Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) are the two main classes of renin–angiotensin–aldosterone system inhibitors recommended for hypertension management by international guidelines. |
ACEis and ARBs both effectively reduce blood pressure (BP) by different mechanisms of action. |
Clinical evidence suggests ACEis provide additional benefits beyond BP control with regard to reducing cardiovascular and mortality risk in patients living with hypertension and other cardiovascular comorbidities. |
1 Introduction
2 Should the ACEi and ARB Drug Classes be Considered Equivalent?
2.1 Differences in the Mechanisms of Action
2.2 Clinical Evidence for ACEi and ARB Efficacy in Different Clinical Scenarios
Study | Patient population | HTN (%) | Treatment (follow-up) | Main outcomes | |
---|---|---|---|---|---|
Elderly patients | |||||
HYVET [56] | Aged ≥ 80 years (n = 3845) | 100 | Thiazide-like diuretic (indapamide) ± ACEi (perindopril) vs placebo (median 1.8 years) | All-cause mortality: HR 0.79, 95% CI 0.65–0.95; p = 0.02 CV mortality: HR 0.77, 95% CI 0.60–1.01; p = 0.06 Death from stroke: HR 0.61, 95% CI 0.38–0.99; p = 0.046 Any CV event: HR 0.66, 95% CI 0.53–0.82; p < 0.001 Any HF event: HR 0.36, 95% CI 0.22–0.58; p < 0.001 | |
SCOPE [57] | Aged 70–89 years (n = 4964) | 100 | ARB (candesartan) vs placebo (mean 3.7 years) | All-cause mortality; no significant difference CV mortality; no significant difference MACE (CV mortality, nonfatal MI, or stroke): RR 0.89, 95% CI 0.75–1.06; p = 0.19 Nonfatal stroke: RR 0.72, 95% CI 0.53–0.99; p = 0.04 All stroke: RR 0.76, 95% CI 0.58–1.07; p = 0.056 | |
Patients with high CV risk | |||||
HOPE [58] | Aged ≥ 55 years with high CV risk (n = 9297) | 47 | ACEi (ramipril) versus placebo (mean 5 years) | MACE (CV death, MI, or stroke): RR 0.78, 95% CI 0.70–0.86; p < 0.001 All-cause mortality: RR 0.84, 95% CI 0.75–0.95; p = 0.005 CV mortality: RR 1.03, 95% CI 0.85–1.26; p = 0.74 | |
ASCOT-BPLA [59] | Aged 40–79 years with ≥ 3 CV risk factors (n = 19,257) | 100 | ACEi (perindopril) + amlodipine versus atenolol + bendroflumethiazide (median 5.5 years) | Total CV events/procedures: HR 0.84, 95% CI 0.78–0.90; p < 0.0001 All-cause mortality: HR 0.89, 95% CI 0.81–0.99; p = 0.0247 CV mortality: HR 0.76, 95% CI 0.65–0.90; p = 0.0010 | |
TRANSCEND [60] | Aged ≥ 55 years with CVD or T2D with end-organ damage and ACEi intolerance (n = 5926) | 76 | ARB (telmisartan) versus placebo (median 56 months) | CV death, MI, stroke, or HHF: HR 0.92, 95% CI 0.81–1.05; p = 0.216 MACE (CV death, MI, or stroke): HR 0.87, 95% CI 0.76–1.00; p = 0.048 All-cause mortality: HR 1.05, 95% CI 0.91-1.22; p = 0.491 CV mortality: HR 1.03, 95% CI 0.85–1.24; p = 0.778 | |
VALUE [61] | Aged ≥ 50 years with CV risk factors or CVD (n = 15,313) | 100 | ARB (valsartan) versus amlodipine (mean 4.2 years) | All-cause mortality: HR 1.04, 95% CI 0.94–1.14; p = 0.45 CV morbidity and mortality: HR 1.03, 95% CI 0.94–1.14; p = 0.49 MI: HR 1.19, 95% CI 1.02–1.38; p = 0.02 | |
