Abstract
An open‐label, long‐term study evaluated safety and tolerability of azilsartan medoxomil/chlorthalidone (AZL‐M/CLD) vs olmesartan/hydrochlorothiazide (OLM/HCTZ) in hypertensive participants with stage 3 chronic kidney disease. Initial therapy was AZL‐M/CLD 20/12.5 mg (n = 77) or OLM/HCTZ 20/12.5 mg (n = 76), but could be up‐titrated (AZL‐M/CLD to 40/25 mg; OLM/HCTZ to 40/25 mg [US] or 20/25 mg [Europe]) with other agents added during weeks 4‐52. Primary endpoint was proportion of participants with ≥ 1 adverse event (AE) through week 52. Baseline demographics were similar. AEs did not differ between groups (88.3%, AZL‐M/CLD vs 76.3%, OLM/HCTZ; P = .058). AZL‐M/CLD showed greater systolic BP reductions after initial dosing (P = .037) but not during long‐term follow‐up (P = .588). A greater proportion of participants up‐titrated to the highest dose with OLM/HCTZ (48.7%) vs AZL‐M/CLD (29.9%) (P = .021) and were taking additional antihypertensive medications (26.3% vs 16.9%). Both AZL‐M/CLD and OLM/HCTZ showed similar efficacy and tolerability.
Keywords: cardiovascular, hypertension, kidney, nephropathy, outcomes, renal
1. BACKGROUND
Inadequately controlled blood pressure greatly increases the risk of cardiovascular disease, cerebrovascular disease, and kidney failure.1 In large meta‐analyses the risk of both stroke and ischemic heart disease decreases when systolic blood pressure (SBP) falls to levels below 140 and in many cases below 130 mm Hg.2, 3 Moreover, data from randomized trials of advanced proteinuric kidney disease provide clear evidence of slowing kidney disease progression when renin‐angiotensin‐aldosterone system (RAAS) blockers are used as part of a BP‐lowering regimen.4 Despite the availability of multiple classes of antihypertensive agents, hypertension remains inadequately controlled; only about two‐thirds of persons who receive antihypertensive therapy maintain adequate BP control.5
Within the angiotensin receptor blocker (ARB) class, the magnitude of BP lowering is different, as documented in prospective comparative studies using ambulatory blood pressure monitoring.6 The same is true of BP‐lowering differences between hydrochlorothiazide and chlorthalidone, favoring chlorthalidone.7 Moreover, only 1 ARB combination with chlorthalidone (azilsartan medoxomil/chlorthalidone [AZL‐M/CLD]) is available in most parts of the world and has been studied in the general population of persons with hypertension. This study focuses on participants with chronic kidney disease (CKD), one of the most common causes of resistant hypertension.8
Current international guidelines require a BP of 130/80 mm Hg for those with CKD who have > 300 mg/d of albuminuria.9 The current study examined the long‐term safety and efficacy of the combination of AZL‐M/CLD compared to olmesartan/hydrochlorothiazide (OLM/HCTZ) over a 52‐week period in participants with an estimated glomerular filtration rate (eGFR) of 30‐59 mL/min/1.73 m2.
2. METHODS
2.1. Study design
This phase 3, randomized, open‐label, long‐term safety study included a 14‐day screening period, a 52‐week open‐label treatment period (with dose titration at any visit between Week 4 through Week 42 to reach target BP), and a 2‐week adverse event (AE) follow‐up period. Eligible participants were randomly assigned on Day 1 in a 1:1 ratio to receive treatment with AZL‐M/CLD or OLM/HCTZ. Randomization was stratified by the stage of CKD (stage 3A [baseline eGFR ≥ 45 and < 60 mL/min/1.73 m2] and stage 3B [baseline eGFR ≥ 30 and < 45 mL/min/1.73 m2]), diabetes status (diabetic and nondiabetic), and region (United States and Europe). Participants were required to discontinue all current antihypertensive medications or those that could affect BP (ie, nonsteroidal anti‐inflammatory drugs) for 2 days before they received their first dose of study drug.
