- ACRONYMS AND DEFINITIONS
- ACE - Angiotensin converting enzyme
- ADA - American Diabetes Association
- AHA/ACC - American Heart Assoc / American College of Cardiology
- ARB - Angiotensin II receptor blocker
- BP - Blood pressure
- CCB - Calcium channel blockers
- CrCl - Creatinine clearance
- DBP - Diastolic blood pressure
- DKD - Diabetic kidney disease
- EF - Ejection Fraction
- GFR - Glomerular Filtration Rate
- HCTZ - Hydrochlorothiazide
- HFrEF - Heart failure with reduced ejection fraction
- NKF - National Kidney Foundation
- NYHA - New York Heart Association heart failure classification
- RAAS - Renin-Angiotensin-Aldosterone System
- RCT - Randomized controlled trial
- SBP - Systolic blood pressure
- SCr - Serum creatinine
- UACR - Urinary albumin-to-creatinine ratio
- DRUGS IN CLASS
- Angiotensin II receptors blockers
- Azilsartan (Edarbi®)
- Candesartan (Atacand®)
- Irbesartan (Avapro®)
- Losartan (Cozaar®)
- Olmesartan (Benicar®)
- Telmisartan (Micardis®)
- Valsartan (Diovan®)
- Combination products with thiazide diuretics
- Atacand HCT® (candesartan + HCTZ)
- Avalide® (irbesartan + HCTZ)
- Benicar HCT® (olmesartan + HCTZ)
- Diovan HCT® (valsartan + HCTZ)
- Edarbyclor® (azilsartan + chlorthalidone)
- Hyzaar® (losartan + HCTZ)
- Micardis HCT® (telmisartan + HCTZ)
- Combination products with amlodipine
- Azor® (olmesartan + amlodipine)
- Exforge® (valsartan + amlodipine)
- Twynsta® (telmisartan + amlodipine)
- Combination products with neprilysin inhibitors
- Entresto® (valsartan + sacubitril)
- ARB + CCB + HCTZ
- Exforge HCT® (valsartan + amlodipine + HCTZ)
- Tribenzor® (olmesartan + amlodipine + 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. The final step in the RAAS is the synthesis of angiotensin II. Angiotensin II stimulates a number of physiologic actions including vasoconstriction, aldosterone secretion, and sympathetic outflow. Angiotensin II receptors are present in the adrenal glands, heart, blood vessels, brain, and kidneys.
- Angiotensin II receptor blockers (ARBs) block angiotensin II receptors and prevent their stimulation, thus inhibiting 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 INDICATIONS
- Azilsartan (Edarbi®)
- Hypertension
- Candesartan (Atacand®)
- Hypertension
- Heart failure
- Irbesartan (Avapro®)
- Hypertension
- Nephropathy in type 2 diabetes
- Losartan (Cozaar®)
- Hypertension
- Left ventricular hypertrophy in patients with hypertension - Cozaar is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients
- Nephropathy in type 2 diabetes
- Olmesartan (Benicar®)
- Hypertension
- Telmisartan (Micardis®)
- Hypertension
- Cardiovascular risk reduction - reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors
- Valsartan (Diovan®)
- Hypertension
- Heart failure
- Post-myocardial infarction - in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction, Diovan is indicated to reduce cardiovascular mortality
- HYPERTENSION
- Overview
- All ARBs are FDA-approved to treat hypertension
- Most of the blood pressure lowering effect of ARBs is seen within 2 weeks
- Maximal blood pressure lowering is typically seen within 4-6 weeks [1,25,27]
- STUDY
- A Cochrane meta-analysis looked at the blood pressure-lowering effects of ARBs in patients with hypertension
- The analysis included 46 trials that encompassed 13,451 patients
- No one ARB was found to be superior or worse than any other ARB
- The average baseline BP in the trials was 156/101 mmHg
- Effect on Systolic Blood Pressure
- Average reduction of 12 mmHg when BP was measured 1 - 12 hours after the ARB was taken
- Average reduction of 8 mmHg when BP was measured at the very end of the dosing interval (trough level)
- Effect on Diastolic Blood Pressure
- Average reduction of 7 mmHg when BP was measured 1 - 12 hours after the ARB was taken
- Average reduction of 5 mmHg when BP was measured at the very end of the dosing interval (trough level) [2]
- Professional recommendations
- See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations
- HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF)
- Overview
- Like ACE inhibitors, ARBs have also been shown to improve outcomes in heart failure with reduced ejection fraction. Candesartan and valsartan are FDA-approved for HFrEF, and losartan has also proven effective in a large trial. A study that compared candesartan to placebo is detailed below along with a trial that compared valsartan to captopril and both drugs combined.
