Abstract
A majority of patients with hypertension fail to achieve blood pressure (BP) control despite treatment with commonly prescribed drugs. This randomized, double‐blind phase III trial assessed the superiority of sacubitril/valsartan 200 mg (97/103 mg) to continued olmesartan 20 mg in reducing ambulatory systolic BP after 8‐week treatment in patients with mild to moderate essential hypertension uncontrolled with olmesartan 20 mg alone. A total of 376 patients were randomized to receive either sacubitril/valsartan (n = 188) or olmesartan (n = 188). Superior reductions in 24‐hour mean ambulatory systolic BP were observed in the sacubitril/valsartan group vs the olmesartan group (−4.3 mm Hg vs −1.1 mm Hg, P < .001). Reductions in 24‐hour mean ambulatory diastolic BP and pulse pressure and office systolic BP and diastolic BP were significantly greater with sacubitril/valsartan vs olmesartan (P < .014). A greater proportion of patients achieved BP control with sacubitril/valsartan vs olmesartan. The overall incidence of adverse events was comparable between the groups. Compared with continued olmesartan, sacubitril/valsartan was more effective and generally safe in patients with hypertension uncontrolled with olmesartan 20 mg.
Keywords: blood pressure, efficacy, hypertension, olmesartan, sacubitril/valsartan, safety
1. INTRODUCTION
Hypertension is a leading risk factor for stroke, cardiovascular diseases, and premature deaths worldwide,1, 2, 3 with an estimated prevalence of 31.1% among adults in 2010 worldwide, which is predicted to increase with the increasing prevalence of obesity and the aging of the population.4 In the United States, the age‐adjusted prevalence of hypertension among adults 20 years and older, as estimated in the National Health and Nutrition Examination Survey 2009–2012, is 32.6% (≈80 million adults).1 Of these, approximately one half (47.4%) have uncontrolled blood pressure (BP).5 Compared with patients with treated controlled hypertension, patients with treated uncontrolled hypertension had a 1.57‐fold and 1.74‐fold higher risk of all‐cause and cardiovascular mortality, respectively.6 Despite a decrease in the prevalence of hypertension in the United States, the age‐adjusted hypertension‐related death rate increased by 23.1% from 2000 to 2013.4, 7
Commonly prescribed antihypertensive drugs include angiotensin‐converting enzyme inhibitors, angiotensin II receptor blockers (ARBs), diuretics, calcium channel blockers, and β‐blockers.8 Most patients with hypertension require combination therapy with two or more antihypertensive drugs to achieve BP goals.8, 9 Various mechanisms implicated in the pathophysiology of hypertension may not always be completely targeted by the currently available therapies.10 The natriuretic peptide system together with the renin‐angiotensin system and sympathetic nervous system have an important role in cardiovascular homeostasis.11
Sacubitril/valsartan (LCZ696), a first‐in‐class angiotensin receptor neprilysin inhibitor, delivers systemic exposure to a neprilysin inhibitor prodrug, sacubitril (which rapidly converts into active sacubitril), and an ARB, valsartan. Previous studies with sacubitril/valsartan have demonstrated significant reductions in office and ambulatory BP compared with valsartan12 or placebo.13
Olmesartan is a commonly prescribed ARB that has been marketed worldwide for the treatment of hypertension. Compared with olmesartan, sacubitril/valsartan has been demonstrated to be superior in reducing central aortic and brachial pressures in elderly patients with systolic hypertension and stiff arteries.14 The present study was designed to evaluate the efficacy and safety of sacubitril/valsartan compared with olmesartan in patients with essential hypertension uncontrolled with olmesartan monotherapy.
