RENIN INHIBITORS (ALISKIREN)
















ALTITUDE Study - Aliskiren vs Placebo in Diabetic Kidney Disease, NEJM (2012) [PubMed abstract]
  • The ALTITUDE study enrolled 8561 patients with type 2 diabetes who had either proteinuria or evidence of cardiovascular disease
Main inclusion criteria
  • Type 2 diabetes
  • Proteinuria (micro or macro) or cardiovascular disease
  • Taking an ACE inhibitor or ARB
Main exclusion criteria
  • Potassium > 5.0 mmol/L
  • NYHA class III or IV heart failure
  • GFR < 30 ml/min
  • SBP > 170, DBP > 110
Baseline characteristics
  • Average age 64 years
  • Average SBP - 137, DBP - 74
  • Average A1C - 7.8%
  • Average GFR - 57 ml/min
  • Patients with proteinuria - 84%
  • Albumin-to-creatinine ratio (geometric mean) - 207 mg/g
  • Drug: ACE inhibitor - 45% | ARB - 55%
Randomized treatment groups
  • Group 1 (4274 patients) - Aliskiren 150 mg once daily. Increase to 300 mg once daily if tolerated.
  • Group 2 (4287 patients) - Placebo
  • Aliskiren was started at 150 mg once daily and increased to 300 mg after 4 weeks if tolerated
Primary outcome: Composite of time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level.
Results

Duration: After a median of 32.9 months, the trial was stopped early due to futility
Outcome Aliskiren Placebo Comparisons
Primary outcome 18.3% 17.1% HR 1.08, 95%CI [0.98 - 1.20], p=0.12
Hyperkalemia (defined as > 6.0 mmol/L) 11.2% 7.2% p<0.001
Overall mortality 8.8% 8.4% HR 1.06, 95%CI [0.92 - 1.23], p=0.42
  • Blood pressure increased in both groups during the trial, but increased less in the aliskiren group (by 1.3 mmHg SBP and 0.6 mmHg DBP) [5]

Findings: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful.





ASTRONAUT Trial - Aliskiren vs Placebo in Heart Failure, JAMA (2013) [PubMed abstract]
  • The ASTRONAUT trial enrolled 1639 patients who were hospitalized with heart failure
Main inclusion criteria
  • Hospitalized with heart failure
  • EF ≤ 40%
  • BNP ≥ 400 pg/ml
Main exclusion criteria
  • GFR < 40 ml/min
  • Potassium > 5.0 mEq/L
  • Sodium < 130 mEq/L
  • Heart attack, stroke, or cardiac surgery within 3 months
Baseline characteristics
  • Average age 65 years
  • Average EF - 28%
  • Average BNP - 447 pg/ml
  • Average GFR - 67 ml/min
  • Taking ACE/ARB - 84%
  • Taking aldosterone antagonist - 57%
  • Taking beta blockers - 83%
Randomized treatment groups
  • Group 1 (808 patients) - Aliskiren 150 mg once a day, increase to 300 mg a day if tolerated
  • Group 2 (807 patients) - Placebo
  • Aliskiren or placebo was added to patient's current therapy
Primary outcome: Composite of cardiovascular death or rehospitalization for heart failure at 6 months and 12 months
Results

Duration: 12 months
Outcome Aliskiren Placebo Comparisons
Primary outcome (6 months) 24.9% 26.5% HR 0.92, 95%CI [0.76 - 1.12], p=0.41
Primary outcome (12 months) 35% 37.3% HR 0.93, 95%CI [0.79 - 1.09], p=0.36
All-cause death (12 months) 17.8% 18.3% HR 0.99, 95%CI [0.78 - 1.24], p=0.92
Hyperkalemia 20.9% 17.5% HR 1.19, 95%CI [0.98 - 1.46], p=0.09
Renal impairment or failure 16.6% 12.1% HR 1.37, 95%CI [1.08 - 1.75], p=0.01
Hypotension 17.1% 12.6% HR 1.36, 95%CI [1.07 - 1.72], p=0.01

