Searching for a New Indication

Tibin K. Titus, Mercer University College of Pharmacy

Hypertension is a worldwide problem with its prevalence increasing in the aging population. Complications of hypertension include stroke and cardiovascular diseases. [1] Angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), diuretics, and calcium channel blockers are recommended as first line therapy. [2]

Sacubitril/valsartan (Entresto®) is a combination product consisting of an angiotensin receptor neprilysin inhibitor, sacubitril, and an ARB, valsartan. [3] Previous studies with sacubitril/valsartan have demonstrated significant reductions in office and ambulatory BP compared with valsartan or placebo. [4]

 

Efficacy and safety of sacubitril/valsartan in patients with essential hypertension uncontrolled by olmesartan: a randomized, double-blind, 8-week study
Design Multicenter, randomized, double-blind, active-controlled, phase III trial; N= 375
Objective To evaluate the efficacy and safety of sacubitril/valsartan compared with olmesartan in patients with uncontrolled hypertension with olmesartan monotherapy

 

Study Groups Sacubitril/valsartan (n= 188); olmesartan (n= 187)
Methods Patients receiving antihypertensive treatment at screening entered a washout period of 1-2 weeks, during which the antihypertensive medication was discontinued. Patients were randomized 1:1 to receive sacubitril/valsartan 200 mg once daily or olmesartan 20 mg once daily for 8 weeks. Office BP readings were measured with an automated BP device. Ambulatory BP readings were performed by a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the nondominant arm of the patient.

 

Inclusion criteria: patients ≥18 years with mild to moderate essential hypertension, patients with uncontrolled BP (office SBP ≥145 mm Hg and <180 mm Hg) taking olmesartan 20 mg once daily

 

Exclusion criteria: 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 within 12 months

 

Duration 8 weeks
Primary Outcome Measure  Reduction of the 24-hour mean ambulatory SBP from baseline to week 8

 

Baseline Characteristics
Sacubitril/valsartan 200 mg (n= 188) Olmesartan 20 mg (n= 187)
Age, y 57.1 ± 10.19 58.0 ± 9.09
Women, n (%) 91 (48.4) 92 (49.2)
Race, n (%)
White 109 (58.0) 107 (57.2)
Black 32 (17.0) 31 (16.6)
Asian 33 (17.6) 34 (18.2)
Native American 10 (5.3) 10 (5.3)
Pacific Islander 1 (0.5) 0 (0.0)
Other 3 (1.6) 5 (2.7)
Duration of hypertension, y 10.1 ± 8.02 10.8 ± 9.16
History of hypertension, No. (%) 186 (98.9) 186 (99.5)
Diabetes mellitus, No. (%) 67 (35.6) 59 (31.6)
Obesity, No. (%) 86 (45.7) 100 (53.5)
Office SBP, mm Hg 157.1 ± 9.54 157.8 ± 10.17
Office DBP, mm Hg 90.4 ± 10.24 91.2 ± 8.89
Mean ambulatory SBP, mm Hg
24-h 139.0 ± 15.53 139.3 ± 12.98
Daytime 142.8 ± 15.59 143.3 ± 13.56
Nighttime 132.7 ± 17.64 133.2 ± 14.75
Mean ambulatory DBP, mm Hg
24-h 81.6 ± 11.94 82.5 ± 9.29
Daytime 84.8 ± 12.32 85.7 ± 9.58
Nighttime 76.0 ± 13.13 76.9 ± 10.31
Results
24h mean ambulatory SBP
Sacubitril/valsartan 200 mg (n= 188) Olmesartan 20 mg (n= 187) p value
Ambulatory SBP -4.3 mm Hg -1.1 mm Hg <0.001
Ambulatory DBP -2.3 mm Hg -0.4 mm Hg <0.001
Ambulatory PP -2.0 mm Hg -0.8 mm Hg 0.001
Mean Ambulatory
Ambulatory SBP Daytime -4.5 mm Hg -1.1 mm Hg 0.013
Nighttime -4.7 mm Hg -2.4 mm Hg 0.092
Ambulatory DBP Daytime -2.3 mm Hg -0.3 mm Hg 0.026
Nighttime -2.5 mm Hg -1.2 mm Hg 0.141
Adverse Events Common Adverse Events: headache (2.7% sacubitril/valsartan vs 3.2% olmesartan) dizziness (sacubitril/valsartan 1.1% vs olmesartan 2.1%)
Serious Adverse Events: myalgia (0.5% sacubitril/valsartan vs 1.1% olmesartan)
Percentage that Discontinued due to Adverse Events: sacubitril/valsartan (1.1%), olmesartan (2.7%)
Study Author Conclusions Sacubitril/valsartan was more effective than olmesartan 20 mg in lowering ambulatory and office BP.

 

 

Although this study showed a statistical significance, there may not be enough compelling evidence for the use of this drug in hypertensive patients. The dose of valsartan in sacubitril/valsartan is 103 mg, which is equivalent to 160 mg of valsartan. [3] This dose is higher than the usual starting dose for hypertension treatment. The dose of olmesartan used, however, is the usual starting dose for hypertension. [5] Therefore, these two doses may not produce therapeutically equivalent effects and may have skewed the results to favor sacubitril/valsartan group. Despite the statistical significance, the results’ clinical significance may be questioned as the difference between the two groups is 3 mmHg (-4.3 mmHg vs. -1.1 mmHg). When considering the cost differences between the two drugs ($519.54 [7] vs. $251.28 [8]) and the corresponding clinical difference in SBP reduction, it may not be reasonable to have patients pay significantly more for a small difference in blood pressure. Finally, baseline medication history was not provided. This lack of information is important, as the patients may have been on other drugs that can also affect BP and the study results. Overall, the study did not provide sufficient evidence to consider sacubitril/valsartan for treatment of essential hypertension.

 

References:

  1. Centers for Disease Control and Prevention. High Blood Pressure. https://www.cdc.gov/bloodpressure/about.htm. January 24, 2018.
  2. Whelton PK, Carey RM, Aronow WS. 2017 Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. J Am Coll Cardiol. 2017.pii: S0735-1097(17)41519-1.
  3. Sacubitril/valsartan [package insert]. East Hanover, NJ: Novartis; July 2015.
  4. Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomized, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375:1255-1266.
  5. Benicar® [package insert]. Parsippany, NJ: Daiichi Sankyo; June 2008.
  6. Cheung DG, Aizenberg D, Gorbunov V, et al. Efficacy and safety of sacubitril/valsartan in patients with essential hypertension uncontrolled by olmesartan: A randomized, double-blind, 8-week study. J Clin Hypertens (Greenwich). 2018;20(1):150-158.
  7. Sacubitril and Valsartan. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH: Lexicomp, Inc. http://online.lexi.com. Updated January 5, 2018. Accessed January 30, 2018.
  8. Olmesartan. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH: Lexicomp, Inc. http://online.lexi.com. Updated January 5, 2018. Accessed January 30, 2018.

 

 

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