- ACRONYMS AND DEFINITIONS
- ACE - Angiotensin converting enzyme
- ADA - American Diabetes Assoc
- AHA - American Heart Association
- ARB - Angiotensin II receptor blocker
- BP - Blood pressure
- CAD - Coronary artery disease
- CCB - Calcium channel blocker
- CHF - Congestive heart failure
- CrCl - Creatinine clearance
- CVD - Cardiovascular disease
- DBP - Diastolic blood pressure
- DKD - Diabetic kidney disease
- EF - Ejection fraction
- GFR - Glomerular filtration rate
- 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
- DRUGS IN CLASS
- ACE inhibitors
- Benazepril (Lotensin®)
- Captopril (Capoten®)
- Enalapril (Vasotec®, Epaned®)
- Fosinopril (Monopril®)
- Lisinopril (Prinivil®, Zestril®, Qbrelis®)
- Moexipril (Univasc®)
- Perindopril (Aceon®)
- Ramipril (Altace®)
- Trandolapril (Mavik®)
- Quinapril (Accupril®)
- Combination products with hydrochlorothiazide (HCTZ)
- Accuretic® (Quinapril + HCTZ)
- Capozide® (Captopril + HCTZ)
- Lotensin HCT® (Benazepril + HCTZ)
- Monopril HCT® (Fosinopril + HCTZ)
- Prinzide® (Lisinopril + HCTZ)
- Quinaretic® (Quinapril + HCTZ)
- Uniretic® (Moexipril + HCTZ)
- Vaseretic® (Enalapril + HCTZ)
- Zestoretic® (Lisinopril + HCTZ)
- Combination products with calcium channel blockers
- Lotrel® (Benazepril + amlodipine)
- Prestalia® (Perindopril + amlodipine)
- Tarka® (Trandolapril + verapamil)
- 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. Angiotensin converting enzyme (ACE) catalyzes one step in the RAAS pathway - the conversion of angiotensin I to angiotensin II. Angiotensin II stimulates a number of physiologic actions including vasoconstriction, aldosterone secretion, and sympathetic outflow.
- ACE inhibitors block the ACE enzyme and attenuate 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
- Benazepril (Lotensin®)
- Hypertension
- Captopril (Capoten®)
- Hypertension
- Heart failure
- Left ventricular dysfunction after myocardial infarction - captopril tablets are indicated to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction ≤40% and to reduce the incidence of overt heart failure and subsequent hospitalizations for congestive heart failure in these patients
- Diabetic Nephropathy
- Enalapril (Vasotec®)
- Hypertension
- Heart failure
- Asymptomatic left ventricular dysfunction - In clinically stable asymptomatic patients with left ventricular dysfunction (EF ≤35 percent), enalapril decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure
- Fosinopril (Monopril®)
- Hypertension
- Lisinopril (Prinivil®, Zestril®)
- Hypertension
- Heart failure
- Acute myocardial infarction - lisinopril is indicated for the reduction of mortality in treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction
- Moexipril (Univasc®)
- Hypertension
- Perindopril (Aceon®)
- Hypertension
- Stable coronary artery disease - to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction
- Ramipril (Altace®)
- Hypertension
- Reduction in the risk of myocardial infarction, stroke, and death from cardiovascular causes - ramipril is indicated in patients 55 years or older at high risk of developing a major cardiovascular event
- Heart failure post-myocardial infarction
- Trandolapril (Mavik®)
- Hypertension
- Heart failure post myocardial infarction or left ventricular dysfunction post myocardial infarction
- Quinapril (Accupril®)
- Hypertension
- Heart failure
- HYPERTENSION
- Overview
- All ACE inhibitors are FDA-approved to treat hypertension
- A randomized controlled trial that compared captopril to a number of other blood pressure medications is detailed below along with the results from a Cochrane meta-analysis
- The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
- Male veteran
- DBP 95 - 109 mmHg off medications
Baseline characteristics
- Average age 59 years
- Average BP 152/99 mmHg
- Black race - 48%
- Current smoker - 32%
Randomized treatment groups
- Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
- Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
- Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
- Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
- Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
- Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
- Group 2 (186 patients) - Placebo
- There was a washout period of 4 - 8 weeks before randomization
- Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results
Average BP reduction at the end of the titration phase (SBP/DBP mmHg) | ||||||
---|---|---|---|---|---|---|
HCTZ | Atenolol | Captopril | Clonidine | Diltiazem | Prazosin | Placebo |
14 / 10 | 11 / 12 | 9 / 10 | 16 / 12 | 13 / 14 | 12 / 11 | 3 / 5 |
|
Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.
