ACE INHIBITORS

















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
Captopril vs Others for Hypertension in Male Veterans, NEJM (1993) [PubMed abstract]
  • 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
  • Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
  • All medications were significantly better than placebo for blood pressure reduction
  • The incidence of side effects with captopril was similar to placebo

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.
Blood pressure lowering efficacy of ACE inhibitors for primary hypertension, Cochrane meta-analysis (2008) [PubMed abstract]
  • 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



Overview
  • ACE inhibitors have consistently been shown to improve outcomes in patients with heart failure and are universally recommended in these patients
  • One of the first trials to compare an ACE inhibitor to placebo in heart failure patients is detailed below
SOLVD Trial - Enalapril vs Placebo in Heart Failure, NEJM (1991) [PubMed abstract]
  • 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
  • After 3 years, open-label ACE inhibitors were being used by 23% of patients in Group 1
  • Blood pressure was significantly lower in Group 2 by 4.7/4.0 mmHg over the course of the study

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
  • The AHA 2017 heart failure guidelines state that ARBs or ACE inhibitors are indicated for patients with chronic HFrEF to reduce morbidity and mortality in conjunction with evidence-based beta blockers and aldosterone antagonists in selected patients
  • Patients who cannot tolerate ACE inhibitors because of cough or angioedema should be tried on an ARB [47]



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.
PEACE Trial - Trandolapril vs Placebo in Patients with Stable CAD, NEJM (2004) [PubMed abstract]
  • 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
  • At 3 years, 8.3% of patients in Group 2 were taking an open-label ACE inhibitor

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.
ALLHAT study - Chlorthalidone vs Lisinopril vs Amlodipine for CVD, JAMA (2002) [PubMed abstract]
  • 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



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.
CSG Study - Captopril vs Placebo in the Treatment of Diabetic Kidney Disease, NEJM (1993) [PubMed abstract]
  • 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
  • The captopril group had a lower average blood pressure throughout the study by about 2 mmHg

Findings: Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone
BENEDICT Study - Trandolapril vs Trandolapril/Verapamil vs Verapamil vs Placebo for Prevention of Diabetic Kidney Disease, NEJM (2004) [PubMed abstract]
  • 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.
ACE Inhibitors and ARBs compared to other antihypertensives for DKD outcomes, BMJ meta-analysis (2016) [PubMed abstract]
  • 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



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
Benazepril vs Placebo in Nondiabetic Kidney Disease, NEJM (2006) [PubMed abstract]
  • 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
  • Doubling of the serum creatinine was significantly lower in Group 1 than in Group 2 (p=0.02)
  • The incidence of end-stage renal disease was significantly lower in Group 1 than in Group 2 (p=0.02)
  • The incidence of adverse events was similar between the 2 groups. (Patients who could not tolerate benazepril were excluded during the run-in phase)

Findings: Benazepril conferred substantial renal benefits in patients without diabetes who had advanced renal insufficiency
ACE inhibitors and progression of nondiabetic renal disease, Annals of Internal Medicine (2001) [PubMed abstract]
  • 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]



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.
CHARM-ADDED Trial - Candesartan + ACE Inhibitor vs ACE Inhibitor in Heart Failure, Lancet (2003) [PubMed abstract]
  • 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
  • At 6 months, SBP and DBP were reduced more from baseline in the candesartan group than in the placebo group (difference in reduction 4.6/3 mmHg)

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
Adverse effects of combining ACE Inhibitors and ARBs for left ventricular dysfunction, Archives of IM meta-analysis (2007) [PubMed abstract]
  • 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]
StraightHealthcare analysis
  • 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.






Cough
Overview
  • 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)
Overview
  • ACE inhibitors can raise potassium levels
  • The risk depends greatly on a patient's concurrent medical conditions
  • For patients with hypertension and no other medical problems, the risk is minimal. For patients with kidney disease, heart failure, and other comorbidities, the risk is higher.
  • Patients on ACE inhibitors should have their potassium checked periodically. High-risk patients should have their potassium checked more frequently.
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]

Angioedema

Increase in serum creatinine
Overview
  • Serum creatinine is a measure of kidney function. ACE inhibitors may cause an increase in serum creatinine levels.
  • The risk and significance of serum creatinine increases on ACE inhibitors depends on a person's concurrent medical problems
  • In patients taking ACE Inhibitors for hypertension, small increases are seen in up to 2% of patients. In patients with heart failure who are taking diuretics, increases are seen in up to 12% of patients. [24-27]
  • Patients on ACE inhibitors should have their kidney function assessed periodically. High-risk patients should have their kidney function checked more frequently.
Factors associated with a rise in creatinine levels on ACE inhibitor therapy
  • Kidney disease
  • Advanced age
  • Diabetes
  • Heart failure
  • Patients taking certain medications (ex. diuretics)
  • Renal artery stenosis
AHA recommendations
  • The AHA recommends that renal function and potassium be checked within 1 - 2 weeks of starting an ACE inhibitor or ARB [15]






Kidney disease
Overview
  • While ACE inhibitors are proven to be beneficial in the treatment and prevention of kidney disease, their inhibitory effects on the RAAS system may be detrimental when kidneys are severely compensated
  • Elevations in potassium, serum creatinine, and BUN may occur in patients with significant kidney disease
  • The risk of adverse effects from ACE inhibitors in patients with kidney disease depends greatly on the degree of kidney disease and other concurrent medical problems (ex. heart failure, diabetes, etc.)
  • In general, ACE inhibitors should be started at the lowest dose possible and titrated slowly in patients with significant kidney disease
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
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
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

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
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
Quinapril (Accupril®)
  • Manufacturer makes no specific recommendation

Renal artery stenosis

Black patients
Overview
  • Black patients are at greater risk of experiencing angioedema with ACE inhibitors (see angioedema above)
  • ACE inhibitors appear to be less effective at lowering blood pressure in black patients when compared to other classes of blood pressure medications
STUDY
Systematic review: antihypertensive drug therapy in black patients, Annals of Internal Medicine (2004) [PubMed abstract]
  • 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
Summary
  • Other classes of blood pressure medications tend to be more effective in lowering blood pressure in black patients, but ACE inhibitors still improve clinical outcomes in these patients, and therefore, should still be used when indicated (e.g. heart failure, kidney disease).

Pregnant and nursing



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 - ACE inhibitors have been reported to increase the effect of diabetes medications. This effect appears to be rare and typically resolves after the first month. Diabetics should be aware of the potential 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 have the potential to raise potassium levels. When taken with other medications that raise potassium, the risk may be compounded. While it is often appropriate to prescribe ACE inhibitors with these medications, patients and providers should be aware of the potential risks (see elevated potassium above)
  • 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)
  • Potassium supplements (K-Dur®, etc.) - ACE inhibitors can elevate potassium levels. Potassium levels should be monitored frequently in patients taking potassium supplements and ACE inhibitors.
  • Salt substitutes (No-Salt®, etc.) - Salt substitutes typically contain a high amount of potassium. 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
Overview
  • Only enalapril undergoes significant liver metabolism
Enalapril (Vasotec®)
Captopril (Capoten®)