Abstract
The effects of race and age on 24‐hour mean ambulatory systolic blood pressure (maSBP) responses to sequential 4‐week periods of angiotensin receptor blocker therapy (valsartan [VAL] 160 mg/d then 320 mg/d and combination VAL/hydrochlorothiazide [HCTZ] 320/12.5 mg/d) were compared in 304 patients with stage 1 or 2 hypertension. There were lesser blood pressure (BP) responses from baseline with VAL monotherapy in black than Caucasian patients (−2.9 and −4.0 mm Hg vs −8.2 and −9.3 mm Hg, respectively; P<.001 each) but VAL/HCTZ BP responses were similar in both groups (−12 vs −15 mm Hg). Participants 65 years and older had lower BP responses with VAL 160 mg/d and 320 mg/d than those younger than 65 years (−2.8 and −4.5 mm Hg vs −6.5 and −7.5 mm Hg, respectively; P<.001) but similar responses to VAL/HCTZ (−14 vs −17 mm Hg). No BP response differences were found between those older than and those younger than 55 years. The authors conclude that: (1) adding low‐dose HCTZ (12.5 mg daily) to VAL is more effective than VAL titration, irrespective of age or race, (2) VAL BP efficacy is lower in blacks than Caucasians, and (3) ARB responses are diminished in patients older than 65 years. Guidelines for stage 1 or 2 hypertension that suggest age 55 should determine initial monotherapy choice (eg, ARB vs thiazide diuretic) or that fail to recommend initial ARB‐thiazide combination therapy should be reconsidered.
Angiotensin receptor blockers (ARBs) are well tolerated and effective as initial antihypertensive monotherapy1 with blood pressure (BP) responses similar to other renin‐angiotensin system (RAS) blockers.2 The efficacy of RAS blockers varies considerably within and between individuals. RAS activity varies with salt intake, declines steadily with age3 and is usually lower in persons of African descent.4 A salt‐race interaction also occurs, with similar BP decreases to angiotensin‐converting enzyme (ACE) inhibitors in both black and white patients on a low‐salt diet but smaller effects in black patients on a high‐salt diet.5 There are also conflicting results regarding the impact of age on ARB responses. In older individuals, the effect of valsartan (VAL) on clinic systolic BP (SBP) was slightly less than that of hydrochlorothiazide (HCTZ), whereas there was no age effect on corresponding 24‐hour ambulatory BP values.6, 7 It might be logical to assume that the variability in ARB responsiveness is parallel to the wide population variation in RAS activity; however, renin profiling has not generally proved useful in predicting sustained BP responses to RAS blockers.8, 9
Despite these variabilities and uncertainties, three recent guidelines have recommended that race and age should be important factors in hypertension management decisions: calcium channel blockers or diuretics (and not ACE inhibitors or ARBs) should be used as first‐line agents in people of African descent and in patients older than 55 to 60 years.10, 11, 12 All of these guidelines were touted as “evidence‐based” yet no data were offered by the guideline groups to support such practices. A related area of concern is the optimal dose of ARBs. Recent practice guidelines continue to recommend ARB titration despite the fact that ARB dose‐response curves are quite shallow, with minimal BP differences between midlevel and maximal clinical doses.13 A recent Canadian study for improved BP control tested the value of dose‐titration by following four steps: initial therapy with ARB, ARB titration, addition of thiazide diuretic, and addition of calcium channel blocker.14 This regimen improved primary care BP control rates but can probably be streamlined. Overall, better BP control often depends on the use of an appropriate combination therapy.15 Therefore, the question remains whether combination therapy should be utilized more often as first‐step therapy.
The purpose of the present study was to determine the efficacy of VAL titration (doubling the dose) compared with the addition of low‐dose HCTZ to an existing VAL treatment. Specific attention was paid to race and age as modifiers of ARB responsiveness, as suggested in current guidelines.
Methods
Eligibility Criteria
All patients signed informed consent forms according to the Declaration of Helsinki. The study enrolled men and women aged 18 to 80 years, with previously treated or untreated mild to moderate hypertension, defined as mean seated (ms) diastolic BP (DBP) ≥95 and <110 mm Hg after a washout period of 2 to 4 weeks for those receiving antihypertensive therapy. Key exclusion criteria included severe hypertension (msDBP ≥110 mm Hg or ms SBP ≥180 mm Hg), history of proteinuria (>1 g/d), history of renal failure or hepatic disease, clinically significant cardiac arrhythmias or valvular disease, coronary artery disease within 6 months, a cerebrovascular event within 12 months, type 1 diabetes or poorly controlled type 2 diabetes, pregnant or nursing women, and women of child‐bearing age not practicing effective methods of contraception.
Treatment
This was a 12‐week, multicenter, open‐label, forced‐titration study comprising three sequential treatment phases (Figure 1) carried out in 37 US centers. All patients discontinued previous antihypertensive treatment at the initial study visit and were not taking antihypertensive medication for ≥14 days before the active study drug was initiated. Following this 2‐ to 4‐week screening/washout period, eligible patients received VAL 160 mg/d for 4 weeks, followed by a forced titration to VAL 320 mg/d for 4 weeks, followed by the addition of low‐dose HCTZ 12.5 mg/d for 4 weeks. Patients were instructed to take the study medication daily between 7 am and 10 am. On days during which 24‐hour ambulatory BP monitoring (ABPM) was applied, study medication was administered following the application and not administered again until removal of the ABPM device. No other antihypertensive agent or diuretics were allowed during the study (except ophthalmic β‐blocker eye drops), even if prescribed for another indication.
