Continuing Education Activity

Aliskiren is a direct renin inhibitor medication that is FDA approved to treat hypertension in adults and children six years and older. It may be used as monotherapy or in combination with other antihypertensive agents. This activity reviews the indications, contraindications, activity, adverse events, mechanism of action, and other critical elements of aliskiren use in hypertension management and highlights the role of the interprofessional team in managing the care of patients receiving therapy with aliskiren.

Objectives:

• Identify the mechanism of action of aliskiren.
• Describe the potential adverse effects of aliskiren.
• Summarize the place aliskiren can have in hypertension management, given the current data.
• Explain how interprofessional team collaboration and communication can improve case outcomes in patients who may be on aliskiren therapy for hypertension.

Indications

Aliskiren is FDA-approved to treat hypertension in adults and children six years and older. It may be used as monotherapy or in combination with other antihypertensive agents.[1] It is currently available in combination products with hydrochlorothiazide, with amlodipine, as well as with both amlodipine and hydrochlorothiazide.

Aliskiren first received approval in 2007 after demonstrating its antihypertensive effects in six randomized, double-blind, placebo-controlled trials. All patients included had mild to moderate hypertension. Most patients demonstrated a blood pressure-lowering effect within two weeks of treatment. These studies showed a mean reduction in systolic blood pressure of 2.9 to 10 mmHg and a mean decrease in diastolic blood pressure of 3.3 to 8.6 mmHg.[2][3][4]

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 guideline is a significant change from the 2014 JNC 8 Guidelines (Evidence-based guideline for managing high blood pressure in adults: a 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 strongly focus on decreasing the risk of cardiovascular disease. Their current recommendation is that patients with elevated blood pressure should receive treatment with medication to reduce 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 mellitus 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 cardiovascular death or heart failure hospitalization.[5][6] Aliskiren does not have an indication for these disease states and would probably not be a substitute for ACEIs or ARBs for these patients.

At this time, aliskiren remains a medication that would be most appropriate for use as an add-on therapy for patients already managed with one or more medications that have demonstrated the ability to decrease cardiovascular risk.[7][8]

Savoia C. et al. conducted a clinical trial on sixteen patients with mild essential hypertension and type 2 diabetes mellitus.[9] The researchers compared the vasorelaxant effects of aliskiren (N = 9) and ramipril (N= 7) from small artery biopsies. The doses used on the patients were 150 mg once daily for aliskiren and 5 mg once daily for ramipril. A micromyograph evaluated the endothelium-mediated vasorelaxant effects of acetylcholine plus or minus N omega-nitro-L-arginine methyl ester HCL in norepinephrine pretreated vessels. Both aliskiren and ramipril reduced blood pressure. Aliskiren demonstrated statistically improved endothelium-mediated relaxation, and it increased the formation of endothelial p1177 nitric oxide synthase. Savoia C. et al. concluded that aliskiren caused quicker peripheral vasodilation in mild hypertensive type 2 diabetes mellitus patients.

Bokuda K. et al. conducted a study on thirty-nine patients with hypertension and chronic kidney disease.[10] The patients received one-time aliskiren or amlodipine treatment. Vascular, renal, and elements of the renin-angiotensin system were evaluated before treatment, at twelve weeks, and again at twenty-four weeks. The aliskiren cohort significantly reduced the cardio-ankle vascular index, protein excretion, and urinary albumin. These researchers concluded that aliskiren demonstrated additional renal and vascular protection in addition to its blood-pressure-lowering effects.

Mechanism of Action

Aliskiren is active in the renin-angiotensin-aldosterone system (RAAS).[11] Renin secretion occurs by specialized cells found in the juxtaglomerular apparatus within the kidney based on changes in blood volume and renal perfusion as sensed by the macula densa in the distal tubule of the nephron. Renin is responsible for converting angiotensinogen to angiotensin I. Angiotensin I is then converted to angiotensin II by the angiotensin-converting enzyme (ACE), which is present in the capillaries of the lungs as well as endothelial cells present in the kidneys. Angiotensin II is believed to be the first active mediator in the RAAS system and exerts its effects by binding 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 decreases 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.

O'Rawe et al. conducted a phase I clinical trial to determine the safety and tolerability of several drugs which target the renin-angiotensin system in patients with glioblastoma.[12] The glioblastoma stem cells contain elements of the renin-angiotensin system. Thus, inhibiting the renin-angiotensin system in glioblastoma stem cells might have anticancer effects. Patients who relapsed from standard treatment, e.g., surgery, radiation, and temozolomide, and met inclusion criteria received oral doses of aliskiren, aspirin, celecoxib, cilazapril, curcumin/piperine, metformin, and propranolol. Ten patients out of seventeen completed the pharmacotherapy regimen. Two patients reported mild side effects. The overall median survival was 19.9 months compared with 14.6 months for standard therapy. O’Rawe et al. state that this difference is not statistically significant. However, the trend of greater survival time for relapsed patients receiving drugs that target the renin-angiotensin system is a promising lead.

Administration

Aliskiren is available as 150 mg or 300 mg tablets. Patients usually initiate therapy 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 administration is via the oral route. It should be taken daily at the same time. Patients may take aliskiren with or without a meal, but the recommendation is for consistent administration with regard to meals. 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, respectively.

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, respectively.

A combination formulation with aliskiren and amlodipine was discontnued.[13]

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, 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[14], 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 two 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 is necessary for patients who have volume depletion.

Monitoring

Medical staff should observe patients taking aliskiren for hyperkalemia and impaired renal function. Serum potassium requires periodic monitoring. Patients at risk include those with renal insufficiency, diabetes mellitus, combination use with ARBs or ACEs, and patients using potassium supplements or potassium-sparing diuretics. Renal function also should be monitored periodically. Individual patients will be at higher risk of developing acute renal failure while taking aliskiren. These patients include those taking ARBs, ACEIs, non-steroidal anti-inflammatory drugs (NSAIDs), and patients with renal artery stenosis, severe heart failure, post-myocardial infarction, or volume depletion.[15][16]

Toxicity

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

Enhancing Healthcare Team Outcomes

Healthcare workers, including nurse practitioners who prescribe aliskiren for hypertension in adults, should know the contraindications and precautions. Patients taking aliskiren requires monitoring for hyperkalemia and impaired renal function. Serum potassium also requires periodic observation. Patients at risk include those with renal insufficiency, diabetes mellitus, combination use with ARBs or ACEs, and patients using potassium supplements or potassium-sparing diuretics. Renal function is also something clinicians should watch. Individual patients will be at higher risk of developing acute renal failure while taking aliskiren. These patients include those taking ARBs, ACEIs, non-steroidal anti-inflammatory drugs (NSAIDs), and patients with renal artery stenosis, severe heart failure, post-myocardial infarction, or volume depletion.

ALiskiren therapy, as part of a patient's overall hypertensive control regimen, requires an interprofessional healthcare team. When initiating aliskiren, the clinician should consult a pharmacist, who can look over the entire medication regimen and assist with deciding the appropriateness of adding aliskiren, and what other changes might be necessary for the patient's regimen. Nurses can provide administration counseling, monitor the patient as described above, and assess pharmacotherapy adherence. If the nurse or pharmacist notes any issues, they should be able to communicate these to the prescriber promptly, giving their clinical opinion regarding the patient's condition. With this type of interprofessional team coordination, aliskiren therapy can achieve optimal outcomes with minimal adverse events. [Level 5]