A titration‐to‐target BP approach was used to guide the administration of the study drug. Target BP was < 130/80 mm Hg per treatment guidelines in the United States and Europe for participants with CKD at the time of the study. AZL‐M/CLD was titrated from an initial dose of 20/12.5 mg to a maximum dose of 40/25 mg. OLM/HCTZ was titrated from 20/12.5 mg to 40/25 mg in the United States and to a maximum dose of 20/25 mg in Europe, according to the product label approved in each region. After AZL‐M/CLD or OLM/HCTZ had been titrated to the highest approved dose (or lower, if highest dose was not tolerated), participants could receive other antihypertensive medications (apart from other ARBs or thiazide‐type diuretics) if needed to reach target BP (Figure 1). The dose of study drug or of the add‐on antihypertensive medication could be down‐titrated or temporarily discontinued if a participant was not tolerating the study treatment.
Figure 1.
Treatment and titration schedule. aEligible subjects were instructed via the telephone to discontinue their current antihypertensive medications on Days −2 and −1 before they came to the clinic for the Day 1 visit. bEligible subjects who were enrolled in the study were administered study drug in the clinic on Day 1. cEach subject returned to the clinic approximately 2 wk after any dose titration for an unscheduled visit to have vital signs assessed, to undergo a subpanel of clinical laboratory tests (serum creatinine, BUN, chloride, bicarbonate, potassium, and sodium), and to receive study drug. Subjects also returned to the clinic approximately 2 wk after any dose decrease for an unscheduled visit to have vital signs assessed, receive study drug, and repeat clinical laboratory tests, if necessary. The investigator could have requested an unscheduled visit for reasons other than dose titration at any time; the procedures performed at this visit were at the discretion of the investigator. Note: Study drug was titrated according to a titration‐to‐target blood pressure approach
Sitting and standing BP and pulse rate were measured at screening, at each visit during the open‐label treatment period, and at unscheduled visits.
2.2. Participants
The protocol conformed to the Declaration of Helsinki, International Conference for Harmonization/Good Clinical Practice, Title 21 of the Food and Drug Administration Code of Federal Regulations (CFR) (Parts 50, 54, 56, and 312) for sites in the United States, and any local or regional regulatory guidelines, and the study was reviewed and approved by the appropriate institutional review board (IRB) or independent ethics committee (IEC). Before initiating any study procedures, each patient was informed of the study details and signed an IRB/IEC–approved informed consent form. A total of 59 study sites screened hypertensive persons; 46 (18 in the United States and 28 in Europe) enrolled and were randomly assigned to receive the study drug. Eligible persons were at least 18 years old, had an eGFR in the range of ≥ 30 to < 60 mL/min/1.73 m2 (CKD stage 3) at screening, were treated with 2 or 3 antihypertensive medications (prescribed primarily for the treatment of hypertension) and stable therapy (defined as ≥ 6 weeks on the same medications), and had a mean sitting clinic SBP ≥ 135 and ≤ 160 mm Hg at screening and on Day 1 prior to the first dosing of the study drug.
2.3. Safety assessment
The safety assessments were AE monitoring, clinical laboratory tests, vital sign measurements, 12‐lead ECGs, and physical examinations. Evaluation focused on treatment‐emergent adverse events (TEAEs), defined as AEs that occurred after the first dose of study drug, and no later than 14 days after the last dose of study drug for TEAEs, or no later than 30 days after the last dose of study drug for serious AEs (SAEs). Each event was categorized as nonserious or serious and whether or not it resulted in discontinuation of treatment. Investigators were instructed to report serum creatinine elevations ≥ 30% from baseline and more than the upper limit of normal (ULN) as an AE of special interest. Participants with serum creatinine elevation ≥ 50% above baseline and more than the ULN or postbaseline eGFR ≤ 20 mL/min/1.73 m2 were discontinued from the study if the value was confirmed by a repeat test within 5‐7 days. Participants with an SAE at the final visit were followed after study drug discontinuation until the elevations in serum creatinine fell to ≤ 17.68 μmol/L (≤ 0.2 mg/dL) above screening or baseline values or stabilized. Safety laboratory parameters, including those related to renal function (serum creatinine and urea nitrogen), electrolyte homeostasis (serum potassium, sodium, chloride, calcium, and magnesium), and metabolic function (serum uric acid, glucose, and fasting lipids) were evaluated at each visit.
