Hypertension is the leading risk factor for cardiovascular

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1 Original Paper The Effects of an Olmesartan Medoxomil Based Treatment Algorithm on 24-Hour Blood Pressure Levels in Elderly Patients Aged 65 and Older Dean J. Kereiakes, MD; 1 Joel Neutel, MD; 2 Kathy A. Stoakes, RN, BSN; 3 William F. Waverczak, MS; 3 Jianbo Xu, MS; 3 Ali Shojaee, PharmD; 3 Robert Dubiel, PharmD 3 This study examined the effect of olmesartan medoxomil (OM) hydrochlorothiazide (HCTZ) on mean 24-hour ambulatory blood pressure, mean seated cuff (Se) blood pressure (BP), and SeBP goal achievement in elderly (65 years and older) patients with hypertension. After a 2- to 3-week placebo run-in period, patients received OM 20 mg, up-titrated to OM 40 mg, and then added HCTZ 12.5 mg to 25 mg in a stepwise manner at 3-week intervals if SeBP remained mm Hg. The primary end point was change from baseline in mean 24-hour ambulatory systolic BP. At study end, mean 24-hour ambulatory BP had decreased by mm Hg (n=150) and mean SeBP by mm Hg (n=176; all P< vs base- From The Christ Hospital Heart and Vascular Center and the Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, OH; 1 the Department of Clinical Pharmacology, Orange County Research Center, Tustin, CA; 2 Medical Affairs, Daiichi Sankyo, Inc., Parsippany, NJ 3 Address for correspondence: Dean J. Kereiakes, MD, Medical Director, the Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, 2123 Auburn Avenue, Suite 424, Cincinnati, OH lindner@fuse.net Manuscript received April 30, 2009; revised May 29, 2009; accepted June 1, 2009 doi: /j x line). Drug-related treatment-emergent adverse events, most commonly dizziness (3.4%), hypotension (2.2%), and headache (1.1%), were observed in 11.8% of patients. An OM-based treatment algorithm effectively lowers BP in an elderly patient population throughout the 24-hour dosing interval without compromising tolerability. J Clin Hypertens (Greenwich). 2009;11: ª 2009 Wiley Periodicals, Inc. Hypertension is the leading risk factor for cardiovascular morbidity and mortality worldwide. The incidence of hypertension increases with age, as does the risk of experiencing fatal cardiovascular disease. 1 3 Approximately two thirds of adults older than 60 years in the United States are classified as hypertensive, almost twice the prevalence of that seen in younger individuals. 4 Moreover, the most recent National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004 showed an increase of approximately 10% in hypertension prevalence among the elderly (aged 60 years and older) compared with the previous survey ( ). 5 The development of hypertension in elderly individuals is mainly due to an increase in systolic blood pressure (SBP), which occurs as a result of normal aging of the cardiovascular system, and is an independent predictor of fatal cardiovascular disease in the elderly. 1,2,6,7 VOL. 11 NO. 8 AUGUST 2009 THE JOURNAL OF CLINICAL HYPERTENSION 411

2 Previous studies have demonstrated a reduction in cardiovascular events with antihypertensive treatment in elderly patients with hypertension Data from long-term clinical trials show that elderly patients with either uncontrolled SBP diastolic blood pressure (DBP) or isolated systolic hypertension (ISH) derive a greater benefit from treatment compared with younger individuals. 13,14 Clinical inertia is a particular problem in the management of hypertension, and older age is associated with greater clinical inertia. 15 This phenomenon is due to the failure of health care providers to increase the intensity of treatment in order to meet or maintain treatment goals. 16 As a result, inadequate control of hypertension remains a major problem, even in individuals who have been diagnosed and who are receiving antihypertensive therapy. For this reason, physicians who treat patients with hypertension must be aware of, and should strive to achieve, blood pressure (BP) goals. 