INTRODUCTION — Inhibitors of the renin-angiotensin system (RAS), particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are commonly used in the treatment of hypertension. The role of the RAS in hypertension and the use of specific inhibitors of this system to treat hypertension will be reviewed here.
The use of RAS inhibitors in patients with kidney disease and diabetes is discussed separately:
●(See "Choice of drug therapy in primary (essential) hypertension".)
●(See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
●(See "Treatment of hypertension in patients with diabetes mellitus".)
●(See "Treatment of diabetic kidney disease".)
The importance of local (ie, tissue) RAS activity in low-renin hypertension and the effects of angiotensin II on the heart are presented elsewhere:
●(See "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Renin-angiotensin system'.)
The safety of ACE inhibitors and ARBs in patients with coronavirus disease 2019 (COVID-19) is discussed in another topic:
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS — Since the introduction of captopril in 1977 [1], angiotensin-converting enzyme (ACE) inhibitors have become widely used for the treatment of hypertension and three of its major complications: acute myocardial infarction, congestive heart failure, and chronic kidney disease. Fifty to 60 percent of White patients have a good response to monotherapy with ACE inhibitors, a response rate similar to other first-line antihypertensive drugs [2]. ACE inhibitors have the additional advantages of having a more favorable side effect profile than sympathetic blockers, beta blockers, and diuretics [3]. Various professional societies have recommended ACE inhibitors and angiotensin II receptor blockers (ARBs) as first- or second-line therapy in the treatment of hypertension [4-7]. (See "Choice of drug therapy in primary (essential) hypertension" and "Chronic coronary syndrome: Overview of care" and "Treatment of hypertension in patients with heart failure" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
Specific indications for use — There are a number of settings in which ACE inhibitors are the antihypertensive drugs of choice because of possible benefits in addition to lowering the blood pressure. (See "Choice of drug therapy in primary (essential) hypertension".)
These include:
●Heart failure with reduced ejection fraction (HFrEF) [8] (see "Use of diuretics in patients with heart failure" and "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'Mineralocorticoid receptor antagonist' and "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'ACE inhibitor' and "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults")
●Proteinuric chronic kidney disease, both diabetic and nondiabetic [9] (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus" and "Treatment of hypertension in patients with diabetes mellitus")
●After a myocardial infarction in most patients, particularly those with heart failure or reduced systolic function [10] (see "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use")
Antihypertensive response — The decline in blood pressure seen with ACE inhibitors appears to be primarily due to decreased formation of angiotensin II, but decreased degradation of kinins could contribute by both direct vasodilation and increasing the production of vasodilator prostaglandins [11].
Black patients may be less sensitive than White patients to ACE inhibitors as monotherapy for hypertension [12]. However, the addition of even a low dose of a thiazide diuretic to an ACE inhibitor leads to a fall in blood pressure that is comparable with that seen in White patients [13].
The utility of ACE inhibitors with diuretics is not limited to Black patients, since these drugs have a synergistic effect, attaining goal blood pressure in up to 85 percent of patients with mild hypertension [13]. The antihypertensive response to diuretics is often limited by the hypovolemia-induced increase in renin release and subsequent angiotensin II production [14]; this effect is prevented by converting enzyme inhibition, leading to a more prominent reduction in blood pressure (see "Use of thiazide diuretics in patients with primary (essential) hypertension"). For similar reasons, dietary sodium restriction can also enhance the response to an ACE inhibitor [15].
ACE inhibitors minimize some of the metabolic changes induced by diuretic therapy. Hypokalemia, for example, is less prominent because the reduction in angiotensin II formation induced by the ACE inhibitor leads to decreased secretion of aldosterone. ACE inhibitors also do not induce glucose intolerance, hyperlipidemia, or hyperuricemia; may increase insulin sensitivity; and may minimize or prevent diuretic-induced elevations in serum glucose, cholesterol and uric acid levels [16].
Apart from diuretics, calcium channel blockers can be used effectively with ACE inhibitors, and, as shown in the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, may have clinical advantages over diuretics when achieved blood pressure is similar. Combination of an ACE inhibitor with a beta blocker may be less useful because of inferior antihypertensive activity compared with other ACE inhibitor combinations [17]. This relative lack of efficacy may be due in part to similar mechanisms of action, as angiotensin II formation and renin secretion are respectively reduced. (See "Choice of drug therapy in primary (essential) hypertension".)