Figure 1.
Study design. ABPM indicates ambulatory blood pressure monitoring; HCTZ, hydrochlorothiazide.
Assessments
Clinic (office) BP readings were recorded in accordance with the 1993 American Heart Association Medical scientific statement on BP determination16 using a calibrated automatic sphygmomanometer (Omron automatic BP monitor, model #HEM‐705CP; Omron Healthcare, Inc., Lake Forest, IL) and appropriately sized cuff. The primary means of assessing efficacy in this study, 24‐hour ABPM, was performed at four time points: ie, 24 hours prior to starting treatment (at completion of the screening/washout phase); 24 hours prior to starting each of the subsequent treatment phases (at weeks 4 and 8); and 24 hours prior to the end‐of‐study visit (at week 12). The Spacelabs 90207 ABPM device (Spacelabs Healthcare Supplies, Issaquah, WA) was applied to the patient's nondominant arm after confirming no use of nonsteroidal anti‐inflammatory drugs or sympathomimetics within 48 hours. To ensure proper application and function of the ABPM device, the mean of three ABPM readings (manually initiated by an experienced coordinator) was compared with the mean of three sphygmomanometer‐determined DBP readings. If the difference between techniques exceeded 7 mm Hg, the ABPM device was reprogrammed and the correlation procedure was repeated. Safety assessments included regular monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs), physical examination, vital signs and body weight measurement, and basic laboratory values (hematology, blood chemistry, and urinalysis).
Statistical Analyses
Demographic and clinical baseline characteristics were summarized using standard descriptive statistics (mean, standard deviation). The original protocol was powered to detect changes in 24‐hour mean ambulatory BP (maBP) in all three treatment phases, the smallest of which was expected to be the difference in 24‐hour mean ambulatory DBP (maDBP) between weeks 4 and 8 (VAL 160 vs 320 mg daily dose). The study required a minimum of 265 patients completing the study to detect a minimum difference in maDBP of 1.5 mm Hg between weeks 4 and 8, with a statistical power of 90% at P<.05. The primary dependent variable was subsequently changed to 24‐hour mean ambulatory SBP (maSBP), and it was thought that the number of patients completing the study should be increased by approximately 10%. Allowing for multiple comparisons, stratification variables, and an expected dropout rate of 10%, a target of 362 enrollees was sought.
The 24‐hour ambulatory BP levels were calculated as the average of hourly means. The daytime period was defined as the period after 6 am up to 10 pm, the nighttime period as the period after 10 pm up to 6 am, and the trough BP period as the last 4 hours of the dosing interval. Differences between treatment phases were analyzed as paired differences (paired t tests) from baseline to the end of each treatment phase (differences between week 0 and weeks 4, 8, and 12, respectively). Analyses were also performed to determine the proportion of patients who achieved ambulatory and clinic (office) BP goals (<130/80 and <140/90 mm Hg, respectively) during the treatment phases. Further analyses included evaluation of the effects of two additional stratification variables, race (Caucasian vs black), and age, with the population dichotomized two ways: ≥65 vs <65 years and ≥55 vs <55 years. BP control rates between groups were analyzed by chi‐square test. Similar analyses were performed for all other BP variables. Safety was analyzed in all intention‐to‐treat (ITT) patients exposed to one or more doses of the study drug, with calculation of the proportion of patients experiencing AEs and assessment of changes in laboratory data (specifically potassium and creatinine) from baseline using a last‐observation‐carried‐forward approach.
Results
Of the 362 patients enrolled, 304 (84%) completed the study. The most common reasons for treatment discontinuation were protocol violations (n=15; 4.1%), lost to follow‐up (n=12; 3.3%), consent withdrawal (n=12; 3.3%), and AEs (n=9; 2.5%). All 362 patients received one or more doses of the study medication and therefore were included in both the efficacy and safety ITT, whereas 279 patients (77%) met the per‐protocol criteria.
Baseline demographic and clinical characteristics of the ITT population are summarized in Table 1. The study population had a mean age of 51.8 years and primarily comprised patients who were younger than 65 years (90%), male (57%), and Caucasian (52%). Baseline maSBP and maDBP were 141.2 and 89.5 mm Hg, respectively, with many patients (59%) having a maSBP value ≥130 but <150 mm Hg.
Table 1.