NAVIGATOR [62] | Aged ≥ 55 years with impaired glucose tolerance and ≥ 1 CV risk factor or aged ≥ 50 years with established CVD (n = 9518) | 78 | ARB (valsartan) versus placebo (median 5.0 years) | All-cause mortality: HR 0.90, 95% CI 0.77–1.05; p = 0.17 CV mortality: HR 1.09, 95% CI 0.85–1.40; p = 0.52 Extended composite CV outcomea: HR 0.99, 95% CI 0.86–1.14; p = 0.85 CV death, MI, stroke, or HHF: HR 0.99, 95% CI 0.86–1.14; p = 0.85 | |
ONTARGET [63] | Aged ≥ 55 years with CVD or T2D with end-organ damage (n = 25,620) | 69 | ARB (telmisartan) versus ACEi (ramipril) (median 56 months) | CV mortality, MI, stroke, or HHF: HR 1.01, 95% CI 0.94–1.09; p = 0.004 for noninferiority CV mortality, MI, or stroke: HR 0.99, 95% CI 0.91–1.07 MI: HR 1.07, 95% CI 0.94–1.22 | |
Patients with CAD | |||||
EUROPA [65] | Aged ≥ 18 years with CAD (n = 13,655) | 27 | ACEi (perindopril) versus placebo (mean 4.2 years) | All-cause mortality: RR 0.89, 95% CI 0.77–1.02); p = 0.1 CV mortality: RR 0.86, 95% CI 0.72–1.03; p = 0.107 CV mortality, MI, or cardiac arrest: RR 0.80, 95% CI 0.71–0.91; p = 0.0003 | |
PEACE [66] | Aged ≥50 years with CAD and preserved LV function (n = 8290) | 46 | ACEi (trandolapril) versus placebo (median 4.8 years) | All-cause mortality: HR 0.89, 95% CI 0.76–1.04; p = 0.13 CV mortality: HR 0.95, 95% CI 0.76–1.19; p = 0.67 CV mortality, nonfatal MI, CABG, or PCI: HR 0.96, 95% CI 0.88–1.06; p = 0.43 | |
QUIET [67] | Aged 18–75 years with CAD and preserved LV function (n = 1750) | 47 | ACEi (quinapril) versus placebo (median 27 months) | Ischemic events: RR 1.04, 95% CI 0.89–1.22; p = 0.6 Angioplasty for previous nonintervened vessels: n = 79 (quinapril) versus 114 (placebo); p = 0.018 Angiographic progression of CAD: 47% (quinapril) versus 49% (placebo); p = 0.71 | |
Patients with acute MI | |||||
SAVE [68] | Aged 21–80 years with MI with LVEF ≤ 40% (n = 2231) | 43 | ACEi (captopril) versus placebo (mean 42 months) | All-cause mortality: HR 0.81, 95% CI 0.68–0.97; p = 0.019 CV mortality: HR 0.79, 95% CI 0.65–0.95; p = 0.014 Severe HF: HR 0.67, 95% CI 0.50–0.80; p < 0.001 Hospitalization for CHF: HR 0.78, 95% CI 0.63–0.96; p = 0.019 Recurrent MI: HR 0.75, 95% CI 0.60–0.95; p = 0.015 | |
CONSENSUS II [72] | Aged ≥ 18 years with acute MI (n = 6090) | NR | ACEi (enalapril) versus placebo (41–180 days) | All-cause mortality: HR 1.10, 95% CI 0.93–1.29; p = 0.26 Death due to progressive HF: 4.3% (enalapril) versus 3.4% (placebo); p = 0.06 | |
AIRE [69] | Aged ≥ 18 years with acute MI and HF (n = 2006) | 28 | ACEi (ramipril) versus placebo (mean 15 months) | All-cause mortality: HR 0.73, 95% CI 0.60–0.89; p = 0.002 Death, reinfarction, stroke, or severe/resistant HF: HR 0.81, 95% CI 0.69–0.95; p = 0.008 | |
TRACE [70] | Aged ≥ 18 years with recent acute MI (n = 1749) | 23 | ACEi (trandolapril) versus placebo (24–50 months) | All-cause mortality: RR 0.78, 95% CI 0.67–0.91; p = 0.001 CV mortality: RR 0.75, 95% CI 0.63–0.89; p = 0.001 Sudden death: RR 0.76, 95% CI 0.59–0.98; p = 0.03 Progression to severe HF: RR 0.71, 95% CI 0.56–0.89; p = 0.003 Recurrent MI: RR 0.86, 95% CI 0.66–1.13; p = 0.29 | |
