 patients (amlodipine/losartan: n=66; amlodipine 5 mg: n=57; amlodipine 10 mg: n=32) were included in the responder analysis pooled from the trials. Figure 3 shows the proportion of patients treated with amlodipine/losartan who achieved BP response compared with those who treated with amlodipine 5 mg monotherapy. Significantly more patients treated with amlodipine/losartan 5/50 mg achieved a positive response compared with amlodipine 5 mg patients (93.9% vs 80.7%; P=.0297). At 8 weeks, patients treated with amlodipine/losartan also experienced a significantly greater reduction in SBP compared with patients treated with amlodipine 5 mg (30.94 vs 22.08, P=.001). Similarly, patients treated with amlodipine/losartan experienced a significantly greater reduction in DBP compared with patients treated with amlodipine 5 mg (15.73 vs 12.24, P=.02; Figure 4).
Figure 3.
Proportion of patients achieving blood pressure response: amlodipine/losartan 5/50 mg vs amlodipine 5 mg monotherapy.
Figure 4.
Mean blood pressure reduction amlodipine/losartan 5/50 mg vs amlodipine 5 mg monotherapy after 8 weeks. SBP indicates systolic blood pressure; DBP, diastolic blood pressure.
Patients treated with amlodipine/losartan and amlodipine 10 mg both experienced a positive response rate (93.94% vs 96.88%), but this difference was not statistically significant (Figure 5). Figure 6 shows the mean change from baseline in BP with amlodipine/losartan 5/50 mg vs amlodipine 10 mg monotherapy. At 8 weeks of therapy, treatment with amlodipine/losartan resulted in a significantly greater reduction in SBP compared with amlodipine 10 mg (30.94 mm Hg vs 24.71 mm Hg, P=.02) while the reduction in DBP was similar between the two groups (15.73 mm Hg vs 16.54 mm Hg, P=not significant).
Figure 5.
Proportion of patients achieving blood pressure response with amlodipine/losartan 5/50 mg vs amlodipine 10 mg.
Figure 6.
Mean blood pressure reduction with amlodipine/losartan 5/50 mg vs amlodipine 10 mg monotherapy at 8 weeks. SBP indicates systolic blood pressure; DBP, diastolic blood pressure; NS, not signficant.
Multivariate logistic regression adjusted for covariates such as age, sex, height, weight, baseline SBP, baseline DBP, smoking status, drinking status, history of cardiovascular comorbidities, and history of antihypertensive use shows that the odds of response to therapy were significantly greater for patients treated with amlodipine/losartan 5/50 mg compared with amlodipine 5 mg (adjusted OR, 5.33; 95% CI, 1.42–25.5). When compared with amlodipine 10 mg, patients treated with amlodipine/losartan 5/50 mg had similar odds of response to therapy (adjusted OR, 0.67; 95% CI, 0.017–9.51).
Discussion
In this pooled study, we found that patients who took amlodipine/losartan 5/50 mg and 5/100 mg showed a consistent reduction in BP across all quartiles of SBP and DBP. The results show a trend towards greater reduction among patients with higher baseline SBP and DBP. Patients taking amlodipine/losartan 5/50 mg also had a greater rate of BP goal attainment at 8 weeks of treatment compared with those taking amlodipine 10 mg. A large majority (>90%) of uncontrolled hypertension patients responded to the starting dose of amlodipine/losartan (5/50 mg) treatment, with a significantly higher odds of response to the therapy vs the starting dose of amlodipine (5 mg) monotherapy, with a similar odds of response to therapy vs maximum dose amlodipine (10 mg) monotherapy. The starting dose of amlodipine/losartan (5/50 mg) showed greater reductions in both 8‐week mean SBP and DBP from baseline compared with amlodipine 5 mg. When compared with the maximum dose of amlodipine (10 mg), amlodipine/losartan 5/50 mg significantly improved 8‐week mean SBP reduction but had similar 8‐week mean DBP reduction from baseline.