17 Elderly individuals often have variable BP and are susceptible to orthostatic hypotension during treatment. Therefore, a stepped approach is appropriate when introducing antihypertensive therapy, with gradual dosage titration to avoid adverse events (AEs) Maintenance of BP control throughout the entire 24-hour period is important to avoid the morning BP surge in patients with hypertension, which may trigger early morning cardiovascular events Thus, the use of long-acting agents that provide consistent control throughout a 24-hour dosing interval is important. 24 Olmesartan medoxomil is a long-acting angiotensin receptor blocker (ARB) that has been shown to be effective as monotherapy or in combination with hydrochlorothiazide (HCTZ) in a broad range of patients, including the elderly, and has demonstrated minimal side effects in numerous clinical trials Olmesartan medoxomil based treatment algorithms have been shown to achieve respective seated cuff (Se) BP goals in patients with stage 1 and stage 2 hypertension. 25,28 Here we report the results of an ARB-based treatment regimen. The Benicar Efficacy: New Investigation Shows Olmesartan Medoxomil Treatment Increasingly Leads Various Elderly Populations to Safe BP Reductions (BeniSILVER) study was undertaken to evaluate the efficacy and safety of an olmesartan medoxomil based treatment algorithm in elderly patients (65 years and older) with hypertension. Ambulatory BP monitoring (ABPM) was used to evaluate 24-hour BP control, including achievement and maintenance of ambulatory SBP DBP prespecified study targets, throughout the dosing interval. PATIENTS AND METHODS Patients Individualsaged65yearsandolderwhowerenot institutionalized were eligible for the trial if they had either newly diagnosed hypertension or uncontrolled hypertension while taking antihypertensive medication (ie, SeSBP SeDBP mm Hg). Patients with secondary hypertension of any etiology were excluded, as were those with angina, clinically significant cardiac conduction defects, atrial fibrillation or flutter, any arrhythmia requiring medication, or hemodynamically significant valvular disease. Also excluded were patients with a history of myocardial infarction, coronary angioplasty, bypass surgery or heart failure within the past 6 months, those with a history of cerebrovascular accident or transient ischemic attack within 12 months, and those with other serious systemic diseases including those of the renal, pulmonary, hepatic, gastrointestinal, endocrine, and hematologic systems, including cancer (other than basal cell carcinoma). Patients with type 1 diabetes mellitus were not eligible for study entry, but those with type 2 diabetes mellitus could be included if they had been on a stable treatment regimen for 4 weeks and had a plasma glucose level <160 mg dl at screening. Individuals with a history of drug or alcohol abuse (within 2 years), those with a history of an allergic response to an angiotensin II inhibitor, or having angioneurotic edema were not eligible for the trial. In addition, patients who worked a night shift were also ineligible for the trial. The use of systemic antihypertensive agents and drugs that have the potential to interfere with BP control (eg, certain central nervous system agents, appetite suppressants, phosphodiesterase inhibitors) were prohibited during the study. All patients provided written informed consent before undergoing any study procedures. Study Design This open-label, multicenter, blinded-end point study consisted of a 2- to 3-week placebo run-in phase and a 12-week active treatment phase (Figure 1). Patients receiving an ongoing antihypertensive regimen were weaned from their medication 24 hours before entering the placebo run-in phase. Consenting patients who met all inclusion and exclusion criteria, completed all screening procedures, and had been off all antihypertensive 412 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 8 AUGUST 2009