- The CHARM-ALT trial enrolled 2028 patients with heart failure who were not taking an ACE inhibitor
Main inclusion criteria
- NYHA II - IV heart failure
- EF ≤ 40%
- Intolerant to ACE inhibitors
Baseline characteristics
- Average age 66 years
- Average EF - 30%
- Average BP - 130/77 mmHg
- NYHA class: II - 48% | III - 49% | IV - 3.6%
- Heart failure type: Ischemic - 68% | Idiopathic - 19% | Hypertensive - 6%
- Baseline meds: Diuretic - 85% | Beta blocker - 55% | Spironolactone - 24%
- Reason for ACE intolerance: Cough - 72% | Hypotension - 13% | Renal dysfunction - 11% | Other - 10%
Randomized treatment groups
- Group 1 (1013 patients) - Candesartan with a target dose of 32 mg once daily (average dose at 6 months was 23 mg)
- Group 2 (1015 patients) - Placebo once daily
- Candesartan was started at a dose of 4 - 8 mg once daily and doubled at a minimum of every 2 weeks to a target of 32 mg
Primary outcome: Cardiovascular death or unplanned admission to hospital for the management of worsening heart failure
Results
Duration: Median of 33.7 months | |||
Outcome | Candesartan | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 33% | 40% | HR 0.77, 95%CI [0.67 - 0.89], p=0.0004 |
Overall mortality | 26.2% | 29.2% | HR 0.87, 95%CI [0.74 - 1.03], p=0.11 |
Hospitalization for heart failure | 20.9% | 28.7% | p=0.0001 |
Drug discontinuation | 24% | 22% | p=0.49 |
Hypotension causing drug discontinuation | 3.7% | 0.9% | p<0.0001 |
Increase in creatinine causing drug discontinuation | 6.1% | 2.7% | p<0.0001 |
Hyperkalemia causing drug discontinuation | 1.9% | 0.3% | p=0.0005 |
|
Findings: Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and
intolerance to ACE inhibitors
- The VALIANT trial enrolled 14,703 patients with acute myocardial infarction that was complicated by heart failure or left ventricular dysfunction
Main inclusion criteria
- Myocardial infarction within past 0.5 - 10 days
- Clinical or radiologic signs of heart failure or EF < 35% on ECHO or < 40% on radionuclide ventriculography
Main exclusion criteria
- SBP < 100
- Serum creatinine ≥ 2.5 mg/dl
- Previous intolerance to ACE or ARB
- Significant heart valve disease
Baseline characteristics
- Average age 65 years
- Average BP - 122/72
- Average EF - 35%
- History of prior heart failure - 15%
- Received PCI - 35%
- Baseline meds: ACE/ARB - 41% | Beta blocker - 70% | Diuretics - 60%
Randomized treatment groups
- Group 1 (4909 patients) - Valsartan with a target dose of 160 mg twice a day (mean dose achieved 247 mg/day)
- Group 2 (4885 patients) - Valsartan with a target dose 80 mg twice daily + Captopril with a target dose 50 mg three times a day (mean dose achieved 116 mg/day and 105 mg/day, respectively)
- Group 3 (4909 patients) - Captopril with a target dose of 50 mg three times a day (mean dose achieved 117 mg/day)
- Initial valsartan dose was 20 mg and initial captopril dose was 6.25 mg. Study drugs were titrated to target over a 3-month period if possible.
Primary outcome: All-cause mortality
Results
Duration: Median of 24.7 months | ||||
Outcome | Valsartan | Val + Cap | Captopril | Comparisons |
---|---|---|---|---|
Primary outcome | 19.9% | 19.3% | 19.5% | 1 or 2 vs 3 p>0.50 |
Hospitalization for myocardial infarction or heart failure | 18.7% | 17.1% | 19.3% | 1 vs 3 p=0.50 | 2 vs 3 p=0.005 |
Hypotension causing drug discontinuation | 1.4% | 1.9% | 0.8% | 1 or 2 vs 3 p<0.05 |
Renal dysfunction causing drug discontinuation | 1.1% | 1.3% | 0.8% | 1 vs 3 p>0.05 | 2 vs 3 p<0.05 |
Hyperkalemia causing drug discontinuation | 0.1% | 0.2% | 0.1% | 1 or 2 vs 3 p>0.05 |
Cough causing drug discontinuation | 0.6% | 2.1% | 2.5% | 1 vs 3 p<0.05 | 2 vs 3 p>0.05 |
Drug discontinuation due to any adverse event | 5.8% | 9% | 7.7% | 1 or 2 vs 3 p<0.05 |
Average blood pressure at 1 year | 127/75 | 125/75 | 127/76 | N/A |
Findings: Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan
with captopril increased the rate of adverse events without improving survival.