SMILE [71] | Aged 18–80 years with recent MI (n = 1556) | 40 | ACEi (zofenopril) versus placebo (1 year) | All-cause mortality (1 year): HR 0.71, 95% CI 0.49–0.94; p = 0.011 Death or severe CHF (6 weeks): HR 0.66, 95% CI 0.46–0.92; p = 0.018 | |
OPTIMAAL [73] | Aged ≥ 50 years with acute MI and HF (n = 5477) | 36 | ARB (losartan) versus ACEi (captopril) (mean 2.7 years) | All-cause mortality: RR 1.13, 95% CI 0.99–1.28; p = 0.69 MI mortality: RR 1.10, 95% CI 0.99–1.22; p = 0.085 CV mortality: RR 1.17, 95% CI 1.01–1.34; p = 0.032 | |
VALIANT [74] | Aged ≥ 18 years with acute MI and HF, LV dysfunction, or both (n = 14,703) | 55 | ARB (valsartan) versus ACEi (captopril) (median 24.7 months) | All-cause mortality: HR 1.00, 95% CI 0.90–1.11; p = 0.004 for non-inferiority; p = 0.98 for superiority CV mortality: HR 0.98, 95% CI 0.87–1.09; p = 0.62 | |
Patients with HF | |||||
CONSENSUS [75] | Severe CHF (n = 253) | 22 | ACEi (enalapril) versus placebo (mean 188 days) | All-cause mortality (6 months): 40% reduction; p = 0.002 All-cause mortality (12 months): 31% reduction; p = 0.001 All-cause mortality (end of study): 27% reduction; p = 0.003 Any cardiac death: p = 0.001 Death due to congestive HF: 50% reduction; p = 0.001 | |
SOLVD [76] | Aged < 80 years with HF with EF ≤ 35% | 42 | ACEi (enalapril) versus placebo (mean 41.4 months) | All-cause mortality: HR 0.84, 95% CI 0.74–0.95; p = 0.0036 Death or hospitalization for HF: HR 0.74, 95% CI 0.66–0.82; p < 0.0001 | |
CHARM-Alternative [77] | Aged ≥ 18 years with HF with LVEF ≤ 40% with ACEi intolerance (n = 2028) | 50 | ARB (candesartan) versus placebo (median 33.7 months) | All-cause mortality: HR 0.83, 95% CI 0.70–0.99; p = 0.033 CV death or hospitalization for CHF: adjusted HR 0.70, 95% CI 0.60–0.81; p < 0.0001 CV death: adjusted HR 0.80, 95% CI 0.66–0.97; p = 0.02 Hospitalization for CHF: adjusted HR 0.61, 95% CI 0.51–0.73; p < 0.0001 MI: HR 1.52, 95% CI 1.06–2.18; p = 0.025 | |
Val-HeFT [78] | Aged ≥18 years with HF with LVEF < 40% (n = 5010) | 7 | ARB (valsartan) versus placebo (mean 23 months) | All-cause mortality: RR 1.02, 95% CI 0.88–1.18; p = 0.80 Morbidity and mortalityb: RR 0.87, 95% CI 0.77–0.97; p = 0.009 | |
Patients with prior stroke | |||||
PROGRESS [81] | Prior stroke or TIA (n = 6105) | 48 | ACEi (perindopril) + indapamide versus placebo (mean 3.9 years) | All-cause mortality: RR 0.96, 95% CI 0.82–1.12 Recurrent stroke: RR 0.72, 95% CI 0.62–0.83; p < 0.0001 Non-fatal stroke: RR 0.71, 95% CI 0.61–0.83 CV death: RR 0.91, 95% CI 0.75–1.12 Non-fatal MI: RR 0.62, 95% CI 0.45–0.86 | |
PROFESS [82] | Aged ≥ 55 years with recent ischemic stroke (n = 20,332) | 74 | ARB (telmisartan) versus placebo (mean 2.5 years) | Recurrent stroke: HR 0.95, 95% CI 0.86–1.04; p = 0.23 Major CV eventc: HR 0.94, 95% CI 0.87–1.01; p = 0.11 | |
Patients with T2D | |||||