3 Figure 1. Patient disposition during the study. BP indicates blood pressure; ABPM, ambulatory BP monitoring; HCTZ, hydrochlorothiazide; OM, olmesartan medoxomil. medication for 24 hours entered the 2- or 3-week placebo run-in phase. Patients who took 80% of the study medication during the placebo run-in phase were eligible for the active treatment phase provided they had a mean SeSBP of 150 to 199 mm Hg and a mean SeDBP 109 mm Hg at 2 consecutive study visits during the placebo run-in. The difference in SeSBP must have been 10 mm Hg between the 2 qualifying study visits. Patients fulfilling the qualifying SeBP criteria subsequently had their BP measured by an ABPM device. The mean daytime (8 am 4 pm) ambulatory SBP was required to be 140 to 199 mm Hg and the mean daytime ambulatory DBP was required to be 109 mm Hg in order to enter the active treatment phase. All patients started active treatment with olmesartan medoxomil 20 mg once daily. Patients were up-titrated to the next dose level at 3-week intervals if their mean SeBP was mm Hg. Olmesartan medoxomil was increased to 40 mg once daily at week 3 and HCTZ 12.5 mg once daily was added, as necessary, at week 6. Finally, thedoseofhctzwasincreasedto25mgonce daily (in combination with olmesartan medoxomil 40 mg d) at week 9. Patients with a mean SeBP < mm Hg at any visit maintained current therapy, but were up-titrated to the next dose level if SeSBP increased to 140 mm Hg and or SeDBP increased to 90 mm Hg at any subsequent visit. Patients with mean SeBP > mm Hg or < mm Hg with symptomatic hypotension at any visit were required to withdraw from the study. Assessments At each clinic visit, SeBP and heart rate were determined in triplicate on the patient s nondominant arm by an automated BP monitor to obtain mean SeBP. ABPM was performed at baseline and at the end of the 12-week active treatment phase with an oscillometric device. At week 12, ABPM was started in the morning immediately before taking the last dose of study medication. Compliance was assessed by pill counts at each study visit. Baseline glomerular filtration rates (GFRs) were calculated post hoc using the method of Levey and colleagues 29 to identify patients with stage 3 chronic kidney disease. Stage 3 chronic kidney disease was defined as a GFR 30 and <60 ml min 1.73 m 2. The primary efficacy variable was the change from baseline in mean 24-hour ambulatory SBP after 12 weeks of treatment. Secondary ambulatory BP efficacy variables included the change from baseline in mean 24-hour ambulatory DBP, the change from baseline in mean daytime (8 am 4 pm) and nighttime (10 pm 6 am) ambulatory SBP DBP, the change from baseline in mean 24-hour ambulatory SBP DBP during the last 6, 4, and 2 hours of the 24-hour dosing interval after 12 weeks of treatment; the proportion of patients achieving ambulatory VOL. 11 NO. 8 AUGUST 2009 THE JOURNAL OF CLINICAL HYPERTENSION 413

4 Table I. Baseline Characteristics of Patients (Efficacy Population) Mean agesd (range), y ( ) Race, No. (%) Caucasian 146 (83.0) Black 28 (15.9) Asian 2 (1.1) Sex, No. (%) Male 92 (52.3) Female 84 (47.7) Mean weightsd, kg Mean heightsd, cm Body mass index 30 kg m 2, 65 (36.9) No. (%) Mean SeSBP SeDBPSD, mm Hg a Mean 24-hour ambulatory SBP DBPSD, mm Hg Hypertension stage, No. (%) Stage 1 60 (34.1) Stage (65.9) Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure; SeDBP, seated DBP; SeSBP, seated SBP; SD, standard deviation. a Average of the mean blood pressure measurements at visit 4. SBP DBP prespecified study targets including mean 24-hour, daytime and nighttime, and during the last 6, 4, and 2 hours of the 24-hour dosing interval at the end of study; and the proportion of patients who were nondippers at baseline and converted to dippers after 12 weeks of active treatment (ambulatory BP dippers were defined as patients with a nocturnal decrease in ambulatory SBP and or DBP 10% of their mean daytime ambulatory BP). Other secondary efficacy variables involved changes in mean SeBP: the change from baseline in mean SeBP at each titration step and after 12 weeks of treatment, the incremental change in mean SeBP within each titration step, and the proportion of patients achieving mean SeBP goals during the study. Any AEs reported by patients or observed by the investigators at any visit were recorded and graded as mild (aware of sign or symptom, but easily tolerated), moderate (discomfort to cause interference with usual activity), or severe (incapacitating with inability to work or do usual activity), and as unrelated, unlikely related, possibly, probably, or