- STUDY
- A Cochrane meta-analysis looked at the effects of ACE inhibitors on blood pressure in patients with hypertension
- The analysis included 92 trials that encompassed 12,954 patients. The average baseline blood pressure in the trials was 157/101 mmHg.
- No single ACE inhibitor was found to be superior or inferior to any other
- Effect on systolic blood pressure
- Average reduction of 11 mmHg when BP was measured 1 - 12 hours after the ACE inhibitor 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 6 mmHg when BP was measured 1 - 12 hours after the ACE inhibitor 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 EF (HFrEF)
- Overview
- ACE inhibitors have consistently been shown to improve outcomes in heart failure with reduced ejection fraction. One of the first trials to evaluate ACE inhibitors in HFrEF is detailed below.
- The SOLVD trial enrolled 2569 patients with heart failure and an ejection fraction ≤ 35%
Main inclusion criteria
- Congestive heart failure
- EF ≤ 35%
- Not taking an ACE inhibitor
Main exclusion criteria
- Age > 80 years
- Significant heart valve disease
- Serum creatinine > 2 mg/dl
- Myocardial infarction within a month
Baseline characteristics
- Average age - 61 years
- Average EF - 25%
- Average BP - 125/77 mmHg
- NYHA class: I - 11% | II - 57% | III - 30% | IV - 1.7%
- Baseline meds: Diuretics - 85% | Digoxin - 67% | Beta blockers - 7.5% | Potassium-sparing diuretic - 9%
Randomized treatment groups
- Group 1 (1284 patients) - Placebo twice a day
- Group 2 (1285 patients) - Enalapril target dose of 10 mg twice a day (average dose 11.2 mg/day)
- Eligible patients went through a run-in phase before randomization where they were given enalapril. Patients who could not tolerate enalapril were excluded.
- Enalapril was started at 2.5 - 5 mg twice daily and titrated to 10 mg twice daily if tolerated
Primary outcome: All-cause mortality
Results
Duration: Average of 41.4 months | |||
Outcome | Placebo | Enalapril | Comparisons |
---|---|---|---|
Primary outcome | 39.7% | 35.2% | RR 0.84, 95%CI [0.74 - 0.95], p=0.0072 |
Death or hospitalization for heart failure | 57.3% | 47.7% | RR 0.74, 95%CI [0.66 - 0.82], p<0.0001 |
Hospitalization for cardiovascular reason | 63% | 57% | p<0.001 |
Serum creatinine > 2 mg/dl | 7.7% | 10.7% | p<0.01 |
Serum potassium > 5.5 mEq/L | 2.5% | 6.4% | p<0.01 |
|
Findings: The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic
congestive heart failure and reduced ejection fractions.
- AHA recommendations
- CARDIOVASCULAR DISEASE PREVENTION
- Overview
- After ACE inhibitors were shown to improve outcomes in heart failure, a number of studies were performed to evaluate their effects in patients with CVD who did not have clinical heart failure
- Two early studies found that ACE inhibitors improved outcomes in patients with CAD [PMID 10639539, PMID 13678872]. Both of these studies were performed before statins were universally recommended in these patients. The PEACE study detailed below compared trandolapril to placebo in patients with CAD who were receiving standard therapy including statins.
- The ALLHAT trial which is also detailed below compared lisinopril to chlorthalidone and amlodipine in patients who had documented CVD or were at high risk for CVD.