- AHA recommendations
- Summary
- Like ACE inhibitors, ARBs improve outcomes in patients with HFrEF. Combining ARBs and ACE inhibitors (see combination therapy below) does not improve efficacy and increases the risk of side effects.
- Candesartan and valsartan are FDA-approved for HFrEF, and losartan has also proven effective in a large trial [PMID 10821361]
- The heart failure drug Entresto® contains valsartan
- DIABETIC KIDNEY DISEASE (DKD)
- Overview
- Diabetic kidney disease occurs in 20 - 40% of patients with diabetes, and it is the leading cause of end-stage kidney disease in the United States
- ACE inhibitors have been shown to improve renal outcomes in DKD so ARBs have also been studied
- Two randomized controlled trials that evaluated the effects of ARBs in DKD are presented below. In the CSG trial, irbesartan was compared to amlodipine and placebo for the treatment of DKD. In the ROADMAP trial, olmesartan was compared to placebo for the prevention of DKD. A meta-analysis that compared the effects of ARBs and ACE inhibitors to other antihypertensive classes in DKD is also presented.
- The CSG trial enrolled 1715 diabetics with hypertension and proteinuria
Main inclusion criteria
- Age 30 - 70 years
- Type 2 diabetes
- Treated hypertension or untreated BP > 135/85
- Proteinuria ≥ 900 mg/day
- Serum creatinine 1 - 3 mg/dl in women or 1.2 - 3 mg/dl in men
Baseline characteristics
- Average age 59 years
- Average BP - 159/87
- Average serum creatinine - 1.67 mg/dl
- Median 24-hour protein - 2.9 grams
- Average A1C - 8.2%
Randomized treatment groups
- Group 1 (579 patients) - Irbesartan 75 - 300 mg once daily
- Group 2 (567 patients) - Amlodipine 2.5 - 10 mg once daily
- Group 3 (569 patients) - Placebo
- Patients were treated to a target BP of < 135/85. Non-study ACE inhibitors, ARBs, and calcium channel blockers were not allowed.
Primary outcome: Composite of doubling of the baseline serum creatinine concentration, the development of end-stage
renal disease, or death from any cause
Results
Duration: Average of 2.6 years | ||||
Outcome | Irbesartan | Amlodipine | Placebo | Comparisons |
---|---|---|---|---|
Primary outcome | 32.6% | 41.1% | 39% | 1 vs 2 p=0.005 | 1 vs 3 p=0.03 |
End-stage renal disease | 14.2% | 18.3% | 17.8% | 1 vs 2 p=0.06 | 1 vs 3 p=0.19 |
Doubling of serum creatinine | 16.9% | 25.4% | 23.7% | 1 vs 2 p<0.001 | 1 vs 3 p=0.009 |
Overall mortality | 15% | 14.6% | 16.3% | 1 vs 2 p=0.75 | 1 vs 3 p=0.69 |
Hyperkalemia leading to drug discontinuation | 1.9% | 0.5% | 0.4% | 1 vs 2 p=0.01 | 1 vs 3 p=0.01 |
Average blood pressure during trial | 140/77 | 141/77 | 144/80 | N/A |
|
Findings: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes.
This protection is independent of the reduction in blood pressure it causes.
- The ROADMAP trial enrolled 4447 diabetics without proteinuria
Main inclusion criteria
- Type 2 diabetes
- Normoalbuminuria (UACR [mg/g]: ≤ 35 for females, ≤ 25 for males)
- At least one of the following - dyslipidemia, hypertension, obesity, smoker, or high waist circumference
Main exclusion criteria
- CrCl < 30 ml/min
- SBP > 200, DBP > 110
- Treatment with ARB or ACE inhibitor within last 6 months
- Cardiovascular event within 6 months
- Renal-vascular disease
Baseline characteristics
- Average age 58 years
- Average A1C - 7.7%
- Average BP 136/81
- Average GFR 85 ml/min
- Average duration of diabetes - 6.1 years
Randomized treatment groups
- Group 1 (2232 patients) - Olmesartan 40 mg once daily
- Group 2 (2215 patients) - Placebo
- ACE inhibitors and non-study ARBs were not allowed in either group. Other classes of BP meds were allowed.