definitely treatment-related. In addition, safety was assessed by monitoring of laboratory values and physical examinations at screening and week 12. Serious AEs were any events that resulted in death, were life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability incapacity, or were an important medical event. Statistical Analysis The efficacy population comprised all patients who received 1 dose of active study medication and had both a baseline and 1 postbaseline BP measurement. The safety population included all patients who received 1 dose of olmesartan medoxomil. Summary statistics were calculated for continuous and categoric variables. When a patient withdrew from the study during active treatment, his her last postbaseline BP value was carried forward to the end of the study using the last observation carried forward method for 12- week study end points. For assessment of changes at each titration step, their last BP measurement was carried forward to the end of the period in which it was taken. The last value was not carried forward into subsequent treatment periods. All within-group changes from baseline to end of study in mean 24-hour ABPM or mean SeBP were expressed as mean change, with standard error and a 2-sided 95% confidence interval (CI), andanalyzedusing1-samplet test and P values to 4 decimal places. RESULTS The study was conducted at 37 centers in the United States. A total of 396 patients were screened for enrollment, 309 (78.0%) entered the placebo run-in period, and 178 entered the active treatment phase. Overall, 176 individuals received 1 dose of active study medication, had a baseline and 1 postbaseline mean SeBP assessment, and thus comprised the efficacy cohort (Figure 1). A total of 155 individuals completed 12 weeks of therapy. Baseline and week 12 mean 24-hour ambulatory BP data were collected for 150 patients. The baseline characteristics of patients comprising the efficacy cohort are presented in Table I. The mean age was 71.9 years and most were Caucasian (83.0%) and had stage 2 hypertension (65.9%). Patient medical histories showed that 19 patients had type 2 diabetes mellitus. In addition, 33 patients were identified as having stage 3 chronic kidney disease as determined by calculated GFRs. At week 12, of the 155 patients who completed the study, one patient was receiving olmesartan medoxomil 20 mg monotherapy, 3 patients were receiving olmesartan medoxomil 40 mg monotherapy, 28 patients were receiving olmesartan medoxomil HCTZ mg, and 123 were receiving olmesartan medoxomil HCTZ mg. 414 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 8 AUGUST 2009

5 Figure 2. Mean hourly change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) as assessed by 24-hour ambulatory blood pressure monitoring (ABPM) from baseline to end of study with olmesartan medoxomil hydrochlorothiazide. BP indicates blood pressure. Efficacy Mean 24-Hour Ambulatory BP. Baseline and week 12 mean 24-hour ambulatory BP data were collected in 150 patients (Figure 2). Baseline mean 24-hour ambulatory SBP DBP was mm Hg, and at the end of the active treatment period, the mean 24-hour ambulatory SBP DBP was mm Hg (Figure 2). Overall, reductions were statistically significant at the end of the study (Figure 3). The reductions in mean ambulatory BP daytime, nighttime, and last 6, 4, and 2 hours of the dosing interval at 12 weeks were statistically significant (Figure 3A) (P<.0001). At baseline, 48 of 150 (32.0%) patients were nondippers. At the end of the study, 24 (50%) of these patients became dippers. Of 102 dippers at baseline, 21% became nondippers at week 12. After 12 weeks of treatment, 88.7%, 82.7%, 73.3%, 56.7%, and 44.0% of patients had achieved the mean 24-hour ambulatory BP prespecified study targets of < mm Hg, < mm Hg, < mm Hg, < mm Hg, and < mm Hg, respectively (Figure 4). The achievement of individual mean 24-hour ambulatory SBP and DBP prespecified study targets were also high (data not shown). For example, 88.7% of patients achieved a mean 24-hour ambulatory SBP <140 mm Hg and 99.3% achieved a mean 24-hour ambulatory DBP of <90 mm Hg. The proportion of patients achieving