Dose — As with other antihypertensive agents, proper dose can minimize the incidence of side effects (table 1). To minimize the risk of first-dose hypotension due to an abrupt decline in angiotensin II levels, the patient should not be volume depleted. The initial dose can be reduced by one-half in older adult patients or those with heart failure who are at higher risk for hypotension. Side effects other than those related to hypotension can occur with ACE inhibitors, the most common being cough [18], less commonly hyperkalemia, and rarely angioedema [19]. ACE inhibitors are contraindicated during pregnancy [20]. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers".)
The duration of action varies with different ACE inhibitors. Some ACE inhibitors can be given once daily (eg, trandolapril, lisinopril, and benazepril). The use of longer-acting agents once daily should improve patient compliance, reduce costs, maintain smoother control, and ensure that the abrupt rise in pressure upon awakening in the early morning is blunted, hopefully thereby reducing the incidence of serious cardiovascular events at this time.
After the initiation of therapy, the patient should be reexamined in a few weeks to allow the full antihypertensive effect to occur. If there is no or little fall in blood pressure with an adequate dose, the drug can be stopped and different class of drug started, a concept called "sequential monotherapy." Alternatively, another drug may be added, such as a calcium channel blocker. (See "Choice of drug therapy in primary (essential) hypertension".)
If the patient's blood pressure is reduced by the ACE inhibitor but the goal pressure is not achieved, the dose can be gradually increased to the maximum levels noted in the table (table 1). However, the addition of a second drug from a different class will provide much greater antihypertensive effect [21].
In patients with extensive atherosclerosis or renal insufficiency who are more likely to have renovascular stenoses, a repeat plasma creatinine concentration should be obtained within one to two weeks of ACE inhibitor or ARB initiation to ensure that renal perfusion has been maintained. However, a modest and nonprogressive increase in the plasma creatinine in such patients should not prompt discontinuation of therapy. (See "Renal effects of ACE inhibitors in hypertension", section on 'Renovascular hypertension'.)
ANGIOTENSIN II RECEPTOR BLOCKERS — Angiotensin II receptor blockers (ARBs) interfere with the RAS by impairing the binding of angiotensin II to the AT1 receptor on the cell membrane, thereby inhibiting the action of angiotensin II [22]. Blockade of the action of angiotensin II leads to elevations in plasma levels of renin, angiotensin I, and angiotensin II. However, this build-up of precursors does not overwhelm the receptor blockade, as evidenced by a persistent fall in both blood pressure and plasma aldosterone levels [23].
Differences between ACE inhibitors and ARBs — There are substantial pharmacologic differences in the actions of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), but few clinical differences have been documented. At least three factors may contribute to the pharmacologic differences (figure 1):
●ACE is a kininase. Thus, inhibiting this enzyme, which normally degrades bradykinin, with an ACE inhibitor leads to increased kinin levels, an effect not seen with an ARB. This is likely responsible for the cough that may be seen with ACE inhibitors (but not with ARBs), although high bradykinin levels may also provide additional vasodilation and other benefits not observed with ARBs.
●By decreasing angiotensin II production, ACE inhibitors reduce the effect of both AT1 and AT2 receptors; only the former are inhibited by the ARBs.
●In the heart, kidney, and perhaps the blood vessels, the production of angiotensin II may be catalyzed by enzymes other than ACE, such as chymase [24]. The effect of the angiotensin II produced by this reaction can be inhibited by the ARBs but not by ACE inhibitors. However, the role of these non-ACE enzymes for the generation of angiotensin II in vivo, if any, is uncertain.
Efficacy and dose — The ARBs have an effect similar to that seen with monotherapy with other antihypertensive drugs (table 1) [25]. However, several studies have shown that losartan, when given once daily, does not control blood pressure to the same magnitude as other ARBs (irbesartan, telmisartan, candesartan, and valsartan) [26-29]. On the other hand, losartan produces a slight fall in plasma uric acid that does not occur with the other ARBs, an effect that is due to enhanced uric acid excretion [30]. This appears to be mediated at least in part by direct inhibition of the proximal urate-anion exchanger that is responsible for urate reabsorption [31].