- Patients were treated to a target BP of 130/80
Primary outcome: Development of microalbuminuria
Results
Duration: Median of 3.2 years | |||
Outcome | Olmesartan | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 8.2% | 9.8% | HR 0.77, 95%CI [0.63 - 0.94], p=0.01 |
Doubling of serum creatinine | 1% | 1% | p>0.05 |
Overall mortality | 1.2% | 0.7% | HR 1.70, 95%CI [0.90 - 3.22], p=0.10 |
Hypotension | 2.6% | 0.3% | p<0.001 |
Hyperkalemia | 0.5% | 0.4% | p=0.50 |
|
Findings: Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of
fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern.
- STUDY
- A meta-analysis published in the BMJ in 2016 compared outcomes in diabetics who were prescribed ACE inhibitors or ARBS to those who were prescribed other blood pressure medications
- The analysis included 19 randomized controlled trials (25,414 patients) totaling 95,910 patient-years of follow-up. The average follow-up of the trials was 3.8 years.
- ACE inhibitors were used in 14 trials, and ARBs were used in 6. The comparison drug was a calcium channel blocker in 15 trials, a thiazide diuretic in 3 trials, and a beta blocker in 2 trials.
- The majority of the trials (n=17) enrolled patients with hypertension
- The following results were seen:
- End-stage renal disease (ACE/ARB vs all other): RR 0.99, 95% CI [0.78 - 1.28]
- Overall mortality (ACE/ARB vs all other): RR 0.99, 95% CI [0.93 - 1.05]
- Heart attack (ACE/ARB vs all other): RR 0.87, 95% CI [0.64 - 1.18]
- Heart failure (ACE/ARB vs all other): RR 0.90, 95% CI [0.76 - 1.07]
- In meta-regression analysis, the presence of nephropathy at baseline had no significant effect on results
- Findings: In people with diabetes, RAS blockers are not superior to other antihypertensive drug classes such as thiazides, calcium channel blockers, and beta blockers at reducing the risk of hard cardiovascular and renal endpoints.
- Professional recommendations
- Summary
- When compared to other blood pressure medications, ACE inhibitors and ARBs are superior for treating and preventing proteinuria
- When it comes to improving hard renal outcomes like end-stage renal disease, there is no evidence that ACE inhibitors or ARBs are superior to other classes of blood pressure medications
- Patients with diabetic kidney disease should focus on blood sugar and blood pressure control to help prevent progression of their disease
- NONDIABETIC KIDNEY DISEASE
- There are no good long-term trials that have evaluated the effects of ARBs on significant clinical outcomes in patients with nondiabetic kidney disease
- ACE inhibitors have been shown to be beneficial in patients with significant proteinuria (> 500 mg/day) [41]
- Whether ARBs would also be of benefit is certainly possible, but unproven
- GOUT
- Overview
- Gout is an inflammatory joint disease caused by elevated uric acid levels
- Losartan promotes uric acid excretion in the kidneys and therefore may be beneficial in the treatment of gout. As for other ARBs, candesartan and irbesartan were not found to have a significant effect on uric acid excretion in studies. The remaining ARBs have not been evaluated extensively. [46]
- The effect of losartan on uric acid levels has been evaluated in several small studies
- In one study, 12 patients with gout who were receiving allopurinol (200 mg twice a day) were given losartan 50 mg a day for 2 months. Uric acid levels decreased from an average of 6.0 mg/dl to 5.5 mg/dl. [PMID 12759298]
- In another study, 162 patients without gout who had an average uric acid level of 7.09 mg/dl were given losartan 50 - 100 mg a day for 8 weeks. The average uric acid level decreased to 6.03 mg/dl. [PMID 16281062]
- Professional recommendations
- COMBINING ARBS AND ACE INHIBITORS | Heart failure
- Overview
- ARBs and ACE inhibitors block the Renin-Angiotensin-Aldosterone System (RAAS) at different steps (see RAAS illustration). Since both drugs have been proven to be beneficial in heart failure, there has been interest in using them together.
