There is a paucity of information regarding dose responses to hydrochlorothiazide (HCTZ). Historically, daily doses of HCTZ often exceeded 100 mg in the treatment of hypertension,1but current practice usually limits the daily dose to 25 mg because of the belief that efficacy is maintained while side effects are reduced at this dose. Current practice also dictates that effective 2-drug combinations are necessary in most patients to sustain blood pressure (BP) control, especially in patients with stage 2 or severe hypertension.2A thiazide diuretic is the most common component in drug combinations and is often combined with a β-blocker, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker (ARB).2,3 When the renin-angiotensin system is blocked sufficiently, thiazide diuretics enhance BP lowering and increase the proportion of patients achieving goal BP.4–11 In addition, the coadministration of one of these agents with a thiazide diuretic may help to offset some of the potential adverse events associated with diuretic therapy,7–10,12 including diuretic-induced hypokalemia, hyperglycemia, and increased serum uric acid.11,13–15 The present study was undertaken to extend observations of the effects of HCTZ in the presence of effective angiotensin receptor blockade. In this study, patients with stage 2 hypertension already receiving combined therapy with an ARB, olmesartan medoxomil (OM) 40 mg daily and HCTZ 25 mg daily, were up-titrated to HCTZ 50 mg daily with monitoring of BP effects, clinical symptoms, and laboratory values—particularly concentrations of serum potassium, glucose, and uric acid.
The authors studied the combination of hydrochlorothiazide (HCTZ) 50 mg/d plus olmesartan medoxomil (OM) 40 mg/d in stage 2 systolic hypertension during an extension phase of an open-label 12-week dose titration study. Subjects whose blood pressure remained above 120/80 mm Hg (n=105) on OM 40/HCTZ 25 mg/d subsequently received OM 40/HCTZ 50 mg/d for 4 weeks. Increasing HCTZ from 25 mg/d to 50 mg/d decreased systolic blood pressure by 3.6 mm Hg, increased BP control rates (<140/90 mm Hg) from 70.4% to 77.5%, and increased BP normalization rates (<120/80 mm Hg) from 15.4% to 27.8%. The combination was well tolerated. Compared with OM 40 mg/d monotherapy, neither dose of HCTZ affected serum potassium, but both increased serum glucose by about 5%. There was a dose-dependent increase in uric acid but no acute gout attacks. OM 40/HCTZ 50 mg/d is an effective strategy for managing stage 2 systolic hypertension.
A detailed description of the study design can be found in the companion paper by Izzo et al.16 This elective extension phase added a 4-week period of OM/HCTZ 40/50 mg daily for patients whose mean BP was still ≥120/80 mm Hg.
Efficacy data for the primary study are reported in the companion paper.16 Data presented here include efficacy differences between OM/HCTZ40/25 mg and OM/HCTZ 40/50 mg daily. A total of 105 subjects entered the extension phase. There were no differences in mean systolic BP (SBP) or diastolic BP (DBP) baseline values for the entire OM/HCTZ 40/25-mg/d group (171.4/95.7 mm Hg) compared with those electing to enter the extension phase (171.3/96.0 mm Hg).
The combination dose of OM/HCTZ (40/25 mg/d) significantly reduced mean SBP and DBP from baseline by 34.5 and 13.7 mm Hg, respectively (P<.001). Doubling the HCTZ dosage to 50 mg/d provided additional mean reductions from baseline of 3.6/2.0 mm Hg relative to OM/ HCTZ 40/25 mg/d (Figure 1). The greater mean reductions in seated BP observed in the OM/ HCTZ 40/50-mg/d group enabled more subjects to achieve a combined BP goal of <140/90 mm Hg (Figure 2): a cumulative total of 119 out of 169 subjects (70.4%) achieved this BP goal by the end of the OM/HCTZ 40/25-mg/d titration step, whereas OM/HCTZ 40/50 mg/d resulted in an additional 12 subjects achieving the goal BP (131/169 subjects; cumulative total, 77.5%). A similar result was seen in the proportion of subjects who were able to achieve BP normalization (defined as SBP/DBP <120/80 mm Hg). Increasing the HCTZ dose from 25 mg/d to 50 mg/d enabled an additional 20 subjects to attain this BP goal, nearly doubling the proportion of subjects achieving BP normalization (15.4% vs 27.2%, respectively). SBP goal (defined as SBP <140 mm Hg) rates also increased to 81.1% from 75.1% with the increased dose of HCTZ, and SBP normalization occurred in 27.8% of the efficacy cohort by the end of the extension phase, compared with 16.0% at the end of the OM/HCTZ 40/25-mg/d phase in the primary study.
