Two post hoc analyses in self-identified black and white patients with hypertension evaluated the angiotensin II receptor blocker azilsartan medoxomil (AZL-M) and the fixed-dose combination of AZL-M with chlorthalidone (AZL-M/CLD) versus the ARB olmesartan (OLM) and the OLM fixed-dose combination with hydrochlorothiazide (OLM/HCTZ). One analysis pooled 1,610 patients from two 6-week randomized controlled trials to compare once daily AZL-M 40 mg, AZL-M 80 mg, OLM 40 mg, and placebo. The second analysis included 1,020 patients from a 12-week randomized controlled trial to compare once daily AZL-M/CLD 40/25 mg, AZL-M/CLD 80/25 mg, and OLM/HCTZ 40/25 mg. Efficacy end points were 24-hour mean ambulatory and clinic systolic and diastolic blood pressure (SPB/DBP) and the percentage of patients achieving clinic SBP/DBP targets. Treatment with AZL-M 80 mg lowered mean clinic SBP by 12.5 mm Hg (p <0.01 vs OLM), treatment with AZL-M/CLD 40 mg/25 mg lowered mean ambulatory SBP by 31.0 mm Hg and mean clinic SBP by 39.3 mm Hg (both p <0.05 vs OLM/HCTZ), and treatment with AZL-M/CLD 80 mg/25 mg lowered mean ambulatory SBP by 34.4 mm Hg (p <0.01 vs OLM/HCTZ) and mean clinic SBP by 39.2 mm Hg (p <0.05 vs OLM/HCTZ). Target BP goals were achieved more frequently with AZL-M versus OLM and with AZL-M/CLD versus OLM/HCTZ. In conclusion, in both black and white patients, BP was lowered more effectively with AZL-M versus OLM and with AZL-M/CLD versus OLM/HCTZ. The AZL-M/CLD 40 mg/25 mg combination resulted in a statistically significant reduction in BP in both black and white patients.
Azilsartan medoxomil (AZL-M, Edarbi, Arbor Pharmaceuticals LLC, Atlanta, Georgia) is a potent long-acting angiotensin II receptor blocker (ARB) that was approved by the US Food and Drug Administration in 2011 for the treatment of hypertension at a dose of 40 mg to 80 mg once daily, alone or in combination with other antihypertensive agents. A randomized controlled trial (RCT) in 413 black patients with primary clinic systolic blood pressure (SBP) between 150 and 180 mm Hg found that AZL-M significantly reduced ambulatory and clinic SBP and diastolic blood pressure (DBP) compared with placebo and was well tolerated.
A single-pill fixed-dose combination of AZL-M with the thiazide-like diuretic chlorthalidone (AZL-M/CLD, Edarbyclor, Arbor Pharmaceuticals LLC) was approved by the Food and Drug Administration in 2011 for the treatment of hypertension at a dose of 40 mg of AZL-M and 12.5 or 25 mg of CLD once daily. In different RCTs, AZL-M and AZL-M/CLD lowered BP to a greater extent versus the ARB olmesartan (OLM [Benicar, Daiichi Sankyo, Inc., Parsippany, New Jersey])
respectively. As these RCTs included a substantial number of black patients, 2 separate-pooled analyses were conducted in the present study to evaluate the efficacy and safety of AZL-M versus OLM and of AZL-M/CLD versus OLM/HCTZ in this subgroup.
Self-identified black and white patients with hypertension from 2 randomized, double-blind placebo-and-active-controlled clinical trials were included in a pooled post hoc subgroup analysis of AZL-M. In 1 of the RCTs, reported by Bakris et al (NCT00696241),
1,275 patients were randomized to treatment with AZL-M (20-mg, 40-mg, and 80-mg dose groups), OLM 40 mg (the maximal approved dose), or placebo. In the other RCT, reported by White et al (NCT00696436),
1,291 patients were randomized to treatment with AZL-M (40-mg and 80-mg dose groups), OLM, the ARB valsartan, or placebo. Treatment assignment in both studies was stratified by race (i.e., black or nonblack). Inclusion criteria common to both RCTs were age ≥18 years and a diagnosis of primary hypertension as defined by the following: sitting trough clinic SBP ≥150 mm Hg to ≤180 mm Hg and ambulatory 24-hour mean SBP ≥130 mm Hg to ≤170 mm Hg. Both RCTs were 6 weeks in duration, and ambulatory BP monitoring was performed at baseline (following a 2-week run-in period) and at the final visit. The 1,610 patients who were pooled from these RCTs for the AZL-M subgroup analysis had been randomized to 1 of 4 different treatment regimens: AZL-M 40 mg daily, AZL-M 80 mg daily, OLM 40 mg daily, or placebo (patients who had been randomized to AZL-M 20 mg daily were excluded). Approximately 90% of the pooled black patients and 75% of the pooled white patients were enrolled in the United States (Table 1).