- The VALIANT trial compared the combination of valsartan and captopril (combination therapy) to each drug alone in patients with recent myocardial infarction and heart failure (see VALIANT trial above). For the primary outcome, combination therapy was not superior to each drug alone. Combination therapy was superior to captopril alone for a composite outcome of hospitalization for myocardial infarction or heart failure. Combination therapy had significantly more side effects than individual therapy. [12]
- The CHARM-ADDED trial detailed below compared combination therapy with candesartan and an ACE inhibitor to an ACE inhibitor alone. A meta-analysis that combined the results of 4 trials is also reviewed.
- The CHARM-Added trial enrolled 2548 patients with NYHA class II-IV heart failure who were being treated with an ACE inhibitor
Main inclusion criteria
- EF ≤ 40%
- NYHA class II - IV heart failure (if NYHA class II had to have had hospitalization for cardiac reasons within 6 months)
- Treatment with ACE inhibitor
Baseline characteristics
- Average age 64 years
- Average EF - 28%
- NYHA class: II - 24% | III - 73% | IV - 3%
- Heart failure type: Ischemic - 63% | Idiopathic - 27% | Hypertensive - 6.5%
- Baseline meds: ACE inhibitor - 100% | Diuretic - 90% | Beta blocker - 56% | Spironolactone - 17%
Randomized treatment groups
- Group 1 (1276 patients) - Candesartan target dose of 32 mg once daily (mean dose at 6 months was 24 mg)
- Group 2 (1272 patients) - Placebo once daily
- Candesartan was started at 4 - 8 mg once daily and doubled every 2 weeks to a target of 32 mg if tolerated
Primary outcome: Composite of cardiovascular death or hospitalization for heart failure
Results
Duration: Median of 41 months | |||
Outcome | Candesartan | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 37.9% | 42.3% | HR 0.85, 95%CI [0.75 - 0.96], p=0.011 |
Hospitalization for heart failure | 25.3% | 30% | p=0.002 |
Overall mortality | 30% | 32% | HR 0.89, 95%CI [0.77 - 1.02], p=0.086 |
Drug discontinuation for adverse event | 24% | 18% | p=0.0003 |
Hypotension leading to drug discontinuation | 4.5% | 3.1% | p=0.079 |
Increase in creatinine leading to drug discontinuation | 7.8% | 4.1% | p=0.0001 |
Hyperkalemia leading to drug discontinuation | 3.4% | 0.7% | p<0.0001 |
|
Findings: The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular
events in patients with CHF and reduced left-ventricular ejection fraction
- STUDY
- A meta-analysis in the Archives of Internal Medicine compared the adverse effects of ACE inhibitor + ARB therapy to ACE inhibitor therapy in patients with heart failure and left ventricular dysfunction
- The analysis included four studies that encompassed 17,337 patients with an average follow-up of 25 months
- The following effects were seen when ACE + ARB therapy was compared to ACE inhibitor alone:
- Worsening kidney function (Combo vs ACE): RR 2.17, 95% CI [1.59 - 2.97]
- Hyperkalemia (Combo vs ACE): RR 4.87, 95% CI [2.39 - 9.94]
- Symptomatic hypotension (Combo vs ACE): RR 1.50, 95% CI [1.09 - 2.07]
- Drug discontinuation due to adverse effects (Combo vs ACE): RR 1.38, 95% CI [1.22 - 1.55] [34]
- Findings: Combination ARB plus ACE inhibitor therapy in subjects with symptomatic left ventricular dysfunction was accompanied by marked increases in adverse effects
- AHA recommendations
- The AHA/ACC 2017 heart failure guidelines do not recommend combining an ACE inhibitor and an ARB [47]
- Summary
- Combination therapy with an ACE inhibitor and an ARB showed a modest benefit in the CHARM-ADDED study. Combination therapy is associated with a greater risk of potentially serious side effects. Patients who require additional therapy while taking an ACE inhibitor or ARB should be considered for Entresto.