Baseline Demographic and Clinical Characteristics
| Variable | ITT Population (n=362) |
|---|---|
| Age, y | 51.8 (9.7) |
| Age ≥55, No. (%) | 129 (35.6) |
| Age ≥65, No. (%) | 36 (9.9) |
| BMI, kg/m2 | 30.5 (5.9) |
| Male sex, No. (%) | 207 (57) |
| Black race, No. (%) | 123 (34) |
| Heart rate, beats per min | 75.8 (9.8) |
| Serum potassium, mmol/L | 4.19 (0.4) |
| Serum creatinine, mg/dL | 0.85 (0.2) |
| Clinic msSBP, mm Hg | 155.2 (11.7) |
| Clinic msDBP, mm Hg | 98.3 (4.6) |
| 24‐h maSBP, mm Hg | 141.2 (12.2) |
| maSBP <130 mm Hg, No. (%) | 61 (19) |
| maSBP ≥130 mm Hg, No. (%) | 193 (59) |
| maSBP ≥150 mm Hg, No. (%) | 71 (22) |
| 24‐h maDBP, mm Hg | 89.5 (8.5) |
| Daytime maSBP, mm Hg | 145.2 (12.2) |
| Daytime maDBP, mm Hg | 93.5 (8.7) |
| Nighttime maSBP, mm Hg | 133.3 (14.4) |
| Nighttime maDBP, mm Hg | 81.6 (10.1) |
Abbreviations: BMI, body mass index; BP, blood pressure; ITT, intention‐to‐treat; maDBP, mean ambulatory diastolic blood pressure; maSBP, mean ambulatory systolic blood pressure; msDBP, mean seated diastolic blood pressure; msSBP, mean seated systolic blood pressure. Values are expressed as mean (standard deviation) unless otherwise indicated.
BP Endpoints
Statistically significant reductions in 24‐hour maSBP/maDBP (7.2/4.4 mm Hg) were observed postdose from baseline to week 8 (VAL 320; both P<.0001), with significant reductions also occurring from baseline to weeks 4 (VAL 160) and 12 (VAL 320/HCTZ 12.5, both P<.0001; Figure 2).
Figure 2.
Postdosing 24‐hour ambulatory systolic blood pressure (SBP) (a) and diastolic blood pressure (DBP) (b). Hourly values for baseline (no drug), week 4 (valsartan 160 mg), week 8 (valsartan 320 mg), and week 12 (valsartan/hydrochlorothiazide 320/12.5 mg). Doses administered between 7 am and 10 am.
Very small reductions (−1.1/−0.4 mm Hg; P=.0003/P=.1) were observed in maSBP/maDBP values from week 4 (VAL 160) to week 8 (VAL 320). An additional reduction in maSBP/maDBP of −7.0/−4.7 mm Hg (both P<.0001) occurred between weeks 8 and 12 (VAL 320/HCTZ 12.5). Results similar to those in the ITT population were seen in the per‐protocol analyses (data not shown). Consistent reductions from baseline in postdose hourly maDBP and maSBP by week are shown in Table 2 for the entire 24‐hour dosing period.
Table 2.
Changes From Baseline in Clinic and 24‐Hour Ambulatory BP With Corresponding BP Control Rates
| Week 4 (VAL 160 mg) | Week 8 (VAL 320 mg) | Week 12 (VAL/HCTZ 320/12.5 mg) | |
|---|---|---|---|
| Clinic BP changes, mm Hg | |||
| No. | 349 | 320 | 307 |
| msSBP | −8.4 (12.8)a | −11.5 (13.9)a, ,b | −18.1 (15.3)a , c |
| msDBP | −6.0 (7.9)a | −7.4 (9.2)a , b | −11.5 (9.2)a , c |
| Ambulatory BP changes, mm Hg | |||
| No. | 325 | 307 | 303 |
| 24‐h maSBP | −6.1 (9.5)a | −7.2 (11.0)a , b | −14.3 (11.5)a , c |
| 24‐h maDBP | −4.0 (6.8)a | −4.4 (7.5)a | −9.1 (7.8)a , c |
| Daytime maSBP | −6.4 (9.9)a | −7.3 (11.4)a , b | −14.1 (12.2)a , c |
| Daytime maDBP | −4.2 (7.4)a | −4.6 (8.4)a | −9.1 (8.7)a , c |
| Nighttime maSBP | −5.9 (11.1)a | −7.4 (13.1)a , b | −14.2 (12.9)a , c |
| Nighttime maDBP | −3.7 (8.1)a | −4.4 (8.9)a | −8.8 (8.5)a , c |
| Trough maSBP | −4.9 (11.3)a | −6.5 (12.5)a , b | −14.0 (13.6)a , c |
| Trough maDBP | −2.9 (9.0)a | −3.7 (9.2)a | −9.0 (9.6)a , c |
| BP control rates | |||
| Ambulatory BP (maSBP/maDBP <130/80 mm Hg), % | 24 | 29.6 | 47.9d |
| Clinic BP (msSBP/msDBP <140/<90 mm Hg), % | 23.5 | 33.4 | 52.8d |
Abbreviations: BP, blood pressure; HCTZ, hydrochlorothiazide; maDBP, mean ambulatory diastolic BP; maSBP, mean ambulatory systolic BP; msDBP, mean sitting diastolic BP; msSBP, mean sitting systolic BP; VAL, valsartan. Trough BP is defined as the last 4 hours of the postdosing period. Values are expressed as mean (standard deviation). a P<.0001 vs baseline. b P<.05 vs week 4. c P<.0001 vs week 8. d P<.0001 vs week 4 and 8.