- The PEACE study enrolled 8290 patients with stable CAD and an EF > 40%
Main inclusion criteria
- CAD documented by myocardial infarction, PCI, or CABG ≥ 3 months before enrollment, or ≥ 50% obstruction of coronary vessel on angiography
- EF > 40%
- Toleration of and compliance with trandolapril during run-in phase
Main exclusion criteria
- Taking ACE/ARB
- CABG or PCI within previous 3 months
- Serum creatinine > 2 mg/dl
- Potassium > 5.5 mEq/L
Baseline characteristics
- Average age 64 years
- History of PCI or CABG - 72%
- Average BP - 134/78
- Average EF - 58%
- Baseline meds: Antiplatelet therapy - 90% | Lipid-lowering drug - 70% | Beta blocker - 60%
Randomized treatment groups
- Group 1 (4158 patients) - Trandolapril target dose of 4 mg once daily
- Group 2 (4132 patients) - Placebo once daily
- Trandolapril was started at 2 mg once daily and increased to 4 mg after 6 months if tolerated
- In the trandolapril group, 69% of patients achieved the 4 mg/day dose
Primary outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or coronary revascularization
Results
Duration: Median of 4.8 years | |||
Outcome | Trandolapril | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 21.9% | 22.5% | HR 0.96, 95%CI [0.88 - 1.06], p=0.43 |
Overall mortality | 7.2% | 8.1% | RR 0.89, 95%CI [0.76 - 1.04], p=0.13 |
Nonfatal myocardial infarction | 5.3% | 5.3% | RR 1.0, 95%CI [0.83 - 1.20], p=1.00 |
Decrease in BP from baseline at 36 months (mmHg) | 4.4/3.6 | 1.4/2.4 | p<0.001 |
Cough | 39.1% | 27.5% | p<0.01 |
Syncope | 4.8% | 3.9% | p=0.04 |
Drug discontinuation due to side effects | 14.4% | 6.5% | p<0.001 |
|
Findings: In patients with stable coronary heart disease and preserved left ventricular function who are receiving "current standard" therapy and in whom the rate of
cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor provides further benefit
in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization.
- The ALLHAT study enrolled 33,357 patients with hypertension and either a history of CVD or risk factors for CVD
Main inclusion criteria
- Age > 55 years
- SBP ≥ 140 and/or DBP ≥ 90 or treated hypertension
- One of the following: previous MI or stroke, left ventricular hypertrophy (LVH), type 2 diabetes, smoker, low HDL (< 35 mg/dl)
Main exclusion criteria
- History of hospitalized or treated symptomatic heart failure
- EF < 35%
Baseline characteristics
- Average age 67 years
- Women - 47%
- Average BP - 146/84
- Receiving treatment for hypertension - 90%
- Race: White - 47% | Black - 32% | Hispanic - 16%
- Qualifying risk factor: CVD - 52% | Diabetes - 36% | Smoker - 22% | LVH - 21% | Low HDL - 12%
Randomized treatment groups
- Group 1 (15,255 patients) - Chlorthalidone 12.5 - 25 mg a day
- Group 2 (9048 patients) - Amlodipine 2.5 - 10 mg/day
- Group 3 (9054 patients) - Lisinopril 10 - 40 mg/day
- Treatment was titrated to a BP goal of < 140/90
- If BP goal was not met taking the maximum tolerated dosage of the initial medication, open-label Step 2 agent (atenolol, 25-100 mg/d, reserpine, 0.05-0.2 mg/d, or clonidine, 0.1-0.3 mg twice per day), or an open-label Step 3 agent (hydralazine, 25-100 mg twice per day) could be added
- There was another arm of the study that used doxazosin. That arm was stopped early due to an increased risk of major CVD events. See ALLHAT doxazosin for more.
Primary outcome: Composite of fatal coronary heart disease or nonfatal myocardial infarction
Results
Duration: Average of 4.9 years | ||||
Outcome | Chlorthalidone | Amlodipine | Lisinopril | Comparisons |
---|---|---|---|---|
Primary outcome (6-year rate) | 11.5% | 11.3% | 11.4% | 1 vs 2 p=0.65 | 1 vs 3 p=0.81 |
Overall mortality (6-year rate) | 17.3% | 16.8% | 17.2% | 1 vs 2 p=0.20 | 1 vs 3 p=0.90 |
Stroke (6-year rate) | 5.6% | 5.4% | 6.3% | 1 vs 2 p=0.28 | 1 vs 3 p=0.02 |
Heart failure (6-year rate) | 7.7% | 10% | 8.7% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
Achieved BP goal (< 140/90) at 1 year | 57.8% | 55.2% | 50.6% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
Potassium < 3.5 mEq/L at 2 years | 12.7% | 2.6% | 1.5% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
New-onset diabetes at 4 years | 11.6% | 9.8% | 8.1% | 1 vs 2 p=0.04 | 1 vs 3 p<0.001 |
Findings: Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.
