INTRODUCTION — Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are widely used in the treatment of hypertension, chronic kidney disease, and heart failure. In addition to efficacy, these agents have the additional advantage of being particularly well tolerated since they produce few idiosyncratic side effects and do not have the adverse effects on lipid and glucose metabolism seen with higher doses of diuretics or beta blockers [1,2]. (See "Antihypertensive drugs and lipids".)
The specific side effects that are observed with ACE inhibitors and ARBs will be reviewed here. The use of these drugs in disorders such as hypertension, heart failure, and proteinuric chronic kidney disease are discussed elsewhere:
The safety of ACE inhibitors and ARBs in patients with coronavirus disease 2019 (COVID-19) is presented in another topic:
ACE INHIBITORS — Although high-dose captopril therapy was initially associated with a variety of presumed sulfhydryl group-related complications such as rash, neutropenia, taste abnormalities, and even the nephrotic syndrome, these problems have become uncommon since the maximum dose was reduced to 100 to 150 mg/day and particularly since clinicians have begun using other angiotensin-converting enzyme (ACE) inhibitors.
The side effects that do occur are primarily related directly or indirectly to reduced angiotensin II formation. These include hypotension, acute kidney injury, hyperkalemia, and problems during pregnancy . There are other complications (cough, angioedema, and anaphylactoid reactions) that are thought to be related to increased kinins since ACE is also a kininase (see 'Cough' below). This is an important distinction clinically because the side effects related to reduced angiotensin II, but not those related to kinins, are also seen with the angiotensin II receptor blockers (ARBs). (See "Renin-angiotensin system inhibition in the treatment of hypertension".)
Hypotension — Weakness, dizziness, or syncope may result from an excessive reduction in blood pressure. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), hypotensive symptoms sufficient to discontinue the drug occurred in 1.7 percent of the 8576 patients who received ramipril . First-dose hypotension, which can be marked in hypovolemic patients with high baseline renin levels, can be minimized by not beginning therapy if the patient is volume depleted and/or by discontinuing prior diuretic therapy for three to five days. Hypotension can also occur after the initiation of therapy in patients with heart failure . The risk can be minimized by beginning with a very low dose, such as 2.5 mg BID of enalapril. (See "Treatment of hypertension in patients with heart failure".)
Reduction in GFR — A reduction in glomerular filtration rate (GFR), which is usually modest (approximately 5 to 25 percent) but may be severe (>30 percent), is observed in some patients treated with ACE inhibitors (and other inhibitors of the renin angiotensin system) who have bilateral renal artery stenosis, hypertensive nephrosclerosis, heart failure, polycystic kidney disease, or chronic kidney disease [5,6]. As an example, an elevation in serum creatinine sufficiently severe to warrant discontinuation of the drug occurred in 0.7 percent of the patients who received ramipril and 0.8 percent of those who received telmisartan in the ONTARGET trial, which enrolled patients with vascular disease or high-risk diabetes. A doubling of the serum creatinine in this trial occurred in 1.8 and 1.7 percent, respectively . (See "Renal effects of ACE inhibitors in hypertension" and "Renal effects of ACE inhibitors in heart failure" and "Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of hypertension".)
In each of these disorders, intrarenal perfusion pressure may already be reduced, a setting in which GFR is maintained in part by an angiotensin II-induced increase in resistance at the efferent (postglomerular) arteriole. Blocking this response with an ACE inhibitor (or other inhibitor of the renin angiotensin system) will sequentially relax the efferent arteriole, lower intraglomerular pressure, and reduce GFR . Patients with acute volume loss due to vomiting and/or diarrhea may be particularly susceptible .
The rise in the serum creatinine concentration generally begins a few days after the institution of therapy since angiotensin II levels are rapidly reduced. Thus, kidney function should be checked three to five days after an ACE inhibitor is begun in a patient who has renal artery stenosis or who is at high risk for this problem (as in an older patient with severe hypertension and atherosclerotic vascular disease) . (See "Establishing the diagnosis of renovascular hypertension".)