2.4. Efficacy
The efficacy assessments were sitting clinic SBP and diastolic blood pressure (DBP) at screening and each visit. BP was determined as the mean of 3 readings obtained ≈ 24 hours after the previous dose of study medication (trough BP values), using a manual or semiautomated sphygmomanometer. Three clinic BP measurements were obtained at 2‐minute intervals after the patient was seated quietly for at least 5 minutes with feet on the floor and arm supported at the heart level. In addition, a single BP measurement was obtained after the patient remained standing for 2 minutes to evaluate for orthostatic hypotension. Heart rate was also measured in both the sitting and standing positions.
2.5. Endpoints
The primary endpoint was the percentage of participants with ≥ 1 AE through Week 52. Additional endpoints include changes from baseline in SBP and DBP and the proportion of participants reaching the BP target.
2.6. Analysis of endpoints
All analyses were based on observed values. All endpoints were summarized by treatment and study visit where appropriate, using descriptive statistics. Post hoc inferential analyses were performed on the primary endpoint and change from baseline in SBP and DBP, and 2‐sided P‐values were considered statistically significant when ≤ .05. Treatment difference for the primary endpoint, percentage of participants with ≥ 1 AE through Week 52, was compared using Fisher's Exact Test.
Changes from baseline in SBP and DBP were summarized by treatment and study visit using descriptive statistics. Treatment differences for each time point were tested using an analysis of covariance (ANCOVA), with baseline BP as a covariate. An additional post hoc analysis consisted of determining the time‐weighted average change from baseline, which was also tested using ANCOVA, with baseline BP as a covariate. The number and percentage of participants reaching target BP (responder rates) were summarized by treatment and study visit for the following categories: SBP < 130 mm Hg; DBP < 80 mm Hg; SBP < 130 mm Hg and DBP < 80 mm Hg.
Change from baseline data and responder rate data were summarized using descriptive statistics for the following subgroups: region (United States, Europe), CKD stage (stage 3a, stage 3b), diabetes status (diabetic, nondiabetic), race (Caucasian, Black, Other), sex (male, female), age (< 65, ≥ 65, ≥ 75 years), BMI (< 30, ≥ 30 kg/m2), and baseline hypertension level (SBP < 140, SBP 140‐160, SBP ≥ 160, DBP < 90, DBP ≥ 90 mm Hg).
All analyses were performed on the safety analysis set, which included all participants who took at least 1 dose of study medication.
3. RESULTS
3.1. Patient disposition and baseline demographics
A total of 339 participants were screened; 186 (54.9%) failed screening and did not enter the open‐label treatment period. A total of 153 participants were randomly assigned to treatment, 77 to AZL‐M/CLD and 76 to OLM/HCTZ (Figure 2). Demographic and baseline characteristics of the AZL‐M/CLD and OLM/HCTZ groups were generally similar (Table 1).
Figure 2.
Participant disposition. aSpecific reasons given for discontinuation of study drug were noncompliance with study procedures and blood pressure out of range. bProtocol deviation was related to concomitant medications; subject persistently failed to take add‐on antihypertensive medication per the protocol
Table 1.