As in the primary analysis, the clinic msSBP and msDBP (Table 2) in the ITT population significantly declined after forced titration with VAL and addition of HCTZ. From baseline to every time point, there were significant reductions in clinic msSBP and msDBP (all P<.0001) along with reductions from week 4 (VAL 160) to week 8 (VAL 320) in msSBP (−3.1 mm Hg; P=.0003) and msDBP (−1.1 mm Hg; P=.027) and from week 8 to week 12 (VAL/HCTZ 320/12.5; −6.6/−4.1 mm Hg, each P<.0001). The forced‐titration schedule resulted in progressive reductions in 24‐hour maSBP and maDBP. With respect to all BP variables (postdose 24‐hour maSBP and maDBP and clinic msSBP and msDBP), the highest reductions occurred between weeks 8 and 12 (Table 2).
The proportions of patients who ultimately achieved BP control, defined separately as ambulatory (maSBP/maDBP <130/80 mm Hg) and clinic (msSBP/msDBP <140/90 mm Hg) BP goals, increased with each subsequent treatment phase, with the highest proportion of responders observed with VAL/HCTZ combination therapy (Table 2). Clinic BP control rates (msBP, <140/90 mm Hg) were 24% and 33% for VAL 160 and 320 mg, respectively, and 53% for VAL/HCTZ. There was a similar response for ambulatory BP control rates (maBP <130/80 mm Hg): 24% and 30% for VAL 160 and 320 mg, respectively, and 48% for VAL/HCTZ. The added benefit of HCTZ was most evident in patients uncontrolled on VAL monotherapy. The addition of HCTZ increased the clinic and ambulatory BP control rates to 40.2% and 30.1%, respectively, in patients previously uncontrolled on VAL monotherapy.
Race and Age Stratification
Approximately 34% (n=123) of patients were black and 10% (n=36) were 65 years and older (elderly). Among black patients, 57% were male and only 3% were 65 years and older. For patients 65 years and older, 75% were male and 72% were Caucasian. Baseline ambulatory but not clinic SBP and DBP levels were slightly higher in the black than in the Caucasian patients (maSBP/maDBP 3/4 mm Hg). Ambulatory and clinic SBP levels were higher in patients 65 years and older compared with their younger counterparts (maSBP 6.7 mm Hg vs msSBP 11.4 mm Hg), but the ambulatory and clinic DBP levels were similar.
In response to VAL monotherapy, black patients and patients 65 years and older had lower ambulatory BP responses compared with Caucasians and patients younger than 65 years (Tables 3 and 4). The addition of HCTZ 12.5 mg daily to VAL 320 mg daily elicited greater responses in the black patients and patients older than 65 years, resulting in similar ambulatory BP levels and BP control rates in all subgroups by the end of the study. Comparison of clinic to ambulatory measures showed that the race effect was similar between ABPM and clinic BP levels, but the age effect (specifically, ≥65 years) was only observed for ambulatory but not clinic BP levels (Table 4). The addition of HCTZ, but not VAL titration, eliminated most of the racial and age‐related differences in BP responses and control rates. Another factor in the final control rates was the higher baseline BP in black patients and those older than 65 years. Upon stratification by age, patients younger than 55 years (n=233; 64%) compared with those 55 years and older (n=129; 36%) had baseline BP differences similar to the cutoff point for patients aged 65 years. The BP‐lowering effect and BP control rates of VAL monotherapy, however, tended to be similar between patients younger than 55 years compared with those 55 years and older.
Table 3.
Race Effect on BP Changes From Baseline and BP Control Rates
| Week (Treatment) | Ambulatory BP Changes (mm Hg) and Control Rates (bold) | Clinic BP Changes (mm Hg) and Control Rates (bold) | ||
|---|---|---|---|---|
| Caucasian (n=172) | Black (n=107) | Caucasian (n=183) | Black (n=117) | |
| Week 4 (VAL 160 mg) | −8.2 (5.5)/−5.5 (4.2) | −2.9 (5.5)a/−2.0 (4.2)a | −10.6 (12)/−7.7 (7.6) | −4.8 (12.1)a/−3.1 (7.6)a |
| 30.2% | 13.1% b | 28.8% | 11.8% b | |
| Week 8 (VAL 320 mg) | −9.3 (7.1)/−6.0 (5.1) | −4.0 (7.2)a/−2.2 (5.1)a | −13.9(14.3)/−9.4 (9.3) | −8.0 (14.6)a/−4.2 (9.5)a |
| 39.0% | 16.2% b | 41.7% | 18.9% b | |
| Week 12 (VAL/HCTZ 320/12.5 mg) | −14.9 (7.2)/−9.6 (5.0) | −12.2 (7.2)c/−7.7 (5.0)c | −17.8 (15.4)/−12.1 (9.2) | −17.6 (16.0)/−10.1 (9.6) |
| 54.6% | 35.0% c | 55.6% | 47.0% | |
Abbreviations: BP, blood pressure; HCTZ, hydrochlorothiazide; VAL, valsartan. Values are expressed as mean (standard deviation) unless otherwise indicated. Systolic BP values are the upper and diastolic BP values are the lower numbers. BP control rates for ambulatory (mean ambulatory systolic BP/mean ambulatory diastolic BP <130/80 mm Hg) and clinic (mean sitting systolic BP/mean sitting diastolic BP <140/90 mm Hg) BP. a P<.0001. b P<.001. c P<.05.
