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.  Angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), diuretics, and calcium channel blockers are recommended as first line therapy. 
Sacubitril/valsartan (Entresto®) is a combination product consisting of an angiotensin receptor neprilysin inhibitor, sacubitril, and an ARB, valsartan.  Previous studies with sacubitril/valsartan have demonstrated significant reductions in office and ambulatory BP compared with valsartan or placebo. 
|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
|Primary Outcome Measure|| Reduction of the 24-hour mean ambulatory SBP from baseline to week 8
|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.  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.  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  vs. $251.28 ) 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.
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