Demographic and baseline characteristics
| Demographic variable | AZL‐M/CLD (n = 77) | OLM/HCTZ (n = 76) |
|---|---|---|
| Age, y (mean [SD]) | 67.9 (8.24) | 68.9 (9.10) |
| Sex, n, male/female | 32/45 | 45/31 |
| Race, n, Caucasian/Black/Asian | 57/18/2 | 62/12/2 |
| Region, n, US/Europe | 39/38 | 37/39 |
| Weight, kg (mean [SD]) | 83.5 (17.90) | 90.1 (21.59) |
| BMI, kg/m2 (mean [SD]) | 30.4 (6.23) | 31.6 (6.52) |
| Diabetes, n (%) | 33 (42.9) | 32 (42.1) |
| eGFR, mL/min/1.73 m2 (mean [SD]) | 48.3 (10.21) | 47.7 (8.76) |
| Baseline eGFR category, n (%) | ||
| CKD stage 3a (eGFR ≥ 45 and < 60 mL/min/1.73 m2) | 40 (51.9) | 39 (51.3) |
| CKD stage 3b (eGFR ≥ 30 and < 45 mL/min/1.73 m2) | 31 (40.3) | 33 (43.4) |
| ≥ 60 mL/min/1.73 m2 | 6 (7.8) | 4 (5.3) |
| SBP, mm Hg (mean [SD]) | 151.1 (10.30) | 149.0 (7.80) |
| DBP, mm Hg (mean [SD]) | 84.8 (10.31) | 84.7 (9.68) |
| SBP categories, n (%) | ||
| < 140 mm Hg | 11 (14.3) | 10 (13.2) |
| ≥ 140 to < 160 mm Hg | 60 (77.9) | 64 (84.2) |
| ≥ 160 to < 180 mm Hga | 5 (6.5) | 2 (2.6) |
| DBP categories, n (%) | ||
| < 90 mm Hg | 52 (67.5) | 50 (65.8) |
| ≥ 90 mm Hg | 25 (32.5) | 26 (34.2) |
AZL‐M/CLD, azilsartan medoxomil/chlorthalidone; BMI, body mass index; CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; OLM/HCTZ, olmesartan/hydrochlorothiazide; SBP, systolic blood pressure; SD, standard deviation.
These subjects were included in the study when they should not have been but because they had baseline values not expected and this was a safety study they evaluated all data and did not exclude these subjects.
A total of 32 (20.9%) participants prematurely and permanently discontinued the study (16 [20.8%] in the AZL‐M/CLD treatment group and 16 [21.1%] in the OLM/HCTZ treatment group) (Figure 2). The most common reasons for premature discontinuation of the study drug were AEs (21 participants [13.7%]) and voluntary withdrawals (9 participants [5.9%]: 5 in the AZL‐M/CLD treatment group and 4 in the OLM/HCTZ treatment group). The percentages of participants who discontinued treatment because of an AE or voluntary withdrawal were similar in the 2 treatment groups. The overall discontinuation rate may have been influenced in part by the protocol‐specified guidance instructing investigators to discontinue participants with confirmed creatinine elevations ≥ 50% from baseline and > ULN or eGFR ≤ 20 mL/min/1.73 m2.
3.2. Efficacy
Mean sitting clinic BP was similar in both treatment groups at baseline. At Week 2 (ie, prior to any dose titration), the decreases in SBP were greater in the AZL‐M/CLD treatment group than the OLM/HCTZ treatment group (P = .037 at Week 2). After Week 4, incremental SBP reductions were observed in both treatment groups with dose titration; after long‐term follow‐up, SBP reductions were similar between groups (P = .588); however, a greater proportion of participants up‐titrated to the highest dose with OLM/HCTZ (48.7%) vs AZL‐M/CLD (29.9%) (P = .021) and were taking additional antihypertensive medications (26.3% vs 16.9%). Note that there were geographic similarities in the number of people in the United States and Europe receiving OLM/HCTZ, 48.6% and 48.7%, respectively. The post hoc analysis of the time‐weighted average change from baseline showed no statistical difference (P = .423) toward greater overall reduction in SBP in the AZL‐M/CLD treatment group (Figure 3). Additionally, there was no difference in the percentage of people who reached a target systolic and diastolic BP of < 130/80 mm Hg at the final visit, 59.4% (95% CI, 46.9‐71.7) in the AZL‐M/CLD group and 72.9% (95% CI, 60.9‐82.8) in the OLM/HCTZ treatment group.
