24-Hour ambulatory blood pressure response to combination valsartan/hydrochlorothiazide and amlodipine/hydrochlorothiazide in stage 2 hypertension by ethnicity: the EVALUATE study

Several studies reported racial/ethnic differences in blood pressure (BP) response to antihypertensive monotherapy. In a 10-week study of stage 2 hypertension, 320/25 mg valsartan/hydrochlorothiazide (HCTZ) reduced ambulatory BP (ABP) significantly more effectively than 10/25 mg amlodipine/HCTZ. Results (post hoc analysis) are described in Caucasians (n=256), African Americans (n=79), and Hispanics (n=86). Compared with clinic-measured BP (no significant treatment-group differences in ethnic subgroups), least-squares mean reductions from baseline to week 10 in mean ambulatory systolic BP (MASBP) and mean ambulatory diastolic BP (MADBP) favored valsartan/HCTZ over amlodipine/HCTZ in Caucasians (-21.9/-12.7 mm Hg vs -17.6/-9.5 mm Hg; P=.0004/P<.0001). No treatment-group differences in MASBP/MADBP were observed in African Americans (-17.3/-10.6 vs -17.9/-9.5; P=.76/P=.40) or Hispanics (-17.9/-9.7 vs -14.2/-7.2; P=.20/P=.17). Based on ABP monitoring, valsartan/HCTZ is more effective than amlodipine/HCTZ in lowering ABP in Caucasians. In African Americans and Hispanics, both regimens are similarly effective.     

Efficacy and safety of irbesartan/HCTZ combination therapy as initial treatment for rapid control of severe hypertension

Severe hypertension is difficult to control. This prospective, randomized, double-blind, active-controlled, multicenter trial compared efficacy and safety of once-daily irbesartan/hydrochlorothiazide (HCTZ) combination therapy with irbesartan monotherapy in severe hypertension. Patients who were untreated or uncontrolled on monotherapy (seated diastolic blood pressure [BP] ≥110 mm Hg) received fixed-dose irbesartan 150 mg/HCTZ 12.5 mg combination therapy for 7 weeks, force-titrated to irbesartan 300 mg/HCTZ 25 mg at week 1 (n=468); or irbesartan 150 mg monotherapy, force-titrated to 300 mg at week 1 (n=269). Significantly more patients on combination therapy achieved seated diastolic BP <90 mm Hg at week 5 (primary end point) compared with monotherapy recipients (47.2% vs 33.2%; P= .0005). Likewise, significantly more patients attained goals per the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) (<140/90 mm Hg) at week 5 (34.6% vs 19.2%, respectively; P< .0001), while the mean difference between combination and monotherapy in seated diastolic BP and seated systolic BP was 4.7 mm Hg and 9.7 mm Hg ( P< .0001). Greater and more rapid BP reduction with irbesartan/HCTZ was achieved without additional side effects.     

Initial Combination Therapy With Irbesartan/Hydrochlorothiazide for Hypertension: An Analysis of the Relationship Between Baseline Blood Pressure and the Need for Combination Therapy

Hypertension treatment guidelines recommend initiating 2-drug therapy whenever blood pressure (BP) is ≥20 mm Hg systolic or ≥10 mm Hg diastolic above goal. This post hoc pooled analysis of 2 multicenter, randomized, double-blind, active-controlled forced-titration studies in 1235 patients with moderate and severe hypertension examined how baseline BP levels relate to the need for combination therapy by comparing the antihypertensive efficacy and tolerability of once-daily fixed-dose irbesartan/hydrochlorothiazide (HCTZ) 300/25 mg compared with irbesartan 300-mg or HCTZ 25-mg monotherapies. In study 1, patients with severe hypertension (seated diastolic BP [SeDBP] ≥110 mm Hg) were treated for 7 weeks with irbesartan or irbesartan/HCTZ combination therapy, with forced-titration after week 1. In study 2, patients with moderate hypertension (seated systolic BP [SeSBP] 160–180 mm Hg or SeDBP 100–110 mm Hg) were treated for 12 weeks with irbesartan/HCTZ, irbesartan monotherapy, or HCTZ monotherapy, with forced-titration after week 2. The relationship between baseline BP and the likelihood of achieving BP goals (SeSBP <140 mm Hg or SeDBP <90 mm Hg; SeSBP <130 mm Hg or SeDBP <80 mm Hg) as well as the antihypertensive response was evaluated at week 7/8. The need for combination therapy increased with increasing baseline BP and lower BP goals across the range of BP levels studied, with a comparable adverse effect profile to monotherapy. These results suggest that the likelihood of achieving an early BP goal for a given BP severity should be considered when choosing initial combination therapy vs monotherapy.     

