Olmesartan medoxomil-based antihypertensive therapy evaluated by ambulatory blood pressure monitoring: efficacy in high-risk patient subgroups.

Hypertension affects approximately 26% of the world's adult population and is a recognized major risk factor for morbidity and mortality associated with cardiovascular, cerebrovascular, and renal diseases. However, despite the availability of a range of effective antihypertensive agents and a growing awareness of the consequences of high blood pressure (BP), the treatment and control of hypertension remains suboptimal. A number of patient subgroups are categorized as 'high risk' and may have hypertension that is more difficult to treat, including obese individuals, patients with stage 2 hypertension, those with type 2 diabetes mellitus (T2DM), patients with coronary artery disease or a history of stroke, and Black patients. As the benefits of lowering BP in patients with hypertension are unequivocal, particularly in high-risk patients, treating high-risk patients with hypertension to BP goals and maintaining 24-hour BP control is important to help reduce cardiovascular risk and improve outcomes. Although the BP goals recommended in current consensus guidelines for the management of patients with hypertension are based on cuff BP measurements, ambulatory BP monitoring (ABPM) provides a valuable diagnostic tool and allows a more accurate assessment of BP levels throughout the 24-hour dosing period. ABPM is a better predictor of prognosis than office BP measurement and is also useful for assessing whether antihypertensive therapy remains effective in the critical last few hours of the dosing period, which usually coincides with the morning BP surge associated with arousal and arising. ABPM has been adopted by new evidence-based guidelines in the United Kingdom to confirm a suspected diagnosis of hypertension, which is an indication of the growing importance of ABPM in the management of hypertension. This review provides an overview of the efficacy and safety of antihypertensive therapy based on olmesartan medoxomil ± hydrochlorothiazide and amlodipine/olmesartan medoxomil in high-risk patient populations enrolled in studies that reported ambulatory BP endpoints. The studies identified in this review showed that a titrate-to-BP goal strategy using olmesartan medoxomil- or amlodipine/olmesartan medoxomil-based antihypertensive therapy was an effective and well-tolerated approach for maintaining BP control throughout the full 24-hour dosing period in high-risk patients with difficult-to-treat hypertension.

Efficacy and tolerability of nebivolol: does age matter? A retrospective analysis of three randomized, placebo-controlled trials in stage I-II hypertension.

OBJECTIVES: This retrospective analysis examined the efficacy and tolerability of nebivolol, a ß(1)-selective, vasodilatory ß-blocker, in four different age groups of patients with hypertension. METHODS: Data were pooled from three 12-week, randomized, placebo-controlled trials (placebo, n = 205; nebivolol [1.25-30/40 mg/day], n = 1811) and stratified into age quartiles (Group 1: 22-46 years; Group 2: 47-53 years; Group 3: 54-62 years; Group 4: 63-84 years). Only patients treated with placebo and the three commonly used nebivolol dosages (5, 10, and 20 mg/day) are presented. Baseline-to-endpoint changes in trough sitting diastolic blood pressure (DBP), systolic blood pressure (SBP), and heart rate (HR) were analyzed for each age quartile using an analysis of covariance (ANCOVA) model. Tolerability was assessed by means of adverse event (AE) rates. RESULTS: The analysis comprised 205 placebo-treated patients and 1380 patients treated with nebivolol dosages of 5, 10, or 20 mg/day. Older age was associated with higher SBP values at baseline. In all age groups, each of the three most frequently used nebivolol dosages significantly reduced DBP, compared with placebo (-9.1 to -11.8 mmHg versus -3.4 to -5.9 mmHg; p ≤ 0.008 overall). For SBP, a statistically significant effect versus placebo was observed for all dosages and age groups except for 5 and 10 mg/day in Group 4. Within each group, treatment with nebivolol (all three dosages) and placebo resulted in similar AE rates (nebivolol: 26.1-36.6%; placebo: 36.2-42.6%) and AE-related discontinuation rates (1.8-3.8% versus 0-4.3%). In each age group, there were no significant nebivolol-placebo differences in the rates of patients who experienced clinically significant changes or abnormal endpoint levels of metabolic parameters. CONCLUSIONS: This retrospective analysis suggests that nebivolol monotherapy is efficacious and well tolerated across various age groups, with the efficacy in reducing SBP somewhat diminishing in patients over 62 years of age.

Which diuretic is the preferred agent for treating essential hypertension: hydrochlorothiazide or chlorthalidone?