Table 1Demographics and baseline characteristics, azilsartan medoxomil versus olmesartan versus placebo, data from two pooled randomized controlled trials
The subgroup analysis of AZL-M/CLD in this study included self-identified black and white hypertensive patients from a double-blind active-controlled clinical trial reported by Cushman et al (NCT01033071),
in which 1,071 patients were randomized to treatment with fixed-dose combinations of AZL-M/CLD force titrated to a high dose of either 40/25 mg daily or 80/25 mg daily, or with a fixed-dose combination of OLM/HCTZ force titrated to 40/25 mg daily. Randomization to treatment groups was stratified by race (i.e., black or nonblack). Inclusion criteria in the RCT were age ≥18 years and a diagnosis of hypertension defined as a clinic seated SBP ≥160 mm Hg to ≤190 mm Hg. The duration of the RCT was 12 weeks, and ambulatory BP monitoring was performed before baseline and at the final visit. The subgroup analysis of AZL-M/CLD included 1,020 patients from the 3 different arms of the Cushman et al RCT. Again, approximately 90% of the pooled black patients and 75% of the pooled white patients were enrolled in the US (Table 2).
Table 2Demographics and baseline characteristics, azilsartan medoxomil plus chlorthalidone versus olmesartan plus hydrochlorothiazide
The exclusion criteria for all 3 RCTs that were the basis for these subgroup analyses included known or suspected secondary hypertension, severe diastolic hypertension, estimated glomerular filtration rate (eGFR) <30 ml/min/per 1.73 m2, type 1 or poorly controlled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8%), and clinically relevant or unstable cardiovascular disease. Although RCT participants who did not self-identify as black (or African American) or white were included in the statistical modeling used for these subgroup analyses, only those results obtained for the black and white subgroups are reported here.
The primary and key secondary efficacy end points for the 2 RCTs contributing data to the pooled AZL-M subgroup analysis were changes in 24-hour mean ambulatory SBP and changes in clinic trough sitting SBP from baseline to week 6; other secondary endpoints included changes in 24-hour mean ambulatory DBP and changes in clinic trough sitting DBP from baseline to week 6. An additional end point was the percentage of participants achieving clinic SBP and/or DBP targets at week 6 (“responders”). The clinic SBP/DBP target was <130/<80 mm Hg for patients with diabetes or chronic kidney disease (CKD) and <140/<90 mm Hg for all other patients. The primary and secondary efficacy end points for the RCT contributing data to the AZL-M/CLD subgroup analysis were changes in clinic SBP and DBP from baseline to week 12, changes in 24-hour mean ambulatory SBP and DBP from baseline to week 12, and the percentage of subjects achieving the same clinic SBP and/or DBP targets at week 12 (“responders”). Safety and tolerability parameters for all 3 of the RCTs included adverse events (AEs) and clinical laboratory test results collected during the randomized evaluation.
In a modified intention-to-treat analysis, patients were evaluated according to the treatment group to which they were randomized. All participants who received at least 1 dose of double-blind medication were included in the safety analysis, under the actual treatment received. Efficacy analyses of ambulatory and clinic BP were based on the full analysis set (those patients who received at least 1 dose of double-blind medication), using last observation carried forward imputation. For each subgroup (black and white), changes from baseline to final on-treatment BP values were evaluated, using an analysis of covariance model with treatment, race, and the interaction of treatment and race as fixed effects, and with baseline value as covariate. All statistical tests were 2-sided using a significance level of 0.05, and 95% confidence intervals (CIs) were calculated.
A total of 1,610 patients were pooled for the AZL-M subgroup analysis—284 blacks and 1,326 whites (see Supplementary Figure S1 for the disposition). The study was completed by 90.8% (258/284) of patients in the black subgroup and by 91.9% (1,219/1,326) in the white subgroup. The AZL-M/CLD subgroup analysis included 1,020 (n = 237 black; n = 783 white) patients (see Supplementary Figure S2). This study was completed by 82.3% (195/237) of patients in the black subgroup and by 83.4% (653/783) of patients in the white subgroup. The most common reasons for study discontinuation by both blacks and whites in both subgroup analyses were AEs and voluntary withdrawal.
