- ACRONYMS AND DEFINITIONS
- ACC - American College of Cardiology
- AHA - American Heart Association
- CrCl - Creatinine clearance
- EF - Ejection Fraction
- FDA - Food and Drug Administration
- GFR - Glomerular filtration rate
- HCTZ - Hydrochlorothiazide
- HFrEF - Heart failure with reduced ejection fraction
- RAAS - Renin-angiotensin-aldosterone-system
- DRUGS IN CLASS
- Renin inhibitors
- Aliskiren (Tekturna®)
- Combination products with HCTZ
- Tekturna HCT® (aliskiren + HCTZ)
- MECHANISM OF ACTION
- Renin-angiotensin-aldosterone system (RAAS)
- The RAAS is a complex system that plays a critical role in the regulation of blood pressure and body fluid equilibrium. The primary action of the RAAS is to conserve sodium and water and increase blood pressure in response to decreased renal arterial pressure, decreased serum sodium levels, and increased sympathetic tone. Renin is an enzyme secreted by the kidneys that converts angiotensinogen to angiotensin I - the first step in the RAAS. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II stimulates a number of physiologic actions including vasoconstriction, aldosterone secretion, and sympathetic outflow.
- Aliskiren inhibits renin and attenuates the effects of the RAAS
- RAAS inhibitors and diuretics illustration - illustration of the mechanism of RAAS inhibitors and diuretics
- RAAS steps illustration - illustration of the steps in the RAAS system
- FDA-APPROVED INDICATION
- Aliskiren (Tekturna®) - Hypertension
- HYPERTENSION
- Overview
- Aliskiren is FDA-approved to treat hypertension. The effects of aliskiren on blood pressure were evaluated in the Cochrane meta-analysis detailed below.
- STUDY
- A Cochrane meta-analysis looked at the effects of aliskiren on blood pressure
- The effect was stratified by dosage and is presented as aliskiren minus placebo
- Aliskiren 75 mg a day (3 studies)
- Lowered systolic blood pressure an average of 2.94 mmHg
- Lowered diastolic blood pressure an average of 2.29 mmHg
- Aliskiren 150 mg a day (6 studies)
- Lowered systolic blood pressure an average of 5.45 mmHg
- Lowered diastolic blood pressure an average of 3.00 mmHg
- Aliskiren 300 mg a day (6 studies)
- Lowered systolic blood pressure an average of 8.66 mmHg
- Lowered diastolic blood pressure an average of 4.97 mmHg [1]
- Professional guidelines
- See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations
- Summary
- Aliskiren is only approved for hypertension, and it confers no obvious benefit over ACE inhibitors or ARBs which have been in use much longer and have much more efficacy data
- DIABETIC KIDNEY DISEASE
- Overview
- The ALTITUDE study evaluated the addition of aliskiren to an ACE inhibitor or ARB in patients with type 2 diabetes who had either proteinuria or evidence of cardiovascular disease
- The study was stopped early when no benefit was observed and there was possible harm from the addition of aliskiren
- 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 |
|
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.
- ADA recommendations
- Summary
- The ALTITUDE study found no benefit of adding aliskiren to an ACE inhibitor or ARB in patients with diabetes and kidney disease
- The combination is likely harmful given the significant increase in hyperkalemia seen in the aliskiren group. In 2012, the FDA warned against combining aliskiren with an ACE inhibitor or ARB in patients with diabetes or decreased kidney function.
- HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF)
- Overview
- Several large randomized controlled trials have looked at the effects of aliskiren in heart failure with reduced ejection fraction. The ASTRONAUT trial compared aliskiren to placebo and the ATMOSPHERE trial compared aliskiren to enalapril and the combination of aliskiren and enalapril.
- 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.
- 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.
- AHA recommendations
- AHA heart failure guidelines do not mention aliskiren
- Summary
- In the ATMOSPHERE and ASTRONAUT trials, adding aliskiren to standard heart failure treatment conferred no benefit while increasing the risk of side effects
- The results of this trial are consistent with other trials where combining RAAS drugs (ACE inhibitors, ARBs, renin inhibitors) has lead to more side effects without improved outcomes
- Aliskiren should not be added to other RAAS drugs in heart failure patients
- In patients who cannot tolerate an ACE inhibitor or an ARB, aliskiren may be beneficial, but this has not been tested in a randomized controlled trial
- SIDE EFFECTS
- High potassium (hyperkalemia)
- Aliskiren blockage of the RAAS reduces aldosterone secretion, and this can lead to hyperkalemia. The risk of hyperkalemia from aliskiren is largely dependent upon the patient's concomitant medical problems. For patients with hypertension and no other issues, the risk is minimal. For patients with kidney disease, heart failure, and other comorbidities, the risk is much higher. Factors that increase the risk of hyperkalemia are listed below.
- Factors associated with an increased risk of hyperkalemia
- Kidney disease
- Advanced age
- Diabetes
- Heart failure
- Patients taking certain medications (see drug interactions below)
- Summary
- Patients on RAAS inhibitors like aliskiren should have their potassium levels checked periodically. See RAAS inhibitor-induced hyperkalemia for recommendations on managing hyperkalemia.