Table 4.
Age Effects: Changes From Baseline and BP Control Rates for Different Age Dichotomizations
| Week (Treatment) | Ambulatory BP Changes (mm Hg) and Control Rates (bold) | Clinic BP Changes (mm Hg) and Control Rates (bold) | ||
|---|---|---|---|---|
| Age 55 cutoff | <55 y (n=208) | ≥55 y (n=117) | <55 y (n=233) | ≥55 y (n=129) |
| Week 4 (VAL 160 mg) | −6.3 (5.8)/−4.4 (4.3) | −5.6 (5.7)/−3.1 (4.3)a | −8.1 (12.9)/−5.9 (7.9) | −9.0 (12.8)/−6.3 (8.0) |
| 25.5% | 21.4% | 28.1% | 18.3% a | |
| Week 8 (VAL 320 mg) | −8.0 (7.2)/−5.3 (5.0) | −5.8 (7.1)a/−2.8 (5.1)a | −11.5 (14.5)/−7.4 (9.6) | −11.5 (14.6)/−7.3 (9.6) |
| 33.3% | 24.1% | 38.5% | 24.5% a | |
| Week 12 (VAL/HCTZ 320/12.5 mg) | −13.3 (7.3)/−9.1 (5.0) | −15.8 (7.3)a/−9.1 (5.1) | −16.7 (16.3)/−11.0 (9.9) | −20.5(16.2)a/−12.2 (9.7) |
| 50.5% | 44.0% | 52.4% | 53.4% | |
| Age 65 cutoff | <65 y (n=292) | ≥65 y (n=33) | <65 y (n=326) | ≥65 y (n=36) |
|---|---|---|---|---|
| Week 4 (VAL 160 mg) | −6.5 (5.6)/−4.2 (4.3) | −2.8 (5.6)a/−1.8 (4.2)a | −8.5 (12.7)/−6.0 (8.0) | −7.9 (12.8)/−6.6 (7.9) |
| 25.3% | 12.1% | 25.9% | 12.5% b | |
| Week 8 (VAL 320 mg) | −7.5 (7.2)/−4.7 (5.1) | −4.5 (6.9)a/−2.1 (5.0)a | −11.6 (14.5)/−7.4 (9.6) | −10.9 (14.8)/−7.5 (9.8) |
| 32.4% | 9.4% b | 35.8% | 12.9% b | |
| Week 12 (VAL/HCTZ 320/12.5 mg) | −13.9 (7.5)/−9.0 (5.1) | −16.7 (7.2)a/−9.4 (5.0) | −17.9 (6.5)/−11.5 (9.9) | −20.1 (16.3)/−11.4 (9.8) |
| 48.5% | 45.2% | 53.2% | 48.9% |
Abbreviations: HCTZ, hydrochlorothiazide; VAL, valsartan. Blood pressure (BP) control rates for ambulatory (mean ambulatory systolic BP/mean ambulatory diastolic BP<130/80 mm Hg) and clinic (mean sitting systolic BP/mean sitting diastolic BP<140/90 mm Hg) BP. Values are expressed as mean (standard deviation) unless otherwise indicated. Systolic BP values are the upper and diastolic BP values are the lower numbers. a P<.05. b P<.001 for group comparisons.
Safety/Tolerability
AEs occurred in 148 patients (40.9%) throughout the study and were mostly mild or moderate in severity. The most commonly reported individual AEs (>2%) were headache (6.6%), dizziness (4.1%), sinusitis (3.0%), arthralgia (2.5%), and diarrhea (2.2%). Hypotension and orthostatic hypotension were infrequent, reported in one patient (0.2%) each. Nine patients (2.5%) had AEs that led to withdrawal from the study. Four patients (1.1%) experienced a total of six SAEs, all requiring hospitalization, but none were considered related to the study drugs. No deaths occurred during the study, but one patient died from cardiac arrest 9 days after being withdrawn from the study for nonadherence with the visit schedules. No clinically significant changes were observed from baseline to the end of the study in body weight, sitting pulse rate, or laboratory assessment of potassium (mean decrease, 0.04 mmol/L) or creatinine (mean increase, 0.06 mg/dL). No patient withdrew from the study because of laboratory abnormalities.
Discussion
Our results generally support a conceptual paradigm that BP responses to ARBs are lower in black patients and to a lesser degree in the elderly (≥65 years in this study). The difference in BP response to VAL monotherapy with respect to race was noticeable: approximately 5 mm Hg less in both ambulatory and clinic SBP responses in blacks compared with Caucasians. With respect to age, if the population was dichotomized around age 55, there were trivial (<2 mm Hg) differences in response of 24‐hour ambulatory mean (but not clinic mean SBP) to VAL monotherapy. Thus, our findings are not consistent with the British National Institute for Health and Care Excellence guideline, which suggests using a cutoff of age 55 for initial use of ACE inhibitors and ARBs.10 We did not dichotomize around age 60, so it is not clear whether guidance based on that threshold is valid. What is clear is the value of adding low‐dose HCTZ compared with titration of ARB. Furthermore, the value of HCTZ is even greater in individuals with lower responsiveness to ARB monotherapy (ie, blacks and elderly patients). Ambulatory BP control rates were reported using the current standard (mean 24‐hour BP <130/80 mm Hg). Differences in BP control rates were clearly evident on 24‐hour ambulatory BP, which appears to be a more robust predictor of outcomes than clinic BP.17, 18 At the very least, ambulatory monitoring limits the “white‐coat effect” and may also be an important measure of efficacy, typically in patients who demonstrate a poorer initial response to ARB therapy (eg, black and elderly patients).