Even with optimal management, some patients are unable to tolerate ACE inhibitors. Termination of the ACE inhibitor should be considered if hyperkalemia cannot be controlled (see 'Hyperkalemia' below) or the serum creatinine concentration increases more than 30 percent above the baseline value within the first six to eight weeks when blood pressure is reduced. Such a decline in kidney function is uncommon if the patient is not volume depleted, diuretics have been transiently withheld prior to initiation of therapy, and the patient does not have bilateral renovascular disease. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
Another rare cause of acute kidney injury that is of unproven relation to ACE inhibitors is the development of renal artery thrombosis . This complication appears to occur most often in patients with marked (≥95 percent) stenotic lesions who have an excessive reduction in blood pressure. It is therefore unclear whether there is any specific predisposing effect of the ACE inhibitor.
Hyperkalemia — Angiotensin II and an elevation in the plasma potassium concentration are the major factors that increase the release of aldosterone, which is the major hormonal stimulus to urinary potassium excretion. In addition to the direct effect of systemic angiotensin II, angiotensin II generated locally within the adrenal zona glomerulosa may mediate the potassium-induced stimulation of aldosterone . Blocking both of these actions with an ACE inhibitor (or ARB) will reduce aldosterone secretion, thereby impairing the efficiency of urinary potassium excretion.
The overall incidence of hyperkalemia (defined as a serum potassium concentration above 5.5 mEq/L) in patients treated with an ACE inhibitor or ARB is approximately 3.3 percent . However, there is marked variability in risk. ACE inhibitors and ARBs generally raise the serum potassium concentration by less than 0.5 mEq/L in patients with relatively normal kidney function. More prominent hyperkalemia may be seen in patients with chronic kidney disease, diabetes, concurrent use of a drug promoting potassium retention such as a potassium-sparing diuretic or a nonsteroidal antiinflammatory drug, or among older adults [12-14].
Patients with moderately severe to severe heart failure represent a setting in which multiple factors can contribute to the development of hyperkalemia. These include decreased renal perfusion due to the fall in cardiac output and, often, combined therapy with a mineralocorticoid receptor antagonist (spironolactone or eplerenone) . (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)
There is also an increased risk of hyperkalemia among chronic hemodialysis patients who are treated with an ACE inhibitor or ARB. This was shown in a prospective study of 251 hemodialysis patients in which there was an association between a predialysis serum potassium concentration of ≥5.5 mEq/L and the use of an ACE inhibitor or ARB . Use of these agents was associated with an increased risk of hyperkalemia (odds ratio of 2.2, 95% CI 1.4-3.4), which was observed in patients with and without residual kidney function. Dietary measures were the only intervention required to manage the hyperkalemia. Anuria appears to be particularly associated with an increased risk . (See "Patient education: Low-potassium diet (Beyond the Basics)".)
Only one study has assessed the effect on potassium levels of angiotensin blockade in peritoneal dialysis patients. In this report of 29 stable normokalemic peritoneal dialysis patients, the risk of hyperkalemia with either an ACE inhibitor or an ARB was principally observed among those undergoing inadequate dialysis (Kt/V less than 2.0) or with low solute transport characteristics .
There are several mechanisms by which angiotensin II inhibition can lead to hyperkalemia in patients with end-stage kidney disease: decreased urinary potassium excretion in patients with residual kidney function; and decreased colonic excretion that accounts for a significant percentage of total potassium loss in such patients [18,19].
Among hemodialysis patients first receiving an ACE inhibitor or an ARB, more frequent measurement of the serum potassium concentration should be performed for one month . Once stable, monthly measurements are recommended.
Among patients with chronic kidney disease who are not dialysis dependent, issues surrounding the use of ACE inhibitors and hyperkalemia are discussed separately. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
Cough — A dry, hacking cough has been described in 5 to 20 percent of patients treated with an ACE inhibitor [3,21-23]. The best data come from a meta-analysis of 125 trials in which cough was noted in approximately 11 percent of patients treated with ACE inhibitors . Cough is much less common with ARBs. (See 'ARBs' below.)