ADVANCE [83] | Aged ≥ 55 years with T2D and major CVD or ≥ 1 CV risk factor (n = 11,140) | 69 | ACEi (perindopril) + indapamide versus placebo (mean 4.3 years) | All-cause mortality: RR 0.86, 95% CI 0.75–0.98; p = 0.025 CV mortality: RR 0.82, 95% CI 0.68–0.98; p = 0.027 Total coronary events: RR 0.86, 95% CI 0.76–0.98; p = 0.020 Total renal events: RR 0.79, 95% CI 0.73–0.85; p < 0.0001 | |
RENAAL [86] | Aged 31–70 years with T2D and nephropathy (n = 1513) | 93 | ARB (losartan) versus placebo (mean 3.4 years) | All-cause mortality: HR 1.02, 95% CI 0.71–1.27; p = 0.88 Doubling of serum creatinine, ESRD, or death: HR 0.84, 95% CI 0.72–0.98; p = 0.02 ESRD: HR 0.72, 95% CI 0.58–0.89; p = 0.002 CV morbidity or mortalityd: HR 0.90; p = 0.26 HHF: HR 0.68; p = 0.005 | |
IDNT [87] | Aged 30–70 years with T2D and nephropathy (n = 1715) | 100 | ARB (irbesartan) versus placebo (mean 2.6 years) | All-cause mortality: adjusted RR 0.94, 95% CI 0.70–1.27; p = 0.69 Composite CV outcomee: adjusted RR 0.91, 95% CI 0.72–1.14; p = 0.40 Doubling of sCR, ESRD, or death: adjusted RR 0.81, 95% CI 0.67–0.99; p = 0.03 Doubling of sCR: adjusted RR 0.71, 95% CI 0.54–0.92; p = 0.009 ESRD: adjusted RR 0.83, 95% CI 0.62–1.11; p = 0.19 | |
IRMA-2 [88] | Aged 30–70 years with T2D and microalbuminuria (n = 590) | 100 | ARB (irbesartan) versus placebo (median 2 years) | Nonfatal CV events: 4.5% (irbesartan) versus 8.7% (placebo); p = 0.11 Diabetic nephropathy: adjusted HR 0.32, 95% CI 0.15–0.65; p < 0.001 | |
ORIENT [89] | Aged 30–70 years with T2D (n = 577) | 92 | ARB (olmesartan) versus placebo (mean 3.4 years) | All-cause mortality: aHR 0.99, 95% CI 0.53–1.86 Composite CV outcomef: aHR 0.64, 95% CI 0.43–0.98; p = 0.039 CV mortality: aHR 2.81, 95% CI 0.76–10.38 Doubling of sCR, ESRD, or death: aHR 0.97, 95% CI 0.75–1.24; p = 0.791 Doubling of sCR: aHR 0.94, 95% CI 0.73–1.23 ESRD: aHR 1.08, 95% CI 0.78–1.49 | |
ROADMAP [90] | Aged 18–75 years with T2D + ≥ 1 CV risk factor (n = 4449) | NR | ARB (olmesartan) versus placebo (median 3.2 years) | All-cause mortality: HR 1.70, 95% CI 0.90–3.22; p = 0.10 CV mortality: HR 4.94, 95% CI 1.43–17.06; p = 0.01 All CV complications: HR 0.87, 95% CI 0.65–1.18; p = 0.37 |
2.2.1 Elderly Patients
2.2.2 High Cardiovascular Risk
2.2.3 Coronary Syndromes
2.2.4 Heart Failure
2.2.5 Stroke
2.2.6 Type 2 Diabetes
3 Recommended RAASi Therapy: Hypertension Guidelines
Guidelines | Preferred RAASi | Other antihypertensive drugs |
---|---|---|
ACC/AHA [55] | First-line agents for initial therapy include ACEis or ARBs (I, A) | Thiazide diuretics, CCBs |
ESC/ESH [11] | Antihypertensive therapy should include ACEis or ARBs (I, A) ARBs may be preferred in patients of Black-African descent due to risk of angioedema with ACEis ARBs are associated with lower rates of treatment discontinuation for AEs | β-blockers, CCBs, or diuretics combined with either ACEi or ARB |
Hypertension Canada [93] | Diastolic hypertension (± systolic hypertension) Monotherapy with ACEis or ARBs (Grade B) OR an SPC of an ACEi + CCB (Grade A), an ARB + CCB (Grade B), or an ACEi or ARB + diuretic (Grade B) | Diuretics, β-blockers (patients aged <60 years), long-acting CCBs |
Isolated systolic hypertension without other indications ARBs (Grade B) | Thiazide/thiazide-like diuretics, long-acting dihydropyridine CCBs | |
