Aliskiren

Article Author:
Tibb Jacobs
Article Editor:
Jamie Terrell
Updated:
10/27/2018 12:31:20 PM
PubMed Link:
Aliskiren

Indications

Aliskiren is FDA approved to treat hypertension in adults and children 6 years and older. It may be used as monotherapy or in combination with other antihypertensive agents. It is currently available as a combination product with hydrochlorothiazide as well as with amlodipine and hydrochlorothiazide.

Aliskiren was first approved in 2007 after its antihypertensive effects were demonstrated in six randomized, double-blind, placebo-controlled trials. All patients included had mild to moderate hypertension. Most patients demonstrated blood pressure lowering effect within 2 weeks of treatment. These studies demonstrated a mean reduction in systolic blood pressure of 2.9 to 10 mmHg and a mean reduction in diastolic blood pressure of 3.3 to 8.6 mmHg.

In November of 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) released updated treatment guidelines for patients with high blood pressure. According to the 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, most patients will have a blood pressure goal of less than 130/80 mmHg. This is a significant change from the 2014 JNC 8 Guidelines (Evidence-based guideline for the management of high blood pressure in adults: report from panel members appointed to the Eighth Joint National Committee JNC8). The JNC 8 guidelines recommended a blood pressure goal of 140/90 mmHg for most patients and an even higher blood pressure goal for elderly patients. For patients over the age of 60, the JNC 8 guideline recommended a blood pressure goal of less than 150/90 mmHg.  

In addition to the new lower blood pressure goals, the ACC/AHA guidelines have a strong focus on decreasing risk of cardiovascular disease. Their current recommendation is that patients with elevated blood pressure should be treated with medication in order to decrease cardiovascular risk by lowering blood pressure. However, aliskiren does not currently have outcome data available demonstrating cardiovascular disease (CVD) risk reduction with its use. The ACC/AHA guidelines emphasize the importance of blood pressure lowering over drug selection, but initial recommendations for most patients currently include calcium channel blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors (ACEI), and angiotensin-receptor blockers (ARB) because of their evidence of CVD risk reduction.

There is also no outcome data for using aliskiren in patients with diabetes and nephropathy, patients with coronary artery disease, or post-MI patients. The ATMOSPHERE study found aliskiren not to be inferior to enalapril in congestive heart failure patients in the primary composite endpoint of CV death or heart failure hospitalization. Aliskiren does not have an indication for these disease states and would probably not be used as a substitute for ACEIs or ARBs for these patients.

At this time, aliskiren remains a medication that would be most appropriately used as add-on therapy for patients that are already managed with one or more medications that have demonstrated the ability to decrease cardiovascular risk.  

Mechanism of Action

Aliskiren is active in the renin-angiotensin-aldosterone system (RAAS). Renin is secreted by the kidney based on changes in blood volume and renal perfusion. Renin is responsible for the conversion of angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II binds to the AT1 receptor and works as a vasoconstrictor, causing the release of catecholamines and promoting aldosterone secretion and sodium reabsorption. These effects together act to increase blood pressure. Angiotensin II also can inhibit renin release, causing negative feedback to the renin-angiotensin-aldosterone system. 

Aliskiren acts as a renin inhibitor, which blocks the conversion of angiotensinogen to angiotensin I. This effect subsequently decreases the formation of angiotensin II. Angiotensin II acts on the AT1 receptor, which is responsible for vasoconstriction, aldosterone secretion, and catecholamine release. Hence blood pressure is decreased by decreasing the amount of angiotensin II to reach the AT1 receptor, thereby causing a decrease in vasoconstriction, aldosterone secretion, and catecholamine release. Any agent that works to inhibit the RAAS can suppress the negative feedback loop.

Administration

Aliskiren is available as 150 mg or 300 mg tablets. Patients are usually initiated on 150 mg daily and may be increased to 300 mg daily if necessary. Doses over 300 mg daily did not demonstrate any additional blood pressure lowering but did show an increased rate of diarrhea. Aliskiren is also available as oral pellets for patients who cannot swallow tablets. The pellets are available as a 37.5 mg capsule.

Aliskiren is administered orally. It should be administered daily at the same time. Aliskiren may be administered with or without a meal, but the consistent administration with regard to meals is recommended. High-fat meals can decrease the absorption of aliskiren.

Aliskiren is also available in combination with hydrochlorothiazide in multiple strengths: 150-12.5 mg, 150-25 mg, 300-12.5 mg, and 300-25 mg.

It is also available in combination with amlodipine and hydrochlorothiazide: 150-5-12.5 mg, 300-5-12.5 mg, 300-5-25 mg, 300-10-12.5 mg, and 300-10-25 mg.

Adverse Effects

According to the package insert, the primary adverse effect of aliskiren is diarrhea with 2.3% of patients experiencing it. Other common adverse effects include a cough, skin rash, headaches, and dizziness.

Clinical lab findings seen in clinical trials include: increased blood urea nitrogen or serum creatinine, small decreases in hemoglobin and hematocrit, increases in serum potassium, increased serum uric acid, and increased creatine kinase.

Serious adverse reactions reported in clinical trials include fetal toxicity, anaphylactic reactions, head and neck angioedema, and hypotension.  

Contraindications

According to the manufacturer, aliskiren is contraindicated in patients with a known hypersensitivity to any component, in pediatric patients less than 2 years, and in patients with diabetes mellitus who are taking an ACE inhibitor or an angiotensin receptor blocker.

Patients should not use aliskiren in pregnancy or if they are taking an ARB or ACEI. Caution should be used in patients who have volume depletion.

Monitoring

Patients taking aliskiren should be monitored for hyperkalemia and impaired renal function. Serum potassium should be monitored periodically. Patients at risk include those with renal insufficiency, diabetes, combination use with ARBs or ACEs, and patients using potassium supplements or potassium-sparing diuretics. Renal function also should be monitored periodically. Certain patients will be at higher risk of developing acute renal failure while taking aliskiren. These patients include those taking ARBs, ACEIs, non-steroidal antiinflammatory drugs (NSAIDs), as well as patients with renal artery stenosis, severe heart failure, post-myocardial infarction, or are volume depleted.

Toxicity

There is limited data with regard to overdose in humans. Most likely patients would present with hypotension. If this occurs, supportive treatment would be appropriate.