Expedited blood pressure control with initial angiotensin II antagonist/diuretic therapy compared with stepped-care therapy in patients with ambulatory systolic hypertension

OBJECTIVES: The present study investigated whether initiating therapy with a combination of losartan (L) and hydrochlorothiazide (HCTZ) allows for faster blood pressure (BP) control and fewer medications than the usual stepped-care approach in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension. METHODS: Patients with a mean daytime systolic ambulatory BP (ABP) of 135 mmHg or higher were randomly assigned to receive L 50 mg plus HCTZ 12.5 mg titrated to L 100 mg plus HCTZ 25 mg versus HCTZ 12.5 mg plus atenolol 50 mg. Amlodipine 5 mg was then added, if needed, to achieve a BP goal of less than 130 mmHg. Treatment titration was based on ABP. RESULTS: Significantly more patients randomly assigned to L/HCTZ (63.5%) than stepped-care (37.5%; P=0.008) achieved the primary end point (daytime systolic BP of less than 130 mmHg). Initial L/HCTZ induced significantly greater decreases in ABP during each 24 h period after six weeks of therapy. Although reductions in systolic and diastolic ABP were not statistically different at the end of the study, ABP reduction was significantly greater (P<0.001) with the L/HCTZ-based regimen. Twice as many patients in the L/HCTZ group achieved the goal ABP with no more than two drugs (30.0% versus 14.7%; P=0.03). Moreover, tolerability was significantly better (P=0.006) in the L/HCTZ group, with a 40.0% incidence of adverse events, versus 65.6% in the stepped-care group. CONCLUSION: Initiating antihypertensive therapy with the combination of L/HCTZ in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension reaches a target BP faster in a higher proportion of patients, with fewer adverse events and less need for a third drug regimen than the conventional stepped-care approach.     

The JNC 7 approach compared to conventional treatment in diabetic patients with hypertension: a double-blind trial of initial monotherapy vs. combination therapy

The JNC 7 states that persons with blood pressure (BP) more than 20/10 mm Hg above goal should be started on combination drug therapy. This criterion includes patients with BP >160/100 mm Hg and diabetics with hypertension. The goal BP for persons with diabetes mellitus is <130/80 mm Hg. A randomized, double-blind trial force titrated initial combination therapy utilizing an angiotensin receptor blocker (ARB) combination (losartan/hydrochlorothiazide [LOS/HCTZ]) compared with an angiotensin-converting enzyme (ACE) inhibitor (ramipril), for 8 weeks, and tested the hypothesis that combination therapy is more likely to achieve goal BP vs. monotherapy. At 4 weeks, 30.5% of LOS/HCTZ and 14.4% of ramipril recipients achieved goal diastolic BP (p<0.001). More participants achieved goal systolic BP in the ARB/HCTZ group at 4 weeks (29.8% vs. 14.4%; p<0.001). At 4 weeks, mean diastolic BP had decreased 10.2+/-7.4 mm Hg in the LOS/HCTZ group compared with 6.4+/-6.8 mm Hg in the ramipril group (p<0.001), and systolic BP had fallen 15.4+/-13.1 mm Hg in the ARB/HCTZ compared with 9.2+/-10.2 mm Hg in the ACE-inhibitor group (p<0.001). Significant differences favoring the combination were also noted at 8 weeks. Drug-related adverse experiences were 10.3% for the combination compared with 12.7% for the monotherapy group. Initial combination therapy with an ARB/HCTZ was more effective than ACE-inhibitor monotherapy in achieving BP goals in participants with diabetes with no significant differences in the incidence of adverse experiences. These observations confirm other studies of combination therapies, such as b blocker/diuretic, ACE inhibitor/diuretic, or ACE inhibitor/calcium channel blocker. The use of two medications will achieve goal BP in more patients than monotherapy. This observation is important in treatment of high-risk patients with diabetes.     