2. METHODS
2.1. Study design
This was an 8‐week, multicenter, randomized, double‐blind, double‐dummy, parallel‐group, active‐controlled, phase III trial conducted at 53 centers across Argentina, Guatemala, the Philippines, Russia, Spain, and the United States in patients with essential hypertension uncontrolled by olmesartan 20 mg once daily. As shown in Supplementary Figure S1, after initial screening, patients receiving antihypertensive treatment at screening entered a washout period of 1 to 2 weeks, during which the antihypertensive medication was discontinued. After the washout period, eligible patients with an office systolic BP (SBP) ≥145 mm Hg and <180 mm Hg entered the active single‐blind run‐in period. Patients who were not receiving any antihypertensive treatment at screening were directly entered in the active single‐blind run‐in period. During this period, patients received olmesartan 20 mg once daily and placebo to match sacubitril/valsartan 200 mg (97/103 mg) once daily for 4 weeks. Patients with uncontrolled hypertension (office SBP ≥145 and <180 mm Hg) with olmesartan 20 mg once daily were randomized 1:1 to receive sacubitril/valsartan 200 mg once daily or olmesartan 20 mg once daily for 8 weeks.
The study protocol was approved by independent ethics committees or institutional review boards at every treatment center and was conducted in accordance with the ethical principles of the Declaration of Helsinki. The study was registered as EUDract number 2013‐001783‐36 and at ClinicalTrials.gov under the code NCT01876368.
2.2. Study participants
Patients 18 years and older with mild to moderate essential hypertension, either untreated (either newly diagnosed or with a history of hypertension who had not received any antihypertensive drugs for ≥4 weeks) with an office SBP ≥150 mm Hg and <180 mm Hg at screening and after washout or who were receiving antihypertensive therapy (used antihypertensive treatment within 4 weeks prior to screening) and had an office SBP ≥145 mm Hg and <180 mm Hg after washout were included. Patients with uncontrolled BP (office SBP ≥145 mm Hg and <180 mm Hg) with olmesartan 20 mg once daily who had successfully completed ambulatory BP monitoring (ABPM) and passed technical requirements for ABPM quality after the single‐blind run‐in period were randomized.
The key exclusion criteria were malignant or severe hypertension (office diastolic BP [DBP] ≥110 mm Hg and/or office SBP ≥180 mm Hg), secondary forms of hypertension, history of angioedema, previous or current diagnosis of New York Heart Association class II to IV heart failure or clinically significant cardiac arrhythmias, history of myocardial infarction during 12 months before screening, or evidence of severe renal impairment (requiring dialysis or with estimated glomerular filtration rate <30 mL/min per 1.73 m2). All patients provided written informed consent prior to initiating any study‐related procedure.
2.3. Efficacy
2.3.1. Primary end point
The primary end point was the superiority of sacubitril/valsartan 200 mg over olmesartan 20 mg in reducing the 24‐hour mean ambulatory SBP after 8 weeks of treatment in patients with essential hypertension who did not adequately respond to olmesartan 20 mg.
2.3.2. Secondary end points
Secondary end points included the changes in 24‐hour mean ambulatory DBP, office SBP and DBP, office and 24‐hour mean ambulatory pulse pressure (PP), and daytime and nighttime 24‐hour mean ambulatory SBP/DBP after 8 weeks of treatment; postdosing hour mean ambulatory BP over 24 hours; the proportion of patients achieving office BP (<140/90 mm Hg) control; office SBP response (<140 mm Hg or a reduction of ≥20 mm Hg from baseline) and office DBP response (<90 mm Hg or a reduction of ≥10 mm Hg from baseline) after 8 weeks of treatment; and safety and tolerability. The postdosing hour mean ambulatory BP over 24 hours was also analyzed for dipper (a patient whose mean ambulatory SBP drops at nighttime by ≥10% compared with daytime mean ambulatory SBP) and nondipper subgroups.
2.3.3. Office BP measurement
Arterial BP and pulse rate were measured with an automated BP device (Omron BP monitor HEM‐705CP) in accordance with the Guidelines for Management of Hypertension.15 Sitting and standing BP measurements were recorded at trough (immediately before dosing at the clinic). Four separate sitting BP readings were obtained at 2‐minute intervals. Patients were then instructed to stand, and a single standing BP measurement was recorded after standing for 2 minutes.
2.3.4. Ambulatory BP monitoring
Twenty‐four‐hour ABPM assessments (SpaceLabs 90207) were performed in all patients twice (24 hours before randomization and at week 8 [or earlier if discontinued]) during the study, with the option to repeat assessment at each visit for failure to meet ABPM quality control criteria. The ABPM device was attached to the nondominant arm of the patient.