ISH [94] | ACEi or ARB (in an SPC with dihydropyridine CCB) Benefits of ACEis and ARBs in RCTs varied between different patient populations Choice between RAASi drug will depend on patient characteristics and drug availability, costs, and tolerability | Dihydropyridine CCB (in combination with ACEi or ARB) |
LASH [21] | Grade 1 hypertension Monotherapy with ACEis or ARBs (low CV risk) OR an SPC with ACEi or ARB + CCB or diuretic (moderate or high CV risk) | Diuretics, CCBs, or β-blockers |
Grade 2 or 3 hypertension Combination therapy is recommended, regardless of CV risk | ||
NICE [92] | Step 1 ACEis or ARBs in hypertensive adults who: (a) have diabetes and are of any age or family origin; OR (b) are aged < 55 years but not of Black-African or African-Caribbean descent | CCBs [hypertensive patients aged ≥ 55 years without diabetes or who are of Black-African or African-Caribbean descent without diabetes (any age)] |
Step 2 ACEis or ARBs plus another antihypertensive drug | CCB or thiazide-like diuretic may be added | |
WHO [95] | ACEis or ARBs Combination therapy, preferable as an SPC, is recommended as initial therapy to improve adherence | Diuretics (thiazide or thiazide-like) or long-acting dihydropyridine CCBs |
4 Recommended RAASi Therapy: Cardiovascular Guidelines
Comorbidity guideline | Preferred RAASi | Other antihypertensive drugs |
---|---|---|
CVD prevention | ||
ESC [97] | RAASi (ACEi or ARB) with a CCB or diuretic (I, A) | Other combinations of ACEis, ARBs, β-blockers, CCBs, and thiazide/thiazide-like diuretics can be used |
CAD | ||
AHA/ACC/ASH [20] | ACEis should be prescribed in all CAD patients with stable angina who have hypertension, diabetes, LVEF ≤ 40%, or CKD unless contraindicated (I, A) ARBs are recommended in these patients if ACEis not tolerated (I, A) | β-blockers, CCBs, thiazide or thiazide-like diuretics, and (in selected patients) MRAs |
LASH [21] | ACEis are recommended as a first-line option in patients with recent MI | β-blockers (in patients with CAD) |
Acute STEMI | ||
ACC/AHA [19] | ACEis should be started within 24 h to all STEMI patients with anterior infarction, HF, or LVEF ≤ 40%, unless contraindicated (I, A) ARBs should be given in these patients if ACEis not tolerated (I, B) ACEis are reasonable for all STEMI patients if not contraindicated (IIa, A) | β-blockers and MRAs (if not contraindicated) |
ESC [16] | ACEis are recommended, starting within first 24 h of STEMI in patients with HF, LV systolic dysfunction, diabetes, or anterior infarct (I, A) ARBs (preferably valsartan) can be used if ACEis are not tolerated (I, B) ACEis should be considered in all patients in the absence of contraindications (IIa, A) | β-blockers, MRAs (except for patients with renal failure or hyperkalemia) |
Non-STEMI ACS | ||