Comparison of aliskiren/hydrochlorothiazide combination therapy and amlodipine monotherapy in patients with stage 2 systolic hypertension and type 2 diabetes mellitus

Patients with stage 2 hypertension and diabetes are at high cardiovascular risk and require large blood pressure (BP) reductions to reach treatment goals. This randomized double-blind study compared aliskiren/hydrochlorothiazide (HCTZ) combination therapy with amlodipine monotherapy in 860 patients with mean sitting systolic BP (msSBP) ≥160 mm Hg to <200 mm Hg and type 2 diabetes. Patients received either once-daily aliskiren/HCTZ 150/12.5 mg or amlodipine 5 mg for 1 week then force-titrated to double the doses for 7 weeks. Baseline BP was 167.7/91.4 mm Hg. At week 8 end point, aliskiren/HCTZ provided significantly greater reductions in msSBP than amlodipine (28.8 mm Hg vs 26.2 mm Hg; P<.05). Mean sitting diastolic BP reductions were similar with aliskiren/HCTZ (9.9 mm Hg) and amlodipine (9.0 mm Hg). Achievement of BP control (<130/80 mm Hg) was significantly greater with aliskiren/HCTZ (23.2%) than amlodipine (13.8%; P<.0001). Aliskiren/HCTZ provides substantial msSBP reductions and greater BP control rates than amlodipine, and offers an attractive treatment option for patients with hypertension and diabetes mellitus.     

Peripheral and central blood pressure responses of combination aliskiren/hydrochlorothiazide and amlodipine monotherapy in African American patients with stage 2 hypertension: the ATLAAST trial

Efficacy of antihypertensive agents on central blood pressure (BP) in African Americans is not well studied. The authors report on an 8-week double-blind, randomized study of African American patients with stage 2 hypertension that compared brachial and central BP responses (substudy of 53 patients) to combination aliskiren/hydrochlorthiazide (HCTZ) and amlodipine monotherapy. Following a 1- to 4-week washout, initial therapy was aliskiren/HCTZ 150/12.5 mg (n=166) or amlodipine 5 mg (n=166) for 1 week, forced-titrated to aliskiren/HCTZ 300/25 mg or amlodipine 10 mg for 7 weeks. Mean seated systolic BP reductions from baseline was similar with both treatments (-28.6 mm Hg with aliskiren/HCTZ vs -28.2 mm Hg with amlodipine). In the substudy, significantly greater reductions in central systolic BP was observed with aliskiren/HCTZ vs amlodipine (-30.1 mm Hg vs -21.2; P=.031), although 24-hour mean ambulatory BP reductions between the two groups were similar. Central pressure is considered an important risk factor in African Americans, and these findings may suggest a new treatment option for these patients.     

Efficacy and tolerability of a fixed-dose combination of telmisartan plus hydrochlorothiazide in patients uncontrolled with telmisartan monotherapy.

The antihypertensive effects of a telmisartan 80 mg/hydrochlorothiazide (HCTZ) 12.5 mg fixed-dose combination and telmisartan 80 mg monotherapy were compared in patients with a history of mild-to-moderate essential hypertension and inadequate BP control (DBP > or = 90 mm Hg) following 8 weeks of telmisartan monotherapy. At the end of this period, 491 patients (62.9% men; mean age 55.3 years) whose DBP was > or = 90 mm Hg were double-blind randomised to once-daily telmisartan 80 mg/HCTZ 12.5 mg (n = 246) or telmisartan 80 mg (n = 245). Trough (24 h post-dose) clinic BP was measured after 4 and 8 weeks of double-blind therapy. At the end of double-blind treatment, patients receiving telmisartan 80 mg/HCTZ 12.5 mg had significant additional decrements in clinic SBP/DBP over telmisartan 80 mg of -5.7/-3.1 mm Hg (P < 0.01). Most of the additional effect occurred during the first 4 weeks of treatment. The proportion of patients with normalised BP (SBP < 140 mm Hg and DBP < 90 mm Hg) was significantly greater in the telmisartan 80 mg/HCTZ 12.5 mg group than the telmisartan 80 mg group (41.5%vs 26.1%;P < 0.05). Both treatments were well tolerated. The incidence of adverse events was similar except for diarrhoea, which occurred more frequently in the telmisartan 80 mg/HCTZ 12.5 mg group, and oedema, which occurred more frequently in the telmisartan group. Our results indicate that a telmisartan 80 mg/HCTZ 12.5 mg fixed-dose combination confers significant additional BP reductions compared with continuation of telmisartan monotherapy in non-responders.     