Figure 3.
Mean (+/SD) systolic and diastolic BP over 52 wk with AZL‐M/CLD vs OLM/HCTZ (observed values)
There was no difference in the percentage of participants who achieved target BP after 52 weeks; however, up‐titration to the highest approved doses of randomized combination drugs and addition of other antihypertensive medications were higher in the OLM/HCTZ group (Table 2). At study end, more OLM/HCTZ than AZL‐M/CLD participants were on the highest study drug dose (48.7% vs 29.9%, respectively; P = .021) but there was no statistical difference between groups for using additional antihypertensive medications (26.3% vs 16.9%, respectively).
Table 2.
Number and percentage of participants on each dose of study drug and on additional antihypertensive medications according to the last dispensing
| Treatment | Number of participants (%) | Additional antihypertensive medications | ||
|---|---|---|---|---|
| Study drug dosea | ||||
| Low dose | Medium dose | High dose | ||
| AZL‐M/CLD (N = 77) | 20/12.5 mg | 40/12.5 mg | 40/25 mg | |
| 35 (45.5) | 19 (24.7) | 23 (29.9) | 13 (16.9) | |
| OLM/HCTZ (N = 76) | 20/12.5 mg | 40/12.5 mg (US only) | 40/25 mg (US) or 20/25 mg (EU) | |
| 33 (43.4) | 6 (7.9) | 37 (48.7) | 20 (26.3) | |
AZL‐M/CLD, azilsartan medoxomil/chlorthalidone; EU, Europe; OLM/HCTZ, olmesartan/hydrochlorothiazide; US, United States.
Without regard to use of additional antihypertensive medications.
3.3. Safety and tolerability
3.3.1. Adverse events
The cumulative percentage of participants who reported at least 1 TEAE (primary endpoint) was 88.3% in the AZL‐M/CLD treatment group and 76.3% in the OLM/HCTZ treatment group (Table 3) for the duration of the study. The most frequently reported (> 5% of participants) AEs were increased blood creatinine (44.2% vs 38.2%), headache (10.4% vs 2.6%), and dizziness (7.8% vs 6.6%) for AZL‐M/CLD vs OLM/HCTZ treatment groups, respectively (Table 3).
Table 3.
Overview of treatment‐emergent adverse events (TEAE) (safety population) and those reported by preferred term affecting ≥ 5% of participants in either treatment group
| Adverse event | AZL‐M/CLD (n = 77) | OLM/HCTZ (n = 76) | ||
|---|---|---|---|---|
| No. of events | No. of participants (%) | No. of events | No. of participants (%) | |
| Any TEAEa | 257 | 68 (88.3) | 233 | 58 (76.3) |
| Mild | 187 | — | 115 | — |
| Moderate | 61 | — | 103 | — |
| Severe | 9 | — | 15 | — |
| Leading to discontinuation | — | 17 (22.1) | — | 15 (19.7) |
| SAE | 9 | 8 (10.4) | 12 | 9 (11.8) |
| Deaths | — | 0 | — | 1 (1.3) |
| Preferred term | ||||
|---|---|---|---|---|
| Increased serum creatinine | 34 (44.2) | 29 (38.2) | ||
| Dizziness | 6 (7.8) | 5 (6.6) | ||
| Headache | 8 (10.4) | 2 (2.6) | ||
| Asthenia | 3 (3.9) | 4 (5.3) | ||
| Bronchitis | 4 (5.2) | 3 (3.9) | ||
| Hyperuricemia | 3 (3.9) | 4 (5.3) | ||
| Hypokalemia | 4 (5.2) | 3 (3.9) | ||
| Hypotension | 4 (5.2) | 3 (3.9) | ||
| Diarrhea | 1 (1.3) | 4 (5.3) | ||
| Pharyngitis | 0 | 4 (5.3) | ||
AZL‐M/CLD, azilsartan medoxomil/chlorthalidone; OLM/HCTZ, olmesartan/hydrochlorothiazide; SAE, serious adverse event.