- AHA recommendations
- The 2015 AHA recommendations on the treatment of hypertension in patients with CAD state that blood pressure lowering is more important than the class of antihypertensive used. They do not recommend one class of drugs over another. [48]
- Summary
- In the PEACE trial, trandolapril was not superior to placebo in the secondary prevention of CVD
- In the ALLHAT trial, lisinopril was equivalent to amlodipine and chlorthalidone for the primary outcome of fatal coronary heart disease or nonfatal myocardial infarction. Because of its diuretic effect, chlorthalidone was superior to both amlodipine and lisinopril for preventing heart failure. Overall mortality did not differ between the 3 treatments.
- In patients with CVD, achieving good blood pressure control is more important than the class of antihypertensive that is used to achieve it
- 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
- Two randomized controlled trials that evaluated the effects of ACE inhibitors in DKD are presented below. In the CSG study, captopril was compared to placebo for the treatment of DKD. In the BENEDICT study, trandolapril was compared to placebo for the prevention of DKD. A meta-analysis that compared the effects of ACE inhibitors and ARBs to other antihypertensive classes in DKD is also presented.
- The CSG study enrolled 409 type 1 diabetics with proteinuria (≥ 500 mg/day)
Main inclusion criteria
- Age 18 - 49 years
- Type 1 diabetes for at least 7 years
- Diabetic retinopathy
- Urinary protein excretion ≥ 500 mg/day
- Serum creatinine ≤ 2.5 mg/dl
Main exclusion criteria
- NYHA class III or IV heart failure
- Potassium ≥ 6 mEq/L
Baseline characteristics
- Average age 35 years
- Average BP 138/85
- Average A1C - 11.7%
- Average serum creatinine 1.3 mg/dl
- Average 24-hour urinary protein - 2750 mg/day
Randomized treatment groups
- Group 1 (207 patients) - Captopril 25 mg three times a day
- Group 2 (202 patients) - Placebo
- Patients were treated to a target BP of 140/90
- Other classes of BP meds were allowed except for ACE inhibitors and calcium channel blockers
Primary outcome: Doubling of the baseline serum creatinine concentration to at least 2 mg/dl
Results
Duration: Median of 3 years | |||
Outcome | Captopril | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 12% | 21% | RR 0.57, 95%CI [0.35 - 0.94], p=0.007 |
Composite of death, dialysis, or kidney transplant | 11% | 21% | RR 0.54, 95%CI [0.32 - 0.90], p=0.006 |
Drug discontinuation | 16% | 9% | p=0.10 |
|
Findings: Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone
- The BENEDICT trial enrolled 1204 diabetics with hypertension and normoalbuminuria
Main inclusion criteria
- Age ≥ 40 years
- Type 2 diabetes
- Taking hypertension meds or SBP ≥ 130 or DBP ≥ 85
- Urinary albumin excretion < 20 mcg/min
- Serum creatinine ≤ 1.5 mg/dl
Main exclusion criteria
- HgA1C ≥ 11%
- Nondiabetic kidney disease
Baseline characteristics
- Average age 62 years
- Average duration of diabetes - 7.9 years
- Average A1C - 5.8%
- Average BP - 150/87
- Average serum creatinine - 0.9 mg/dl
- Average urinary albumin excretion - 5.5 mcg/min
Randomized treatment groups
- Group 1 (301 patients) - Trandolapril 2 mg once daily
- Group 2 (300 patients) - Trandolapril 2 mg + verapamil sustained-release 180 mg per day
- Group 3 (303 patients) - Verapamil sustained-release 240 mg per day
- Group 4 (300 patients) - Placebo
- There was a washout period of 3 - 6 weeks before randomization where calcium channel blockers and RAS inhibitors were discontinued
- Patients were treated to a target BP of 120/80. Additional meds were allowed if needed in the following order: step 1 - HCTZ or furosemide; step 2 - doxazosin, prazosin, clonidine, methyldopa, or beta-blockers; step 3 - minoxidil or long-acting dihydropyridine calcium channel blockers
Primary outcome: Development of persistent microalbuminuria (overnight albumin excretion ≥ 20 μg per minute at two consecutive visits)
Results
Duration: Median of 3.6 years | |||||
Outcome | Trandolapril | Tran/Vera | Verapamil | Placebo | Comparisons |
---|---|---|---|---|---|
Primary outcome | 6% | 5.7% | 11.9% | 10% | 1 vs 4 p=0.01 | 2 vs 4 p=0.01 | 3 vs 4 p=0.54 |
Average BP during study | 139/81 | 139/80 | 141/82 | 142/83 | 1 vs 4 p≤0.002 | 2 vs 4 p≤0.002 | 3 vs 4 p>0.05 |
Findings: In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence
of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.
