Therapeutic Advances in Cardiovascular Disease

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1 Therapeutic Advances in Cardiovascular Disease Original Research Efficacy of amlodipine and olmesartan medoxomil in patients with hypertension: the AZOR Trial Evaluating Blood Pressure Reductions and Control (AZTEC) study Ther Adv Cardiovasc Dis (2010) 4(4) DOI: / ! The Author(s), Reprints and permissions: journalspermissions.nav Henry Punzi, Joel M. Neutel, Dean J. Kereiakes, Ali Shojaee, William F. Waverczak, Robert Dubiel and Jen-Fue Maa Abstract: The aim of the present study was to use ambulatory blood pressure (BP) monitoring (ABPM) to determine the efficacy of a fixed-dose combination of amlodipine (AML) and olmesartan medoxomil (OM) over the 24-hour dosing interval. This 12-week, titrate-to-goal study was conducted in 185 patients with hypertension. Patients were initially treated with AML 5 mg/ day and uptitrated to AML/OM 5/20, 5/40, and 10/40 mg/day every 3 weeks if mean seated BP (SeBP) was 120/80 mmhg. The primary efficacy endpoint was the change from baseline in mean 24-hour systolic BP at week 12 as assessed by ABPM. At baseline, the mean 24-hour ambulatory BP (±standard deviation [SD]) was 144.8±11.1/85.7±7.9 mmhg. At week 12, the change from baseline in mean 24-hour ambulatory BP (±standard error of the mean [SEM]) was 21.4±0.8/ 12.7±0.5 mmhg (p < versus baseline). At baseline, the mean SeBP (±SD) was 158.2±12.6/92.8±8.6 mmhg and at week 12, the mean SeBP change (±SEM) from baseline (last observation carried forward) was 24.1±1.1/ 12.1±0.7 mmhg (p < versus baseline). Proportions of patients achieving mean 24-hour ambulatory BP prespecified study targets were 70.9% (<130/80 mmhg), 48.3% (<125/75 mmhg), and 40.7% (<120/80 mmhg). Cumulatively, 76.8% of patients uptitrated to AML/OM 10/40 mg/day attained an SeBP goal of <140/90 mmhg. The study drug was well tolerated with few adverse events (peripheral edema, 2.2%; dizziness, 1.1%). An AML/OM-based titration regimen effectively reduces BP in patients with hypertension. Keywords: ambulatory blood pressure monitoring, amlodipine, hypertension, olmesartan medoxomil Introduction Hypertension is a major cardiovascular (CV) risk factor, being prevalent in an estimated 73 million adult Americans [Rosamond et al. 2008], and the associated risk of CV disease rises with increasing severity of hypertension [Lloyd-Jones et al. 2005]. Pharmacological intervention plays an important part in treating hypertension with strong observed correlations between aggressive blood pressure (BP) reductions and significant decreases in CV risk [Staessen et al. 2001]. The objective of therapy should be targeted toward achieving BP goals that have demonstrated evidence-based correlation with clinical outcomes [Weber et al. 2004]. BP is often inadequately controlled by treatment with single antihypertensive agents [Cushman et al. 2002]. Combination therapy with two or more complementary antihypertensive agents affects multiple physiological systems involved in BP regulation. Combination therapy generally produces greater BP reductions than monotherapy and can attain control rates in excess of 75% [Neutel et al. 2005]. Improved BP control rates are often achieved without unacceptable increases in the incidence of adverse events (AEs) [Mancia et al. 2007]. Fixed-dose combination therapy may also reduce the risk of nonadherence to prescribed medication. A meta-analysis of four hypertension studies Correspondence to: Henry Punzi, MD Trinity Hypertension Research Institute and Metabolic Research Institute, Punzi Medical Center, 1932 Walnut Plaza, Carrollton, TX 75006, USA punzimedcenter@aol.com Joel M. Neutel, MD Orange County Research Center, Tustin, CA, USA Dean J. Kereiakes, MD The Christ Hospital Heart and Vascular Center and The Carl and Edith Lindner Center for Research and Education at The Christ Hospital, Cincinnati, OH, USA Ali Shojaee, PharmD William F. Waverczak, MS Robert Dubiel, PharmD Jen-Fue Maa, PhD Daiichi Sankyo, Inc., Parsippany, NJ, USA 209

