What are angiotensin-converting enzyme (ACE) inhibitors used to treat?

Angiotensin-converting enzyme (ACE) inhibitors are approved for use in the US by the FDA for the treatments outlined in the table below.^1-14 Ramipril (Altace) is also approved to reduce the risk of myocardial infarction (MI), stroke, or death from cardiovascular causes.¹³

Table 1: FDA approved ACE inhibitor use

*Brand names with asterisks beside them have been discontinued in the US. The generic versions of these drugs continue to be FDA approved and are available in the US.

**Ramipril and trandolapril are approved to treat heart failure following myocardial infarction.

Hypertension

The 2017 hypertension guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) list ACE inhibitors, calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs), and thiazide diuretics as the primary agents used in the treatment of hypertension (Class of Recommendation I, Level of Evidence A).*¹⁵

ACE inhibitors can help prevent death and MIs in hypertensive patients. A meta-analysis of 106 randomized trials sought to compare the efficacy and safety of ACE inhibitors and ARBs in patients with hypertension without heart failure (HF). The results showed that compared with placebo, ACE inhibitors and ARBs reduced the outcomes of all-cause mortality (7.1% vs 7.8% placebo, absolute risk reduction 0.7% p=0.001), cardiovascular death (4.1% vs 4.7%, absolute risk reduction 0.6%, p<0.001), and MI (4.8% vs 5.7%, absolute risk reduction 0.9%, p=0.02).¹⁶

Heart Disease

The 2017 ACC/AHA hypertension guidelines recommend:

• Adults with stable ischemic heart disease (IHD) and hypertension (BP ≥ 130/80 mm Hg) should be treated with ACE inhibitors, ARBs, or beta blockers as first-line therapy (Class of Recommendation I, Level of Evidence B-Randomized).
• Adults with heart failure with preserved ejection fraction (HFpEF) and persistent hypertension after management of volume overload should be prescribed ACE inhibitors or ARBs and beta blockers titrated to attain a systolic BP of less than 130 mm Hg (Class of Recommendation I, Level of Evidence C- Expert Opinion).
• For adults who experience a stroke or transient ischemic attack, treatment with an ACE inhibitor, ARB, or thiazide diuretic is useful (Class of Recommendation I, Level of Evidence A).
• In adults with diabetes mellitus and hypertension, all first-line classes of antihypertensive agents including ACE inhibitors, ARBS, CCBs, and diuretics are useful and effective (Class of Recommendation I, Level of Evidence A). ¹⁵

ACE inhibitors lower the risk of developing HF (29.8% vs 38.6% placebo, absolute risk reduction 8.8%, p<0.001), reduce mortality associated with HF (35.2% vs 39.7% placebo, absolute risk reduction 4.5%, p=0.0036), and reduce hospitalizations associated with HR (47.7% vs 57.3% placebo, absolute risk reduction 9.6%, p<0.0001).^16,17

The Heart Outcomes Prevention Evaluation Study (HOPE) followed a total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or HF. Intervention with an ACE inhibitor resulted in lower rates of death from cardiovascular causes (6.1% vs 8.1% placebo, absolute risk reduction 2%, p<0.001), MI (9.9% vs 12.3% placebo, absolute risk reduction 2.4%, p<0.001), stroke (3.4% vs 4.9% placebo, absolute risk reduction 1.5%, p<0.001), death from any cause (10.4% vs 12.2% placebo, absolute risk reduction 1.8%, p=0.005), revascularization procedures (16.0% vs 18.3%, absolute risk reduction 2.3%, p=0.002), cardiac arrest (0.8% vs 1.3%, absolute risk reduction 0.5%, p=0.03), HF (9.0% vs 11.5%, absolute risk reduction 2.5%, p<0.001), and complications related to diabetes (6.4% vs 7.6%, absolute risk reduction 2.2%, p=0.03).¹⁸

HF management guidelines recommend the inhibition of angiotensin by an ACE inhibitor or ARB as a key component of the treatment plan for people with hypertension and reduced ejection fraction (HFrEF).^19-22

Kidney Disease

The 2017 ACC/AHA hypertension guidelines say that in adults with hypertension and chronic kidney disease (stage 3 or higher; or stage 1 or 2 with albuminuria [≥300 mg/d, or ≥300 mg/g albumin-to-creatinine ratio or the equivalent in the first morning void]), treatment with an ACE inhibitor is reasonable to slow kidney disease progression (Class of Recommendation IIa, Level of Evidence B-Randomized).¹⁵

The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) recommends that an ACE inhibitor or ARB be used:

• In diabetic adults with CKD and urine albumin excretion 30-300 mg/24 hours (or equivalent) (2D**)
• In both diabetic and non-diabetic adults with CKD and urine albumin excretion >300 mg/24 hours (or equivalent) (1B**)
• In children with CKD in whom treatment with BP-lowering drugs is indicated, irrespective of the level of proteinuria (2D**) ²³

ACE inhibitors protect against deterioration in renal function in insulin-dependent diabetic nephropathy. In a study of 409 patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was ≥500 mg per day and the serum creatinine concentration was ≤2.5 mg per deciliter (221 μmol per liter), serum creatinine concentrations doubled in 12.1% of the intervention group vs 21.3% of the placebo group (absolute risk reduction 9.2%, p=0.007). The mean rate of increase in serum creatinine at follow-up (average 2.7 years) in the patients in the intervention group was 0.2 ±0.8 mg per deciliter per year (22 ±67 μmol per liter per year) vs 0.5 ±0.8 mg per deciliter per year (42 ±67 μmol per liter per year) in the placebo group (p=0.004). The use of ACE inhibitors reduced death, dialysis, or renal transplantation (11.1% vs 20.8% placebo, absolute risk reduction 9.7%, p=0.006).²⁴

*See ACC/AHA Class of Recommendation and Level of Evidence definitions below:

**See KDIGO grade for overall quality of evidence and description for grading recommendations below:

*The additional category “Not Graded” was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

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