- 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
- Overview
- The effect of ACE inhibitors on nondiabetic kidney disease has been studied in a number of studies
- A randomized controlled trial that compared benazepril to placebo in nondiabetic kidney disease is presented below along with a meta-analysis that pooled the results of 11 studies
- The study enrolled 224 patients with nondiabetic chronic renal insufficiency
Main inclusion criteria
- Serum creatinine 3.1 - 5 mg/dl and CrCl of 20 - 70 ml/min
- Nondiabetic kidney disease
- Persistent proteinuria defined as ≥ 300 mg/day for ≥ 3 months
Main exclusion criteria
- Diabetes
- ACE or ARB therapy within past 6 weeks
- NYHA class III or IV heart failure
- Treatment with steroids, NSAIDs, or immunosuppressants
- Renovascular disease
- Cardiovascular event within 1 year
Baseline characteristics
- Average age 45 years
- Average BP 152/85
- Average serum creatinine 4.0 mg/dl
- Average CrCl - 27 ml/min
- Average urinary protein excretion - 1.65 grams/day
- Average potassium - 4.55 mEq/L
- Kidney disease type: Glomerular - 61% | Hypertension - 17% | Polycystic kidneys - 11% | Interstitial - 4%
Randomized treatment groups
- Group 1 (207 patients) - Benazepril 10 mg twice a day
- Group 2 (202 patients) - Placebo twice a day
- Before randomization, all eligible patients underwent an 8-week run-in phase where tolerability of benazepril therapy had to be demonstrated
- Other blood pressure medications excluding ACE inhibitors and ARBs were permitted. Patients were treated to a target BP of 130/80.
Primary outcome: Composite of doubling of the serum creatinine level, end-stage renal disease, or death
Results
Duration: Average of 3.4 years | |||
Outcome | Benazepril | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 41% | 60% | p=0.004 |
Median rate of decline in GFR | 6.8 ml/min/year | 8.8 ml/min/year | p=0.006 |
|
Findings: Benazepril conferred substantial renal benefits in patients without diabetes who had advanced renal insufficiency
- STUDY
- A meta-analysis in the Annals of Internal Medicine pooled the participants from 11 studies that compared ACE inhibitors to other medications in nondiabetic kidney disease
- The pooled studies encompassed 1860 nondiabetic patients and had an average follow-up of 2.2 years
- The following results were seen when ACE inhibitors were compared to other blood pressure medications:
- End-stage renal disease (ACE vs other): RR 0.69, 95%CI [0.51 - 0.94]
- Composite of doubling of the baseline serum creatinine concentration or end-stage renal disease (ACE vs other): RR 0.70, 95%CI [0.55 - 0.88]
- When the results were adjusted for levels of proteinuria, the benefit was only significant for patients with a baseline proteinuria of > 500 mg/day [16]
- Findings: Antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibitors in slowing the progression of nondiabetic renal disease. The beneficial effect of ACE inhibitors is mediated by factors in addition to decreasing blood pressure and urinary protein excretion and is greater in patients with proteinuria. Angiotensin-converting inhibitors are indicated for treatment of nondiabetic patients with chronic renal disease and proteinuria and, possibly, those without proteinuria.