The cough has the following clinical features:
●It usually begins within one to two weeks of instituting therapy, but it can be delayed up to six months.
●Females are affected more frequently than males.
●It typically resolves within one to four days of discontinuing therapy, but this can take up to four weeks .
●It generally recurs with rechallenge, either with the same or a different ACE inhibitor.
●It does not occur more frequently in patients with asthma, but it may be accompanied by bronchospasm .
The mechanism responsible for the ACE inhibitor-induced cough is not known, but increased local concentrations of kinins, substance P, prostaglandins, or thromboxane may be important:
●Both kinins and substance P are metabolized by converting enzyme; thus, their levels are increased by converting enzyme inhibition . Kinins, for example, may induce bronchial irritation and cough via enhanced production of prostaglandins, which may then stimulate afferent C-fibers in the airway.
●Activation of the arachidonic acid pathway with ACE inhibition may also lead to elevated levels of thromboxane, which can potentiate bronchoconstriction. The possible role of thromboxane in ACE inhibitor-induced cough was evaluated in a double-blind crossover study of nine patients who had developed cough while taking enalapril . The patients were treated with placebo or picotamide (600 mg twice daily), an agent that inhibits thromboxane synthetase and antagonizes the thromboxane receptor. Active therapy resulted in a significant reduction in thromboxane levels and stopped the cough in eight of the nine patients within 72 hours. Inadequate absorption of picotamide occurred in the one nonresponder.
Nonsteroidal antiinflammatory drugs and aspirin can reportedly improve the cough related to ACE inhibitors [27-31]. However, these have not been studied in large trials, and some may increase the risk of hyperkalemia, particularly among individuals with decreased kidney function.
It remains unclear why cough occurs only in some patients treated with ACE inhibitors. It has been suggested that genetic factors may be important. However, common genetic variants for ACE, the B2 bradykinin receptor, or chymase (another enzyme that can convert angiotensin I to angiotensin II) do not explain the variation in susceptibility to cough.
Treatment — When the ACE inhibitor is discontinued, improvement often begins within four to seven days . Readministration of an ACE inhibitor is associated with a high rate of recurrent cough (67 percent in a randomized trial) .
Patients who have had a good antihypertensive response to the ACE inhibitor can be switched to an ARB since these drugs are associated with a much lower rate of cough than ACE inhibitors .
Anemia — ACE inhibitors (and ARBs) can suppress the production of erythropoietin. This is more likely to occur in the presence of chronic kidney disease due to accumulation of N-acetyl-seryl-aspartyl-lysyl-proline , which inhibits stem cell multiplication . Consequently, these drugs can be useful in treating posttransplant erythrocytosis [36,37] or the increase in red cells associated with high altitudes . (See "Kidney transplantation in adults: Posttransplant erythrocytosis", section on 'ACE inhibitors or ARBs in all patients'.)
Angioedema and anaphylactoid reactions — Angioedema is a rare but potentially fatal complication of ACE inhibitors that, in a large clinical trial (ONTARGET), occurred in 0.3 percent of the more than 8500 patients treated with ramipril . Half of 111 patients with an initial episode of angioedema while taking an ACE inhibitor had recurrent angioedema after the drug was discontinued, suggesting an underlying mechanism unrelated to the ACE inhibitor . In the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial, 86 of 12,557 subjects (0.7 percent) given enalapril experienced angioedema over a 12-week period . The pathogenesis of ACE inhibitor-induced angioedema and the treatment of this condition are discussed in detail separately. (See "ACE inhibitor-induced angioedema".)
Anaphylactoid reactions are also seen when ACE inhibitors are used in patients treated with high-flux hemodialysis using polyacrylonitrile (PAN) dialyzers. (See "Reactions to the hemodialysis membrane", section on 'Type A reactions'.)