2.4. Safety
Adverse events (AEs), serious AEs, and pregnancies were collected from the time of consent to the end of the randomized treatment period. Regular assessments included regular monitoring of hematology, blood chemistry, and urinalysis performed at a central laboratory, as well as vital signs, physical examination findings, and body weight.
2.5. Statistical Analysis
The sample size of 223 completed patients per group was calculated based on the primary efficacy variable, change from baseline in 24‐hour mean ambulatory SBP, and a standard deviation of 13 mm Hg. The sample size was calculated to ensure 90% power to detect statistical significance for the comparison between the treatments for superiority assessment under the alternative hypothesis that the treatment difference was 4 mm Hg at a two‐sided significance level of 0.05. Assuming a 15% dropout rate, the total targeted sample size for randomization was 526.
Efficacy was assessed using full analysis set. Changes in ABPM measurements were analyzed using an analysis of covariance model for repeated measures with treatment, region, postdosing hours (1 to 24), and treatment‐by‐postdosing hour interaction as factors and baseline as a covariate. Change from baseline in daytime (>6 am and ≤10 pm)/nighttime (>10 pm and ≤6 am) mean ambulatory SBP/DBP was analyzed with region, treatment, time (daytime, nighttime), and treatment‐by‐time interaction as factors and baseline 24‐hour mean ambulatory SBP/DBP as a covariate. Changes in office BP were analyzed using the analysis of covariance model with treatment and region as factors and the baseline value as a covariate. BP control or response rates were analyzed using a logistic regression model with treatment and region as factors and baselines as a covariate. SAS PROC MIXED procedure (SAS Institute Inc) with compound symmetry covariance structure was used for the analysis.
All treatment comparisons were performed at the two‐sided significance level of 0.05. The 95% confidence interval for treatment difference was provided. Assessment of safety was primarily based on the frequency of events.
3. RESULTS
3.1. Study patients
A total of 765 patients were screened and 575 patients entered the run‐in period (Figure 1). Of these, 199 patients discontinued before randomization, including 170 patients who failed to meet the randomization criteria (one of the criteria was uncontrolled BP with olmesartan 20 mg once daily). This study was planned to randomize approximately 526 patients; however, as a result of early termination, only 376 patients were randomized. The decision for early termination was made for administrative reasons based on internal prioritization within the clinical development plan for sacubitril/valsartan and not because of any safety/efficacy concerns. Due to the randomization of fewer patients than the estimated sample size, the power dropped from 90% to 81% to detect statistical significance of sacubitril/valsartan 200 mg vs olmesartan 20 mg. Of 376 patients randomized, 354 (94.1%) patients completed the study (Figure 1).
Figure 1.
Patient disposition
Most patients were white (57.6%), male (51.2%), younger than 65 years (76.5%), and did not have diabetes mellitus (66.4%), with an estimated glomerular filtration rate ranging from 60 to <90 mL/min per 1.73 m2 (59.7%). The treatment groups were generally comparable with respect to the baseline BP (Table 1). Overall, 32.3% of patients were dippers at baseline.
Table 1.