OM/HCTZ combination therapies were generally safe and well tolerated. Increasing the dose of HCTZ from 25 mg/d to 50 mg/d increased the incidence of drug-related clinical adverse events (AEs) from 9/144 (6.3%) to 13/106 (12.3%), but these were largely mild, and the most common AEs (dizziness and fatigue) were not dose related (Figure 3table I). One serious treatment-emergent AE, dehydration, occurred in a subject in the OM/HCTZ 40/50-mg/d group and was classified as being possibly related to the study drug.
|Drug-Related Adverse Event, No. (%)†||40/25 (n=144)||40/50 (n=106)|
|Any clinical‡||9 (6.3)||13 (12.3)|
|Dizziness||7 (4.9)||6 (5.7)|
|Fatigue||3 (2.1)||2 (1.9)|
|Any laboratory||8 (5.6)||17 (16.0)|
|Blood creatinine >3.0 mg/dL||3 (2.1)||6 (5.7)|
|Blood uric acid >13.0 mg/dL||1 (0.7)||8 (7.6)|
|Blood urea nitrogen >50 mg/dL||0 (0)||8 (7.6)|
|γ-Glutamyltransferase >300 U/L||3 (2.1)||2 (1.9)|
|*Only events considered by the investigator as definitely, probably, or possibly related to the study drug are included. A single subject could experience ≥1 adverse event. †Adverse events listed are those that occurred at the particular dose shown for that titration step only (ie, the numbers shown are not cumulative). ‡Clinical adverse events do not include laboratory adverse events. OM indicates olmesartan medoxomil; HCTZ, hydrochlorothiazide.|
The incidence of drug-related laboratory AEs increased with HCTZ 50 mg/d (Figure 3, Table I). The most frequently reported (≥2%) drug-related laboratory AEs in the OM/HCTZ 40/25-mg/d and OM/HCTZ 40/50-mg/d groups were increased levels of blood creatinine, uric acid, urea, and γ-glutamyltransferase; however, these elevations were considered not to be of clinical significance. Red blood cell parameters, white blood cell count, differential white blood cell count, and platelets generally showed little change from baseline to the final visit regardless of dose. Similarly, the mean and median values for total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, urea nitrogen, creatinine, calcium, phosphorus, total protein, albumin, sodium, bicarbonate, chloride, cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides showed little change from baseline to the final visit.
Mean serum potassium, glucose, and uric acid levels remained within normal accepted limits during treatment with all OM/HCTZ combinations (Table II). Mean glucose and uric acid levels increased with increasing doses of HCTZ; however, this trend was not clinically significant. Mean potassium levels remained essentially unchanged for all doses. Despite the slight elevation in uric acid levels in some subjects, there were no reported incidences of gout.
|Metabolic Variable, Mean± SD (No.)||Baseline||40/25||40/50|
|Potassium, mEq/L||4.30±0.43 (166)||4.28±0.45 (138)||4.24±0.51 (85)|
|Glucose, mg/dL||103.9±24.56 (167)||109.0±30.12 (140)||109.6±34.49 (85)|
|Uric acid, mg/dL||6.03±1.31 (168)||7.38±1.79 (141)||7.57±1.68 (86)|
SBP control has been historically difficult to achieve, even with combination drug therapy during clinical trials.17–22 Increasing the dose of HCTZ could provide a cost-effective alternative, but there are no US Food and Drug Administration (FDA)-approved combination antihypertensive therapies that include HCTZ 50 mg, although the thiazide can be given as a separate medication. Current results demonstrate that increasing the dose of HCTZ to 50 mg daily in subjects with stage 2 hypertension receiving the maximum approved dose of an ARB can reduce BP by an additional 3/2 mm Hg. This additional effect allows up to 78% of stage 2 hypertensives to achieve BP control (<140/90 mm Hg) and up to 27% to achieve full BP normalization (<120/80 mm Hg), compared with 70% and 15% on a lesser dose of the thiazide. The increased antihypertensive efficacy was associated with a greater number of minor clinical or metabolic AEs, but the ultimate significance of these AEs is not clear. Overall, the OM/HCTZ combinations tested had no effect on serum potassium. Compared with therapy using OM 40 mg/d alone, addition of HCTZ in doses of either 25 mg/d or 50 mg/d caused small increases in serum glucose (each about 5%). There was a continuing dose-dependent increase in uric acid at OM/HCTZ 40/50 mg daily, but no gout attacks were noted.
We conclude that increasing the dose of HCTZ from 25 mg to 50 mg in subjects receiving adequate ARB therapy is reasonably effective and well tolerated. Increased HCTZ doses of 50 mg daily are thus realistic clinical options, but individual clinicians must determine whether the benefit of increased BP control outweighs the possible potential increased risk in each patient.
Acknowledgment and disclosure:We would like to express our thanks to Alan J. Klopp, PhD, for his editorial assistance in the preparation of this manuscript. This study was supported by Daiichi Sankyo, Inc.
Appendix The study investigators included Neville Bittar, MD; Deanna Cheung, MD; Steven Chrysant, MD, PhD; Meera Dewan, MD; David Ferrara, MD; F. Wilford Germino, MD; Larry Gilderman, DO; Joseph L. Izzo, Jr, MD; Joel M. Neutel, MD; Alan Niederman, MD; Edward Portnoy, MD; Bruce Rankin, DO, CCRI; William Smith, MD; Melvin Tonkin, MD; Jeffrey Wayne, MD; and Robert Weiss, MD.