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

Aliskiren: Limited Role in Hypertension Management with Significant Contraindications

Aliskiren can be used as monotherapy or in combination with thiazide diuretics or calcium channel blockers for hypertension treatment, but it is absolutely contraindicated in combination with ACE inhibitors or ARBs in patients with diabetes, and should be avoided in patients with renal impairment. 1, 2

Critical Contraindications and Safety Concerns

Absolute Contraindications

• Do not combine aliskiren with ACE inhibitors or ARBs in diabetic patients due to FDA contraindication based on the ALTITUDE trial, which showed increased risk of stroke, hyperkalemia, hypotension, and end-stage renal disease 1, 2
• Avoid in patients with bilateral renal artery stenosis, as aliskiren may cause acute renal failure similar to other renin-angiotensin system blockers 1, 3
• Contraindicated in pregnancy (Category D after first trimester) - discontinue immediately when pregnancy is detected due to fetal toxicity risk 2
• Do not use in pediatric patients under 2 years of age 2

Major Safety Warnings

• Avoid combination with ACE inhibitors or ARBs in patients with renal impairment (CrCl <60 mL/min), as this increases risk of renal complications, hyperkalemia, and hypotension 1
• The ALTITUDE trial was stopped early specifically because adding aliskiren to standard RAS blockade in high-risk diabetic patients caused more harm than benefit 1
• The APOLLO trial (aliskiren in elderly patients) was also discontinued, though without evidence of harm 1

When Aliskiren May Be Appropriate

Monotherapy Indications

• Starting dose: 150 mg once daily for adults and pediatric patients ≥6 years weighing ≥50 kg 2
• Titrate to 300 mg once daily if blood pressure remains uncontrolled after 2 weeks (majority of effect achieved by 2 weeks) 2
• Aliskiren effectively lowers systolic and diastolic blood pressure in younger and elderly hypertensive patients as monotherapy 1

Appropriate Combination Therapy

• Aliskiren + thiazide diuretic (hydrochlorothiazide): Provides additive blood pressure lowering and is a rational combination 1
• Aliskiren + calcium channel blocker (amlodipine): Demonstrates greater antihypertensive effect when combined 1
• These combinations are acceptable because they do not involve dual RAS blockade 1

Major Limitations and Clinical Reality

Lack of Outcomes Data

• No trials demonstrate that aliskiren reduces cardiovascular or renal morbidity/mortality in hypertension 1
• No aliskiren-based trials with hard endpoints are expected in the near future 1
• In heart failure, adding aliskiren to standard treatment showed no beneficial effect on mortality and hospitalization 1

Practical Disadvantages

• Low bioavailability (2.6%) requiring consistent dosing patterns with regard to meals 2
• Avoid concomitant use with cyclosporine or itraconazole due to significant drug interactions 2
• Increased risk of hyperkalemia in chronic kidney disease or with potassium supplements/potassium-sparing drugs 1

Monitoring Requirements

Essential Monitoring Parameters

• Monitor serum creatinine periodically to assess renal function 2
• Monitor potassium levels periodically, especially in patients with CKD or on other medications affecting potassium 2
• Correct volume/salt depletion before initiating to avoid hypotension 2

Common Pitfalls to Avoid

• Never assume aliskiren is equivalent to ACE inhibitors or ARBs - it lacks the extensive outcomes data supporting those drug classes 1
• Do not use aliskiren as a substitute for proven therapies in patients with diabetes and nephropathy - the ALTITUDE trial specifically showed harm in this population 1
• Avoid the temptation to combine aliskiren with ACE inhibitors or ARBs even in non-diabetic patients with renal impairment, as this dual RAS blockade strategy is contraindicated 1
• Do not prescribe aliskiren as first-line therapy when thiazide diuretics, ACE inhibitors, ARBs, or calcium channel blockers are appropriate and have proven cardiovascular outcomes benefits 1

Clinical Bottom Line

Aliskiren occupies a narrow niche in hypertension management. While it effectively lowers blood pressure as monotherapy or combined with thiazides/calcium channel blockers, the absence of cardiovascular outcomes data, the failed ALTITUDE and APOLLO trials, and the absolute contraindication with ACE inhibitors/ARBs in diabetics severely limit its clinical utility 1. Consider aliskiren only when standard first-line agents are contraindicated or not tolerated, and never in combination with other RAS blockers in diabetic or renally impaired patients 1, 2.