ARBs typically exhibit a “flat” or shallow BP dose‐response curve, with a minimal incremental benefit (0–2 mm Hg difference in trough SBP) between midrange and full doses (eg, VAL 160 vs 320 mg daily or olmesartan 20 vs 40 mg daily or irbesartan 150 vs 300 mg).19, 20, 21 BP responses to ARBs were less in black hypertensive patients compared with Caucasian hypertensive patients although overall BP responses were similar in both races when low‐dose HCTZ was added to VAL. In this study, all patients substantially benefited from the addition of HCTZ 12.5 mg to VAL therapy, similar to other studies on VAL.19, 20 Unlike ARBs, there is a steeper BP dose‐response to thiazide diuretics over the range of 12.5 to 50 mg daily. When added to olmesartan, each doubling of HCTZ dose from 12.5 to 50 mg incrementally reduced SBP by about 5 mm Hg.22, 23 On the other hand, dose manipulations pose important clinical challenges. Historically, physicians have titrated and added drugs sequentially in several steps over weeks or months, but in recent years it has become apparent that such practices are usually unnecessarily tedious, costly, lead to delays in BP control, and cause significant patient frustration. The present results underscore the relative futility of ARB titration. Because the side effects of ARBs are no greater than those of placebo (and less in some studies) and the use of higher doses is safe, the wisdom of ARB titration should be challenged. The results of this study also suggest that current recommendations for initial combination therapy may need to be expanded to lower levels of pretreatment BP. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)24 guidelines were the first to recommend initial combination therapy for individuals with stage 2 hypertension. Resistance to a broader application of combination therapy has traditionally been based on risks of AEs, particularly first‐dose hypotension. Clinical experience with two‐ and three‐drug combinations of ARBs, thiazides, and amlodipine has shown that AE rates are not increased, including the incidence of hypotension. In fact, coadministration of initial full‐dose triple therapy (ARB, thiazide, and amlodipine) resulted in effective and safe BP control in patients with stage 2 hypertension.25, 26 More recently, the Systolic Blood Pressure Intervention Trial (SPRINT)27 was terminated early because participants treated to the lowest BP targets (BP levels, <120/80 mm Hg) had fewer AEs than those treated to traditional 140/90 mm Hg thresholds. Thus, a strong argument can be made for initial combination therapy in patients with stage 1 hypertension.
Conclusions
In this study, BP‐lowering efficacy with VAL was less in black than in Caucasian hypertensive patients and in those older than 65 years. The addition of low‐dose HCTZ to VAL monotherapy was superior to VAL uptitration (160–320 mg daily) in lowering BP; however, irrespective of age or race. Hypertensive treatment guidelines that discourage ARB use in hypertensive patients aged 55 to 60 years or initial use of antihypertensive combinations in stage 1 hypertension should be reconsidered.
Disclosures
All authors participated in the development and writing of the paper and approved the final manuscript for publication. The final manuscript in its entirety was written by the first author, who is responsible for the content. The sponsor reviewed the work for factual content but did not exert editorial control over its contents. Dr J. L. Izzo, Jr, declares no conflict of interest. Drs Y. Jia and D. H. Zappe were employed by Novartis Pharmaceuticals, Inc. at the time of the study.
Acknowledgments
This study was sponsored by Novartis Pharmaceuticals. The authors recognize the contributions of the individual centers; site principal investigators are listed in the Appendix. The authors also thank Xiangyi Meng, Novartis, for statistical analysis and Amol Gujar, Novartis Healthcare Pvt. Ltd., for providing editorial support.