2 Therapeutic Advances in Cardiovascular Disease 4 (4) showed that fixed-dose combinations of a diuretic with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), or an ACE inhibitor with a calcium channel blocker (CCB), significantly decreased the risk of nonadherence by 24% compared with free-drug combination regimens [Bangalore et al. 2007]. Recently, fixed-dose combinations comprising ARBs and dihydropyridine CCBs (DHP-CCBs) have been approved in the United States. ARBs act on the renin angiotensin system (RAS) by blocking the binding of angiotensin II to AT 1 receptors. ARBs reduce CV, renal, and mortality outcomes in patients with chronic kidney disease [Balamuthusamy et al. 2008] and patients at high CV risk [Yusuf et al. 2008b], including those with congestive heart failure [Lee et al. 2004] and poststroke patients [Yusuf et al. 2008a]. DHP-CCBs bind L-type calcium channels in vascular smooth muscle, blocking calcium entry and allowing arterial smooth muscle relaxation. The resultant vasodilation and reduced peripheral resistance causes BP to decrease [Basile, 2004]. The potent vasodilatory activity of CCBs can reinforce the antihypertensive effects of drugs affecting the RAS pathway such as ARBs or ACE inhibitors [Jamerson et al. 2004; Jinno et al. 2004]. The combination of a DHP-CCB (amlodipine [AML]) with an ACE inhibitor (benazepril) provided exceptional BP control in the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) randomized comparative study [Jamerson et al. 2007] and significantly reduced CV mortality/ morbidity compared with the combination of benazepril and hydrochlorothiazide (HCTZ; relative risk, 0.80; 95% confidence interval [CI]: ) [Jamerson et al. 2008]. When coadministered as combination therapy, the actions of one agent may ameliorate the adverse effects of another. Peripheral edema, one of the most common AEs associated with DHP-CCBs, occurs as a result of the arterial vasodilation that promotes BP lowering [Weir, 2003]. This side effect can be reduced by the concomitant administration of ARBs or ACE inhibitors, thus providing greater BP-lowering efficacy with less edema [Weir, 2003; Kuschnir et al. 1996]. Combinations of AML and ARBs have been shown to be safe and effective [Chrysant et al. 2008; Philipp et al. 2007]. In factorial-design clinical studies, it has been shown that combining AML with OM or valsartan (VAL) reduces peripheral edema compared with CCB monotherapy [Chrysant et al. 2008; Philipp et al. 2007]. Furthermore, the incidence of edema decreases in patients who receive an AML/ARB combination following initial AML monotherapy compared with those remaining on AML monotherapy [Schrader et al. 2009; Volpe et al. 2009]. In a pivotal clinical study, the efficacy of an AML + olmesartan medoxomil (OM) combination was demonstrated using office-based seated cuff BP (SeBP) measurements [Chrysant et al. 2008]. Efficacy measurements were recorded in the morning at trough drug levels [Chrysant et al. 2008]. However, achieving BP control throughout the 24-hour dosing interval is important, especially during the last few hours when a BP surge is observed [Gosse et al. 2004]. Ambulatory BP monitoring (ABPM) is a valuable tool for diagnosis and monitoring responses to therapy by allowing assessment over a 24-hour period [Chavanu et al. 2008; Punzi, 1998]. The present study (AZTEC: AZOR Trial Evaluating Blood Pressure Reductions and Control) was conducted to evaluate the efficacy and safety of an AML/OM-based titration regimen in patients with hypertension after 12 weeks of active treatment. ABPM was used to determine whether treatment with the AML/OM based titration regimen enabled BP control over the 24-hour dosing interval. Ambulatory BP and SeBP changes from baseline, the achievement of BP goals and targets, and the tolerability of the AML/OM based titration regimen were also assessed. Patients and methods Study design The AZTEC study was a 16-week prospective, open-label, multicenter (18 sites), single-arm titration study comprising screening, a 3- to 4- week placebo run-in period, and a 12-week active treatment phase. Screening was performed within 14 days of the first dose of placebo run-in medication. Patients underwent physical examinations and provided complete medical histories including the nature of any antihypertensive medication taken during the previous 3 months

3 H Punzi, JM Neutel et al. A 12-lead electrocardiogram was taken in the supine position. Clinical laboratory specimens were taken after 8 hours of fasting. Patients receiving antihypertensive medication were weaned off their treatment for at least 24 hours before receiving the first placebo dose. During the placebo run-in period, patients visited the clinic weekly and compliance was determined by pill count. After the placebo run-in period, qualifying patients received AML 5 mg/day for 3 weeks and were uptitrated as necessary at 3-week intervals to AML/OM 5/20 mg/day followed by AML/OM 5/40 mg/day and AML/OM 10/ 40 mg/day. Medication was administered once daily as a single pill at 08:00 (±90 minutes). In this study, patients were uptitrated to the next dose level if SeBP was 120/80 