The association between higher baseline BP and increased BP reduction as well as the higher proportion of patients reaching BP goal with amlodipine/losartan FDC provides a representation of the clinical profiles of patients who might benefit from amlodipine/losartan FDC. These findings support guidelines (eg, JNC 7 and European Society of Cardiology) that advocate early initiation with combination therapy consisting of two antihypertensive drugs with complementary mechanisms of action.11
Several combination therapies are shown to be effective in hypertension. Calcium channel blockers and angiotensin‐converting enzyme (ACE) inhibitors have long been considered effective.24 However, their use may be limited in some patients because of the associated higher incidence of side effects compared with angiotensin receptor blockers (ARBs). Consequently, more studies of calcium channel blockers and ARBs have been initiated and proven equally effective as their component monotherapies.25, 26, 27 Although the use of antihypertensive combination therapy has increased substantially in recent years, such therapies are still underutilized.28 FDCs have been associated with improved patient adherence and fewer safety and tolerability issues and have been proven cost‐effective compared with their monotherapy components.29
Study Limitations
A few limitations to be addressed for this study are that the trials included in the analysis were conducted in Korean populations and therefore may limit generalizability to other populations. This may be ameliorated to a certain degree since, unlike ACE inhibitors, ARBs have not been reported to have differences in response to BP reduction based on ethnicity. One study in the analysis was limited to patients with stage 2 hypertension, whereas the others included all patients with essential hypertension. Although this may not be a source of bias due to the randomized design, it is worth mentioning. Our population was generally younger (mean age of 55 years) compared with many trials; therefore, selection bias may be a concern and calls for a larger study in a more diverse population.
Conclusions
The results of this study demonstrated that patients treated with amlodipine/losartan showed significant reductions in BP compared with patients treated with amlodipine alone. In addition, patients treated with dual therapy had a better responder rate for BP reduction compared with patients treated with monotherapy. Our findings support the recommendations of JNC 7 guidelines for management of hypertension, which suggest the use of combination therapy early in the treatment of hypertension.
Acknowledgments and disclosures
Merck & Co., Inc., Whitehouse Station, NJ, provided financial support for the conduct of the study. Editorial assistance was provided by Jennifer Rotonda, PhD, of Merck & Co., Inc. SU is a research fellow at Merck & Co., Inc. DW, MEH, and KPF are employees of Merck & Co., Inc. and may own stock or hold stock options in the company. SR reports personal fees from Merck & Co., Inc. and from Bristol Myers Squibb Inc. outside the submitted work.
J Clin Hypertens (Greenwich). 2014;16:671–677. © 2014 Wiley Periodicals, Inc.
References
- 1. Martiniuk AL, Lee CM, Lawes CM, et al. Hypertension: its prevalence and population‐attributable fraction for mortality from cardiovascular disease in the Asia‐Pacific region. J Hypertens. 2007;25:73–79. [DOI] [PubMed] [Google Scholar]
- 2. Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367:1747–1757. [DOI] [PubMed] [Google Scholar]
- 3. Lewington S, Clarke R, Qizilbash N, et al. Age‐specific relevance of usual blood pressure to vascular mortality: a meta‐analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913. [DOI] [PubMed] [Google Scholar]
- 4. Whitworth JA. 2013 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21:1983–1992. [DOI] [PubMed] [Google Scholar]
- 5. Ezzati M, Lopez AD, Rodgers A, et al. Selected major risk factors and global and regional burden of disease. Lancet. 2002;360:1347–1360. [DOI] [PubMed] [Google Scholar]
- 6. Lawes CM, Vander HS, Rodgers A. Global burden of blood‐pressure‐related disease, 2001. Lancet. 2008;371:1513–1518. [DOI] [PubMed] [Google Scholar]
- 7. Dusing R. Overcoming barriers to effective blood pressure control in patients with hypertension. Curr Med Res Opin. 2006;22:1545–1553. [DOI] [PubMed] [Google Scholar]