- COMBINING ARBS AND ACE INHIBITORS | Kidney disease
- Overview
- A number of trials have evaluated ACE + ARB combinations in treating both diabetic and nondiabetic kidney disease
- One of the earliest trials, the COOPERATE trial, found a benefit with combination therapy in patients with non-diabetic kidney disease. Unfortunately, this study was later retracted after a number of inconsistencies and questionable practices were discovered. Information from this trial should not be considered. [35]
- Short-term trials have shown that ACE + ARB combination therapy decreases proteinuria (protein in the urine) when compared to ACE inhibitor therapy alone in patients with both diabetic and nondiabetic kidney disease [36, 37]
- No long-term studies have been performed to evaluate the effects of combination therapy on hard renal outcomes like end-stage kidney disease
- Summary
- At this time, there is no proven long-term benefit of using ACE + ARB combinations in patients with kidney disease
- SIDE EFFECTS
- Cough (lack of)
- Unlike ACE inhibitors, ARBs do not cause a dry cough. Randomized trials have consistently shown that the incidence of cough with ARBs is no different than placebo. This also holds true in patients who have a history of ACE inhibitor-induced cough. [1, 23-27]
- High potassium (hyperkalemia)
- ARB blockage of the RAAS reduces aldosterone secretion, and this can lead to hyperkalemia. The risk of hyperkalemia from ARBs 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)
- AHA recommendations
- The AHA recommends that renal function and potassium be checked within 1 - 2 weeks of starting an ACE inhibitor or ARB [15]
- Summary
- Patients without significant comorbidities typically tolerate ARBs fine. Patients with kidney disease, heart failure, diabetes, and other conditions should have their potassium levels checked more frequently. See RAAS inhibitor-induced hyperkalemia for recommendations on managing hyperkalemia.
- Angioedema (swelling of mouth, lips, and tongue)
- 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.
- ARBs can cause angioedema, but the incidence is lower than what is seen with ACE inhibitors. This raises the question of whether patients with ACE inhibitor-induced angioedema can safely take ARBs. Results from a handful of small studies that looked at the issue are provided below.
- Studies
- In the CHARM-ALT trial, 39 patients in the candesartan group had a history of ACE inhibitor-induced angioedema. Of these 39, three patients treated with candesartan experienced angioedema. [10]
- A small meta-analysis found that the risk of angioedema from ARBs in patients with a history of ACE inhibitor-induced angioedema is 2 - 17%. [PMID 19055203]
- Summary
- Significant angioedema can be a terrifying experience for patients, and the risk of a recurrence may be too much for some patients to accept. If ARBs are prescribed to patients with a history of ACE inhibitor-induced angioedema, proper precautions (e.g. Epi-pen) should be taken.
- Increase in serum creatinine
- ARB blockage of the RAAS reduces glomerular filtration, and serum creatinine levels may rise. Small increases are generally benign, while sudden large increases may be a sign of renal arterial pressure that is heavily compensated by the RAAS, as is the case in renal artery stenosis.
- Small creatinine increases are seen in about 2% of healthy patients, while patients with certain comorbidities (e.g. heart failure, diabetes, concomitant diuretics, advanced age) are at greater risk. Management of ARB-induced creatinine rises should be individualized with careful consideration of the indication for use, risk of hyperkalemia, and potential benefits of continued therapy.
- Patients on ARBs should have their kidney function assessed periodically, with more frequent monitoring in high-risk patients.
- AHA recommendations
- The AHA recommends that renal function and potassium be checked within 1 - 2 weeks of starting an ACE inhibitor or ARB [15]
- Enteropathy
- Enteropathy is a term that means "disease of the intestine." Enteropathies are caused by a number of conditions including allergies to certain foods (e.g. celiac disease), medications, inflammatory bowel disease (e.g. Crohn's disease), and genetic disorders. Symptoms of enteropathy include chronic diarrhea (> 4 weeks), weight loss, fat malabsorption, and excessive gas.
- ARBs, particularly olmesartan, have been associated with rare cases of a celiac-like enteropathy. The estimated incidence of ARB-induced enteropathy is 10 - 14 cases per 100,000 patients treated with ARBs.
- The mechanism by which ARBs cause enteropathy is unclear. Proposed theories include abnormal immune response to the chemical structure of ARBs and ARB-mediated inhibition of TGF-B (Transforming Growth Factor-Beta), an important mediator of gut homeostasis.
- A systematic review that looked at 248 cases of ARB-induced enteropathy found the following:
- Olmesartan was the culprit ARB in 94% of cases
- The time between ARB initiation and onset of symptoms ranged from 2 weeks to 13 years
- In cases with histology (N=218), villous atrophy was noted in 92% and intraepithelial lymphocytosis was seen in 60%
- In cases with HLA testing (N=147), HLA-DQ2 or HLA-DQ8 haplotypes were present in 71%
- In cases with celiac antibody testing (N=169), testing was negative in 99%
- Complete resolution of symptoms was reported in 97% of patients after the ARB was discontinued [48,49]
- CONTRAINDICATIONS
- All ARBs
- Known hypersensitivity
- Coadministration with aliskiren in patients with diabetes
- Pregnancy and nursing
- PRECAUTIONS
- Kidney disease
- While ARBs are beneficial in treating and preventing kidney disease, their inhibitory effects on the RAAS system can be detrimental when kidneys are severely compensated, leading to elevations in potassium, serum creatinine, and BUN. The risk of adverse effects depends on the degree of kidney disease and concurrent medical problems (e.g. heart failure, diabetes). To help avoid these issues, ARBs should be started at the lowest dose possible and titrated slowly in patients with significant kidney disease.