Demographic and baseline characteristics
| Sacubitril/valsartan 200 mgn = 188 | Olmesartan 20 mgn = 187 | TotalN = 375 | |
|---|---|---|---|
| Age, y | 57.1 ± 10.19 | 58.0 ± 9.09 | 57.6 ± 9.65 |
| Women, No. (%) | 91 (48.4) | 92 (49.2) | 183 (48.8) |
| Race, No. (%) | |||
| White | 109 (58.0) | 107 (57.2) | 216 (57.6) |
| Black | 32 (17.0) | 31 (16.6) | 63 (16.8) |
| Asian | 33 (17.6) | 34 (18.2) | 67 (17.9) |
| Native American | 10 (5.3) | 10 (5.3) | 20 (5.3) |
| Pacific Islander | 1 (0.5) | 0 (0.0) | 1 (0.3) |
| Other | 3 (1.6) | 5 (2.7) | 8 (2.1) |
| Duration of hypertension, y | 10.1 ± 8.02 | 10.8 ± 9.16 | 10.5 ± 8.61 |
| History of hypertension, No. (%) | 186 (98.9) | 186 (99.5) | 372 (99.2) |
| Body mass index, kg/m2 | 30.5 ± 5.86 | 30.6 ± 5.09 | 30.6 ± 5.48 |
| eGFR, mL/min per 1.73 m2 | 78.6 ± 17.68 | 81.3 ± 16.92 | 80.0 ± 17.33 |
| Diabetes mellitus, No. (%) | 67 (35.6) | 59 (31.6) | 126 (33.6) |
| Obesity, No. (%) | 86 (45.7) | 100 (53.5) | 186 (49.6) |
| Office SBP, mm Hg | 157.1 ± 9.54 | 157.8 ± 10.17 | 157.5 ± 9.85 |
| Office DBP, mm Hg | 90.4 ± 10.24 | 91.2 ± 8.89 | 90.8 ± 9.59 |
| Office PP, mm Hg | 66.7 ± 12.35 | 66.6 ± 12.30 | 66.7 ± 12.31 |
| 24‐h mean ambulatory PP, mm Hg | 57.4 ± 11.22 | 56.8 ± 10.29 | 57.1 ± 10.76 |
| Mean ambulatory SBP, mm Hg | |||
| 24‐h | 139.0 ± 15.53 | 139.3 ± 12.98 | 139.1 ± 14.30 |
| Daytime | 142.8 ± 15.59 | 143.3 ± 13.56 | 143.1 ± 14.59 |
| Nighttime | 132.7 ± 17.64 | 133.2 ± 14.75 | 133.0 ± 16.24 |
| Mean ambulatory DBP, mm Hg | |||
| 24‐h | 81.6 ± 11.94 | 82.5 ± 9.29 | 82.0 ± 10.71 |
| Daytime | 84.8 ± 12.32 | 85.7 ± 9.58 | 85.2 ± 11.03 |
| Nighttime | 76.0 ± 13.13 | 76.9 ± 10.31 | 76.4 ± 11.80 |
| Dipper status, No. (%) | 63 (33.5) | 58 (31.0) | 121 (32.3) |
| Office DBP <90 mm Hg, No. (%) | 85 (45.2) | 71 (38.0) | 156 (41.6) |
Data are presented as mean ± standard deviation unless otherwise indicated.
Abbreviations: DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; LSM, least square mean; PP, pulse pressure; SBP, systolic blood pressure.
3.2. Ambulatory BP measurements
Sacubitril/valsartan 200 mg provided superior reductions in 24‐hour mean ambulatory SBP from baseline to week 8 vs olmesartan 20 mg (Figure 2A; primary end point). The least square mean (LSM) reduction from baseline in 24‐hour mean ambulatory SBP at week 8 was greater in the sacubitril/valsartan group by 3.2 mm Hg (sacubitril/valsartan, –4.3 mm Hg vs olmesartan, –1.1 mm Hg; P < .001). In addition, sacubitril/valsartan provided greater reduction in postdosing hourly mean ambulatory SBP from baseline to week 8 (Figure 2C).
Figure 2.
Change from baseline with sacubitril/valsartan 200 mg vs olmesartan 20 mg at week 8 in (A) postdosing 24‐hour mean ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP); (B) daytime and nighttime mean ambulatory SBP and DBP; (C) postdosing hourly mean ambulatory SBP; and (D) postdosing hourly mean ambulatory DBP. LSM indicates least square mean
Compared with olmesartan, sacubitril/valsartan provided significantly greater least square mean reduction in 24‐hour mean ambulatory DBP from baseline at week 8 (Figure 2A). Moreover, the reduction in postdosing hourly mean ambulatory DBP from baseline to week 8 was greater in the sacubitril/valsartan group than in the olmesartan group (Figure 2D). Reductions (from baseline to week 8) in daytime and nighttime mean ambulatory SBP and DBP were also greater in the sacubitril/valsartan group than in the olmesartan group (Figure 2B); however, the between‐treatment difference in the nighttime BP measurements did not reach statistical significance (Figure 2B). The greater reduction in postdosing hourly mean ambulatory SBP and DBP from baseline to week 8 observed in the sacubitril/valsartan group compared with the olmesartan group were consistent in both dipper and nondipper populations (Figure S2). The least square mean changes from baseline in mean ambulatory PP at week 8 were significantly greater with sacubitril/valsartan than with olmesartan (Figure 2A).