AHA/ACC [13] | Start ACEis and continue indefinitely in all patients with LVEF ≤40% and those with hypertension, diabetes, or stable CKD, unless contraindicated (I, A) ARBs are recommended in patients with HF or MI with LVEF ≤40% if ACEis not tolerated (I, A) ARBs are reasonable in other patients with cardiac or other vascular disease who are ACEi intolerant (IIa, B) ACEis may be reasonable in all other patients with cardiac or other vascular disease (IIb, B) | β-blockers, nondihydropyridine CCBs, MRAs (if not contraindicated) |
ESC [14] | ACEis (or ARBs if ACEis not tolerated) are recommended in patients with HFrEF, diabetes, or CKD (unless contraindicated) to reduce all-cause and CV mortality and CV morbidity (I, A) | β-blockers (in patients with systolic LV dysfunction, HFrEF, or prior MI) and MRAs (in patients with HFrEF) |
CCS | ||
ESC [17] | ACEis (or ARBs) are recommended in patients with hypertension, HF, or diabetes (I, A) ACEis should be considered in CCS patients at very high risk of CV events (IIa, A) | β-blockers (in patients with previous STEMI, LV dysfunction, or systolic HF) |
Acute or chronic HF | ||
AHA/ACC/HFSA [15] | HFrEF ACEis are recommended in patients with chronic HFrEF if ARNi not tolerated (I, A) ARBs is recommended if ACEis not tolerated (I, A) | ARNi (in patients with NYHA II–III symptoms), β-blockers, MRAs (in patients with NYHA II–IV symptoms) |
HFpEF ARBs may be considered in selected patients to decrease hospitalizations, particularly those with low LVEF (2b, B-R) | Diuretics (as needed), ARNi or MRAs | |
ESC [18] | HFrEF ACEis are recommended to reduce the risk of HF hospitalization and death (I, A) ARBs are recommended (with β-blocker and MRA) in symptomatic patients intolerant to ACEis or ARNis (I, B) | β-blockers, MRAs, or diuretics |
HFpEF ACEis or ARBs Optimal hypertension treatment strategy is uncertain | β-blockers, CCBs, and diuretics | |
LASH [21] | ACEis are preferable as first choice antihypertensive treatment | Diuretics, β-blockers, or MRAs |
Diabetes | ||
ADA [98] | ACEis or ARBs recommended as first-line therapy for hypertension in patients with diabetes and CAD | Thiazide-like diuretics, dihydropyridine CCBs, or MRAs (in patients with resistant hypertension) |
ESC [99] | ACEis or ARBs are recommended, particularly in patients with hypertension, microalbuminuria, albuminuria, proteinuria, or LVH (I, A) ACEis are recommended to prevent major CV events in all patients with CCS or ACS and systolic LV dysfunction; an ARB should be administered in patients intolerant to ACEis | CCBs, thiazide/thiazide-like diuretics |
LASH [21] | ACEis or ARBs in patients with diabetes or metabolic syndrome | |
CKD | ||
ACC/AHA [55] | ACEis should be considered to slow kidney disease progression (IIa, B-R) ARBs may be considered if ACEis not tolerated (IIb, C-EO) | |
ESC [11] | ACEis or ARBs are recommended in patients with microalbuminuria or proteinuria (I, A) | Add CCB or diuretic to RAASi |
KDIGO [100] | ACEis or ARBs in patients with hypertension and proteinuria | Direct renin inhibitor or MRAs (if ACEis or ARBs not tolerated), non-dihydropyridine CCBs, β-blockers, diuretics, and α1-blockers |
LASH [21] | ACEis or ARBs are preferable as first choice of antihypertensive therapy |