Relative utility of home, ambulatory, and office blood pressures in the prediction of end-organ damage

BACKGROUND: Home blood pressure (HBP) monitoring plays an increasingly important role in the diagnosis and treatment of hypertension. We evaluated the independent value of HBP compared with ambulatory blood pressure (ABP) and office blood pressure (OBP) in the prediction of cardiovascular end-organ damage in normotensive subjects and untreated patients with mild hypertension. METHODS: One hundred sixty-three subjects underwent measurements of OBP, HBP, ABP, and echocardiography. A physician using a mercury-column sphygmomanometer performed three OBP measurements. The ABP was recorded using a noninvasive ambulatory monitor (mean, 35.4 awake readings per subject). Participants took HBP readings with an automatic, oscillometric device over a 10-week period (mean, 277.9 readings per subject). The left-ventricular mass index (LVMI) was calculated from measurements obtained from two-dimensionally guided M-mode or linear tracings on echocardiography. RESULTS: For systolic and diastolic blood pressures (SBP/DBP), the correlation coefficients of the LVMI with OBP, awake ABP, and HBP were 0.29/0.27, 0.41/0.26, and 0.47/0.35, respectively (all P < .01). In a multivariate regression analysis in which age, sex, body mass index, OBP, awake ABP, and HBP were included, only age, sex, and HBP were significant predictors of LVMI. When only the first 12 home readings were used, the superiority of HBP was no longer evident. CONCLUSIONS: In contrast to OBP and ABP, HBP measurements, when averaged over a 10-week period, are independently related to LVMI. The HBP adds prognostic information over and above OBP and ABP in the prediction of cardiovascular end-organ damage, but this relationship appears to depend on the number of readings taken.     

Assessment of the diurnal blood pressure profile and detection of non-dippers based on home or ambulatory monitoring

BackgroundA unique advantage of ambulatory blood pressure (ABP) monitoring is the assessment of nocturnal blood pressure (BP) and the detection of non-dippers. This study assessed nocturnal BP and non-dippers using a novel home BP (HBP) monitor.MethodsEighty-one hypertensives performed within 2 weeks ABP (24-h, Microlife WatchBP O3) and HBP monitoring (Microlife WatchBPN) during daytime (6 days, duplicate morning and evening measurements) and nighttime (automated asleep measurements, 3 nights, 3 readings/night). Patients' preference in using ABP or HBP was assessed by a questionnaire.ResultsStrong associations were found between ABP and HBP (intraclass correlation coefficients for awake systolic/diastolic 0.75/0.81; asleep 0.87/0.85). No statistically significant difference was found between HBP and ABP (mean difference ± SD awake systolic/diastolic 1.5 ± 10.1/-1.1 ± 6.0 mm Hg, P = 0.20/0.09; asleep -0.4 ± 7.8/-1.0 ± 5.3, P = 0.63/0.09). There was substantial agreement (74%, kappa 0.2) between ABP and HBP in the detection of non-dippers, which was similar to the previously reported test-retest reproducibility of repeated ABP monitoring in the diagnosis of non-dippers. Moderate to severe disturbance from ABP monitoring was reported by 18% of the participants and severe restriction of their daily activities by 9, vs. 3 and 1.5%, respectively for HBP (P < 0.001/ <0.01, for comparisons respectively). Nighttime BP monitoring and cuff discomfort were the main complaints for ABP (46 and 32%, respectively) and HBP (34 and 28%), whereas 89% reported more nighttime sleep disturbance by ABP than HBP (P < 0.001).ConclusionsHBP monitoring appears to be a reliable and well accepted by users alternative to ABP for the assessment of nocturnal BP and the detection of non-dippers.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.82.     