Temporary drug interruption or permanent discontinuation; Investigators were advised to withdraw participants with 2 consecutive creatinine elevations ≥ 50% from baseline and > upper limit of normal. Investigators were instructed to report single creatinine elevations ≥ 30% from baseline and > upper limit of normal as adverse events.
P = .058.
The percentage of participants who either temporarily or permanently discontinued the study drug because of a TEAE was similar between the AZL‐M/CLD group (22.1%) and the OLM/HCTZ group (19.7%). The TEAEs most often leading to discontinuation in AZL‐M/CLD vs OLM/HCTZ were increased blood creatinine (10.4% vs 6.6%, respectively), which was likely influenced by the protocol guidance advising investigators to withdraw participants with 2 consecutive creatinine elevations ≥ 50% from baseline, and > ULN or eGFR ≤ 20 mL/min/1.73 m2. Discontinuation was permanent for 5 participants in the AZL‐M/CLD treatment group and 4 in the OLM/HCTZ treatment group.
Serious AE rates were low overall and similar between the AZL‐M/CLD group (10.4%) and the OLM/HCTZ group (11.8%) (Table 3; Table S1). The most frequently reported SAEs were cardiac disorders (unstable angina, coronary artery disease) with similar rates for both treatment groups. No deaths occurred in the AZL‐M/CLD treatment group and 1 death occurred in the OLM/HCTZ treatment group as a result of pulmonary artery thrombosis, which was considered unrelated to treatment.
3.3.2. Laboratory data
Incidence of serum creatinine elevation ≥ 50% from baseline and > ULN were balanced between treatment groups at all postbaseline visits (12.0% and 13.5%) and at least 2 consecutive visits (5.3% and 4.1%) in the AZL‐M/CLD and OLM/HCTZ treatment groups, respectively (Table S2). Note that most participants with acute elevations in serum creatinine of > 50% either totally or partially resolved within 3 months of continued therapy (Figure 4). Moreover, participants with elevations in serum creatinine ≥ 50% from baseline at final visit had larger mean decreases in BP and urinary albumin/creatinine ratio (UACR) than those who did not have these elevations (Figure S1). Moreover, the elevations in creatinine were not associated with hyperkalemia or progressive increasing loss of kidney function (Figure S1 and Table S2).
Figure 4.
Mean creatinine and sitting clinic systolic blood pressure value over time by creatinine elevation in all participants: safety analysis set
Most of the elevated serum creatinine values were transient or nonprogressive during treatment, reversible after discontinuation of treatment, or reduced and stabilized after 2‐3 months of continued BP lowering therapy and not associated with clinical complications (Table S2). No clinically relevant changes in ECG parameters, laboratory parameters, weight, or vital signs, including heart rate and orthostatic blood pressure, occurred in either treatment group (Table S3).
4. DISCUSSION
It is well known that SBP is the major determinant of mortality in persons over age 50.10, 11 The cohort in this study was substantially older than 50 years, all with CKD stage 3 and about 40% with stage 3b, a group with a 3‐4‐fold higher cardiovascular risk compared with those with stage 3a CKD.12 These results in participants with stage 3 CKD demonstrate that AZL‐M/CLD has comparable BP‐lowering efficacy to OLM/HCTZ but tends to require fewer additional agents and less dose titration. The profile of greater BP lowering with AZL‐M/CLD observed early in the treatment period and prior to dose adjustment is consistent with short‐term, fixed‐dose studies in participants with stages 1 and 2 CKD where AZL‐M/CLD was superior to OLM/HCTZ for BP lowering.13 These results extend the findings to a high cardiovascular risk group, those with stage 3 CKD,14 and provide evidence that the tolerability of AZL‐M/CLD is like that of OLM‐M/HCTZ.