3.3. Office BP measurements
Reductions from baseline at week 8 in office SBP and DBP were significantly greater with sacubitril/valsartan vs olmesartan with a least square mean between‐treatment difference of 4.2 (P = .014) and 3.1 (P = .001), respectively, for office SBP and DBP (Figure 3). Greater reductions in office PP after 8 weeks of treatment in the sacubitril/valsartan group compared with the olmesartan group did not reach statistical significance (Figure 3).
Figure 3.
Change from baseline in office systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with sacubitril/valsartan 200 mg vs olmesartan 20 mg at week 8. LSM indicates least square mean
The proportions of patients who achieved BP control and of those who achieved an adequate SBP/DBP response after 8 weeks of treatment were significantly greater in the sacubitril/valsartan group than in the olmesartan group (Figure 4). About 40.4% of the patients achieved BP control in the sacubitril/valsartan group, compared with 27.8% in the olmesartan group.
Figure 4.
Proportion of patients achieving blood pressure (BP) control (office systolic BP [SBP] <140 mm Hg and office diastolic BP [DBP] <90 mm Hg), office SBP response (<140 mm Hg or reduction ≥20 mm Hg from baseline), and office DBP response (<90 mm Hg or reduction ≥10 mm Hg from baseline) with sacubitril/valsartan 200 mg vs olmesartan 20 mg
3.4. Safety
The overall incidence of AEs during the double‐blind period was comparable between the sacubitril/valsartan (23.4%) and the olmesartan (21.9%) groups (Table 2). Headache was the most frequent AE during the double‐blind period, followed by dizziness.
Table 2.
Incidence of AEs during the double‐blind period by preferred term
| Preferred term | Sacubitril/valsartan 200 mgn = 18 | Olmesartan 20 mgn = 18 |
|---|---|---|
| Deaths | 0 (0) | 0 (0) |
| Any serious AEs | 0 (0) | 2 (1.1) |
| Benign neoplasm of thyroid gland | 0 (0) | 1 (0.5) |
| Cerebrovascular accident | 0 (0) | 1 (0.5) |
| Discontinuations during double‐blind period | ||
| AEs discontinuations | 2 (1.1) | 5 (2.7) |
| Drug‐related AEs discontinuations | 0 (0) | 2 (1.1) |
| Serious AE discontinuations | 0 (0) | 1 (0.5) |
| Any AEsa | 44 (23.4) | 41 (21.9) |
| Headache | 5 (2.7) | 6 (3.2) |
| Arthralgia | 3 (1.6) | 0 (0) |
| Blood bilirubin increased | 2 (1.1) | 0 (0) |
| Bronchitis | 2 (1.1) | 0 (0) |
| Dizziness | 2 (1.1) | 4 (2.1) |
| Hypotension | 2 (1.1) | 2 (1.1) |
| Local swelling | 2 (1.1) | 0 (0) |
| Nasopharyngitis | 2 (1.1) | 1 (0.5) |
| Cough | 1 (0.5) | 2 (1.1) |
| Myalgia | 1 (0.5) | 2 (1.1) |
| Abdominal pain upper | 0 (0) | 2 (1.1) |
Data are presented as number (percentage).
Of all adverse events (AEs), only those with an incidence rate of ≥2 patients in any of the treatment group are mentioned.
The majority of treatment‐emergent AEs during the double‐blind period were mild in severity in both treatment groups (sacubitril/valsartan, 28/44 vs olmesartan, 26/41). A total of four patients reported severe AEs: one in the sacubitril/valsartan group (dizziness) vs three in the olmesartan group (benign neoplasm of thyroid gland, cerebrovascular accident, and drug hypersensitivity). Of these, two were reported as treatment‐emergent serious AEs (benign neoplasm of thyroid gland and cerebrovascular accident in the olmesartan group). No deaths were reported during the study (Table 2). Incidence of AEs of hepatic disorders during the double‐blind period was low (sacubitril/valsartan group: two events, blood bilirubin increased; olmesartan group: one event, transaminase increased).