Since their introduction over 50 years ago thiazide and thiazide-like diuretics have been a mainstay in the treatment of hypertension. Yet despite outcome evidence with chlorthalidone, the preponderance of usage has been with hydrochlorothiazide-either as monotherapy or in combination with other drugs. There is an increasing debate as to whether or not there are significant differences between hydrochlorothiazide and chlorthalidone. Early outcome studies, upon which the recommendations were made, utilized higher doses than those not only commonly employed in clinical practice, but also studied in more recent outcome trials. In addition, data suggests that chlorthalidone may be more potent, in equal doses, in its BP response than hydrochlorothiazide. A fundamental question asked in the debate is whether or not the benefits attributed to chlorthalidone as a thiazide-like diuretic may be reasonably ascribed to thiazides given differences in their pharmacokinetic properties and perhaps some other more recently noted differences.

Efficacy of olmesartan medoxomil and hydrochlorothiazide fixed-dose combination therapy in patients aged 65 years and older with stage 1 and 2 hypertension or isolated systolic hypertension.

BACKGROUND: The incidence of hypertension, particularly isolated systolic hypertension, increases with increasing age, as does the risk of fatal cardiovascular disease. A combination antihypertensive therapy regimen may be required to reach recommended BP goals in older patients. OBJECTIVES: This study set out to report blood pressure (BP) data in elderly patients across the subgroups of stage 1 and stage 2 hypertension (prespecified subgroup) and isolated systolic hypertension (ISH) [post hoc]. DESIGN AND SETTING: This was a subgroup analysis of a prospective, open-label study carried out in a multicenter, outpatient setting (e.g. the BeniSILVER [Benicar Efficacy: New Investigation Shows OM Treatment Increasingly Leads to Various Elderly Populations to Safe BP Reductions; ClinicalTrials.gov identifier: NCT00412932] study). The study included 176 patients with a mean age of approximately 72 years; stage 1 hypertension, 60, stage 2 hypertension, 116, and ISH, 98. INTERVENTION: After a 2- to 3-week placebo run-in period, patients were uptitrated every 3 weeks from olmesartan medoxomil (OM) 20 mg daily to OM 40 mg, OM/hydrochlorothiazide (HCTZ) 40 mg/12.5 mg, and OM/HCTZ 40 mg/25 mg, if seated cuff BP (SeBP) was ≥120/70 mmHg. MEASUREMENTS: Measurements included change from baseline in mean 24-hour ambulatory BP and SeBP after 12 weeks of treatment, percentage of patients achieving a cumulative SeBP goal of <140/90 mmHg (stage 1 and stage 2 cohorts) or seated cuff systolic BP (SeSBP) goal of <140 mmHg (ISH cohort), and the incidence of adverse events (AEs). RESULTS: Combination therapy was required by 159 patients. Changes from baseline in mean 24-hour ambulatory BP (± standard deviation [SD]) were -24.2 (± 11.8)/-11.8 (± 6.9) mmHg, -26.5 (± 11.8)/-12.6 (± 6.7) mmHg, and -24.7 (± 12.5)/-11.2 (± 6.4) mmHg in the stage 1, stage 2, and ISH cohorts, respectively (all p < 0.001 vs baseline). Mean SeBP changes (± SD) from baseline in patients titrated to OM/HCTZ 40 mg/25 mg were -24.6 (± 11.4)/-10.5 (± 7.3) mmHg in the stage 1 cohort, -26.4 (± 17.2)/-11.3 (± 9.7) mmHg in the stage 2 cohort, and -21.5 (± 15.6)/-6.8 (± 7.8) mmHg in the ISH cohort (all p < 0.001). The cumulative proportions of patients achieving an SeBP goal of <140/90 mmHg by week 12 were 88.3%, 56.0%, and 72.4% in the stage 1, stage 2, and ISH cohorts, respectively, while 72.4% of patients achieved an SeSBP of <140 mmHg in the ISH cohort. Treatment-emergent AEs ranged from 32.3% to 32.8%, with <3% of patients reporting drug-related hypotension. CONCLUSION: An OM/HCTZ-based titration regimen enabled elderly patients with hypertension to safely reduce BP throughout the 24-hour dosing interval and allowed the majority of these patients to achieve a BP target of <140/90 mmHg or <140 mmHg.

Noninsulin treatment of type 2 diabetes mellitus in geriatric patients: a review.