CLD is the diuretic used in many of the positive cardiovascular outcome trials of antihypertensive drug treatment, particularly those that enrolled participants with CKD.15, 16 CLD, unlike HCTZ, is highly effective in patients with CKD down to an eGFR of 25 mL/min/1.73 m2.17 It also has a much longer half‐life than HCTZ, although HCTZ does lower BP in people with stage 3 CKD.7 Many clinicians are concerned about the safety profile of CLD because of early reports of hypokalemia, but when combined with AZL‐M, the incidence of hypokalemia and other electrolyte abnormalities does not appear to be increased when compared with OLM‐HCTZ, as indicated in this study.18
The safety and tolerability of these agents were generally similar, other than more headaches reported in the AZL‐M/CLD group than in the OLM/HCTZ group. Moreover, discontinuation rates were similar, despite more headaches in the AZL‐M/CLD group. It is important to note that in this as in many other trials of people with CKD, like the Systolic Blood Pressure Intervention Trial (SPRINT)15 and the African American Study of Kidney Disease (AASK),19 reduction in blood pressure invariably is associated with increases in serum creatinine. These are acute changes generally without hyperkalemia and in most cases resolve within 1‐2 months of continued therapy. Thus, it is inappropriate to stop BP therapy or renin‐angiotensin system blockade in this setting if BP is reduced and well tolerated without hyperkalemia.20, 21, 22 The changes seen in these trials and in the current study, as evidenced by the resolution of kidney function to baseline, support an acute hemodynamic change, which has been repeatedly shown in trials. In this study over 90% of the people had partial or total resolution of kidney function with continued treatment and no significant issues with hyperkalemia.
Medication adherence is a major problem in hypertension management, as fewer than half of participants prescribed multiple antihypertensive medications are taking them.23, 24 This is an even bigger problem in people with CKD, as they take an average of 12 medications a day to manage their risk factors and manifestations of CKD. Thus, the fewer medications needed to achieve BP goals, the greater likelihood of adherence. In this study, there was a similar outcome in BP control; however, significantly more medications were required to achieve that goal in the OLM/HCTZ group.
We conclude that in one of the highest CV risk cohorts, ie, older persons with CKD, use of AZL‐M/CLD to achieve BP targets is safe and requires less dose titration and fewer additional antihypertensive medications to achieve the BP target compared to OLM/HCTZ. The reduction in numbers of medications needed in the AZL‐M/CLD group to achieve BP target should improve adherence.
CONFLICT OF INTEREST
GLB has received grant or research support from Bayer and is a consultant for AbbVie, Janssen, Bayer, and Merck. LZ, SK, and AJ were employees of Takeda during the time of the study. MH and EL are employees of Takeda Development Center Americas, Inc. GLB was a consultant to Takeda at the time of the study. SO has received research grant support or support/reimbursement for travel to meetings or other from AstraZeneca AB/Duke, Bayer, NIH/NHLBI, NHLBI, NIH/NIAMS, Novartis, Actelion, Rox Medical, Medtronic Ardian, and Merck and has consulted for Actelion, Lundbeck, and Novo Nordisk. SO was an investigator in SPRINT for which Takeda and Arbor Pharmaceuticals donated 5% of medication used.
Supporting information
Bakris GL, Zhao L, Kupfer S, et al. Long‐term efficacy and tolerability of azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide in chronic kidney disease. J Clin Hypertens. 2018;20:694–702. 10.1111/jch.13230
Funding information
This study was sponsored by Takeda Development Center Americas, Inc. High‐resolution and color figures for this manuscript were produced by Sam Schmitt of Extenxion Media Group, LLC and Blue Momentum, an Ashfield Company, and were supported by Takeda Development Centers America, Inc.
Kupfer, Zhao, and Juhasz were employees of Takeda at the time of the study.
Clinicaltrials.gov identifier: NCT01309828.
Note
[Corrections updated on March 17, 2018, after initial online publication: Removing reference 19, and renumbering the remaining references and in‐text citations.]
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