- The STOP ACEi study (N=411) published in 2022 randomized patients with GFR < 30 ml/min to discontinue or continue their ACE inhibitor or ARB. The primary outcome was GFR at 3 years. At the end of the study, there was no significant difference in GFR between the groups (discontinue - 12.6 ml/min, continue - 13.3 ml/min, p=0.42). End-stage kidney disease or the initiation of renal replacement therapy occurred in 62% of discontinue patients and 56% of continue patients (HR 1.28, 95%CI [0.99 - 1.65]) [PMID 36326117].
- Azilsartan (Edarbi®)
- No dose adjustment necessary
- Candesartan (Atacand®)
- Use caution
- Irbesartan (Avapro®)
- No dose adjustment necessary unless patient is volume depleted
- Losartan (Cozaar®)
- No dose adjustment necessary unless patient is volume depleted
- Olmesartan (Benicar®)
- No initial dose adjustment is recommended
- Telmisartan (Micardis®)
- No initial dose adjustment is necessary
- Valsartan (Diovan®)
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: has not been studied
- Liver disease
- Azilsartan (Edarbi®)
- Child-Pugh A or B: no dose adjustment necessary
- Child-Pugh C: has not been studied
- Candesartan (Atacand®)
- Child-Pugh B: starting dose should be 8 mg/day when treating hypertension
- Child-Pugh C: has not been studied
- Irbesartan (Avapro®)
- No dose adjustment necessary
- Losartan (Cozaar®)
- Child-Pugh A or B: use starting dose of 25 mg once daily
- Child-Pugh C: has not been studied
- Olmesartan (Benicar®)
- No initial dose adjustment is recommended
- Telmisartan (Micardis®)
- Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency
- Valsartan (Diovan®)
- Child-Pugh A or B: no dose adjustment necessary
- Child-Pugh C: has not been studied
- Renal artery stenosis
- Renal artery stenosis causes a decrease in renal arterial pressure. In response, the afferent arterioles stimulate the RAAS to increase blood pressure and maintain blood flow (see RAAS and the kidneys). If an ARB is initiated, sudden loss of the compensatory RAAS effects can cause decreased renal perfusion and a significant rise in serum creatinine. In severe cases, kidney failure may develop.
- Serum creatinine levels should be checked 1 - 2 weeks after starting an ARB. If sudden large increases in creatinine are noted, patients should be evaluated for renal artery stenosis.
- Black patients
- Compared to other antihypertensive drug classes, ARBs and ACE inhibitors are less effective at lowering blood pressure in black patients. A meta-analysis that compared the effects of ARBs to other blood pressure medications in black patients is detailed below.
- STUDY
- A meta-analysis compared the effects of ARBs to other classes of antihypertensives in black patients
- The analysis found the following:
- ARBs lowered systolic blood pressure (SBP) an average of 3.63 mmHg when compared to placebo
- ARBs lowered diastolic blood pressure (DBP) an average of 2.09 mmHg when compared to placebo
- Compare to:
- Diuretics - average SBP reduction of 11.81 mmHg / DBP reduction of 8.06 mmHg
- Calcium channel blockers - average SBP reduction 12.10 mmHg / DBP 9.40 mmHg [39]
- Findings: Drugs differ in their efficacy for reducing blood pressure in black patients, but there is no solid evidence that efficacy for reducing morbidity and mortality outcomes differs once patients achieve the blood pressure goal
- Professional recommendations
- See hypertension guidelines for recommendations on treating hypertension in black patients
- Pregnant or nursing
- ARBs should not be taken by pregnant women or patients who are nursing. When taken during the second and third trimesters of pregnancy, drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) can reduce fetal renal function and increase the risk of fetal and neonatal morbidity and death.
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All ARBs
- ACE inhibitors - see combining ARBs and ACE inhibitors
- Aliskiren (Tekturna®) - Aliskiren should not be prescribed with ARBs in patients with diabetes or decreased kidney function (GFR<60ml/min)
- Lithium - ARBs can increase lithium levels. This combination should be avoided, or lithium levels should be checked frequently if they are taken together.