The antihypertensive efficacy of ARBs appears to be roughly equivalent to that of the ACE inhibitors. A meta-analysis of 61 studies that directly compared angiotensin II receptor blockers and ACE inhibitors reported no difference in the antihypertensive effects of these agents [25].
In addition, the effects of ARBs and ACE inhibitors on cardiovascular events appear similar. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) compared telmisartan (80 mg/day), ramipril (10 mg/day), and combination therapy (80 + 10 mg/day) with both agents in 25,620 patients with vascular disease or diabetes [32]. The primary outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. Achieved mean blood pressure was lower in patients who received telmisartan compared with ramipril (by 0.9/0.6 mmHg) and in patients who received both agents compared with ramipril (2.4/1.4 mmHg). The cardiovascular outcomes were similar in all three groups, while cough was more common with ramipril, and both hyperkalemia and acute kidney injury were more common with combined therapy. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers".)
In addition, a meta-analysis of nine trials and 11,007 patients that directly compared ACE inhibitors with ARBs in hypertensive patients found similar rates of all-cause mortality and cardiovascular mortality [33]. By contrast, drug withdrawal due to adverse events was significantly more frequent with ACE inhibitors (one additional withdrawal from therapy for every 55 patients treated with ACE inhibitors over four years), mostly due to dry cough. Thus, ARBs are a reasonable alternative to ACE inhibitor therapy in hypertensive patients.
As with other agents that inhibit the RAS, the efficacy of ARBs is enhanced by concomitant administration of low doses of a diuretic [34] and by a reduction in dietary sodium intake. As with ACE inhibitors, ARBs appear to minimize the hypokalemia and hyperuricemia induced by diuretic therapy [34].
SIDE EFFECTS — Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are generally well tolerated. Cough and angioedema are less common with ARBs [32]. Both ACE inhibitors and ARBs are contraindicated in pregnancy. These issues, as well as other side effects from these medications, are discussed in detail separately:
●(See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy".)
ACE inhibitors plus ARBs — A separate issue is the side effects associated with combined angiotensin-converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB) therapy compared with either drug alone. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) cited above of high-risk patients [32,35] found a significant increase in adverse effects (including a possible increase in mortality) with combined therapy compared with an ACE inhibitor alone. As a result, combined therapy is not recommended for the treatment of hypertension.
The data supporting adverse effects and the possible role of combined therapy to slow progression in patients with proteinuric chronic kidney disease are discussed elsewhere:
DIRECT RENIN INHIBITORS — The first effective oral direct renin inhibitor, aliskiren, became available in the United States in March 2007. Aliskiren lowers blood pressure to a degree comparable with most other agents [36]. A number of studies have evaluated the blood pressure-lowering effect of aliskiren in combination with other antihypertensive drugs [36-39]. In one report, the combination of maximum doses of aliskiren and valsartan decreased blood pressure more than maximum doses of either agent alone but not more than would be expected with dual therapy using drugs from different classes [40]. Aliskiren, as with other inhibitors of the RAS, should not be used in pregnancy.
In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial, aliskiren plus losartan was associated with a significant 20 percent greater reduction in proteinuria compared with losartan alone in patients with type 2 diabetes and nephropathy, in the absence of a significantly greater effect on blood pressure [41]. However, this effect on proteinuria did not translate into a clinical benefit. In the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE), 8600 patients with type 2 diabetes and kidney disease already taking either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) were randomly assigned to additional therapy with aliskiren or placebo [42]. The ALTITUDE trial was stopped early because of futility (no benefit on the primary cardiovascular and renal outcomes) and because aliskiren therapy produced a nonsignificantly higher rate of adverse events (ie, nonfatal stroke, hypotension). The ALTITUDE trial is discussed in detail elsewhere. (See "Treatment of diabetic kidney disease".)