mean ambulatory SBP DBP prespecified study targets (< mm Hg, < mm Hg, < mm Hg, < mm Hg, and < mm Hg) during the daytime, nighttime, and last 6, 4, and 2 hours of the dosing interval are presented in Figure 4. The data show that the majority of patients had an ambulatory SBP DBP of < mm Hg throughout the last 6 (88.0%), 4 (84.7%), and 2 (78.7%) hours of the dosing interval after 12 weeks of treatment. Furthermore, 54.0% to 84.0% of patients achieved ambulatory BP targets ranging from < mm Hg to < mm Hg during the last 6 hours of the dosing interval, 42.7% to 80.7% of patients achieved ambulatory BP targets ranging from < to < mm Hg during the last 4 hours of the dosing interval, and 24.7% to 69.3% of patients achieved ambulatory BP targets ranging from < to < mm Hg during the last 2 hours of the dosing interval after 12 weeks of treatment (Figure 4). Mean SeBP. Baseline mean SeSBP SeDBP was mm Hg in the efficacy cohort, and the mean SeSBP SeDBP was mm Hg at the end of the active treatment period. The overall mean change from baseline was ) mm Hg (95% CI: )27.9, )22.9; P<.0001) in SeSBP and ) mm Hg (95% CI: )11.9, )9.1; P<.0001) in SeDBP (Figure 3B). ThemeanchangefrombaselineinmeanSeSBP andmeansedbpforeachtitrationstepispresented in Figure 3B. Progressively greater reductions were achieved with each titration step, and all changes were significant (P<.0001 vs baseline). The proportion of patients achieving SeSBP SeDBP goals during each treatment period and in VOL. 11 NO. 8 AUGUST 2009 THE JOURNAL OF CLINICAL HYPERTENSION 415

6 (A) (B) Figure 3. Blood pressure (BP) lowering efficacy of the olmesartan medoxomil (OM) based treatment algorithm: (A) change from baseline in mean 24-hour, daytime, and nighttime ambulatory BP (SE) and during the last 6, 4, and 2 hours of the 24-hour dosing interval at week 12, as assessed by ambulatory BP monitoring, and (B) change from baseline in mean seated BP (SeBP)SE at the end of the study (last observation carried forward [LOCF]), and at the end of each titration step. *P<.0001 vs baseline. SBP indicates systolic BP; DBP, diastolic BP; HCTZ, hydrochlorothiazide; SE, standard error. the overall efficacy cohort is presented in Table II. Individual SBP goal rates during each treatment period and in the overall efficacy cohort were similar to the combined SBP DBP goal rates, but individual DBP goal rate achievement was higher at all time points (data not shown). Safety and Tolerability Overall, 58 (32.6%) patients who received 1 dose of study medication experienced a treatmentemergent AE during the 12-week treatment period and 21 patients (11.8%) experienced a drug-related AE (Table III). The incidence of individual drug-related AEs occurring in each active treatment period and reported in 2% of patients is presented in Table III. During the entire treatment period, the most common drug-related AEs were dizziness (3.4%) and hypotension (2.2%). Only one serious AE was reported during the trial. The patient developed palpitations and hypertension on day 34 while receiving olmesartan medoxomil 40 mg d, which were considered unlikely to be related to study medication. No lifethreatening AEs were reported, and there were no deaths in this study. There was a modest increase in the mean ( mg dl) and median (3.0 mg dl) change from baseline in plasma glucose level during the study. An elevated glucose level was reported after 416 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 8 AUGUST 2009

7 Figure 4. Proportion of patients achieving mean 24-hour ambulatory systolic blood pressure (SBP) diastolic blood pressure (DBP) prespecified study targets at week 12, daytime, nighttime, and the last 6, 4, and 2 hours of the 24-hour dosing interval. BP indicates blood pressure. Table II. No. and Cumulative Proportion (%) of Patients Achieving Mean SeBP Goals a SBP DBP Goals, mm Hg Treatment Denominator (No.) < < < < Olmesartan medoxomil 20 mg d Efficacy cohort (176) 34 (19.3) 13 (7.4) 13 (7.4) 3 (1.7) Olmesartan medoxomil 40 mg d Efficacy cohort (176) 58 (33.0) 27 (15.3) 27 (15.3) 9 (5.1) Olmesartan medoxomil HCTZ mg d Efficacy cohort (176) 92 (52.3) 57 (32.4) 55 (31.3) 27 (15.3) Olmesartan medoxomil