BACKGROUND: Currently, 42% of the US population with diabetes is aged ≥65 years. OBJECTIVE: The aim of this review was to discuss the efficacy and tolerability of noninsulin therapies for type 2 diabetes mellitus (T2DM), with an emphasis on patients aged ≥65 years. METHODS: PubMed and EMBASE (1977-2010) were searched using the terms geriatric, elderly patients, type 2 diabetes mellitus, metformin, secretagogues, thiazolidinediones (TZDs), alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. Articles were included if they were clinical trials, reviews, or meta-analyses. RESULTS: More than 10 classes of noninsulin treatments are available for T2DM. However, most treatments have been evaluated only in trials in patients aged <65 years, and trials in older populations are scarce. Therefore, health care providers should consider the overall benefit to risk, with a focus on risk factors in older patients. A1C reductions range from 0.6% to 2%, with similar decreases observed for metformin, TZDs, sulfonylureas (SUs), glinides, and GLP-1 receptor agonists Treatment-associated adverse events vary. The prevalence of hypoglycemia is high with the secretagogues, SUs, and glinides (20% with glibenclamide or glipizide, 16% with repaglinide). The TZDs have been associated with an increased risk for heart failure (adjusted ratio = 1.60; 95% CI, 1.21-2.10; P < 0.001) compared with the other oral therapies. Gastrointestinal adverse events have been commonly reported with metformin (38% of patients), which is contraindicated in cases of renal insufficiency. Use of the GLP-1 RAs liraglutide and exenatide have been associated with comparable weight reductions of ∼3 kg and with a low risk for hypoglycemia (prevalence, 4% with exenatide 10 µg; ∼5% with liraglutide 1.2 or 1.8 mg). Treatment with the GLP-1 RAs has been associated with transient gastrointestinal reactions, mainly nausea. CONCLUSIONS: The selection of noninsulin treatments in older patients with T2DM should be individualized based on patient assessment and on careful evaluation of the potential benefits (glycemic and extraglycemic) and risks (ie, hypoglycemia, weight gain, cardiovascular risks). More clinical trials in older patients, especially those aged ≥65 years, with T2DM are needed.

The impact of lactotripeptides on blood pressure response in stage 1 and stage 2 hypertensives.

Nearly 70 million Americans have hypertension, and approximately an equal number have prehypertension. The prevalence of both disorders increases with advancing age and obesity. Many at-risk individuals do not have controlled blood pressure (BP). Lifestyle modification for most persons is the first step in a plan to control these conditions. Non-drug treatments offer an appeal to many patients with modest BP elevation. The authors recently evaluated BP response using 24-hour ambulatory BP monitoring and office BP monitoring of lactotripeptides dosed twice daily in 91 previously treated and treatment-naive patients with stage 1 and stage 2 hypertension. In this population, daytime systolic BP, the primary efficacy end point, significantly decreased (-3.6 mm Hg; P=.013), while placebo did not affect systolic BP (0 mm Hg; P=not significant). Treatment-naive patients exhibited a more robust drop in their daytime systolic BP (-7.6 mm Hg; P=.005) compared with placebo (-3.6 mm Hg; P=not significant). Lactotripeptides may be an effective agent in the management of low-risk and low-grade hypertension and prehypertension.

JNC 8: expectations, challenges, and wishes--a primary care perspective.

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) reports have dramatically shaped the treatment of hypertension in this country and beyond. The JNC recommendations have been the cornerstone in the detection, evaluation, and treatment of high blood pressure (BP) in this country since inception. Their periodic revisions have evolved with the publications of well-designed outcome studies. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), as part of the evolutionary patterns of its predecessors, added prevention to its guidelines. But as we await JNC 8, it may be useful to speculate what changes may be incorporated in the JNC's latest report. This brief commentary provides some expectations, challenges and wishes for JNC 8 from the perspective of a primary care physician.

Efficacy and tolerability of nebivolol monotherapy by baseline systolic blood pressure: a retrospective analysis of pooled data from two multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging studies in patients with mild to moderate essential hypertension.