- Professional recommendations
- The National Kidney Foundation (NKF) states that ACE inhibitors may have a benefit over other BP medications in hypertensive patients with nondiabetic kidney disease and proteinuria
- The NKF states that there is insufficient evidence to conclude that ACE inhibitors are superior to other BP medications in patients without proteinuria [18]
- COMBINING ACE INHIBITORS AND ARBS | Heart failure
- Overview
- ACE inhibitors and ARBs 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). 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
- ACE inhibitors can cause a dry cough in about 1-10% of patients depending on the study [24 - 27]
- ACE cough is more common in women, Chinese individuals (up to 50%), and nonsmokers [5,28]
- The mechanism of the cough is not completely understood but is thought to involve the inhibition of bradykinin degradation [26]
- Characteristics of an ACE cough
- ACE cough is usually a dry cough associated with a tickling or scratching sensation in the throat
- ACE cough may occur immediately after the first dose, or it may be delayed for weeks to months after starting therapy
- ACE cough usually resolves within 1 - 4 weeks after stopping therapy, but may linger up to 3 months [28]
- Treatment
- In patients with ACE cough, stopping and then restarting the ACE inhibitor after the cough resolves will sometimes alleviate the cough [5,28]
- Patients with a bothersome cough may be switched to an ARB
- Other treatments that have shown some success in small trials are listed below
- Treatments with moderate to good success in small trials included:
- Indomethacin 50 mg twice a day for 14 days
- Amlodipine 5 mg a day for 14 days
- Nifedipine 30 mg a day for 14 days
- Ferrous sulfate 256 mg a day for 28 days
- Aspirin 500 mg a day for 7 days [28]
- High potassium (hyperkalemia)
- ACE inhibitor blockage of the RAAS reduces aldosterone secretion, and this can lead to hyperkalemia. The risk of hyperkalemia from ACE inhibitors 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 [5]
- Summary
- Patients without significant comorbidities typically tolerate ACE inhibitors 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
- 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.
- ACE inhibitor-induced angioedema is seen in about 0.01 - 0.3% of patients, and Black patients are at the greatest risk. In a trial that compared ramipril to amlodipine or metoprolol in black patients, 6.4% of the patients in the ramipril group experienced angioedema as compared to 2.3% in the amlodipine group and 2.7% in the metoprolol group [PMID 12435255] The risk of angioedema is also higher in patients receiving concomitant mTOR inhibitors (see drug interactions below)
- A randomized trial published in 2015 showed that the drug icatibant, a selective bradykinin B2 receptor antagonist, was superior to steroids and antihistamines in treating ACE inhibitor-induced angioedema. Icatibant is FDA-approved for the treatment of hereditary angioedema. It is given by subcutaneous injection and is very expensive. [PMID 25629740]
- ACE inhibitors should be stopped and never restarted in patients who have experienced angioedema [24]
- Increase in serum creatinine
- ACE inhibitor 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 ACE inhibitor-induced creatinine rises should be individualized with careful consideration of the indication for use, risk of hyperkalemia, and potential benefits of continued therapy. [24-27]
- Patients on ACE inhibitors 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]
- CONTRAINDICATIONS
- All ACE inhibitors
- Known hypersensitivity
- History of angioedema with any ACE inhibitor
- History of hereditary or idiopathic angioedema
- Coadministration with neprilysin inhibitors (e.g. Entresto®). Do not administer an ACE inhibitor within 36 hours of a neprilysin inhibitor.
- Coadministration with aliskiren in patients with diabetes
- Pregnancy
- PRECAUTIONS
- Kidney disease
- While ACE inhibitors 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, ACE inhibitors 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].
- Benazepril (Lotensin®)
- CrCl < 30 ml/min: recommended starting dose is 5 mg a day. Maximum dose is 40 mg a day.
- Captopril (Capoten®)
- For patients with significant kidney disease, start at lowest dose and titrate slowly
- Enalapril (Vasotec®)
- CrCl ≤ 30 ml/min: recommended starting dose is 2.5 mg a day
- Fosinopril (Monopril®)
- No dose adjustment necessary for any degree of kidney disease
- Lisinopril (Zestril®, Prinivil®)
- CrCl 10 - 30 ml/min: give half the recommended starting dose
- CrCl < 10 ml/min: starting dose is 2.5 mg a day
- Moexipril (Univasc®)
- CrCl ≤ 40 ml/min: starting dose is 3.75 mg a day, and maximum dose is 15 mg a day
- Perindopril (Aceon®)
- CrCl < 30 ml/min: not recommended
- For lesser degrees of renal impairment, starting dose should be 2 mg and dose should not exceed 8 mg
- Quinapril (Accupril®)
- CrCl 30 - 60 ml/min: starting dose is 5 mg a day
- CrCl 10 - 30 ml/min: starting dose is 2.5 mg a day
- CrCl < 10 ml/min: no data available to make recommendation
- Ramipril (Altace®)
- CrCl < 40 ml/min: starting dose is 1.25 mg a day. Maximum dose is 5 mg a day.