The effect of aliskiren on progression of atherosclerotic coronary artery disease in patients with controlled hypertension was examined in the Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS) [43]. In this trial, 613 patients with a systolic blood pressure between 125 and 139 mmHg (most of whom were treated with antihypertensive medications) and two other cardiovascular risk factors were randomly assigned to aliskiren (300 mg/day) or placebo. After 18 months, the atherosclerotic burden and progression of atherosclerosis (measured by coronary intravascular ultrasound) was similar between the groups. In a secondary analysis based upon a small number of events, aliskiren appeared to reduce the rate of cardiovascular events. However, this analysis excluded diabetic patients who were treated with angiotensin inhibitors (approximately 15 percent of the study population), as such patients were removed from the study after publication of the ALTITUDE trial [44]. In addition, adverse events were more common with aliskiren.
An increased risk of hyperkalemia when aliskiren is combined with ACE inhibitors or ARBs has been described in the ALTITUDE trial and in other studies [42,45]. Thus, aliskiren should not be combined with ACE inhibitors or ARBs [46]; it may be used as a third-line agent if patients do not tolerate ACE inhibitors or ARBs.
SUMMARY AND RECOMMENDATIONS
●Inhibitors of the renin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are commonly used in the treatment of hypertension. (See 'Introduction' above.)
●There are a number of settings in which ACE inhibitors are the antihypertensive drugs of choice because of possible benefits in addition to lowering the blood pressure (see 'Specific indications for use' above):
•Heart failure with reduced ejection fraction (HFrEF)
•Proteinuric chronic kidney disease, both diabetic and nondiabetic
•After a myocardial infarction in most patients, particularly those with heart failure or reduced systolic function
●Proper dose of ACE inhibitors can minimize the incidence of side effects (table 1). The duration of action varies with different ACE inhibitors. Some ACE inhibitors can be given once daily (eg, trandolapril, lisinopril, and benazepril). (See 'Dose' above.)
●There are pharmacologic differences in the actions of ACE inhibitors and ARBs. Except for the cough associated with ACE inhibitors, these pharmacologic differences are not associated with clinically meaningful differences in therapeutic effects. At least three factors may contribute to the pharmacologic differences (figure 1) (see 'Differences between ACE inhibitors and ARBs' above):
•ACE is a kininase. Thus, inhibiting this enzyme, which normally degrades bradykinin, with an ACE inhibitor leads to increased kinin levels, an effect not seen with an ARB. This is likely responsible for the cough that may be seen with ACE inhibitors (but not with ARBs), although high bradykinin levels may also provide additional vasodilation and other benefits not observed with ARBs.
•By decreasing angiotensin II production, ACE inhibitors reduce the effect of both AT1 and AT2 receptors; only the former are inhibited by the ARBs.
•In the heart, kidney, and perhaps the blood vessels, the production of angiotensin II may be catalyzed by enzymes other than ACE, such as chymase. The effect of the angiotensin II produced by this reaction can be inhibited by the ARBs but not by ACE inhibitors.
●The ARBs have an effect similar to that seen with monotherapy with other antihypertensive drugs, including ACE inhibitors (table 1).
●The antihypertensive effect of both ACE inhibitors and ARBs is enhanced by concomitant administration of low doses of a diuretic and by a reduction in dietary sodium intake. Both drugs also appear to minimize the hypokalemia and hyperuricemia induced by diuretic therapy. (See 'Dose' above and 'Efficacy and dose' above.)
●Both ACE inhibitors and ARBs are generally well tolerated. Side effects other than those related to hypotension can occur with both drugs, including hyperkalemia and rarely angioedema, as well as acute kidney injury in patients with low effective arterial blood volume (eg, diarrhea, vomiting, and heart failure). Cough is a common side effect of ACE inhibitors. ACE inhibitors and ARBs are contraindicated during pregnancy. (See 'Side effects' above and "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers".)
●Combined therapy with both an ACE inhibitor and ARB is not recommended for the treatment of hypertension. (See 'ACE inhibitors plus ARBs' above.)
●The first effective oral direct renin inhibitor, aliskiren, lowers blood pressure to a degree comparable with most other agents. In combination with an ACE inhibitor or ARB, aliskiren increases the risk of adverse effects and does not lower the risk of cardiovascular event. Thus, aliskiren should not be combined with ACE inhibitors or ARBs. (See 'Direct renin inhibitors' above.)