BACKGROUND: In clinical studies, nebivolol at doses of 2.5 to 40 mg once daily was associated with significant decreases in systolic blood pressure (SBP) and diastolic BP (DBP) in patients with hypertension and was well tolerated. OBJECTIVES: This post hoc analysis of pooled data from 2 previously published registration studies was conducted to further evaluate the antihypertensive efficacy and tolerability of nebivolol in patients with mild to moderate (stage 1-2) hypertension. METHODS: The 2 trials were similarly designed multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging studies in patients 18 years of age and older with stage 1 or 2 hypertension (SBP 140-159 mm Hg and/or DBP 90-99 mm Hg [stage 1] or SBP >or= 160 mm Hg and/or DBP >or= 100 mm Hg [stage 2]). The primary efficacy end point of the 2 studies was the change from baseline in mean trough SiDBP at week 12. A secondary end point was the change from baseline to week 12 in mean trough sitting SBP (SiSBP). The present analysis included only patients who received nebivolol 5, 10, or 20 mg (the doses were common to both studies) or placebo, including analyses stratified by baseline SBP, although DBP represented a criterion for entry into the studies. Baseline SBP stratification levels were 140 to 149 mm Hg, 150 to 159 mm Hg, 160 to 169 mm Hg, and 170 to 179 mm Hg. For the tolerability analysis, the prevalences of treatment-emergent adverse events (AEs) were compared between the 3 nebivolol dose groups and the placebo group. RESULTS: Of the 1716 randomized patients who received study medication in the 2 trials, data from 1385 patients were included in this pooled analysis (759 men, 626 women; median age, ~54 years; 13.6% black). Mean (SD) baseline SiSBP and SiDBP values were 151.9 to 152.7 and 99.2 to 99.5 mm Hg, respectively. Reductions from baseline in trough SiSBP were -10.8 (13.5), -10.7 (14.7), and -12.4 (15.5) mm Hg with nebivolol 5, 10, and 20 mg, respectively, compared with -4.5 (13.4) mm Hg with placebo (all, P < 0.001). Reductions from baseline in trough SiDBP (the primary end point) were -9.8 (7.9), -10.5 (8.2), and -11.1 (8.6) mm Hg with nebivolol 5, 10, and 20 mg, respectively, compared with -5.1 (8.1) mm Hg with placebo (all, P < 0.001). In a subgroup of 1227 patients stratified by baseline SBP, the reductions in SBP and DBP were significantly greater (P < 0.03 and P < 0.001, respectively) with nebivolol at each dose compared with placebo in those with baseline SBP of 140 to 149 mm Hg and 150 to 159 mm Hg (the lowest 2 baseline strata); in the highest 2 baseline strata (SBP 160-169 and 170-179 mm Hg), the reductions in SBP with nebivolol 5 mg and nebivolol 20 mg in the 160 to 169-mm Hg baseline SBP stratum and in DBP with nebivolol 20 mg in the 170 to 179-mm Hg baseline stratum were significantly greater (P < 0.03) compared with placebo. The most common AE in the nebivolol 5-, 10-, and 20-mg groups and the placebo group was headache (36/409 [8.8%], 25/410 [6.1%], 27/410 [6.6%], and 10/156 [6.4], respectively), followed by fatigue (9/409 [2.2%], 10/410 [2.4%], 25/410 [6.1%], and 3/156 [1.9%]) and dizziness (6/409 [1.5%], 9/410 [2.2%], 15/410 [3.7%], and 4/156 [2.6%]). CONCLUSION: The present analysis of pooled data from 2 previously published registration studies found that nebivolol was associated with significant reductions in BP compared with placebo in these patients with stage 1 or 2 hypertension, with a tolerability similar to that of placebo.

The management and treatment of hypertension.

High blood pressure (HBP) is one of the most prevalent conditions seen today by clinicians, affecting an estimated 73 million--or 1 in 3--adult Americans, only one third of whom have achieved control of their hypertension (HBP). Central to the management of this pervasive medical condition are the issues of accurate diagnosis and maintaining control through appropriate treatment. Accurate diagnosis depends primarily on reliable measurement. Over the years, it has become increasingly recognized that blood pressure (BP) measurement occurring in clinical settings produces far less accurate and reliable readings than do other methods, notably 24-hour ambulatory BP monitoring and home BP measurement. Beyond technique, there are additional challenges to obtaining accurate readings, including emotional factors that produce either falsely elevated or lowered results, having the potential to mislead the clinician. The need to overcome obstacles to proper diagnosis and determine effective treatments has reached heightened urgency, especially for patients with compelling comorbidities such as diabetes, renal disease, congestive heart failure, and other cardiovascular diseases. The continuing evolution of the management of HBP is reflected in updated guidelines from the American Heart Association and evidence-based information stemming from recent studies and randomized clinical trials. The appropriate selection of antihypertensive agents, at the proper doses, is a complex issue requiring greater understanding of our pharmacologic options. The contributions of some of the more recent and salient studies and trials are mentioned here, although there is no attempt in this brief review to match drug classes with compelling indications. The trials discussed involve such pharmacologic treatments as diuretic therapy, alpha-blockers, conventional beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. Trial outcomes shed light on the relative benefits and drawbacks of these agents, often within the context of various patient characteristics such as age, comorbidities, and risk status. Successful management of HBP is a multi-faceted and ongoing endeavor, in which developing knowledge constantly tempered by new questions moves us toward the goal of improving the lives of our patients.