mmhg, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) definition of normal BP [Chobanian et al. 2003]. Patients with SeBP <120/80 mmhg remained on their current dosage, but if they subsequently exhibited a loss of BP control (seated systolic BP [SeSBP] 140 mmhg and/or seated diastolic BP [SeDBP] 90 mmhg) they were uptitrated to the next dosage level. Patients with SeBP 200/ 110 mmhg or SeBP <120/80 mmhg with symptomatic hypotension at any visit discontinued the study. The study protocol and consent forms were approved by the institutional review board (IRB) of each participating center. The study was conducted in accordance with the IRB committee at each center and the principles of the Declaration of Helsinki. All patients provided written informed consent prior to study participation. Patients Eligible patients were males or females 18 years of age with mean SeSBP 140 mmhg and 199 mmhg or mean SeDBP 90 mmhg and 109 mmhg with a difference between BP readings of 15 mmhg at the last two consecutive qualification visits during the placebo run-in. In addition, patients displayed a mean 8-hour daytime systolic BP (SBP) 135 mmhg and 199 mmhg and mean 8-hour daytime diastolic BP (DBP) <110 mmhg, as measured by ABPM, after completion of the placebo run-in. Eligible women were not breastfeeding, nor pregnant, and were required to practice protocol-approved birth control; were not able to become pregnant due to hysterectomy or were 6 months posttubal ligation; or were 1 year postmenopause. Patients were excluded if they had a nondominant arm circumference <24 cm or >42 cm (when arm extended, upper arm midpoint circumference) or if they had a serious disorder that limited the ability to evaluate the efficacy or safety of AML/OM including renal, CV, pulmonary, hepatic, gastrointestinal, neurologic, psychiatric, endocrine/metabolic, hematologic, and oncologic (including malignancy except basal cell carcinoma) diseases. A history of myocardial infarction, coronary angioplasty, angina, heart failure, or bypass surgery in the previous 6 months or transient ischemic attack or cerebrovascular accident in the preceding 12 months was exclusionary. Patients with type 1 diabetes mellitus were excluded. Patients with type 2 diabetes were allowed to enter the study if stable on treatment for at least 4 weeks, with a fasting plasma glucose <160 mg/dl at screening. Other exclusion criteria included: noncompliance (<80% medication use during placebo run-in); night shift workers; clinically significant cardiac conduction defects; hemodynamically significant valvular disease; angioneurotic edema; prior allergic response to any CCB or angiotensin II antagonist; and drug or alcohol abuse within the preceding 2 years. A range of medications were excluded that may have interfered with the evaluation of efficacy and tolerability of the study drugs, such as a range of antihypertensive medications including diuretics (thiazide, loop, and potassium-sparing), antiadrenergics, alpha- and beta-blockers, CCBs, ACE inhibitors, vasodilators, and angiotensin II antagonists. Efficacy and tolerability assessments Efficacy analyses were based on the intentto-treat population, defined as all patients who received at least one dose of study medication and had a baseline and at least one postbaseline BP measurement. Patients in the safety population received at least one dose of study medication. SeBP measurements were taken at trough drug levels and were completed before 10:00 using a validated automatic BP-monitoring device (Omron). Following a 5-minute rest period, three separate BP measurements were taken with 2-minute intervals and the cuff was deflated between readings. The mean of three readings was recorded as the SeBP value for the visit. SeBP readings were recorded at screening, once weekly during the placebo run-in, at day 1, 211

4 Therapeutic Advances in Cardiovascular Disease 4 (4) and at weeks 3, 6, 9, and 12 of the active treatment period. In order to determine the primary efficacy endpoint, BP was assessed by ABPM at the end of the placebo run-in period and at week 12 (end of study). On the day of an ABPM assessment patients refrained from taking their study medication until permitted during the clinic visit. At 08:00±1.5 hours, patients were fitted with an ABPM oscillometric device (SpaceLabs 90207; Issaquah, WA, USA) on the nondominant arm. The ABPM device was manually triggered to record BP, and study medication was then administered. After a further manual reading was taken (START TEST), BP was automatically recorded every 20 minutes until at least 08:00 the following