Demographic and baseline characteristics are shown in Table 1 for the AZL-M pooled subgroup analysis and in Table 2 for the AZL-M/CLD subgroup analysis. Demographic and baseline characteristics for black and white patients in each subgroup analysis were generally similar. In the AZL-M pooled patient cohorts, 54% of black patients and 49% of white patients were obese (BMI ≥30 kg/m2), 25% and 18%, respectively, had diabetes mellitus, and 37% and 57% had mild or moderate to severe renal impairment (eGFR ≥60/<90 or ≥30/<60 ml/min/1.73 m2) In the AZL-M/CLD study, 58% of black patients and 54% of white patients were obese, 20% and 15%, respectively, had diabetes mellitus, and 54% and 77% had mild or moderate to severe renal impairment
The effects of each monotherapy on 24-hour mean ambulatory and clinic SBP for black and white patients in the AZL-M subgroup analysis are shown in Figure 1 and Figure 2. Reductions from baseline in ambulatory and clinic SBP were statistically significant or numerically greater with 40-mg and with 80-mg AZL-M compared with 40-mg OLM in both blacks and whites. For black patients, 6-week treatment with 40-mg AZL-M lowered 24-hour mean ambulatory SBP by 7.3 mm Hg (p <0.01 vs placebo) and clinic SBP by 9.7 mm Hg (p <0.5 vs placebo). Six-week treatment with 80-mg AZL-M lowered 24-hour mean ambulatory SBP by 8.1 mm Hg (p <0.001 vs placebo) and clinic SBP by 12.5 mm Hg (p <0.001 vs placebo, p <0.01 vs OLM). For 24-hour mean ambulatory BP monitoring, the SBP-lowering effect of AZL-M with either the 40-mg or 80-mg dose was approximately twice as great in white patients as in black patients. This difference (black vs white) in treatment effect was statistically significant within both the 40-mg and 80-mg AZL-M treatment groups (AZL-M 40 mg least-square [LS] mean difference 6.76 mm Hg, 95% CI 3.90 to 6.92, p < 0.001; AZL-M 80 mg LS mean difference 7.76 mm Hg, 95% CI 4.87 to 10.64, p <0.001). The difference within the 40-mg OLM group was statistically significant (LS mean difference 8.02 mm Hg, 95% CI 5.27 to 10.78, p <0.001).
Changes from baseline to week 6 in 24-hour mean ambulatory and clinic DBP were also significantly or numerically greater with 40-mg and with 80-mg AZL-M than with 40-mg OLM in both blacks and whites (Supplementary Figures S3 and S4). In black patients treated with 40-mg AZL-M for 6 weeks, 24-hour mean ambulatory DBP was reduced by 4.1 mm Hg and clinic DBP was reduced by 3.9 mm Hg (both p ≤0.01 vs placebo). Mean decreases of 5.0 mm Hg (p <0.001 vs placebo) in ambulatory DBP and 3.9 mm Hg (p ≤0.01 vs placebo) in clinic DBP were observed for blacks treated with 80-mg AZL-M. For 24-hour mean ambulatory BP monitoring, the DBP-lowering effect of AZL-M was approximately twice as great in whites as in blacks.
The percentages of blacks and whites in each monotherapy group who met clinic SBP and DBP targets at week 6 are shown in Figure 3. A greater proportion of blacks and whites treated with 40-mg and 80-mg AZL-M than with 40-mg OLM achieved the targets for both clinic SBP and clinic DBP. In all active treatment groups, black patients were less likely than white patients to meet the 6-week target BP values (AZL-M 40 mg: odds ratio [OR] 0.30, 95% CI 0.16 to 0.55; AZL-M 80 mg: OR 0.40, 95% CI 0.23 to 0.71; OLM 40 mg: OR 0.31, 95% CI 0.17 to 0.58).
The effects of each treatment on 24-hour mean ambulatory and clinic SBP for blacks and whites in the AZL-M/CLD subgroup analysis are shown in Figure 4 and Figure 5. Changes from baseline in ambulatory and clinic SBP were significantly or numerically greater with AZL-M/CLD 40 mg/25 mg and with AZL-M/CLD 80 mg/25 mg than with OLM/HCTZ 40 mg/25 mg in both the black and the white patient subgroups. For blacks, 12-week treatment with AZL-M/CLD 40 mg/25 mg lowered 24-hour mean ambulatory SBP by 31.0 mm Hg and clinic SBP by 39.3 mm Hg (p <0.05 vs OLM/HCTZ). Twelve-week treatment with AZL-M/CLD 80 mg/25 mg lowered 24-hour mean ambulatory SBP by 34.4 mm Hg (p <0.01 vs OLM/HCTZ) and clinic SBP by 39.2 mm Hg (p <0.05 vs OLM/HCTZ). For ambulatory SBP, the blood-pressure-lowering effect of AZL-M/CLD for black patients was comparable to the effect for white patients in terms of the size of the reduction. White patients treated with AZL-M/CLD 80 mg/25 mg for 12 weeks had a mean change from baseline in ambulatory SBP of 37.0 mm Hg (p <0.001 vs OLM/HCTZ).