HCTZ mg d Efficacy cohort (176) 118 (67.0) 78 (44.3) 75 (42.6) 35 (19.9) Abbreviations: DBP, diastolic blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood pressure; SeBP, seated blood pressure. a Data for efficacy cohort include the cumulative number (%) within the efficacy cohort who achieved blood pressure goal at each possible titration point, regardless of treatment allocation at that time. Table III. AEs in Patient Cohort Olmesartan medoxomil 20 mg d (N=178) Olmesartan medoxomil 40 mg d (N=169) Olmesartan medoxomil HCTZ mg d (N=159) Olmesartan medoxomil HCTZ mg d (N=125) Entire active treatment period a (N=178) Patients with 1 AE 25 (14.0) 27 (16.0) 36 (22.6) 25 (20.0) 58 (32.6) Patients with 1 6 (3.4) 5 (3.0) 12 (7.5) 8 (6.4) 21 (11.8) drug-related AE Discontinuation 1 (0.6) 4 (2.4) 3 (1.9) 1 (0.8) 9 (5.1) due to AE Incidence of drugrelated AEs 2% Dizziness 1 (0.6) 3 (1.8) 5 (3.1) 1 (0.8) 6 (3.4) Hypotension 0 1 (0.6) 2 (1.3) 2 (1.6) 4 (2.2) Values are expressed as No. (%). Abbreviations: HCTZ, hydrochlorothiazide. 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 up-titration to the next dose level). the addition of HCTZ 12.5 mg d as a drug-related AE in 1 of 178 patients included in the safety population (0.6%). Nine patients discontinued active treatment due to AEs: 4 patients received olmesartan medoxomil 40 mg d, 2 patients received olmesartan medoxomil 20 mg d, 2 patients received olmesartan medoxomil 40 mg d + HCTZ 12.5 mg d, and 1 patient was in the placebo group. The VOL. 11 NO. 8 AUGUST 2009 THE JOURNAL OF CLINICAL HYPERTENSION 417

8 most commonly reported reasons for discontinuation were dizziness (n=3) and hypotension (n=3). No clinically significant changes in serum potassium, creatinine, or uric acid levels were seen after 12 weeks of treatment. Elevated uric acid was reported as a drug-related AE in 1 of the 178 patients included in the safety population (0.6%) after treatment with olmesartan HCTZ mg d. DISCUSSION The results of this trial demonstrate that an olmesartan medoxomil based treatment algorithm can be used to effectively and safely control BP in patients 65 years and older, including those with uncontrolled hypertension on an existing therapeutic regimen. One strength of this study was the use of mean 24-hour ABPM to document BP reductions in addition to ambulatory BP prespecified study cut point achievement rates at the end of 12 weeks of therapy. ABPM results confirm that the therapeutic algorithm produced an overall reduction in mean 24-hour ambulatory SBP DBP of mm Hg, consistent reductions in both daytime and nighttime ambulatory SBP DBP, and significant reductions during the last 6, 4, and 2 hours of the 24-hour dosing interval. This latter finding may be particularly important because it confirms that the durable, long-acting efficacy of olmesartan medoxomil reduces a surge in BP toward the end of the dosing interval. Currently, there are no generally accepted ambulatory BP goal values. However, the American Heart Association (AHA) has defined levels of BP during the 24-hour ABPM period that would be considered normal based on correspondence between these values and clinic BP. 30 The AHA suggests that normal 24-hour, daytime, and nighttime ambulatory BP levels for adults should be < mm Hg, < mm Hg, and < mm Hg, respectively. In our study, the olmesartan medoxomil based treatment regimen enabled 73% of patients 65 years and older to reach a mean 24-hour ambulatory BP of < mm Hg and 67% to reach a daytime ambulatory BP of < mm Hg. Although the present study did not specifically assess the AHAdefined nighttime ambulatory BP level of < mm Hg, 74% and 66% of the elderly patients were able to reach the most stringent ambulatory BP study targets of < mm Hg and < mm Hg, respectively. Hypertension guideline recommended SeBP goals were assessed in the current study. 