Comparison of monotherapy with irbesartan 150 mg or amlodipine 5 mg for treatment of mild-to-moderate hypertension.

OBJECTIVE: The primary objective of this study was to compare the antihypertensive efficacy of the angiotensin II receptor blocker irbesartan 150 mg and the calcium channel blocker amlodipine 5 mg in the treatment of patients with seated diastolic blood pressure (DBP) 95-110 mmHg. DESIGN: Multicentre, randomised, double-blind, comparative pilot study. METHODS: Subjects were 18-65 years of age, with DBP 95-110 mmHg, and of non-African American origin. Following a three week, single-blind, placebo lead-in period, 181 subjects were randomised in a 1:1 ratio to receive once-daily irbesartan 150 mg (n=89) or amlodipine 5 mg (n=92) for four weeks. Trough (24+/-3 hours post-dosing) BP measurements were obtained at baseline and at Weeks 2 and 4 under standardised, controlled conditions. Response was defined as DBP <90 mmHg or a reduction from baseline of 10 mmHg. RESULTS: After four weeks of treatment, the mean (+/-SE) decrease from baseline in DBP was 9.4+/-0.6 mmHg in the irbesartan group vs. 9.6+/-0.6 mmHg in the amlodipine group (p=0.806). The mean decrease from baseline in seated systolic BP was 12.2+/-1.0 mmHg in the irbesartan group vs. 12.0+/-1.0 mmHg in the amlodipine group (p=0.885). Overall, 62% of subjects in the irbesartan group and 63% in the amlodipine group had a response (p=0.609), and 54% and 56% of patients (p=0.596), respectively, had their DBP normalised (<90 mmHg). Adverse events were reported by 21.3% of patients receiving irbesartan and 20.7% receiving amlodipine. Conclusions. Irbesartan 150 mg demonstrated comparable efficacy to amlodipine 5 mg, thereby confirming its value as an antihypertensive treatment option in non-African American patients with DBP 95-110 mmHg.

A Comparison of the Cough Profile of Fosinopril and Enalapril in Hypertensive Patients with a History of ACE Inhibitor-Associated Cough.

OBJECTIVE: Cough frequency and severity with fosinopril and enalapril were assessed in hypertensive patients with previous angiotensin-converting enzyme inhibitor (ACEI)-associated cough. DESIGN: Prospective, multicenter, randomized, 8-week double-blind treatment. PATIENTS: One hundred seventy-nine patients (mild-to-moderate hypertension, nonsmokers, mean age 58 years; 55% females; 72% Caucasian, 6% black, 19% Hispanic) were studied. Patients with other cough etiologies, significant co-morbidity, or confounding medications were excluded. INTERVENTIONS: Patients were randomized to fosinopril 10 mg (n = 85) or enalapril 5 mg (n = 94) once daily. Dosage could be doubled for blood pressure control after 4 weeks. Outcome measurements: The primary end point was all-cough frequency based on patient daily diary ratings; a cumulative cough frequency score was calculated. Secondary end points included cough severity, nonproductive cough frequency, night awakenings, cough time of day, and spontaneously reported cough. RESULTS: Fosinopril and enalapril demonstrated similar blood pressure control. Significant cough profile differences were observed in favor of fosinopril: all-cough frequency was 40.6 plus minus 3.8 (mean plus minus SE) versus 52.8 plus minus 3.6 (p = 0.02); nonproductive cough frequency was 26.7 plus minus 3.5 versus 40.3 plus minus 3.4 (p less-than-or-equal 0.01); and cough time of day was 49.2 plus minus 5.2 versus 66.0 plus minus 5.0 (p = 0.02), for fosinopril and enalapril, respectively. Subgroup analysis revealed all-cough frequency was 33.5 plus minus 6.3 versus 56.6 plus minus 5.3 (p = 0.006) for fosinopril and enalapril, respectively, in patients who previously had cough on one of these two ACEI (predominantly enalapril). Ten (12%) fosinopril and 25 (27%) enelapril patients spontaneously reported cough (p = 0.01). CONCLUSIONS: Hypertensive patients with previous ACEI-associated cough reported less frequent cough with fosinopril compared to enalapril, based on cumulative patient diary scores and spontaneously reported cough. This difference was most apparent in the subgroup of patients who previously experienced cough associated with enalapril therapy. Patients with prior ACEI-associated cough may experience less frequent with fosinopril.