Safety and Tolerability of Fixed-Dose Irbesartan/Hydrochlorothiazide for Rapid Control of Severe Hypertension

This prospective, double-blind, multicenter trial compared the safety and tolerability of irbesartan/hydrochlorothiazide (HCTZ) fixed-dose combination therapy with irbesartan monotherapy in patients with severe hypertension (seated diastolic blood pressure (SeDBP) ≥110 mm Hg, mean BP 172/113 mm Hg at baseline). Patients were randomized 2:1 to 7 weeks' irbesartan/HCTZ 150/12.5 mg to 300/25 mg (n = 468) or irbesartan 150 mg to 300 mg (n = 227). The incidence of treatment-related adverse events (AEs) was similar with combination and monotherapy (11.3% and 10.1%), and most AEs were mild-to-moderate. The combined incidence of prespecified AEs was lower with irbesartan/HCTZ than with irbesartan (8.8% vs. 11.5%). There were no treatment-related serious AEs or deaths. At week 5, more patients achieved SeDBP < 90 mm Hg compared to irbesartan (47% vs. 33%; P = 0.0005). Despite more rapid and aggressive BP lowering, initial fixed-dose irbesartan/HCTZ demonstrated a comparable AE profile to irbesartan monotherapy in patients with severe hypertension.     

24-hour efficacy and safety of Triple-Combination Therapy With Olmesartan, Amlodipine, and Hydrochlorothiazide: the TRINITY ambulatory blood pressure substudy

This 12-week, multicenter, randomized, double-blinded, 4-arm study in 440 patients with moderate to severe hypertension compared ambulatory blood pressure (ABP) responses with a triple-combination regimen (olmesartan medoxomil [OM] 40 mg, amlodipine besylate [AML] 10 mg, and hydrochlorothiazide [HCTZ] 25 mg) and its component dual-combination regimens at similar doses. At week 12, the triple combination resulted in a greater reduction in mean 24-hour systolic and diastolic blood pressure (-30.3/-18.0 mm Hg) compared with the 3 dual-combination regimens (OM 40 mg/AML 10 mg: -23.5/-13.9, OM 40 mg/HCTZ 25 mg: -23.9/-14.5, and AML 10 mg/HCTZ 25 mg: -18.5 mm Hg/-10.7 mm Hg; P<.0001 each). Greater efficacy was also found during daytime and nighttime hours and during the last 6, 4, or 2 hours of the dosing interval. The authors conclude that the triple combination of OM 40 mg/AML 10 mg/HCTZ 25 mg demonstrated superior efficacy and sustained reductions in ABP compared with its dual-combination components.     

Antihypertensive effects of two fixed-dose combinations of losartan and hydrochlorothiazide versus hydrochlorothiazide monotherapy in subjects with ambulatory systolic hypertension

BACKGROUND: The efficacy of losartan (L) in combination with hydrochlorothiazide (HCTZ) has been demonstrated to reduce blood pressure. However, there are limited data on the effects of L/HCTZ combinations versus HCTZ monotherapies in reducing ambulatory systolic blood pressure. The aim of this study was to compare the effects of these treatment approaches in patients with ambulatory systolic hypertension. METHODS: Patients were randomized to receive L 50 mg (n = 60) or HCTZ 12.5 mg (n = 60) for 6 weeks. Patients were then force-titrated to L 50/HCTZ 12.5 mg and to L 100/HCTZ 25 mg or were sham-titrated to HCTZ 12.5 mg and force-titrated to HCTZ 25 mg, respectively. Clinic and 24-h ambulatory blood pressure (ABP) were measured at baseline and after each 6-week treatment period. RESULTS: We found that L 50 and HCTZ 12.5 induced significant and similar decreases in clinic and ABP. The combinations of L 50/HCTZ 12.5 and L 100/HCTZ 25 provided significantly greater decreases in clinic and ABP than did HCTZ monotherapies. The L 50/HCTZ 12.5 and L 100/HCTZ 25 combinations provided significant additional decreases in systolic/diastolic ABP during daytime (-5.3/-2.0 mm Hg; P <.001 and -5.8/-3.4 mm Hg; P <.001) and the other periods of the 24-h interval compared with the levels achieved by the previous treatment, indicating a clear dose-response relationship. However, increasing the dose of HCTZ from 12.5 mg to 25 mg was not associated with additional ABP reductions. CONCLUSIONS: Combinations of L 50/HCTZ 12.5 and L 100/HCTZ 25 provided greater reductions in clinic and ABP than HCTZ monotherapies, with a clear dose-response relationship with regard to ABP. These results support the use of ABP monitoring when assessing the efficacy of antihypertensive therapies.     

