What is the role of Aliskiren (direct renin inhibitor) in the treatment of hypertension?

Aliskiren in Hypertension Treatment

Primary Recommendation

Aliskiren should be reserved as a second-line or alternative antihypertensive agent when first-line therapies (ACE inhibitors, ARBs, calcium channel blockers, or thiazide diuretics) are insufficient or not tolerated, and it must never be combined with ACE inhibitors or ARBs, particularly in patients with diabetes or renal impairment. 1

Evidence for Blood Pressure Lowering

Aliskiren effectively lowers blood pressure as monotherapy at doses of 150-300 mg once daily in both younger and elderly hypertensive patients, with the majority of the antihypertensive effect achieved within 2 weeks. 1, 2

• The drug provides 24-hour blood pressure control with once-daily dosing, demonstrating sustained effects over both short-term (≤12 weeks) and longer-term (up to 54 weeks) treatment periods. 3, 4
• When combined with thiazide diuretics, calcium channel blockers, or other antihypertensives (excluding ACE inhibitors/ARBs), aliskiren provides additional blood pressure reduction beyond monotherapy. 1

Critical Contraindications and Safety Concerns

The most important limitation of aliskiren is the absolute contraindication to combining it with ACE inhibitors or ARBs in patients with diabetes. 1, 2

• The ALTITUDE trial was stopped early due to increased adverse events including renal complications (ESRD and renal death), hyperkalemia, hypotension, and stroke when aliskiren was added to ACE inhibitors or ARBs in diabetic patients at high cardiovascular and renal risk. 1
• The FDA issued a contraindication in April 2012 against using aliskiren with ACE inhibitors or ARBs in patients with diabetes due to risks of kidney impairment, hypotension, and hyperkalemia. 1
• Even in non-diabetic patients, avoid combining aliskiren with ACE inhibitors or ARBs, particularly when creatinine clearance is <60 mL/min. 1

Additional Contraindications

• Pregnancy: Aliskiren is absolutely contraindicated in pregnancy due to fetal toxicity—discontinue immediately when pregnancy is detected. 2
• Bilateral renal artery stenosis: Aliskiren may cause acute renal failure in patients with severe bilateral renal artery stenosis. 1, 5
• Pediatric patients <2 years of age: Aliskiren is contraindicated in this population. 2

Lack of Outcomes Data

No randomized controlled trials demonstrate that aliskiren reduces cardiovascular or renal morbidity and mortality in hypertension. 1

• The APOLLO trial (evaluating cardiovascular outcomes in elderly patients) was stopped despite no evidence of harm, but also without demonstrating benefit. 1
• No beneficial effect on mortality or hospitalization was shown when aliskiren was added to standard treatment in heart failure. 1
• No aliskiren-based antihypertensive trials with hard endpoints are expected in the near future. 1

Monitoring Requirements

When aliskiren is used, monitor for:

• Hyperkalemia: Increased risk in patients with CKD, those on potassium supplements, or potassium-sparing drugs—check potassium levels periodically. 1
• Renal function: Monitor serum creatinine periodically, especially in patients with pre-existing renal impairment. 1
• Hypotension: Correct volume or salt depletion before initiating therapy. 1, 2
• Anaphylactic reactions and angioedema: Though rare, these can occur. 2

Dosing and Administration

• Starting dose: 150 mg once daily (adults and pediatric patients ≥6 years weighing ≥50 kg). 1, 2
• Titration: May increase to 300 mg once daily if blood pressure remains uncontrolled after 2 weeks. 1, 2
• Administration: Establish a routine pattern with regard to meals for consistent absorption. 2

Drug Interactions

• Avoid cyclosporine or itraconazole: These significantly increase aliskiren exposure. 2
• NSAIDs: Increased risk of renal impairment and loss of antihypertensive effect. 2
• P-glycoprotein inhibitors: Can increase aliskiren exposure, though aliskiren itself does not inhibit or induce CYP enzymes. 6

Common Pitfalls to Avoid

• Do not use aliskiren as first-line therapy when ACE inhibitors, ARBs, calcium channel blockers, or thiazide diuretics are appropriate and tolerated—these have proven cardiovascular outcome benefits. 1
• Never combine aliskiren with ACE inhibitors or ARBs in any patient with diabetes, regardless of other considerations. 1
• Do not assume aliskiren provides organ protection beyond blood pressure lowering—the evidence for renoprotective or cardioprotective effects is insufficient. 1
• Avoid in women of childbearing potential without reliable contraception due to teratogenic effects. 2

Clinical Context

While aliskiren effectively lowers blood pressure with a placebo-like tolerability profile at licensed doses, its role is limited by the lack of cardiovascular outcomes data and serious safety concerns when combined with other RAS blockers. 1, 7 The 2017 ACC/AHA and 2013 ESH/ESC guidelines position aliskiren as an alternative agent rather than a preferred option, reflecting these limitations. 1