- Trandolapril (Mavik®)
- CrCl < 30 ml/min: starting dose is 0.5 mg a day
- Liver disease
- Benazepril (Lotensin®)
- No dose adjustment necessary
- Captopril (Capoten®)
- Manufacturer makes no specific recommendation
- Enalapril (Vasotec®)
- Manufacturer makes no specific recommendation
- Fosinopril (Monopril®)
- Drug clearance is decreased in patients with cirrhosis
- Use with caution in these patients
- Manufacturer makes no specific dosage recommendation
- Lisinopril (Zestril®, Prinivil®)
- Manufacturer makes no specific recommendation
- Moexipril (Univasc®)
- Drug clearance is decreased in patients with cirrhosis
- Use with caution in these patients
- Manufacturer makes no specific dosage recommendation
- Perindopril (Aceon®)
- In patients with impaired liver function, plasma concentrations of perindoprilat (active metabolite) were about 50% higher than those observed in healthy subjects
- Manufacturer makes no specific dosage recommendation
- Quinapril (Accupril®)
- Manufacturer makes no specific recommendation
- Ramipril (Altace®)
- Drug clearance is decreased in patients with cirrhosis
- Use with caution in these patients
- Manufacturer makes no specific dosage recommendation
- Trandolapril (Mavik®)
- Drug clearance is decreased in patients with liver disease
- Starting dose in patients with cirrhosis is 0.5 mg a day
- 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 ACE inhibitor 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 ACE inhibitor. If sudden large increases in creatinine are noted, patients should be evaluated for renal artery stenosis.
- It's important to note that ACE inhibitors have been shown to be beneficial in treating renal artery stenosis when tolerated [40]
- Black patients
- The risk of ACE inhibitor-induced angioedema is higher in black patients (see angioedema above). ACE inhibitors are also less effective than other antihypertensives at lowering blood pressure in black patients. Two studies that compared the effects of ACE inhibitors to other blood pressure medications in black patients are detailed below.
- STUDY
- Design: Randomized controlled trial (N=621 | length = 6 months) in black patients with uncontrolled hypertension
- Treatment: Amlodipine 10 mg/HCTZ 25 mg vs Amlodipine 10 mg/Perindopril 8 mg vs Perindopril 8 mg/HCTZ 25 mg
- Primary outcome: Change in the 24-hour ambulatory systolic blood pressure between baseline and 6 months
- Results:
- Primary outcome: Amlodipine/HCTZ was 3.14 mmHg lower than Perindopril/HCTZ (p=0.03). Amlodipine/Perindopril was 3.00 mmHg lower than Perindopril/HCTZ (p=0.04). There was no significant difference between Amlodipine/HCTZ and Amlodipine/Perindopril (p=0.92)
- Findings: These findings suggest that in black patients in sub-Saharan Africa, amlodipine plus either hydrochlorothiazide or perindopril was more effective than perindopril plus hydrochlorothiazide at lowering blood pressure at 6 months.
- STUDY
- A meta-analysis compared the effects of ACE inhibitors to other classes of antihypertensives in black patients
- The analysis found the following:
- ACE Inhibitors lowered systolic blood pressure (SBP) an average of 6.96 mmHg when compared to placebo
- ACE Inhibitors lowered diastolic blood pressure (DBP) an average of 3.84 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 and nursing
- ACE inhibitors should not be taken by pregnant or nursing women. 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 ACE inhibitors
- ARBs - see combining ARBs and ACE inhibitors
- Aliskiren (Tekturna®) - Aliskiren should not be prescribed with ACE inhibitors in patients with diabetes or decreased kidney function (GFR<60 ml/min)
- Diabetes medications - in rare cases, ACE inhibitors have been reported to potentiate the effects of diabetes medications. Diabetics should monitor for hypoglycemia when starting an ACE inhibitor.
- Lithium - ACE inhibitors 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 - ACE inhibitors 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 ACE inhibitors 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 ACE inhibitor-treated patients.
- Examples of medications that may raise potassium levels include:
- Aldosterone antagonists (spironolactone and eplerenone)
- ARBs (valsartan, olmesartan, etc.)