Changes from baseline in 24-hour mean ambulatory and clinic DBP were also significantly or numerically greater with AZL-M/CLD 40 mg/25 mg and with AZL-M/CLD 80 mg/25 mg than with OLM/HCTZ 40 mg/25 mg in both blacks and whites (Supplementary Figures S5 and S6). In blacks treated with AZL-M/CLD 40 mg/25 mg for 12 weeks, ambulatory DBP was reduced by 17.9 mm Hg and clinic DBP by 16.8 mm Hg (p ≤0.01 vs OLM/HCTZ). For blacks treated with AZL-M/CLD 80 mg/25 mg, a mean decrease of 19.5 mm Hg in ambulatory DBP (p <0.01 vs OLM/HCTZ) and a mean decrease of 17.7 mm Hg in clinic DBP (p ≤0.001 vs OLM/HCTZ) were observed. For both ambulatory and clinic DBP, the BP-lowering effect of AZL-M/CLD for blacks was comparable to that for whites in terms of the size of the reduction.
The percentages of blacks and whites in each combination therapy group who met clinic SBP and DBP targets at week 12 are shown in Figure 6. A greater proportion of blacks and whites treated with AZL-M/CLD 40 mg/25 mg and AZL-M/CLD 80 mg/25 mg than with OLM/HCTZ 40 mg/25 mg achieved the targets for both clinic SBP and clinic DBP. In all active treatment groups, black patients were less likely than white patients to meet the 12-week target BP values (AZL-M/CLD 40 mg/25 mg: OR 0.36, 95% CI 0.20 to 0.68; AZL-M/CLD 80 mg/25 mg: OR 0.33, 95% CI 0.17 to 0.64; OLM/HTCZ 40 mg/25 mg: OR 0.44, 95% CI 0.25 to 0.78).
In the AZL-M pooled subgroup analysis, the safety and tolerability of AZL-M at either the 40-mg or 80-mg dose and OLM were similar in regard to treatment-emergent adverse events (TEAEs) (Table 3). Few patients temporarily interrupted or permanently discontinued use of the study drug due to TEAEs. In the AZL-M/CLD subgroup analysis, the incidence of TEAEs associated with AZL-M/CLD was higher than that associated with OLM/HCTZ (Table 4). The most common TEAEs, including an increase in serum creatinine, tended to occur in a dose-dependent manner. In both blacks and whites, the incidence of temporary interruption of study drug or permanent discontinuation from the study was higher with AZL-M/CLD 80 mg/25 mg.
Table 3Treatment-emergent adverse events, azilsartan medoxomil versus olmesartan versus placebo, data from two randomized controlled trials
In the present analysis, AZL-M was more effective than OLM in both black patients and white patients with hypertension. Consistent with previous findings for renin-angiotensin system (RAS)-blocking drugs, AZL-M and OLM as monotherapy induced greater BP reductions in white patients than they did in black patients.
The observation of less BP-lowering efficacy for black patients compared with white patients when ACE inhibitors or ARBs are used as monotherapy has bolstered the belief that the RAS system is less active in blacks than in whites due to a tendency toward suppressed circulating renin activity.
However, the reduced BP response to RAS-blocking drugs has most often been observed within the context of high dietary salt intake, a circumstance under which the therapeutic potential of RAS blockers is diminished.
Our results with AZL-M monotherapy are similar to those achieved with many antihypertensive drugs, regardless of race or ethnicity, and they suggest that AZL-M is a viable treatment choice, even as monotherapy, in black patients.
In the current analysis, this finding holds for black patients with hypertension, for whom a significantly greater reduction in clinic SBP was achieved with the 40 mg/25 mg single-pill dose of AZL-M/CLD than with the 40 mg/25 mg single-pill dose of OLM/HCTZ (–39.3 mm Hg vs 33.3 mm Hg, p <0.05). Further, AZL-M/CLD provided clinically meaningful BP reductions for black patients that were comparable to those achieved for white patients (reductions in 24-hour mean ambulatory and clinic SBP ranging between 30 and 40 mm Hg)—a finding that is supported by results of other studies evaluating RAS-blocking drugs in combination with thiazide or thiazide-like diuretics.