List of Investigators
Dr Lawrence Anastasi (Medical Center of Margate Family Medicine, 9501 Ventnor Avenue, Margate City, NJ 08402), Dr Neville Bittar (Gemini Scientific, 6300 Enterprise Lane, Suite 201, Madison, WI 53719), Dr Albert Carr (Southern Clinical Research and Management, Inc., 1501 Anthony Road, Augusta, GA 30904), Dr John Champlin (Med Center, 6651 Madison Avenue, Carmichael, CA 95608), Dr Deanna Cheung (Memorial Research Medical Clinic, 2865 Atlantic Avenue, Suite 227, Long Beach, CA 90806), Dr Steven Chrysant (Oklahoma Cardiovascular and Hypertension Center, 5850 West Wilshire Boulevard, Oklahoma City, OK 73132), Dr Meera Dewan, P.C. (11912 Elm Street, Suite 26, Omaha, NE 68144), Dr Amin Elashker (Hudson Valley Clinical Research, 117 Mary's Avenue, Suite 104, Kingston, NY 12401), Dr F. Wilford Germino (Orland Primary Care Specialists, 16660 107th Avenue, Orland Park, IL 60467), Dr Lisa Gidday (Arapahoe Internal Medicine, P.C., 7750 South Broadway, Suite 100, Littleton, CO 80122), Dr Larry Gilderman (University Clinical Research, Inc., 1150 North University Drive, Pembroke Pines, FL 33024), Dr Carl Griffin (Lynn Health Science Institute, 5300 North Independence, Suite 130, Oklahoma City, OK 73112), Dr David Headley (Planters Clinic, 405 Market Street, Port Gibson, MS 39150), Dr James Herron (Herron Medical Center, Ltd., 1150 North State Street, Chicago, IL 60610), Dr Robert Hippert (Fleetwood Medical Associates, 805 North Richmond Street, Suite 104, Fleetwood, PA 19522), Dr Thomas Hunt (MetaClin Research, Inc., 3755 Capital of Texas Highway South, Suite 230, Austin, TX 78704), Dr Terence Isakov (Ohio Clinical Research, LLC, 5187 Mayfield Road, Suite 103, Lyndhurst, OH 44124), Dr Eric Klein (Capital Clinical Research Center, 406 Yauger Way SW, Suite A, Olympia, WA 98502), Dr Marc Kozinn (19 Limestone Drive, Suite 11, Williamsville, NY 14221), Dr Robert Madder (Tri‐State Medical Group, Inc., 500 Sharon Road, Beaver, PA 15009), Dr Stephen Ong, Ong Medical Center, 6357 Oxon Hill Road, Oxon Hill, MD 20745), Dr Keith Pierce (Michigan Institute of Medicine, 38525 Eight Mile Road, Livonia, MI 48152), Dr Edward Portnoy (Westlake Medical Research, 1250 La Venta Drive, Suite 101‐A, Westlake Village, CA 91361), Dr George Raad (Metrolina Medical Research, 1700 Abbey Place, Suite 209, Charlotte, NC 28209), Dr Sidney Rosenblatt (Radiant Research – Irvine, 16259 Laguna Canyon Road, Irvine, CA 92618), Dr Douglas Schumacher (Radiant Research – Columbus, 1275 Olentangy River Road, Suite 202, Columbus, OH 43212), Dr K.S. (Stan) Self (Self Center, PC, 306 South Greeno Road, Suite A, Fairhope, AL 36532), Dr William Smith (New Orleans Center for Clinical Research, 2820 Canal Street, New Orleans, LA 70119), Dr Melvin Tonkon (Apex Research Institute, 999 North Tustin Avenue, Suite 120, Santa Ana, CA 92705), Dr Ramon Vargas (Clinical Research Center, 2237 Poydras Street, New Orleans, LA 70119), Dr Frederick Wood (Salus Clinical Research, 25405 Hancock Avenue, Suite 216, Murrieta, CA 92562), Dr Evan Zimmer (BioQuan Research Group, Inc., 12995 NE 7th Avenue, North Miami, FL 33161), Dr Richard Mills (Coastal Carolina Research Center, 1156 Bowman Road, Suite 102, Mt. Pleasant, SC 29464), Dr John Rubino (Multi‐Specialty Research Associates of NC, 3509 Haworth Drive, Suite 100, Raleigh, NC 27609), Dr Jeffrey Rosen (Clinical Research of South Florida, 275 Alhambra Circle, Coral Gables, FL 33134), Dr Andrew Lewin (National Research Institute, 2010 Wilshire Boulevard, Suite 302, Los Angeles, CA 90057), and Dr Duane Wombolt (Clinical Research Associates of Tidewater, 902 Medical Tower, 400 Gresham Drive, Norfolk, VA 23507).
J Clin Hypertens (Greenwich). 2017;19:143–150. DOI: 10.1111/jch.12891. © 2016 Wiley Periodicals, Inc.