31 The 25.4-mm Hg reduction from baseline in SeSBP and 67% goal rate achievement at the end of the study observed in the current trial provide confirmatory evidence for the efficacy of coadministration of olmesartan medoxomil and HCTZ in achieving the recommended SeBP goal of < mm Hg in elderly patients. In a previous study, Izzo and colleagues 25 used a similar treatment algorithm but with a forced-titration approach (ie, all patients had treatment intensified at 3-week intervals until a BP of < mm Hg was achieved). These investigators found that treatment intensification to olmesartan medoxomil HCTZ mg reduced SeBP in elderly (65 years and older) patients by mm Hg, and enabled 61.7% of patients to reach an SeBP goal of < mm Hg. The greater reduction in SeSBP seen in the Izzo study, relative to the present study, is likely explained by a higher baseline SBP (175 mm Hg compared with 165 mm Hg in the current study). To put into perspective the significance of these findings, the recent Hypertension in the Very Elderly Trial (HYVET), 32 conducted in hypertensive patients 80 years and older, showed that a reduction in SBP DBP of mm Hg produced a 39% reduction in the rate of death from stroke and a 23% reduction in the rate of death from cardiovascular causes during 2 years of follow-up. Although patients in HYVET were older than in the present study (mean age, 83 vs 72 years), HYVET demonstrates that even moderate BP reductions in elderly patients have significant tangible benefits in reducing fatal and nonfatal cardiovascular events. In the most recent NHANES survey, although 81% of elderly (60 years and older) patients with hypertension were aware of their hypertension diagnosis and 73% received treatment, only 50% of those receiving treatment for hypertension had their BP controlled to recommended SeBP goals. 4 The present study demonstrates that 67.0% of elderly patients can achieve an SeBP target of < mm Hg with the treatment algorithm used in this study. We did not separately assess the BP goal achievement of < mm Hg for patients with diabetes or chronic kidney disease, and this study was not powered to detect differences in patients with diabetes. The rate of BP control in the community is lower than that achievable in clinical trials, probably because the general population is more heterogeneous (ie, have greater comorbidity, are less motivated, and more noncompliant than patients in a clinical trial) and physicians are less vigilant about treatment intensification. Age is a significant risk factor for clinical inertia in the treatment of 418 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 8 AUGUST 2009

9 hypertension, 15 with greater reluctance by physicians to intensify therapy when indicated in older (vs younger) patients. Since elderly patients derive more potential gain from treatment, because of their higher baseline risk of cardiovascular events, 14 strenuous efforts should be made to overcome clinical inertia in the treatment of elderly hypertensive patients, particularly when safe and well-tolerated treatments are available. Several important points are evident from the present study. First, SeBP control is difficult to achieve in elderly patients, even with multiple drugs and careful titration of treatment. Second, BP control measured by mean 24-hour ABPM is more frequent than when measured by conventional mean SeBP measurement. This is because baseline ambulatory BP tends to be lower than baseline SeBP 33 and, therefore, more patients are likely to achieve BP control when measured by ABPM than by SeBP, even with the same absolute reduction in BP. Third, consistent with previous studies, the olmesartanbased therapy was well tolerated. 25,34 The elderly are particularly susceptible to the AEs of antihypertensive therapy, especially when attempting to achieve aggressive BP targets. In particular, the risk of hypotension, fainting, and falling is of concern in this population. When 2 antihypertensive agents are required to achieve goal BP in elderly patients, slow-dose titration is recommended to minimize the risk of orthostatic hypotension The overall incidence of AEs in the trial was low and the incidence of drug-related dizziness and hypotension was 3.4%. Of note, the incidence of AEs typically associated with HCTZ (eg, hyperglycemia) was also low, with elevated glucose levels judged as being drug-related identified in just one patient. The results of the present study confirm prior data studies showing that treatment with an ARBHCTZ is effective and well tolerated in elderly patients with hypertension, 25,35,36 for either the mixed SBP DBP or ISH types of hypertension These effects have been demonstrated in studies using SeBP measurements 25,35,37,39 or using both SeBP and ABPM measurements. 