day. Safety variables were assessed throughout the placebo run-in and treatment periods, and compliance with study medication was determined by tablet count. Safety variables were assessed by monitoring AEs, changes in vital signs, or physical and laboratory findings. Medical histories were obtained during screening and at week 12. Laboratory analyses including pregnancy tests, serum chemistry, urinalysis, and complete blood counts were performed after 8 hours fasting at screening and week 12. The primary efficacy variable was the change from baseline in mean 24-hour SBP after 12 weeks of treatment, as measured by ABPM. Secondary ambulatory BP variables at week 12 included the change from baseline in mean 24- hour DBP; changes from baseline in mean ambulatory SBP and DBP during the daytime (08:00 16:00), nighttime (00:00 06:00), and the last 2, 4, and 6 hours of dosing; and the proportion of patients achieving various BP targets of <130/80, <125/75, and <120/80 mmhg during 24 hours, daytime, and nighttime and the last 2, 4, and 6 hours of the dosing period. Secondary variables determined by SeBP measurements included changes from baseline in mean SeSBP and SeDBP at 12 weeks in the total cohort and by titration period and the proportions of patients achieving the SeBP goals of <140/90, <130/80, or <120/80 mmhg by titration period. Statistical analysis A planned sample size of approximately 150 patients provided 99% power for demonstrating the within-group ambulatory SBP reduction from baseline to week 12 would be significantly greater than zero. The primary efficacy variable was assessed using a one-sample t-test, and p-values were provided. This statistical test was performed using a two-sided significance level of 5%. The last observation carried forward (LOCF) method was used for the analysis of SeBP changes from baseline. Achievement of ambulatory BP targets was calculated using the number of subjects having both baseline and endof-study ABPM values as the denominator. For SeBP goal rates, cumulative percentages of patients that achieved each BP goal anytime during the active treatment were calculated using the total number of patients in the treatment cohort as the denominator. Results Patient disposition and baseline characteristics A total of 325 patients were screened, of whom 290 entered the placebo run-in period (Figure 1). For the active treatment period, 185 patients met the inclusion criteria. Reasons for withdrawal during the placebo run-in phase are shown in Figure 1. The efficacy and safety populations included all 185 patients who received active treatment. Validated ABPM assessments at both baseline and end of study were available for 172 patients. The mean age of the 185 patients was 56.8 years, with a greater proportion of males than females (Table 1). Patients were primarily White, with approximately 14% and 8% of Black and Asian individuals, respectively, enrolled. Approximately one quarter of the population had diabetes. Baseline mean ambulatory BP (±standard deviation [SD]) for the 172 patients with baseline and end-of-study ambulatory BP values were 144.8±11.1 and 85.7±7.9 mmhg, respectively. Baseline mean SeBP (± SD) was 158.2±12.6 and 92.8±8.6 mmhg, respectively, and 55.7% of patients had Stage 2 hypertension. Of the eight patients who discontinued the study, three were due to AEs, four were at the patients own requests, and one was lost to follow up. At the end of treatment, 134 patients were uptitrated to AML/OM 10/40 mg/day. Two patients with baseline and end-of-study ambulatory BP measurements remained on AML 5 mg/day. Efficacy For the primary efficacy endpoint at week 12, the treatment regimen produced a 24-hour mean ambulatory SBP (± standard error of the mean 212

5 H Punzi, JM Neutel et al. Screened (n=325) Entered placebo run-in (n=290) Entered active treatment (n=185) Withdrew (n=105): Did not meet inclusion/exclusion criteria (71) Patient request (14) Uncontrolled BP (6) Adverse event (5) Lost to follow-up (4) Non-compliance (3) Other (2) Safety cohort (n=185) Efficacy cohort (n=185) Withdrew (n=8): Adverse event (3) Patient request (4) Lost to follow-up (1) Medication received: AML 5 mg (n=185) AML/OM 5/20 mg (n=180) AML/OM 5/40 mg (n=161) AML/OM 10/40 mg (n=134) Completed study (n=177) ABPM at baseline and week 12 (n=172) Figure 1. Patient disposition. ABPM, ambulatory blood pressure monitoring; AML, amlodipine; OM, olmesartan medoxomil. Table 1. Baseline characteristics of patients (efficacy population; N ¼ 185). Mean age, years±sd (range) 56.8±9.3 ( ) Race, n (%) White 144 (77.8) Black 26 (14.1) Asian 14 (7.6) Native American/Alaskan 1 (0.5) Gender, n (%) Male 105 (56.8) Female 80 (43.2) Mean weight, kg±sd 88.7±19.6 Mean height, cm±sd 167.9±12.1 Mean SeSBP/SeDBP, mmhg±sd 158.2±12.6/92.8±8.6 Mean 24-hour ambulatory SBP/DBP a, mmhg±sd 144.8±11.1/85.7±7.9 Hypertension stage, n (%) Stage 1 82 (44.3) Stage (55.7) Diabetes, n (%) 46 (24.9) a Patients with both a baseline and week 12 ambulatory blood pressure (BP) measurement (n ¼ 172). DBP, diastolic BP; SBP, systolic BP; SD, standard deviation; SeDBP, seated DBP; SeSBP, seated SBP. [SEM]) change from baseline of 21.4 (±0.8) mmhg (p < ; Figure 2a). For the secondary endpoint, a 24-hour mean ambulatory DBP (±SEM) change from baseline of 12.7 (±0.5) mmhg was observed (p < ; Figure 2a). The treatment regimen reduced SBP from baseline throughout the 24-hour dosing interval (Figure 2b). The profile of mean hourly DBP measurements also showed reductions from baseline during the entire 24-hour period (Figure 2c). Active treatment also reduced mean ambulatory BP (±SEM) from baseline during the daytime by 23.1±0.9/ 14.0±0.6 mmhg, and during the 213

6 Therapeutic Advances in Cardiovascular Disease 4 (4) (a) 0 SBP DBP SBP DBP Change from baseline (mmhg) Change from baseline (mmhg) Mean DBP (mmhg) (b) Dosing 12.7 End of study (c) Dosing Time (h) Baseline End of study Last hours of dosing interval Daytime Nighttime 2 hours 4 hours 6 hours Mean 24-hour DBP 85.7 mmhg Mean 24-hour DBP 73.0 mmhg SBP DBP Mean SBP (mmhg) Baseline Time (h) Mean 24-hour SBP mmhg Mean 24-hour SBP mmhg (d) Figure 2. Efficacy of amlodipine/olmesartan medoxomil titration regimen. (a) Change from baseline in mean ambulatory systolic blood pressure (SBP; primary endpoint) and diastolic blood pressure (DBP) at week 12 in patients with both a baseline and week 12 ambulatory blood pressure measurement (n ¼ 172; ±standard error of the mean [SEM]; p < versus baseline for all reductions). (b) Hourly mean SBP at baseline and end of study. (c) Hourly mean DBP at baseline and end of study. (d) Change from baseline in mean ambulatory SBP and DBP during the daytime (08:00 16:00), nighttime (00:00 06:00), and the last 2, 4, and 6 hours of the 24- hour dosing interval at week 12 (n ¼ 172; ±SEM; p < versus baseline for all reductions)

7 H Punzi, JM Neutel et al. End of study (LOCF) End of titration period Change from baseline (mmhg) Week 12 N= AML 5 mg n= AML/OM 5/20 mg n= AML/OM 5/40 mg n= AML/OM 10/40 mg n= SBP DBP Figure 3. Change from baseline in mean seated BP (SeBP) (±standard error of the mean) at the end of study (LOCF) and at the end of each titration period (p < versus baseline for all reductions). AML, amlodipine; BP, blood pressure; DBP, diastolic BP; LOCF, last observation carried forward; OM, olmesartan medoxomil; SBP, systolic BP. Patients achieving BP target (%) hour Daytime Nighttime Last 2 hrs Last 4 hrs Last 6 hrs <130/80mmHg <125/75mmHg <120/80mmHg Figure 4. Proportions of patients achieving ambulatory SBP/DBP targets at week 12, during 24 hours, daytime (08:00 16:00), nighttime (00:00 06:00), and the last 2, 4, and 6 hours of the dosing interval. BP, blood pressure; DBP, diastolic BP; SBP, systolic BP. nighttime by 18.5±0.9/ 10.9±0.6 mmhg (all p < ; Figure 2d). Clinically meaningful BP reductions from baseline were also seen during the last 2, 4, and 6 hours of the dosing interval (Figure 2d). The change from baseline in mean SeSBP (±SEM) at week 12 (LOCF) was 24.1 (±1.1) mmhg for the efficacy population of 185 patients (p < ; Figure 3). The change from baseline in mean SeDBP (±SEM) was 12.1 (±0.7) mmhg. As the dosage was uptitrated, changes from baseline in mean SeBP for patients uptitrated to the higher dose increased from 10.1/ 4.7 mmhg (AML 5 mg/day) to 24.6/ 12.3 mmhg (AML/OM 10/40 mg/day; Figure 3). The AML/OM treatment regimen enabled patients to achieve a series of prespecified 24-hour ambulatory BP targets (Figure 4). The proportions of patients achieving these targets were 70.9% (<130/80 mmhg), 48.3% (<125/75 mmhg), and 40.7% (<120/80 mmhg). Similar trends were seen during the daytime, nighttime, and last 2, 4, and 6 hours (Figure 4) of the dosing period. The effect of the treatment regimen on dipper status was assessed. Dippers were defined as 215