Adding Hydrochlorothiazide to Olmesartan/Amlodipine Increases Efficacy in Patients With Inadequate Blood Pressure Control on Dual‐Combination Therapy

This randomized, parallel‐group study in patients inadequately controlled on olmesartan medoxomil/amlodipine (OLM/AML) 40/10 mg assessed the effects of adding hydrochlorothiazide (HCTZ) 12.5 mg and 25 mg, using seated blood pressure (SeBP) measurements and ambulatory blood pressure (BP) monitoring. Enrolled patients were screened and tapered off of therapy if required. All patients received OLM/AML 40/10 mg and those with mean seated BP (SeBP) ≥140/90 mm Hg after 8 weeks (n=808) were randomized (1:1:1) to continue with OLM/AML 40/10 mg or receive OLM/AML/HCTZ 40/10/12.5 or 40/10/25 mg for a further 8 weeks. The primary endpoint was the change in seated diastolic BP (SeDBP) from the start to the end of the randomized treatment period. The addition of HCTZ 25 mg significantly reduced SeDBP (?2.8 mm Hg; P<.0001), lowered seated systolic BP (SeSBP) and ambulatory DBP and SBP, and improved BP goal rates. In patients uncontrolled on OLM/AML 40/10 mg, adding HCTZ led to further BP reductions, particularly in ambulatory BP.     

复方缬沙坦治疗轻中度原发性高血压患者的疗效观察

目的评价复方缬沙坦（缬沙坦80mg／氢氯噻嗪12．5mg复方制剂）治疗经单用缬沙坦80mg控制不良的轻、中度原发性高血压患者疗效和安全性。方法采用多中心、双盲、双模拟、随机、活性药物对照、平行试验方法。对经2周洗脱期的轻、中度原发性高血压患者[坐位舒张压≥95mmHg（1mmHg=0．133kPa）且〈110mmHg]采用单药缬沙坦80mg／d治疗4周,在单药导入结束后,坐位舒张压仍〉190mmHg的864例患者按1：1随机、双盲分为复方缬沙坦组或缬沙坦80mg／d组,继续治疗8周。在治疗4周和结束时评估药物安全性及有效性。结果在轻、中度原发性高血压患者中复方缬沙坦每日1次比单用缬沙坦80mg／d血压进一步下降、达标率提高。治疗结束时平均坐位收缩压多降低3．5mmHg,平均坐位舒张压多下降2．2mmHg,血压控制〈140／90mmHg的患者在复方缬沙坦组和单用缬沙坦80mg／d组分别为53．9％及40．9％。结论轻、中度原发性高血压患者采用复方缬沙坦治疗组降压有效率及达标率均优于每日1次服用缬沙坦80mg／d组。复方缬沙坦适用于缬沙坦单药控制不良的轻、中度原发性高血压患者。     

Comparison of aliskiren/hydrochlorothiazide combination therapy with hydrochlorothiazide monotherapy in older patients with stage 2 systolic hypertension: results of the ACTION study

Patients with stage 2 systolic hypertension require sizable blood pressure (BP) reductions to achieve recommended targets. This randomized double-blind study compared a single-pill combination of the direct renin inhibitor aliskiren and hydrochlorothiazide (aliskiren/HCTZ) with HCTZ monotherapy in older patients (older than 55 years) with systolic BP ≥160 mm Hg and <200 mm Hg. After a 1- to 4-week washout, 451 patients were randomized to once-daily aliskiren/HCTZ 150/12.5 mg or HCTZ 12.5 mg for 1 week, and then double the doses for 7 weeks. Overall baseline BP was 168.8/91.4 mm Hg. At week 4 (primary) end point, aliskiren/HCTZ provided significantly greater BP reductions from baseline than HCTZ monotherapy (29.6/9.3 mm Hg vs 22.3/6.8 mm Hg) and resulted in a greater proportion of patients achieving BP goal of <140/90 mm Hg (51.1% vs 33.3%). Aliskiren/HCTZ therapy provides substantial BP reductions and may thus be a useful treatment option for older patients with stage 2 hypertension.     