36,38 ISH is the most common type of hypertension in individuals older than 60, and approximately 75% of those with hypertension by age 75 have ISH. 40 Although ISH was not a specified entry criterion in the present study, it should be noted that the baseline BP of the study population was consistent with a diagnosis of ISH. One potential limitation of the current study is the open-label noncomparative study design. However, the study accurately reflects real-world clinical practice and thus provides insight into how this particular treatment algorithm may be implemented and the objective results that may be achieved in elderly patients. Another limitation of this study is that there are no current guidelinerecommended ambulatory BP goals, although, as mentioned previously, the AHA has determined suggested targets based on the establishment of a normal range of ambulatory BP derived by a comparison of ambulatory BP levels corresponding with a clinic BP of mm Hg and by relating ambulatory BP to risk in prospective studies. Consequently, it is somewhat difficult to assess the clinical significance of attaining any specific ambulatory BP target until major hypertension guidelines establish recommenced ambulatory BP goals. The ambulatory targets prespecified in the current study encompassed a range of ambulatory BP levels that included some of the AHA suggested targets. Finally, the results obtained from this study are applicable to an elderly population, ie, 65 years and older, and therefore may not necessarily be representative of the general population. The utility of ABPM to assess the antihypertensive efficacy of the olmesartan medoxomil based treatment algorithm in this study is noteworthy. As ABPM provides both daytime as well as nighttime BP-lowering data, it may improve the prediction of cardiovascular risk. 41 In addition, ABPM has the ability to visually demonstrate BP control over the entire dosing period, which is important in assessing antihypertensive efficacy. ABPM also allows the assessment of other challenging BP issues that are otherwise not documented by cuffmeasured BP, such as white-coat hypertension, BP loads, and masked hypertension (a normal clinic BP, but elevated ambulatory BP). 42,43 ABPM measurements provide a more refined assessment of prognosis in hypertensive patients compared with conventional cuff measurements 43 and show a closer correlation with both end-organ damage and cardiovascular events when compared with clinic BP. 33 CONCLUSIONS A stepwise olmesartan medoxomil based treatment algorithm produces clinically significant reductions in SBP and DBP in elderly patients. This regimen provided a significant reduction in ambulatory BP in addition to achievement of ambulatory BP prespecified study targets and SeBP goals in elderly patients. This treatment algorithm was well tolerated with few drug-related AEs. VOL. 11 NO. 8 AUGUST 2009 THE JOURNAL OF CLINICAL HYPERTENSION 419

10 Acknowledgments and disclosures: This study was sponsored by Daiichi Sankyo, Inc. We thank Jennifer M. Kulak, PhD, and Alan J. Klopp, PhD, for providing editorial assistance in the preparation of this manuscript. Dean J. Kereiakes, MD, has received research grants from Pfizer, Cordis (Johnson & Johnson), Boston Scientific, Medtronic, and Daiichi Sankyo, Inc. Joel Neutel, MD, is a member of the speaker s bureau for Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Daiichi Sankyo, Inc., and sanofi-aventis. Jianbo Xu, MS, is a full-time consultant for Daiichi Sankyo, Inc. Kathy A. Stoakes, RN, BSN, William F. Waverczak, MS, Ali Shojaee, PharmD, and Robert Dubiel, PharmD, are all employees of Daiichi Sankyo, Inc. REFERENCES 1 Duprez DA. Systolic hypertension in the elderly: addressing an unmet need. Am J Med. 2008;121(3): Alli C, Avanzini F, Bettelli G, et al. 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