8 Therapeutic Advances in Cardiovascular Disease 4 (4) Table 2. Cumulative proportions of patients achieving seated blood pressure (SeBP) goals. SeBP goals Treatment <140/90 mmhg <130/80 mmhg <120/80 mmhg n (%) n (%) n (%) AML 5 mg/day 44 (23.8) 7 (3.8) 1 (0.5) AML/OM 5/20 mg/day 88 (47.6) 26 (14.1) 5 (2.7) AML/OM 5/40 mg/day 124 (67.0) 38 (20.5) 10 (5.4) AML/OM 10/40 mg/day 142 (76.8) 56 (30.3) 17 (9.2) AML, amlodipine; OM, olmesartan medoxomil. patients with a nocturnal decrease in SBP and/or DBP 10% of the mean daytime SBP and/or DBP. At the end of the study (week 12), 19 patients (11.0%) who were ABPM nondippers at baseline were considered ABPM dippers, while 23 patients (13.4%) who were ABPM dippers at baseline were considered ABPM nondippers. The majority of patients (75.6%) had no change in dipper status between baseline and week 12. For patients who received AML 5 mg/day, 23.8% of patients attained the SeBP goal of <140/90 mmhg (Table 2). More patients achieved the SeBP goal of <140/90 mmhg as treatment was intensified. Cumulatively, 76.8% of patients who were uptitrated to a highest dose level of AML/OM 10/40 mg/day reached the SeBP goal of <140/90 mmhg during the titration period. Safety and tolerability Across the 12-week period, 58 patients (31.4%) reported at least one treatment-emergent AE (TEAE) (Table 3). AEs caused three patients to discontinue the study (hypoesthesia and paraesthesia [mild severity]; hypersensitivity [moderate severity]; transient ischemic attack [moderate severity]). No patients discontinued the study due to symptomatic hypotension. AEs were lower during AML monotherapy compared with combination therapy. The majority of TEAEs were mild to moderate in severity and were unrelated to drug treatment. The most common TEAEs were coded to the system organ classes of infections and infestations, musculoskeletal and connective tissue disorders, nervous system disorders, and general disorders. The most frequently reported of these were nasopharyngitis (6.5%), peripheral edema (3.2%), upper respiratory tract infection (2.7%), dizziness and bronchitis (2.2% each; Table 3). Only 14 patients (7.6%) experienced drug-related (DR) TEAEs. The most common DR TEAE was peripheral edema (4/185, 2.2%). Other DR TEAEs were low: two patients experienced dizziness and no patients reported headache, orthostatic hypotension, or hypotension. Discussion The present study is the first reported use of ABPM to determine the efficacy of a fixed-dose combination of AML/OM therapy. The major efficacy finding of this study is that an AML/ OM-based titration regimen significantly reduced BP throughout the 24-hour dosing interval in patients with hypertension. Safety analysis of the titration regimen showed that treatment was well tolerated. This open-label, single-arm titration study was designed to enroll similar numbers of patients with stage 1 and 2 hypertension. After a 3- to 4-week placebo run-in period, hypertension was confirmed by ABPM. This reduced the risk of enrolling patients with white coat hypertension, which is sometimes apparent during office SeBP assessments. These ABPM measurements also provided the study baseline values for the primary efficacy endpoint. SeBP measurements were used to determine whether patients required dose titration, based on a target of <120/ 80 mmhg, and allowed comparisons with other studies and benchmarking against treatment guidelines. The reduction in mean SeBP at week 12/LOCF was comparable with other studies using AML/ OM combination therapy [Volpe et al. 2009; Chavanu et al. 2008]. In the COACH (Combination of Olmesartan medoxomil and Amlodipine besylate in Controlling High blood 216

9 H Punzi, JM Neutel et al. Table 3. Treatment-emergent adverse events (TEAEs). AML 5 mg/day (n ¼ 185) AML/OM 5/20 mg/day (n ¼ 180) AML/OM 5/40 mg/day (n ¼ 161) AML/OM 10/40 mg/day (n ¼ 134) Active treatment period a (N ¼ 185) Patients with any TEAE, n (%) 17 (9.2) 35 (19.4) 27 (16.8) 29 (21.6) 58 (31.4) Discontinuation due to AE, n (%) 1 (0.5) 0 (0.0) 1 (0.6) 1 (0.7) 3 (1.6) TEAEs reported by at least 2% of patients in the safety cohort General disorders and administration site conditions 4 (2.2) 7 (3.9) 2 (1.2) 3 (2.2) 9 (4.9) Peripheral edema 3 (1.6) 5 (2.8) 2 (1.2) 2 (1.5) 6 (3.2) Infections and infestations 5 (2.7) 19 (10.6) 12 (7.5) 11 (8.2) 29 (15.7) Bronchitis 2 (1.1) 2 (1.1) 2 (1.2) 0 (0.0) 4 (2.2) Nasopharyngitis 1 (0.5) 9 (5.0) 2 (1.2) 5 (3.7) 12 (6.5) Upper respiratory tract infection 1 (0.5) 4 (2.2) 3 (1.9) 2 (0.7) 5 (2.7) Musculoskeletal and connective tissue disorders 3 (1.6) 7 (3.9) 6 (3.7) 9 (6.7) 12 (6.5) Back pain 0 (0.0) 2 (1.1) 1 (0.6) 1 (0.7) 3 (1.6) Joint swelling 1 (0.5) 2 (1.1) 2 (1.2) 3 (2.2) 3 (1.6) Nervous system disorders 4 (2.2) 4 (2.2) 4 (2.5) 3 (2.2) 9 (4.9) Dizziness 2 (1.1) 3 (1.7) 2 (1.2) 1 (0.7) 4 (2.2) Drug-related TEAEs of interest, n (%) Patients with any drug-related TEAE, n (%) 5 (2.7) 9 (5.0) 4 (2.5) 4 (3.0) 14 (7.6) Peripheral edema 2 (1.1) 3 (1.7) 1 (0.6) 1 (0.7) 4 (2.2) Dizziness 1 (0.5) 1 (0.6) 0 (0.0) 0 (0.0) 2 (1.1) Hypotension 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) a Individual adverse events (AEs) were counted only once in the calculation for the entire active treatment period (they were not counted multiple times if they persisted after uptitration to the next dose level). AML, amlodipine; OM, olmesartan medoxomil

