Angioedema involving the extremities, face, lips, tongue, glottis, and/or larynx including some fatal reactions have occurred in patients treated with angiotensin-converting enzyme (ACE) inhibitors. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. ACE inhibitors have been associated with a higher rate of angioedema in black than non-black patients.
Patients receiving coadministration of an ACE inhibitor and a mammalian target of rapamycin (mTOR) inhibitor or a neprilysin inhibitor may be at increased risk for angioedema.
Swelling of the face, mucous membranes of the mouth, lips, and extremities has usually been resolved with discontinuation of the ACE inhibitor. Patients should be advised to immediately report any signs or symptoms suggesting angioedema and discontinue use of their ACE inhibitor until they have consulted with the prescribing physician.
Intestinal angioedema has occurred in patients treated with ACE inhibitors. The patients presented with abdominal pain, with or without nausea or vomiting. 1-14
A 2012 meta-analysis of 26 randomized trials (n=74,875) reported an incidence of 0.3% of ACE inhibitor-induced angioedema (95% confidence interval [CI] [0.28 – 0.32]) compared to 0.07% with placebo (95% CI [0.05 – 0.09]).15
Sudden and potentially life-threatening anaphylactoid reactions have occurred in some patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. 1-14
Changes in renal function, including acute renal failure, can be caused by drugs that inhibit the renin-angiotensin system, such as ACE inhibitors. Patients whose renal function may depend on the activity of the renin-angiotensin system such as those with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post-myocardial infarction, or volume depletion, may be at particular risk of developing acute renal failure on an ACE inhibitor.1-14
The Studies of Left Ventricular Dysfunction (SOLVD) examined the effect of ACE inhibitors on kidney function in 6,758 patients with heart failure and found 16% of patients on ACE inhibitors had decreased renal function compared to 12% in the placebo group. For the purposes of this study, decreased renal function was defined as a rise in serum creatinine of ≥0.5 mg/dL (44 μmol/L) from baseline.16
ACE inhibitors can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure, or death. Patients at risk of excessive hypotension include those with the following: heart failure with systolic blood pressure below 100 mm Hg; ischemic heart disease; cerebrovascular disease; hyponatremia; high dose diuretic therapy; renal dialysis; or severe volume and/or salt depletion of any etiology.
Patients should be cautioned to report lightheadedness, especially during the first few days of therapy. If actual syncope occurs, the patient should discontinue the drug until they have consulted with the prescribing physician. Patients should be cautioned that excessive perspiration, dehydration, vomiting, and diarrhea may lead to hypotension because of the reduction in fluid volume.
In patients undergoing major surgery or during anesthesia with agents that produce hypotension, ACE inhibitors may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. 1-14
Drugs that inhibit the renin-angiotensin system such as ACE inhibitors can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Patients should not use salt substitutes containing potassium without consulting with their physician. 1-14
The definition of hyperkalemia varies, making it difficult to estimate incidence rate. A recent multisite database study of ambulatory patients with diabetes newly starting an ACE inhibitor, ARB, or spironolactone stratified results based on definition of hyperkalemia. Using the least restrictive definition (an ambulatory visit, inpatient hospitalization, or emergency department visit co-occurring within 7 days of coded hyperkalemia diagnosis and/or potassium concentration of ≥5.5 mmol/L), the incidence rate was 3.0%. Restricting to only inpatient hospitalization or emergency department visits co-occurring within 24 hours of coded diagnosis and/or potassium ≥6 mmol/L, the incidence rate was 1.0%.17
ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. The incidence rate of hepatic failure in patients who are taking ACE inhibitors is unknown as this effect is only reported anecdotally.1-14
ACE inhibitors can cause fetal harm when administered to a pregnant woman. Women should stop taking an ACE inhibitor as soon as possible after pregnancy is detected. ACE inhibitors reduce fetal renal function and increase fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. 1-14
In a 1991 summary of 85 pregnancies during which women were exposed to ACE inhibitors, 11 deaths were reported (six stillbirths and five neonatal deaths). Based on limited data, the morbidity from exposure to ACE inhibitors in the second and third trimesters of pregnancy is estimated to be as high as 10% to 20%.18
Neutropenia (<1000/mm3) with myeloid hypoplasia has resulted from use of ACE inhibitors. About half of the neutropenic patients developed systemic or oral cavity infections or other features of agranulocytosis. Patients with the following had increased risk of neutropenia: some degree of renal failure but no collagen vascular disease; collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) and impaired renal function.
Bone marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes. Anemia and thrombocytopenia were sometimes seen.
Neutrophils generally returned to normal levels in about two weeks after discontinuing use of ACE inhibitors. About 13% of cases of neutropenia ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure, immunosuppressant therapy, or a combination of these complicating factors.
Patients should be told to report promptly any indication of infection which may be a sign of neutropenia.2,4-6,10-14
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- Makani H, Messerli FH, Romero J, et al. Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am J Cardiol 2012; 110 (3): 383-391.
- Knight EL, Glynn RJ, McIntyre KM, et al. Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: results from the Study Of Left Ventricular Dysfunction (SOLVD). Am Heart J. 1999; 138: 849–855.
- Raebel MA, Ross C, Cheetham C, et al. Increasingly restrictive definitions of hyperkalemia outcomes in a database study: Effect on incidence estimates. Pharmacoepidemiol Drug Saf 2010;19:19–25. PMID 19937982.
- Hanssens M, Keirse MJ, Vankelecom F, Van Assche FA. Fetal and neonatal effects of treatment with angiotensin-converting enzyme inhibitors in pregnancy. Obstet Gynecol 1991;78:128-35.