References
- 1. Ruilope LM, Rosei EA, Bakris GL, et al. Angiotensin receptor blockers: therapeutic targets and cardiovascular protection. Blood Press. 2005;14:196–209. [DOI] [PubMed] [Google Scholar]
- 2. Deary AJ, Schumann AL, Murfit H, et al. Double‐blind, placebo‐controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens. 2002;20:771–777. [DOI] [PubMed] [Google Scholar]
- 3. Weidmann P, Beretta‐Piccoli C, Ziegler WH, et al. Age versus urinary sodium for judging renin, aldosterone, and catecholamine levels: studies in normal subjects and patients with essential hypertension. Kidney Int. 1978;14:619–632. [DOI] [PubMed] [Google Scholar]
- 4. Chrysant SG, Danisa K, Kem DC, et al. Racial differences in pressure, volume and renin interrelationships in essential hypertension. Hypertension. 1979;1:136–141. [DOI] [PubMed] [Google Scholar]
- 5. Weir MR, Chrysant SG, McCarron DA, et al. Influence of race and dietary salt on the antihypertensive efficacy of an angiotensin‐converting enzyme inhibitor or a calcium channel antagonist in salt‐sensitive hypertensives. Hypertension. 1998;31:1088–1096. [DOI] [PubMed] [Google Scholar]
- 6. Izzo JL Jr, Weintraub HS, Duprez DA, et al. Treating systolic hypertension in the very elderly with valsartan‐hydrochlorothiazide vs. either monotherapy: ValVET primary results. J Clin Hypertens (Greenwich). 2011;13:722–730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Duprez DA, Weintraub HS, Cushman WC, et al. Effect of valsartan, hydrochlorothiazide, and their combination on 24‐h ambulatory blood pressure response in elderly patients with systolic hypertension: a ValVET substudy. Blood Press Monit. 2011;16:186–196. [DOI] [PubMed] [Google Scholar]
- 8. Woods JW, Pittman AW, Pulliam CC, et al. Renin profiling in hypertension and its use in treatment with propranolol and chlorthalidone. N Engl J Med. 1976;294:1137–1143. [DOI] [PubMed] [Google Scholar]
- 9. Weintraub HS, Duprez DA, Cushman WC, et al. Antihypertensive response to thiazide diuretic or angiotensin receptor blocker in elderly hypertensives is not influenced by pretreatment plasma renin activity. Cardiovasc Drugs Ther. 2012;26:145–155. [DOI] [PubMed] [Google Scholar]
- 10. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community. J Clin Hypertens (Greenwich). 2014;16:14–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. National Clinical Guideline Centre . Hypertension: The Clinical Management of Primary Hypertension in Adults: Update of Clinical Guidelines 18 and 34. London, UK: Royal College of Physicians; 2011. [PubMed] [Google Scholar]
- 12. James PA, Oparil S, Carter BL, et al. 2014 evidence‐based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). J Am Med Assoc. 2014;311:507–520. [Erratum appears in JAMA. 2014;311:1809]. [DOI] [PubMed] [Google Scholar]
- 13. Makani H, Bangalore S, Supariwala A, et al. Antihypertensive efficacy of angiotensin receptor blockers as monotherapy as evaluated by ambulatory blood pressure monitoring: a meta‐analysis. Eur Heart J. 2014;35:1732–1742. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Feldman RD, Zou GY, Vandervoort MK, et al. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension. 2009;53:646–653. [DOI] [PubMed] [Google Scholar]
- 15. Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension. J Am Soc Hypertens. 2010;4:90–98. [DOI] [PubMed] [Google Scholar]
- 16. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142–161. [DOI] [PubMed] [Google Scholar]
- 17. Dolan E, Stanton A, Thijs L, et al. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension. 2005;46:156–161. [DOI] [PubMed] [Google Scholar]
- 18. Hansen TW, Jeppesen J, Rasmussen S, et al. Ambulatory blood pressure and mortality: a population‐based study. Hypertension. 2005;45:499–504. [DOI] [PubMed] [Google Scholar]
- 19. Weir MR, Crikelair N, Levy D, et al. Evaluation of the dose response with valsartan and valsartan/hydrochlorothiazide in patients with essential hypertension. J Clin Hypertens (Greenwich). 2007;9:103–112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Pool J, Oparil S, Hedner T, et al. Dose‐responsive antihypertensive efficacy of valsartan, a new angiotensin II‐receptor blocker. Clin Ther. 1998;20:1106–1114. [DOI] [PubMed] [Google Scholar]
- 21. Rump LC, Girerd X, Sellin L, Stegbauer J. Effects of high dose olmesartan medoxomil plus hydrochlorothiazide on blood pressure control in patients with grade 2 and grade 3 hypertension. J Hum Hypertens. 2011;25:565–574. [DOI] [PubMed] [Google Scholar]
- 22. Izzo JL Jr, Neutel JM, Silfani T, et al. Efficacy and safety of treating stage 2 systolic hypertension with olmesartan and olmesartan/HCTZ: results of an open‐label titration study. J Clin Hypertens (Greenwich). 2007;9:36–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Izzo JL Jr, Neutel JM, Silfani T, et al. Titration of HCTZ to 50 mg daily in individuals with stage 2 systolic hypertension pretreated with an angiotensin receptor blocker. J Clin Hypertens (Greenwich). 2007;9:45–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: JNC 7 express. J Am Med Assoc. 2003;289:2560–2572. [DOI] [PubMed] [Google Scholar]
- 25. Izzo JL Jr, Chrysant SG, Kereiakes DJ, et al. 24‐hour efficacy and safety of Triple‐Combination Therapy With Olmesartan, Amlodipine, and Hydrochlorothiazide: the TRINITY ambulatory blood pressure substudy. J Clin Hypertens (Greenwich). 2011;13:873–880. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Calhoun D, Crikelair N, Yen J, Glazer R. Amlodipine/valsartan/hydrochlorothiazide triple combination therapy in moderate/severe hypertension: secondary analyses evaluating efficacy and safety. Adv Ther. 2009;26:1012–1023. [DOI] [PubMed] [Google Scholar]
- 27. SPRINT Research Group , Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood‐pressure control. N Engl J Med. 2015;373:2103–2116. [DOI] [PMC free article] [PubMed] [Google Scholar]