10 Therapeutic Advances in Cardiovascular Disease 4 (4) pressure) study, where no dose titration was employed during the factorial-design period, AML/OM 10/40 mg/day produced changes from baseline in mean SeBP of 30.1/ 19.0 mmhg at week 8 [Chrysant et al. 2008]. Patients in the COACH study had predominantly stage 2 hypertension with a mean baseline SeBP of 164/102 mmhg. In a separate factorial design study in patients with a similar mean baseline SeBP, a combination of AML/OM 5/40 mg/day provided an additional SeBP change of 16.8/ 9.6 mmhg in patients previously treated with AML 5 mg/day [Volpe et al. 2009]. The present study addresses an important aspect of therapy: whether BP control was maintained over 24 hours, particularly during the important last hours of the dosing interval [Gosse et al. 2004; Muller et al. 1989]. Treatment with AML/OM reduced BP throughout the dosing interval for the population as a whole without affecting the normal diurnal oscillation of the BP profile. Ambulatory SBP changes from baseline ranged from 18.8 to 20.6 mmhg over the last 6, 4, and 2 hours of the dosing period after 12 weeks of treatment. This suggests that efficacy was maintained at trough levels of the study drug. Most patients (180/185) received AML/ OM combination therapy, and the continued efficacy of the treatment at the end of the dosing interval was consistent with the pharmacokinetic profiles of these agents when administered concomitantly [Rohatagi et al. 2008]. Over 70% of patients in this study achieved a mean 24-hour BP target of <130/80 mmhg, and over 75% of patients achieved the SeBP goal of <140/90 mmhg. Similar numerical changes from baseline in mean 24-hour and mean SeBP were observed at week 12. The lower rates of achievement of SeBP goals reflected the higher baseline SeBP values compared with the baseline 24-hour ambulatory BP measurement. SeBP measurements were normally recorded at the time when BP was at its highest and coincided with trough drug levels. The titration schedule reported here reflects a common clinical situation where treatment is initiated with antihypertensive monotherapy and uptitrated with the addition of an agent with a complementary mechanism of action. The efficacy of the AML/OM titration regimen is consistent with other studies of these agents. In a previous study where patients were treated with AML 5 mg/day for 8 weeks and then entered a randomized double-blind treatment period, the addition of OM doses up to 40 mg/day allowed a greater proportion to reach SeBP goals of <140/90 mmhg, or <130/80 mmhg for patients with diabetes, compared with maintenance therapy with the CCB alone [Volpe et al. 2009]. This study supports the observation that the majority of patients with hypertension fail to reach their BP goal when receiving monotherapy in that <24% of patients taking AML 5 mg/day achieved the BP goal of <140/90 mmhg. Despite hypertension treatment guidelines that recommend commencing therapy using combinations for many patients, fixed-dose antihypertensive drugs have only recently received indications for use as first-line therapy. Evidence to support the justification for these new indications has been provided by algorithms that predict the probability of patients achieving BP goals on monotherapy alone. Fixed-dose antihypertensives with an indication for use as first-line therapy include the following combinations: AML/OM, AML/VAL, VAL/HCTZ, and aliskiren/hctz. In addition to measuring BP-lowering efficacy, this study has investigated the impact on tolerability of such a strategy. Future guidelines may incorporate lower BP thresholds than are currently in place but may be difficult to implement unless physicians are confident that their patients are not exposed to unwelcome side effects. The present study demonstrated that it is possible to safely treat to aggressive BP targets because this AML/OM treatment regimen was well tolerated. Hypotension, an AE sometimes associated with large BP reductions, was not reported, and only two patients on AML/OM therapy discontinued due to DR TEAEs. Peripheral edema, a frequently reported DR TEAE associated with AML treatment, was reported in only 2.2% of patients. The combination of AML with OM [Volpe et al. 2009; Chrysant et al. 2008] or VAL [Schrader et al. 2009; Philipp et al. 2007] generally reduces edema incidence compared with AML monotherapy. In a long-term study, reduced incidence of peripheral edema has also been reported in patients administered AML/ OM therapy compared with AML alone [Chrysant et al. 2009]. There are no generally accepted values for ambulatory BP targets because treatment guidelines 218