- Medications that can raise potassium levels - ARBs may raise potassium levels and cause hyperkalemia. When taken with other potassium-raising medications, the risk is increased. While it is often appropriate to combine ARBs with other potassium-raising drugs, patients and providers should be aware of the potential risks. See RAAS inhibitor-induced hyperkalemia for recommendations on addressing hyperkalemia in ARB-treated patients.
- Examples of medications that may raise potassium levels include:
- Aldosterone antagonists (spironolactone and eplerenone)
- ACE inhibitors
- Aliskiren (Tekturna®)
- 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. [50]
- 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 (Advil®, Aleve®, etc.) - NSAIDS can attenuate the effect of ARBs. This is more of a concern when NSAIDS are taken on a chronic basis. Cases of decreased kidney function have been reported when NSAIDS were taken with ARBs. The risk appears to be greater with advanced age, dehydration, 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 ARBs can raise potassium levels, caution should be used when consuming salt substitutes.
- Telmisartan (Micardis®)
- Digoxin - telmisartan has been shown to increase digoxin levels. When taken together, digoxin levels should be monitored.
- Ramipril (Altace®) - Ramipril, an ACE inhibitor, should not be taken with telmisartan. Telmisartan has been shown to significantly increase ramipril levels.
- Metabolism and clearance
- Azilsartan (Edarbi®)
- CYP2C9 - substrate
- Candesartan (Atacand®)
- No significant liver metabolism
- Irbesartan (Avapro®)
- CYP2C9 - substrate
- Losartan (Cozaar®)
- CYP2C9 - substrate
- CYP3A4 - substrate
- P-glycoprotein - substrate
- Olmesartan (Benicar®)
- OATP - substrate
- Telmisartan (Micardis®)
- Valsartan (Diovan®)
- OATP - substrate
- DOSING
- LONG-TERM SAFETY
- Losartan was the first ARB approved in the U.S. in 1995. Since then, they have been widely prescribed.
- Over years of widespread use and in a number of large clinical trials, they have proven to be safe and effective
- BIBLIOGRAPHY
- 1 - candesartan PI
- 2 - PMID 18843650
- 3 - PMID 19454737
- 4 - PMID 19588327
- 5 - PMID 21521728
- 6 - PMID 16139131
- 7 - PMID 17398202
- 8 - PMID 10821361
- 9 - PMID 11759645
- 10 - PMID 13678870
- 11 - PMID 13678871
- 12 - PMID 14610160
- 13 - PMID 15520426
- 14 - PMID 19001508
- 15 - PMID 16160202
- 16 - PMID 11565517
- 17 - PMID 11565518
- 18 - PMID 11565519
- 19 - PMID 15459003
- 20 - PMID 21193625
- 21 - PMID 21388309
- 22 - PMID 12241832
- 23 - Eprosartan PI
- 24 - Irbesartan PI
- 25 - Losartan PI
- 26 - Olmesartan PI
- 27 - Valsartan PI
- 28 - Telmisartan PI
- 29 - Azilsartan PI
- 30 - PMID 19055203
- 31 - PMID 13678869
- 32 - PMID 18378520
- 33 - PMID 18707986
- 34 - PMID 17923591
- 35 - PMID 19819378
- 36 - PMID 17367311
- 37 - PMID 16797382
- 38 - PMID 17276798
- 39 - PMID 15492341
- 40 - PMID 16338452
- 41 - PMID 11453706
- 42 - PMID 22560830
- 43 - PMID 23741058 - AHA 2013 Heart Failure GL
- 44 - ADA 2016 Standards of Care in Diabetes
- 45 - PMID 12759298 - losartan in gout
- 46 - PMID 16281062 - losartan in hyperuricemia
- 47 - PMID 28455343 - PMID 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, Circulation (2017)
- 48 - PMID 31217979 - Angiotensin II Receptor Blockers and Gastrointestinal Adverse Events of Resembling Sprue-Like Enteropathy: A Systematic Review, Gastroenterol Rep (Oxf) (2019)
- 49 - PMID 31471672 - Association of Sprue-Like Enteropathy and Angiotensin receptor-1 Antagonists, Wien Klin Wochenschr (2019)
- 50 - PMID 22560830 - Use and safety of unfractionated heparin for anticoagulation during maintenance hemodialysis, Am J Kidney Dis (2021)