Drug-induced pancreatitis — Several reports have implicated ACE inhibitors in drug-induced pancreatitis (DIP) [41-44]. As an example, in a large observational study of more than 700,000 patients with hypertension, DIP occurred significantly more frequently with ACE inhibitors than with dihydropyridine calcium channel blockers although absolute rates were low (approximately 0.06 versus 0.04 percent) . By contrast, ARBs were not associated with a higher incidence of DIP. A potential mechanism may be related to the same pathways causing angioedema, resulting in swelling and obstruction of the pancreatic duct .
Contraindication in pregnancy — ACE inhibitors (and other inhibitors of the renin angiotensin system) are contraindicated in pregnancy since they are associated with an increased incidence of fetal complications. (See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy".)
Overdose — Manifestations of ACE inhibitor overdosing are usually mild . If, however, severe hypotension occurs, intravenous fluids and inotropic support may be required.
ARBS — The angiotensin II receptor blockers (ARBs) are typically well tolerated . The side effect profile is generally similar to that seen with angiotensin-converting enzyme (ACE) inhibitors (eg, increased incidence of hyperkalemia and of acute kidney injury in renovascular hypertension or states of effective volume depletion) [3,16,47,48]. The rate of certain side effects (eg, kidney dysfunction, syncope) appears to be similar with the two classes of drugs; however, ARBs have lower rates of cough and angioedema and perhaps a higher rate of hypotensive symptoms than ACE inhibitors.
Incidence of cough with ARBs — The incidence of cough is lower in patients treated with ARBs . The magnitude of this difference was illustrated in a 2008 meta-analysis of 29 trials that directly compared the rate of cough in ARBs and ACE inhibitors . The respective rates of cough were 3.2 and 9.9 percent, although there was significant statistical heterogeneity among studies presumably due to different rates of prior exposure to the agents.
Similar findings were noted in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) . Cough severe enough to require permanent discontinuation was significantly less common with telmisartan (1.1 versus 4.2 percent with ramipril, relative risk 0.26), despite an identical run-in period.
This benefit of ARBs also applies to patients with a prior history of ACE inhibitor-induced cough. This was illustrated in a randomized trial in which 135 such patients were randomly assigned to repeat therapy with an ACE inhibitor (lisinopril), valsartan, or hydrochlorothiazide . The rate of recurrent cough was much higher with readministration of an ACE inhibitor (67 versus 19 percent with the other drugs).
Angioedema — Available evidence suggests the rate of angioedema with ARB therapy is low. This is discussed separately. (See "ACE inhibitor-induced angioedema", section on 'Future use of related drugs'.)
ARBs appear be safe in patients with symptomatic asthma. In one report, candesartan did not induce cough or worsen bronchial hyperreactivity in such patients . (See "Treatment of hypertension in asthma and COPD".)
Hypotension — Hypotensive symptoms appear to be more common with ARBs than ACE inhibitors. The magnitude of this effect was illustrated in the ONTARGET trial cited above in which hypotensive symptoms severe enough to require permanent discontinuation occurred significantly more often with telmisartan (2.7 versus 1.7 percent with ramipril, relative risk 1.54). These permanent discontinuations occurred despite a run-in period in which both telmisartan and ramipril were prescribed before randomization .
Avoid in pregnancy — As with ACE inhibitors, ARBs are contraindicated in pregnancy [51,52]. An additional concern is that AT1 receptor blockade results in the disinhibition of renin release by angiotensin II and increased formation of all angiotensin peptides . These peptides could activate the AT2 receptor, which is highly expressed in the fetus.
Enteropathy with olmesartan — In 2013, the United States Food and Drug Administration (FDA) reported that olmesartan can produce a "sprue-like enteropathy" characterized by severe chronic diarrhea and weight loss, occurring months to years after initiation of the drug . In many cases, intestinal biopsy revealed villous atrophy, and, in all cases, antibody testing for celiac disease was negative . The condition resolved after discontinuation of olmesartan, but rechallenge with the drug sometimes reproduced the symptoms.