- 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®)
- mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) - the risk of angioedema may be higher in patients taking ACE inhibitors with mTOR inhibitors
- Neprilysin inhibitors (e.g. Entresto®) - do not administer an ACE inhibitor within 36 hours of a neprilysin inhibitor. The combination may increase the risk of angioedema.
- NSAIDS (Advil®, Aleve®, ibuprofen, etc.) - NSAIDS and COX-2 inhibitors can attenuate the effect of ACE inhibitors. This is more of a concern if NSAIDS are to be taken chronically on a regular basis. (see aspirin and ace inhibitors below)
- Salt substitutes (No-Salt®, etc.) - Salt substitutes typically contain a high amount of potassium (16.4 mEq per 1/4 teaspoon). Since ACE inhibitors can raise potassium levels, caution should be used when consuming salt substitutes.
- Fosinopril (Monopril®)
- Antacids (Tums®, Maalox®, etc.) - Antacids decrease the absorption of fosinopril. Fosinopril and antacid dosing should be separated by two hours.
- Quinapril (Accupril®)
- Tetracyclines - quinapril tablets have a significant amount of magnesium. Magnesium can block tetracycline absorption. Tetracycline should be taken 1-2 hours prior to, or 4 hours after quinapril.
- Metabolism and clearance
- Only enalapril undergoes significant liver metabolism
- Enalapril (Vasotec®)
- CYP3A4 - substrate
- Captopril (Capoten®)
- P-glycoprotein - substrate
- ASPIRIN + ACE INHIBITOR
- Overview
- Aspirin is an NSAID, and NSAIDs can decrease the effectiveness of ACE inhibitors. This is particularly a concern when daily aspirin is prescribed to patients on ACE inhibitors.
- A secondary analysis from an early study involving enalapril in heart failure patients (SOLVD trial) found that patients who were taking daily aspirin did not achieve the same benefit from enalapril as patients who were not taking aspirin
- After the SOLVD trial, a meta-analysis was performed on six large trials involving ACE inhibitors to further evaluate the effect of combining ACE inhibitors and aspirin. That meta-analysis is detailed below.
- STUDY
- Results from six long-term studies (N=22,060) involving ACE inhibitors were evaluated to see if daily aspirin affected outcomes among patients taking ACE inhibitors
- Results for major clinical endpoints are as follows
- Death
- Odds of death in patients taking ACE inhibitor with aspirin was 0.86 when compared to controls
- Odds of death in patients taking ACE inhibitor without aspirin was 0.74 when compared to controls
- Difference between the groups was not statistically significant for a p-value< 0.01 (p=.04)
- Heart attack
- Odds of heart attack in patients taking ACE inhibitor with aspirin was 0.86 when compared to controls
- Odds of heart attack in patients taking ACE inhibitor without aspirin was 0.66 when compared to controls
- Difference between the groups was statistically significant for a p < 0.01
- Composite of major vascular events
- Odds of major vascular event in patients taking ACE inhibitor with aspirin was 0.80 when compared to controls
- Odds of major vascular event in patients taking ACE inhibitor without aspirin was 0.71 when compared to controls
- Difference between the groups was not statistically significant for a p < 0.01 (p=0.07) [29]
- Findings: Considering the totality of evidence on all major vascular outcomes in these trials, there is only weak evidence of any reduction in the benefit of ACE-inhibitor therapy when added to aspirin. However, there is definite evidence of clinically important benefits with respect to these major clinical outcomes with ACE-inhibitor therapy, irrespective of whether concomitant aspirin is used.
- AHA recommendations
- The AHA states that it is up to the individual provider whether to prescribe aspirin with ACE inhibitors, and they make no formal recommendation
- Clopidogrel (Plavix®) is cited as a possible alternative since it does not interfere with ACE inhibitors [5]
- Summary
- Aspirin may have a slight negative effect on the efficacy of ACE inhibitors, but this has not been proven in a large randomized trial
- The trials in the meta-analysis were not designed to specifically evaluate this question, so there were baseline differences between patients taking aspirin and those not taking aspirin which can lead to confounding
- The AHA cites clopidogrel as a possible alternative to aspirin. In practice, most patients take ACE inhibitors with aspirin when both are indicated.
- DOSING
- LONG-TERM SAFETY
- ACE inhibitors have been prescribed since the early 1980s
- They are some of the most widely prescribed medications in the world
- ACE inhibitors have been proven to be very safe when prescribed appropriately in long-term use
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