11 H Punzi, JM Neutel et al. have tended to focus on office BP goals. The JNC 7 notes that awake patients with hypertension have an average BP > 135/85 mmhg as measured by ABPM [Chobanian et al. 2003]. The American Heart Association has suggested normal values for ambulatory BP during the daytime (<135/85 mmhg), nighttime (<120/ 70 mmhg), and over 24 hours (<130/ 80 mmhg) based on correspondence between these values and office BP [Pickering et al. 2005]. The Canadian Hypertension Education Program also recommends a daytime ambulatory BP <135/85 mmhg [Campbell et al. 2009]. A recent American Society of Hypertension position paper on when and how to use home (self) and ABPM recommends normal limits for 24- hour and daytime ambulatory BP targets with a sleeping (nighttime) limit of 120/75 mmhg [Pickering and White, 2008]. In the study described here, 69.2% of patients achieved an ambulatory BP of <135/85 mmhg during the daytime and 70.9% achieved <130/80 mmhg during the 24-hour dosing period at week 12. The ambulatory BP targets of <120/70 mmhg or <120/75 mmhg were not assessed in this study, although 69.8% of patients achieved a BP of <120/80 mmhg during the nighttime period. Many patients with hypertension do not reach their recommended BP goal due to clinical or therapeutic inertia. Therapeutic inertia is the failure to intensity therapy, either by increasing the dosage of current medications or adding different agents in order to achieve BP control [Okonofua et al. 2006]. Fixed-dose combinations have been proposed as a strategy to aid adherence and address issues that may contribute to therapeutic inertia [Elliott, 2008]. The limitations of this study include the openlabel and single-arm design. The study did not determine the long-term efficacy of the AML/ OM combination and did not examine patient outcomes. In addition, patients were treated to a more aggressive SeBP target than that suggested by treatment guidelines. However, in patients with stage 1 or 2 hypertension, a stepwise AML/OM titration regimen was well tolerated and produced robust BP reductions from baseline that were maintained throughout the 24-hour dosing interval. This study provides further evidence to support the use of fixed-dose antihypertensive drug combinations for the effective management of hypertension. Acknowledgements This study was supported by Daiichi Sankyo, Inc. We thank Maxwell Chang, BSc, and Christopher J. Jones, PhD, of inscience Communications, a part of the Wolters Kluwer organization, for providing medical writing support funded by Daiichi Sankyo, Inc. Conflict of interest statement Henry Punzi, MD, received a research grant from Daiichi Sankyo, Inc. Joel M. Neutel, MD, is a member of the speaker s bureau for Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Daiichi Sankyo, Inc., and sanofi-aventis. Dean J. Kereiakes, MD, has received research grants from Pfizer, Cordis (Johnson & Johnson), Boston Scientific, Medtronic, and Daiichi Sankyo, Inc. Ali Shojaee, PharmD, William F. Waverczak, MS, Robert Dubiel, PharmD, and Jen-Fue Maa, PhD, are employed by Daiichi Sankyo, Inc. References Balamuthusamy, S., Srinivasan, L., Verma, M., Adigopula, S., Jalandara, N., Hathiwala, S. et al. (2008) Renin angiotensin system blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis. Am Heart J 155: Bangalore, S., Kamalakkannan, G., Parkar, S. and Messerli, F.H. (2007) Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 120: Basile, J. (2004) The role of existing and newer calcium channel blockers in the treatment of hypertension. J Clin Hypertens (Greenwich) 6: Campbell, N.R., Khan, N.A., Hill, M.D., Tremblay, G., Lebel, M., Kaczorowski, J. et al. (2009) 2009 Canadian Hypertension Education Program recommendations: the scientific summary an annual update. Can J Cardiol 25: Chavanu, K., Merkel, J. and Quan, A.M. (2008) Role of ambulatory blood pressure monitoring in the management of hypertension. Am J Health Syst Pharm 65: Chobanian, A.V., Bakris, G.L., Black, H.R., Cushman, W.C., Green, L.A., Izzo Jr, J.L. et al. (2003) The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA 289:

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