The largest experience comes from a French cohort of 4,546,680 patients who initiated therapy with olmesartan, or a different ARB, or an ACE inhibitor . Compared with users of ACE inhibitors, intestinal malabsorption severe enough to cause hospitalization occurred substantially more often among patients taking olmesartan for one to two years (adjusted risk ratio 3.7, 95% CI 1.8-7.3) and among those taking olmesartan for more than two years (adjusted risk ratio 10.6, 95% CI 5.0-22.5; the corresponding two-year number needed to harm was 12,550 treated to cause one additional case of severe enteropathy) . Risk was not increased in users of other ARBs.
Thus, patients starting olmesartan should be cautioned about the possibility of developing diarrhea and weight loss. The drug should be stopped if these symptoms occur and another cause is not found.
Cancer and myocardial infarction risk — A 2010 meta-analysis of five trials of almost 62,000 patients suggested that patients treated with ARBs had a significantly increased risk of new cancers compared with patients in control groups (7.2 versus 6.0 percent, risk ratio 1.08, 95% CI 1.01-1.15) . However, two subsequent meta-analyses failed to confirm this finding [58,59]. One of these studies included 15 trials of almost 140,000 patients . The cancer incidence was similar in patients treated with ARBs and controls, some of whom were treated with ACE inhibitors (6.2 versus 6.3 percent, odds ratio 1.00, 95% CI 0.95-1.04). In June of 2011, the US FDA reviewed the available data and concluded that the use of ARBs for the treatment of hypertension does not increase the risk of cancer .
Years later, large-scale recalls of specific lots of several different ARBs were triggered by the discovery of potentially carcinogenic nitrosamines in the pills, presumably formed by a side reaction during the manufacturing process . The US FDA estimated that one additional case of cancer would be expected for every 8000 patients taking the highest dose of valsartan for four years. Continued vigilance is required to protect the public from these impurities.
The issue of cancer risk in patients receiving combination therapy with ACE inhibitors and ARBs is discussed below. (See 'Possible increased risk of cancer' below.)
A 2004 report suggested an increased risk of myocardial infarction among users of ARBs . However, a subsequent meta-analysis of data from 37 randomized controlled trials showed no increase in risk .
ACE INHIBITORS VERSUS ARBS — The best comparative data regarding the incidence of side effects observed with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) come from the randomized Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) of over 25,000 patients at high risk for cardiovascular events (diabetes or vascular disease), which compared telmisartan to ramipril or both drugs .
In terms of side effects, ONTARGET primarily presented data related to adverse effects of sufficient severity to require permanent discontinuation of the drug. The following findings were noted:
●Ramipril and telmisartan had similar rates of hyperkalemia, defined as a serum potassium greater than 5.5 mEq/L (3.3 and 3.4 percent), acute kidney injury, defined as a doubling of the serum creatinine (1.9 and 2.0 percent), and syncope requiring drug discontinuation (0.2 percent with both drugs).
●The rate of drug discontinuation (including episodes that were not permanent) was modestly but significantly lower with telmisartan than with ramipril (23 versus 24.5 percent, relative risk 0.94) .
COMBINATION OF ACE INHIBITORS AND ARBS — Multiple studies have demonstrated that patients who are treated with both an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) are at higher risk for adverse effects.
Increased adverse effects — The supportive data on increased adverse effects come from the following observations:
●The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), described in the preceding section, evaluated ramipril, telmisartan, and combination therapy in over 25,000 patients at high risk for cardiovascular events (diabetes or vascular disease). Combined therapy compared to ramipril alone was associated with significant increases in the following adverse effects that were severe enough to require drug discontinuation: hypotensive symptoms (4.8 versus 1.7 percent), syncope (0.3 versus 0.2 percent), and kidney dysfunction (1.1 versus 0.7 percent) [3,64]. There was also a significant increase in hyperkalemia, defined as a serum potassium above 5.5 mEq/L (5.7 versus 3.3 percent), and an almost significant increase in overall mortality (12.5 versus 11.8 percent with ramipril alone, risk ratio 1.07, 95% CI 0.98-1.16).