A comparison of the efficacy and safety of irbesartan/HCTZ combination therapy with irbesartan and HCTZ monotherapy in the treatment of moderate hypertension

This prospective, double-blind, parallel-group study randomized patients with moderate hypertension (seated systolic blood pressure (SeSBP) 160-179 mm Hg when seated diastolic blood pressure (SeDBP) <110 mm Hg; or SeDBP 100-109 mm Hg when SeSBP <180 mm Hg) 3:1:1 to treatment with irbesartan 300 mg/hydrochlorothiazide (HCTZ) 25 mg combination therapy (n=328), irbesartan 300 mg monotherapy (n=106) or HCTZ monotherapy 25 mg (n=104). Treatment was initiated at half dose, with forced titration to full dose after two weeks followed by ten further weeks' treatment. The primary efficacy variable was the mean reduction in SeSBP from baseline to week 8. Baseline characteristics were similar between groups, with mean baseline blood pressure approximately 162/98 mm Hg; the mean age was 55 years. At week 8 there was a reduction in SeSBP of 27.1 mm Hg with irbesartan/HCTZ, compared with 22.1 mm Hg with irbesartan monotherapy (P=0.0016) and 15.7 mm Hg with HCTZ (P<0.0001). Both the rate of decline and the total degree of decline achieved were greatest with irbesartan/HCTZ and least with HCTZ. A significantly greater percentage of patients reached a treatment goal of SeSBP <140 mm Hg and SeDBP <90 mm Hg by week 8 with irbesartan/HCTZ (53.4%), compared with irbesartan (40.6%; P=0.0254) and HCTZ (20.2%; P<0.0001) alone. Treatment was well tolerated in all three-treatment groups with a slight increase in adverse events in the combination therapy group. In conclusion, irbesartan/HCTZ (300/25 mg) is well tolerated and achieves rapid and sustained reductions in both systolic blood pressure and diastolic blood pressure in patients with moderate hypertension.     

Addition of manidipine improves the antiproteinuric effect of candesartan in hypertensive patients with type II diabetes and microalbuminuria

BACKGROUND: We sought to compare the effect of manidipine versus hydrochlorothiazide (HCTZ) in addition to candesartan on the urinary albumin excretion rate (UAER) in hypertensive patients with type II diabetes and microalbuminuria. METHODS: After a 2-week washout and run-in period, and 8-week monotherapy with candesartan 16 mg every day, 174 microalbuminuric diabetic hypertensive patients with uncontrolled blood pressure (BP) (>130/80 mm Hg) were randomized to addition of manidipine 10 mg every day (n = 87) or HCTZ 12.5 mg every day (n = 87) for 24 weeks, with a titration after 4 weeks (manidipine or HCTZ dose-doubling) in nonresponder patients. Blood pressure, UAER, creatinine clearance, serum electrolytes, fasting plasma glycemia, and glycosylated hemoglobin were evaluated at baseline (end of run-in period), after candesartan monotherapy, and at the end of the combination treatment period. RESULTS: Both combinations produced greater systolic BP/diastolic BP reduction than candesartan monotherapy (-28/21 mm Hg versus -16/11 mm Hg and -28/20 mm Hg versus -15/11 mm Hg, respectively; all P < .05 versus monotherapy), with no significant difference between the two combinations. The addition of manidipine produced a greater reduction in UAER than candesartan monotherapy (-55.4 mg/24 h v -36.1 mg/24 h, P < .05), whereas the addition of HCTZ did not significantly modify UAER; the difference between the two combinations was statistically significant (P < .05). Similarly, the percentage of patients moving to a normoalbuminuric state (UAER <30 mg/24 h) was increased by the addition of manidipine to candesartan (from 35% to 64%, P < .05), but not by the addition of HCTZ (from 34% to 39%, NS), with a statistical difference between the two combinations (P < .05). CONCLUSIONS: These findings show that, despite equivalent reduction in BP, the addition of manidipine to candesartan further reduced the UAER, whereas the addition of HCTZ did not modify the UAER. This suggests that the antiproteinuric effect of manidipine is partially independent of BP reduction, and is attributable to mechanisms different from those mediated by angiotensin receptor blockade.     

Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide

BACKGROUND: Most patients with hypertension require more than one agent to control blood pressure (BP). The purpose of this study was to assess the efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil in combination with hydrochlorothiazide (HCTZ). METHODS: This was a randomized, double-blind, factorial design study. After a placebo run-in period, eligible patients (n = 502) with a baseline mean seated diastolic blood pressure (SeDBP) of 100 to 115 mm Hg were randomized to one of 12 groups: placebo, olmesartan medoxomil monotherapy (10, 20, or 40 mg/day, HCTZ monotherapy (12.5 or 25 mg/day), or one of six groups of olmesartan medoxomil/HCTZ combination therapy. The primary endpoint was the change in mean trough SeDBP from baseline at week 8. Statistical analyses were conducted to determine whether at least one combination produced a larger reduction in SeDBP at week 8 than the individual corresponding component doses, but did not compare BP reductions with different combination doses. RESULTS: Olmesartan medoxomil plus HCTZ produced greater reductions in both SeDBP and seated systolic blood pressure (SeSBP) at week 8 than did monotherapy with either component. All olmesartan medoxomil/HCTZ combinations significantly reduced SeDBP and SeSBP compared with placebo in a dose-dependent manner. Reductions from baseline in mean trough SeSBP/SeDBP were 3.3/8.2 mm Hg, 20.1/16.4 mm Hg, and 26.8/21.9 mm Hg with placebo, olmesartan medoxomil/HCTZ 20/12.5 mg, and olmesartan medoxomil/HCTZ 40/25 mg, respectively. All treatments were well tolerated. CONCLUSIONS: Olmesartan medoxomil/HCTZ combination therapy produced BP reductions of up to 26.8/21.9 mm Hg and was well tolerated.     

A titrate-to-goal study of switching patients uncontrolled on antihypertensive monotherapy to fixed-dose combinations of amlodipine and olmesartan medoxomil ± hydrochlorothiazide

In the prospective, open-label, titrate-to-goal Blood Pressure Control in All Subgroups With Hypertension (BP-CRUSH) study, 999 patients with hypertension uncontrolled on monotherapy (mean age, 55.6 ± 11.4 years; baseline blood pressure [BP], 153.7 ± 9.2/91.9 ± 8.6 mm Hg) were switched to fixed-dose amlodipine/olmesartan medoxomil (AML/OM) 5/20 mg. Patients were uptitrated every 4 weeks to AML/OM 5/40 mg and 10/40 mg to achieve BP < 120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM+hydrochlorothiazide (HCTZ) 10/40+12.5 mg and 10/40+25 mg to achieve BP <125/75 mm Hg. The primary end point, the cumulative percentage of patients achieving seated systolic BP < 140 mm Hg (< 130 mm Hg for patients with diabetes) by week 12, was 75.8%. The mean (± standard error) BP changes from baseline during the titration periods ranged from -14.2±0.4 mm Hg/-7.7 ± 0.3 mm Hg for AML/OM 5/20 mg to -25.1 ± 0.7 mm Hg/-13.7 ± 0.4 mm Hg for AML/OM+HCTZ 10/40+25 mg. By week 20, the cumulative BP threshold of <140/90 mm Hg was achieved by 90.3% of patients. An ambulatory BP monitoring substudy (n=243) showed that 24-hour efficacy was maintained. Treatment-emergent adverse events (TEAEs), mostly mild to moderate in severity, occurred in 529 patients (53.0%). Drug-related TEAEs occurred in 255 patients (25.5%). This well-tolerated, treat-to-goal algorithm enabled a large proportion of patients with uncontrolled hypertension on monotherapy to safely achieve BP control on single-pill AML/OM combination therapy or triple therapy with the addition of HCTZ. .