The 2010 working group from the International Society of Hypertension in Blacks de-emphasized stepped care in favor of combination therapy for black patients even in the absence of target organ damage or concomitant cardiovascular disease.
Combination therapy was strongly recommended for patients with BP >15/10 mm Hg higher than target BP. As combination therapy can be provided as a single pill rather than as separate pills for multiple agents, adherence to and compliance with prescribed treatment appear to be improved.
CLD, the thiazide-like diuretic included in the fixed-dose combination with AZL-M, has been observed to reduce major cardiovascular events and all-cause mortality compared with placebo and to yield cardiovascular outcomes comparable to those with a calcium channel blockers and an angiotensin-converting enzyme inhibitor.
Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group.
ALLHAT officers, coordinators for the ALLHAT Collaborative Research Group, the Antihypertensive Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
A retrospective observational cohort study from the Multiple Risk Factor Intervention Trial found that compared with HCTZ-treated patients, patients treated with CLD experienced significantly fewer cardiovascular events and had significantly lower SBP.
An open-label trial of AZL-M/CLD versus OLM/HCTZ in patients with stage 3 CKD found that AZL-M/CLD was associated with greater SBP reductions after initial dosing (p = 0.037) although not through 5-year follow-up, while greater proportions of OLM/HCTZ patients were up-titrated to the highest allowable dose (p = 0.021) and were taking additional antihypertensive medications.
Although CLD lowers BP more effectively than HCTZ and can be used to safely treat patients with moderate-to-severe kidney dysfunction, it is still the case that, to date, most single-pill combinations containing thiazide or thiazide-like diuretics available in the US have used HCTZ as the diuretic component rather than CLD.
In addition to being constrained by the limitations inherent to all post hoc analyses, the present study is challenged by the short-term nature of the 3 RCTs from which black-versus-white subgroup data were extracted. The asymmetric sizes of the black and white subgroups could have affected the comparisons. Further, as with any subgroup analysis, the comparisons could have been subject to the multiple testing problem. The use of ambulatory BP monitoring at baseline in the monotherapy RCTs prevented patients with “white coat” hypertension from being enrolled and potentially distorting antihypertensive drug effects over 24 hours.
Our findings in terms of differences from baseline were largely similar between 24-hour mean ambulatory BP and clinic BP.
In conclusion, AZL-M-based therapy is more effective than OLM-based therapy at lowering BP in both black patient and white patients with hypertension. Although AZL-M and OLM monotherapy both provided greater BP reductions in white patients than in black patients, the single-pill fixed-dose combinations of AZL-M/CLD 40 mg/25 mg and AZL-M/CLD 80 mg/25 mg lowered BP as effectively in black patients as in white patients. Because rates of TEAEs and discontinuations were higher with the 80-mg/25-mg AZL-M/CLD combination, the 40-mg/25-mg single-pill AZL-M/CLD combination was the preferred dose independent of race.
This study was funded by Arbor Pharmaceuticals, LLC, Atlanta, Georgia, USA, and by Takeda Development Center Americas, Inc., Deerfield, Illinois, USA. The authors thank representatives of Galen Press, Inc., Austerlitz, New York, supported by Arbor Pharmaceuticals, for providing medical writing services under direction.
Drs. Lloyd and Wu are employees of Takeda Pharmaceutical Company, Ltd. Dr. Ferdinand is a consultant for Amgen, Janssen Pharmaceuticals, Quantum Genomics, Novartis, and Sanofi. Dr. Bakris is a consultant for AbbVie, Bayer, Janssen, Merck, Relypsa, and Vascular Dynamics. Dr. Cushman has received research grant funding from Eli Lilly and is a consultant for Novartis Pharmaceuticals and Takeda Pharmaceuticals. Dr. Weber is a consultant for Arbor Pharmaceuticals, Johnson and Johnson, Sanofi, and Takeda Pharmaceuticals. Dr. White is a consultant for Takeda Pharmaceuticals. The sponsors were involved in the study design, collection, analysis, and interpretation of data as well as data checking of information provided in the manuscript. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.
Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group.
ALLHAT officers, coordinators for the ALLHAT Collaborative Research Group, the Antihypertensive Lipid-Lowering Treatment to Prevent Heart Attack Trial.
Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).