No major differences were noted in changes in hematological and clinical chemistry parameters between the treatment groups. Notable abnormalities in laboratory values were infrequent and comparable between both treatment groups (Table 3). The proportion of patients meeting prespecified criteria for serum potassium <3.5 or ≥5.5 mmol/L was low in both groups. The proportion of patients with orthostatic BP changes at any postbaseline visit was higher in the olmesartan group vs the sacubitril/valsartan group, except at week 2, wherein the proportion was similar. Hypotension was reported in four patients (Table 2). One event of angioedema was reported during the olmesartan run‐in period. However, the event was reported as secondary to lisinopril, which was being taken by the patient during the run‐in period.
Table 3.
Patients who met the specified criteria in selected laboratory parameters
| Sacubitril/valsartan 200 mgn = 188 | Olmesartan 20 mgn = 187 | |
|---|---|---|
| Potassium, mmol/L | ||
| ≥6 | 1 (0.5) | 1 (0.5) |
| >5.5 | 7 (3.7) | 7 (3.8) |
| <3. | 5 (2.7) | 5 (2.7) |
| Creatinine >176.8 μmol/L | 0 (0) | 0 (0) |
| Blood urea nitrogen >14.28 mmol/L | 0 (0) | 0 (0) |
| Sodium <130 mmol/L | 0 (0) | 0 (0) |
Data are presented as number (percentage).
4. DISCUSSION
This study conducted in patients with mild to moderate hypertension uncontrolled with olmesartan 20 mg once daily monotherapy showed that switching to sacubitril/valsartan was superior to continuation of olmesartan in reducing the 24‐hour mean ambulatory SBP from baseline to week 8, meeting the primary end point. Reductions in 24‐hour mean ambulatory DBP and PP and office SBP and DBP were significantly greater with sacubitril/valsartan vs olmesartan. A significantly greater proportion of patients achieved BP control with sacubitril/valsartan vs olmesartan. The overall incidence of AEs was comparable between the treatment groups.
During the past decade, ARBs have become a widely used option in hypertension management because of effective BP reductions and a placebo‐like tolerability profile.16 Olmesartan, a commonly prescribed ARB that has been marketed worldwide for hypertension treatment, has been effective in controlling BP in patients.17 Compared with olmesartan, sacubitril/valsartan has been demonstrated to be superior in reducing central aortic and brachial pressures over 12 weeks in elderly patients with systolic hypertension and stiff arteries in the PARAMETER (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly) study.14 From weeks 12 to 52, requirement of add‐on antihypertensive therapy was significantly lower in patients treated with sacubitril/valsartan vs olmesartan (P < .002).14 In the current study, ≥70% of patients did not respond adequately to olmesartan 20 mg once daily and sacubitril/valsartan showed effective BP‐lowering efficacy in the patients who did not respond adequately to olmesartan 20 mg once daily. BP‐lowering efficacy with sacubitril/valsartan was also observed to be greater compared with another ARB, valsartan, in a study in Asian patients with mild to moderate hypertension.12 A recent study also showed that sacubitril/valsartan was more effective than valsartan alone in lowering BP and PP in patients with systolic hypertension, irrespective of age.18 Furthermore, a meta‐analysis including 8996 patients with mild to moderate hypertension also suggests that sacubitril/valsartan provides better BP reduction compared with an angiotensin‐converting enzyme inhibitor or an ARB.19
5. STUDY STRENGTHS
A key strength of this study is the use of ambulatory BP as the primary end point, which is more reliable20 and has stronger prediction to cardiovascular risk21, 22 than office BP measurements, possibly because it provides diurnal readings (ie, throughout a 24‐hour period).21, 22 Moreover, as SBP is well established as a strong and consistent predictor of stroke and cardiovascular risk in middle‐aged and elderly individuals,23 use of 24‐hour ambulatory SBP as the primary end point suggests that the superior reduction in BP may be associated with a superior effect on cardiovascular risk reduction. Previous studies have reported both ambulatory and office BP‐lowering efficacy with sacubitril/valsartan in patients with hypertension.12, 13, 14, 24, 25
Increased PP indicates large artery stiffening, which can predict incident cardiovascular disease, stroke, chronic kidney disease, and heart failure.26, 27 A significant reduction in PP has been reported with sacubitril/valsartan vs ARBs and placebo.12, 13, 14 In the PARAMETER study, compared with olmesartan, significantly greater reductions from baseline in PP were observed at week 12 with sacubitril/valsartan in elderly patients with systolic hypertension and stiff arteries.14 In this study, the more reliable ABPM showed significant PP reductions with sacubitril/valsartan vs olmesartan over 12 weeks. Greater reductions in office PP with sacubitril/valsartan vs olmesartan did not reach statistical significance, probably because of the smaller number of patients than originally intended for this study.