- 8. Ahmed T, Prokofyeva E. Hypertension. Burlington, MA: Decision Resources, LLC; 2011. Oct. Report No.: PCORCV0311‐111026. [Google Scholar]
- 9. Philipp T, Anlauf M, Distler A, et al. Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study. HANE Trial Research Group. BMJ. 1997;315:154–159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT‐LLT).JAMA. 2002;288:2998–3007. [DOI] [PubMed] [Google Scholar]
- 11. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252. [DOI] [PubMed] [Google Scholar]
- 12. Zanchetti A, Waeber B. Hypertension: which aspects of hypertension should we impact on and how? J Hypertens Suppl. 2006;24:S2–S5. [DOI] [PubMed] [Google Scholar]
- 13. Bangalore S, Kamalakkannan G, Parkar S, et al. Fixed‐dose combinations improve medication compliance: a meta‐analysis. Am J Med. 2007;120:713–719. [DOI] [PubMed] [Google Scholar]
- 14. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–869. [DOI] [PubMed] [Google Scholar]
- 15. Del Vecchio L, Locatelli F. The renoprotective effect of combined antihypertensive drugs. J Nephrol. 2001;14:7–14. [PubMed] [Google Scholar]
- 16. Osswald H, Muhlbauer B. The pharmacological basis for the combination of calcium channel antagonists and angiotensin converting enzyme inhibitors in the treatment of hypertension. J Hypertens Suppl. 1995;13:S21–S28. [DOI] [PubMed] [Google Scholar]
- 17. Hong BK, Park CG, Kim KS, et al. Comparison of the efficacy and safety of fixed‐dose amlodipine/losartan and losartan in hypertensive patients inadequately controlled with losartan: a randomized, double‐blind, multicenter study. Am J Cardiovasc Drugs. 2012;12:189–195. [DOI] [PubMed] [Google Scholar]
- 18. Kang SM, Youn JC, Chae SC, et al. Comparative efficacy and safety profile of amlodipine 5 mg/losartan 50 mg fixed‐dose combination and amlodipine 10 mg monotherapy in hypertensive patients who respond poorly to amlodipine 5 mg monotherapy: an 8‐week, multicenter, randomized, double‐blind phase III noninferiority study. Clin Ther. 2011;33:1953–1963. [DOI] [PubMed] [Google Scholar]
- 19. Park CG, Youn HJ, Chae SC, et al. Evaluation of the dose‐response relationship of amlodipine and losartan combination in patients with essential hypertension: an 8‐week, randomized, double‐blind, factorial, phase II, multicenter study. Am J Cardiovasc Drugs. 2012;12:35–47. [DOI] [PubMed] [Google Scholar]
- 20. Chiang CE, Wang TD, Li YH, et al. 2010 guidelines of the Taiwan Society of Cardiology for the management of hypertension. J Formos Med Assoc. 2010;109:740–773. [DOI] [PubMed] [Google Scholar]
- 21. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:1004–1010. [DOI] [PubMed] [Google Scholar]
- 22. Kohlmann O Jr, Oigman W, Mion D Jr, , et al. The “LOTHAR” study: evaluation of efficacy and tolerability of the fixed combination of amlodipine and losartan in the treatment of essential hypertension. Arq Bras Cardiol. 2006;86:39–51. [DOI] [PubMed] [Google Scholar]
- 23. Kim SH, Ryu KH, Lee NH, et al. Efficacy of fixed‐dose amlodipine and losartan combination compared with amlodipine monotherapy in stage 2 hypertension: a randomized, double blind, multicenter study. BMC Res Notes. 2011;4:461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high‐risk patients. N Engl J Med. 2008;359:2417–2428. [DOI] [PubMed] [Google Scholar]
- 25. Chrysant SG, Melino M, Karki S, et al. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double‐blind, placebo‐controlled, 8‐week factorial efficacy and safety study. Clin Ther. 2008;30:587–604. [DOI] [PubMed] [Google Scholar]
- 26. Chrysant SG, Oparil S, Melino M, et al. Efficacy and safety of long‐term treatment with the combination of amlodipine besylate and olmesartan medoxomil in patients with hypertension. J Clin Hypertens (Greenwich). 2009;11:475–482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Flack JM, Calhoun DA, Satlin L, et al. Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX‐STAND study. J Hum Hypertens. 2009;23:479–489. [DOI] [PubMed] [Google Scholar]
- 28. Neutel JM. Prescribing patterns in hypertension: the emerging role of fixed‐dose combinations for attaining BP goals in hypertensive patients. Curr Med Res Opin. 2008;24:2389–2401. [DOI] [PubMed] [Google Scholar]
- 29. Ofili EO. Dispelling the myth of “aggressive” antihypertensive therapy. J Clin Hypertens (Greenwich). 2006;8:4–11. [DOI] [PMC free article] [PubMed] [Google Scholar]