Findings: Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge.
ATMOSPHERE Trial - Aliskiren vs Enalapril vs Enalapril + Aliskiren in Heart Failure, NEJM (2016) [PubMed abstract]
  • The ATMOSPHERE trial enrolled 7016 patients with chronic heart failure
Main inclusion criteria
  • NYHA class II - IV heart failure
  • EF ≤ 35%
  • BNP ≥ 150 pg/ml or ≥ 100 pg/ml if hospitalized with heart failure within previous 12 months
  • Receiving stable dose of ACE inhibitor and beta blocker
Main exclusion criteria
  • GFR < 40 ml/min
  • Potassium > 5.0 mEq/L
Baseline characteristics
  • Average age 63 years
  • Average EF - 28%
  • Average GFR - 74 ml/min
  • Taking aldosterone antagonist - 37%
  • Taking beta blockers - 92%
Randomized treatment groups
  • Group 1 (2340 patients) - Aliskiren 150 mg once daily. Increased after randomization to 300 mg once daily if tolerated.
  • Group 2 (2336 patients) - Enalapril 5 - 10 mg twice daily
  • Group 3 (2340 patients) - Enalapril 5 - 10 mg twice daily + Aliskiren 150 mg once daily (increased after randomization to 300 mg once daily if tolerated)
  • All patients completed a 1 - 4 week run-in phase where they proved they could tolerate all 3 regimens
  • During the run-in phase, enalapril was dosed at 5 - 10 mg twice daily based on what patient could tolerate
Primary outcome: Composite of death from cardiovascular causes or a first hospitalization for heart failure
Results

Duration: Median of 36.6 months
Outcome Aliskiren Enalapril Combination Comparisons
Primary outcome 33.8% 34.6% 32.9% 1 vs 2 p=0.91 | 3 vs 2 p=0.17
Overall mortality 27.9% 27.7% 25.4% 1 vs 2 p=0.46 | 3 vs 2 p=0.12
Death from CKD, ESRD, or double SCr 1.1% 0.8% 1.7% 1 vs 2 p=0.18 | 3 vs 2 p=0.007
Symptomatic hypotension 10.6% 11% 13.8% 1 vs 2 p=0.67 | 3 vs 2 p=0.005
Serum creatinine ≥ 2.5 mg/dl 2.7% 2.7% 4.1% 1 vs 2 p=1.00 | 3 vs 2 p=0.009
Hyperkalemia (> 6 mmol/L) 3.0% 3.6% 5.0% 1 vs 2 p=0.29 | 3 vs 2 p=0.02

Findings: In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril.















Aliskiren (Tekturna®)

Dosage forms

Tablet
  • 150 mg
  • 300 mg

Dosing

Hypertension
  • Starting: 150 mg once daily
  • Maintenance: 150 - 300 mg once daily
  • Max: 300 mg once daily
  • High fat meals decrease absorption substantially. Take consistently either with or without food.
  • Peak effect seen after 2 weeks

Generic / Price

  • Generic available
  • 30 tablets cost around $60 - $80

Tekturna® HCT (aliskiren + HCTZ)

Dosage forms

Tablet
  • Aliskiren - HCTZ
    • 150 mg - 12.5 mg
    • 150 mg - 25 mg
    • 300 mg - 12.5 mg
    • 300 mg - 25 mg

Dosing

Hypertension
  • Starting: 150/12.5 mg once daily
  • Maintenance: 150/12.5 mg - 300/25 mg once daily
  • Max: 300/25 mg once daily
  • High fat meals decrease absorption substantially. Take consistently either with or without food.
  • Blood pressure effect is largely manifested within 1 week, with maximal effects seen around 4 weeks

Generic / Price

  • No generic
  • 30 tablets cost more than $250