Sacubitril/valsartan was generally safe and well tolerated with no adjudicated angioedema episodes during the treatment period, possibly because neprilysin is a minor enzyme in the bradykinin degradation pathway28 and ARBs are not associated with high risk of angioedema.29, 30 Despite the effective BP reductions in the sacubitril/valsartan group, the incidence of hypotension was comparable with that in the olmesartan group. Only two AEs (headache and dizziness) occurred in ≥2% patients in either group. Previous studies demonstrated that the use of sacubitril/valsartan was generally safe and well tolerated in patients with hypertension and provided significant BP reductions from baseline.12, 13, 24 Long‐term safety was reported over 52 weeks in patients with hypertension24 and over a median time of 24 months in patients with heart failure and reduced ejection fraction.31
6. STUDY LIMITATIONS
Our study has some limitations, including the randomization of fewer patients than the estimated sample size. In addition, the patients with hypertension uncontrolled with olmesartan 20 mg were continued on the same dose of olmesartan 20 mg as comparator. Comparison with higher doses of olmesartan (such as 40 mg) or its combinations is lacking. However, in clinical practice, combination therapy (ie, the addition of low‐dose hydrochlorothiazide) would be a more likely strategy than using the higher dose of olmesartan alone, for efficacy reasons.32 Introducing the additional variable of diuretic combination for comparison was not appropriate for this study but may be addressed in future evaluations of optimal antihypertensive treatment escalation. Another limitation is the 8‐week duration of the treatment and follow‐up period. Although 8 weeks is sufficient time for both investigational regimens to reach their maximum effect, further long‐term results on the safety and efficacy are warranted.
7. CONCLUSIONS
Concomitant ARB and neprilysin‐inhibitor (sacubitril/valsartan 200 mg once daily) was more effective than an ARB (olmesartan 20 mg once daily) alone in lowering ambulatory and office BP and was generally safe in patients with hypertension uncontrolled with olmesartan 20 mg once daily.
DISCLOSURES
Dr Cheung received compensation from Novartis for conducting this clinical trial. Dr Aizenberg has nothing to declare. Dr Gorbunov received personal fees from Servier, Abbott Laboratories, Egis, Pliva, and Bayer. Drs Hafeez and Chen are employees of Novartis. Dr Zhang was an employee of Novartis at the time of conduct of the study.
Supporting information
ACKNOWLEDGMENTS
This study was sponsored by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. The authors thank all investigators, participating centers, and study participants for their time, effort, and commitment to the study. The authors thank Shalini Verma and Sreedevi Boggarapu (Novartis Healthcare Pvt. Ltd., Hyderabad, India) for providing the writing and review support, respectively. All authors participated in the development and review of the article and approved the final version for publication.
Cheung DG, Aizenberg D, Gorbunov V, Hafeez K, Chen CW, Zhang J. Efficacy and safety of sacubitril/valsartan in patients with essential hypertension uncontrolled by olmesartan: A randomized, double‐blind, 8‐week study. J Clin Hypertens. 2018;20:150–158. 10.1111/jch.13153
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