- Diarrhea
- In trials, 2 - 3% of aliskiren-treated patients reported diarrhea compared to 0.6% of placebo-treated patients. Aliskiren-induced diarrhea appeared to be dose-dependent, with patients on higher doses having a greater incidence. [3]
- Cough
- Another class of RAAS-inhibiting drugs called ACE inhibitors is known to cause a dry cough in up to 10% of patients. In trials, 1.1% of aliskiren-treated patients reported a cough compared to 0.6% of placebo-treated patients. In trials comparing aliskiren to ACE inhibitors, the rate of cough with aliskiren was one-third to one-half that of ACE inhibitors. [3]
- Angioedema
- Angioedema is an allergic reaction that causes swelling of the lips, mouth, face, throat, and/or tongue. Angioedema may be mild or life-threatening, and affected patients should seek medical attention immediately. In cases where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be helpful. When there is involvement of the tongue, glottis, or larynx, appropriate therapy (e.g., subcutaneous epinephrine solution 1:1000, 0.3 ml to 0.5 ml) and airway management should be provided.
- Other RAAS-inhibiting drugs, particularly ACE inhibitors, have been known to cause angioedema in some patients. Angioedema has been reported in patients receiving aliskiren, but the overall risk is unknown. In controlled trials, the incidence of angioedema in aliskiren-treated patients was 0.4% compared to 0.5% in placebo-treated patients. [3]
- CONTRAINDICATIONS
- Aliskiren should not be used with an ACE inhibitor or ARB in patients with diabetes or decreased kidney function (CrCl < 60 ml/min)
- Pregnancy
- Patients < 2 years of age
- Concomitant itraconazole (Sporanox®)
- Concomitant cyclosporine (Neoral®)
- PRECAUTIONS
- Kidney disease
- CrCl > 30 ml/min: no dose adjustment recommended
- CrCl ≤ 30 ml/min: use caution; has not been studied.
- Liver disease
- No dose adjustment necessary
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Aliskiren
- ACE inhibitors and ARBs - In April 2012, the FDA issued a warning based on findings from the ALTITUDE study that aliskiren should not be combined with an ACE Inhibitor or an ARB when treating patients with diabetes or decreased kidney function (GFR < 60 ml/min)
- Cyclosporine (Neoral®) - cyclosporine raises aliskiren levels and should not be taken with aliskiren
- Furosemide (Lasix®) - aliskiren may reduce blood levels of furosemide. Monitor diuretic effects when taking aliskiren with furosemide.
- Itraconazole (Sporanox®) - itraconazole raises aliskiren levels and should not be taken with aliskiren
- Medications that can raise potassium levels - aliskiren may raise potassium levels and cause hyperkalemia. When taken with other potassium-raising medications, the risk is increased. See RAAS inhibitor-induced hyperkalemia for recommendations on addressing hyperkalemia in aliskiren-treated patients.
- Examples of medications that may raise potassium levels include:
- Aldosterone antagonists (spironolactone and eplerenone)
- ARBs (valsartan, olmesartan, etc.)
- ACE inhibitors
- Cyclosporine (Neoral®)
- ENaC inhibitors (triamterene, amiloride)
- Finerenone (Kerendia®)
- Heparin - heparin raises potassium secondarily by inhibiting aldosterone synthesis. LMWH does not appear to have the same effect. [7]
- Penicillin G potassium injection (1 million units contains 1.68mEq of potassium)
- Potassium supplements (K-Dur®, etc)
- Tacrolimus (Prograf®)
- Trimethoprim (part of Bactrim® and Septra®)
- Voclosporin (Lupkynis®)
- NSAIDS and COX-2 Inhibitors (Advil®, Aleve®, ibuprofen, naprosyn, Celebrex® etc.) - NSAIDS and COX-2 inhibitors can attenuate the antihypertensive effect of aliskiren. This is more of a concern if NSAIDS are taken on a regular basis. The combination of RAAS inhibitors (including aliskiren) and NSAIDs may cause a decline in kidney function. The risk appears to be greater with advanced age, dehydration (including diuretic therapy), and underlying kidney disease.
- Salt substitutes (No-Salt®, etc.)- Salt substitutes typically contain a high amount of potassium (16.4 mEq per 1/4 teaspoon). Since aliskiren can raise potassium levels, caution should be used when consuming salt substitutes.
- Metabolism and clearance
- CYP3A4 - sensitive substrate
- P-glycoprotein - substrate
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
- LONG-TERM SAFETY
- Aliskiren was FDA-approved in 2007. It is not widely prescribed and long-term safety data is lacking.
- BIBLIOGRAPHY
- 1 - PMID 18843743
- 2 - PMID 18525041
- 3 - Aliskiren PI
- 4 - PMID 17658393
- 5 - PMID 23121378
- 6 - PMID 23478743
- 7 - PMID 22560830 - Use and safety of unfractionated heparin for anticoagulation during maintenance hemodialysis, Am J Kidney Dis (2021)
- 8 - PMID 27043774 - Atmosphere trial