●An increased incidence of adverse events with combination therapy was also demonstrated in a meta-analysis of four randomized trials that compared 17,337 patients with chronic heart failure who received either an ACE inhibitor alone or the combination of an ACE inhibitor and an ARB . (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'General cautions'.)
Compared with patients who received an ACE inhibitor alone, those treated with both agents had significantly higher rates of the following complications: increased medication discontinuation due to adverse effects (15 versus 11 percent); worsening kidney function, defined as an increase in creatinine of 0.5 mg/dL (44.2 micromol/L) or more over baseline (3.3 versus 1.5 percent); hyperkalemia (3.5 versus 0.7 percent); and symptomatic hypotension (2.4 versus 1.5 percent).
Possible increased risk of cancer — In a meta-analysis of trials of antihypertensive drugs, combination therapy with ARBs and ACE inhibitors compared with ACE inhibitors alone was associated with a significant increase in cancer incidence among 28,168 patients from two trials (2.3 versus 2.0 percent; risk ratio 1.14, 95% CI 1.02-1.28) .
By contrast, a second meta-analysis that included these two trials as well as five others found similar rates of cancer incidence in patients treated with combination therapy compared with ACE inhibitors alone (5.33 versus 5.26 percent) . However, there was significant heterogeneity among the seven trials. The cancer incidence tended to be higher with combination therapy in three trials (at a mean follow-up of 48 months) and somewhat lower with combination therapy in the other four trials (at a mean follow-up of 32 months).
Conclusion — Based upon the clear evidence of possible harm, combined ACE inhibitor/ARB therapy should not be considered unless there is compelling evidence of clinical benefit that cannot be attained with other regimens . Similar recommendations apply to the combination of a direct renin inhibitor with an ACE inhibitor or an ARB .
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Side effects from medicines (The Basics)")
●Side effects that occur with angiotensin-converting enzyme (ACE) inhibitors are related to either reduced angiotensin II formation or increased kinins. Those related to reduced angiotensin II formation include hypotension, acute kidney injury, hyperkalemia, and problems during pregnancy. Side effects thought to be related, at least in part, to increased kinins include cough, angioedema, and anaphylactoid reactions. (See 'ACE inhibitors' above.)
●Hyperkalemia and kidney injury may require termination of the ACE inhibitor. Termination should be considered if hyperkalemia cannot be controlled or the serum creatinine concentration increases more than 30 percent above the baseline value within the first six to eight weeks when blood pressure is reduced. (See 'Reduction in GFR' above and 'Hyperkalemia' above.)
●Angiotensin II receptor blockers (ARBs) are associated with lower rates of cough and angioedema and a higher rate of hypotensive symptoms. (See 'ARBs' above.)
●A dry cough occurs in 5 to 20 percent of patients treated with an ACE inhibitor and approximately one-third as many patients treated with an ARB. Treatment consists of lowering the dose or discontinuing the drug. Readministration of the drug is associated with a high rate of recurrent cough. (See 'Cough' above and 'Incidence of cough with ARBs' above.)
●Angioedema is a rare but potentially fatal complication of ACE inhibitors. Angioedema may also occur with ARBs, but the risk is lower. (See 'Angioedema and anaphylactoid reactions' above and 'Angioedema' above.)
●Patients who are on both an ACE inhibitor and an ARB are at higher risk for adverse effects. Thus, combined therapy should not be considered in the treatment of hypertension or other disorders unless there is compelling evidence of benefit. (See 'Combination of ACE inhibitors and ARBs' above.)
●ACE inhibitors and ARBs are contraindicated in pregnancy. (See 'Avoid in pregnancy' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