Definition and Pathophysiology
Angiotensin-converting enzyme (ACE) inhibitors are foundational therapies in cardiovascular medicine, widely utilized for the management of hypertension, chronic ischemic heart disease, heart failure with reduced ejection fraction (HFrEF), and post-myocardial infarction (MI) care. Despite their proven morbidity and mortality benefits, their use is limited by specific adverse effects. Most of these adverse events are related to the suppression of the renin-angiotensin-aldosterone system (RAAS), such as decreases in blood pressure and mild azotemia. However, two distinct side effects—nonproductive cough and angioedema—are specifically related to the potentiation of kinins.
The mechanism of ACE inhibitor-associated cough is thought to involve the sensitization of sensory nerve endings due to the accumulation of bradykinin. ACE is responsible for metabolizing bradykinin and other tachykinins, such as substance P. When ACE is inhibited, the resulting accumulation of these peptides irritates afferent neural pathways in the respiratory tract. This process is not dose-dependent. Similarly, angioedema occurring in the setting of ACE inhibitor therapy is bradykinin-mediated rather than mast cell-mediated, distinguishing it from classic allergic reactions.
Clinical Presentation and Symptoms
ACE Inhibitor-Induced Cough
ACE inhibitor-induced cough occurs in 5% to 30% of patients taking these agents. The cough is characteristically nonproductive and dry. Patients may describe a persistent tickle or sensitivity in the throat. In recent years, the concept of a distinct "cough hypersensitivity syndrome" has emerged, emphasizing the putative role of sensitized sensory nerve endings and afferent neural pathways in causing chronic refractory cough, akin to chronic neuropathic pain. This syndrome presents with a dry or minimally productive cough and a tickle or sensitivity in the throat, and is made worse with talking, laughing, or exertion. It is more common in women than in men and can last for years.
ACE Inhibitor-Induced Angioedema
Angioedema secondary to ACE inhibitor therapy occurs in approximately 1% of patients. It manifests as localized, transient swelling of the subcutaneous or submucosal tissues, most frequently involving the face, lips, tongue, and upper airway. Due to the risk of airway compromise, it represents a medical emergency.
Evaluation and Physical Examination
The evaluation of chronic cough in a patient taking an ACE inhibitor should begin with a comprehensive history and physical examination. Clinicians should inquire about historical clues suggesting alternative etiologies, such as a sensation of postnasal drip, frequent throat clearing, sneezing, and rhinorrhea, which may indicate upper airway cough syndrome. Symptoms of retrosternal burning after meals or on recumbency, frequent eructation, hoarseness, and throat pain may point toward gastroesophageal reflux.
Physical examination should include a speculum examination of the nose to look for excess mucoid or purulent secretions, inflamed and edematous nasal mucosa, or polyps. Examination of the posterior pharyngeal wall may reveal secretions or a cobblestoned appearance of the mucosa. Laryngoscopy may be performed to assess for glottic inflammation, which can be a manifestation of recurrent reflux to the level of the throat, though it remains a nonspecific finding.
In patients presenting with angioedema, a rapid assessment of the airway is paramount to evaluate for impending respiratory compromise.
Diagnostics
The diagnosis of ACE inhibitor-induced cough is primarily clinical and relies on the temporal association of the cough with the medication. Specific diagnostic criteria for cough hypersensitivity syndrome are lacking; the diagnosis is suspected when alternative etiologies are excluded by diagnostic testing or failed therapeutic trials.
If alternative causes of cough are suspected, specific diagnostic pathways may be pursued. Spirometry can establish a diagnosis of asthma if it demonstrates airflow obstruction that varies over time or reverses in response to a bronchodilator. A negative response to a bronchoprovocation challenge (e.g., with methacholine) can exclude asthma with certainty. In patients capable of taking reliable measurements, home expiratory peak flow monitoring can serve as a cost-effective method to support or discount a diagnosis of asthma.
For suspected gastroesophageal reflux, quantification of the frequency and level of reflux requires invasive procedures, such as nasopharyngeal placement of a catheter with a pH probe into the esophagus for 24 hours, or endoscopic placement of a radiotransmitter capsule. Newer techniques can also measure esophageal pressures (manometry) and nonacid reflux. However, the precise interpretation of test results that permits an etiologic linking of reflux events and cough remains debated.
Patients who fail to respond to treatment targeting the common causes of chronic cough, or who have had these causes excluded by appropriate diagnostic testing, should undergo chest computed tomography (CT). Diseases causing cough that may be missed on a standard chest radiograph include tumors, early interstitial lung disease, bronchiectasis, and atypical mycobacterial pulmonary infection. Conversely, patients with chronic cough who have normal findings on chest examination, lung function testing, oxygenation assessment, and chest CT can be reassured as to the absence of serious pulmonary pathology.
Biomarkers and Laboratory Findings
Routine biomarkers are not utilized specifically for the diagnosis of ACE inhibitor cough. However, sputum analysis can aid in evaluating alternative etiologies. Eosinophilic bronchitis, an uncommon condition that causes chronic cough with a normal chest radiograph, is characterized by sputum eosinophilia in excess of 3% without airflow obstruction or bronchial hyperresponsiveness.
Measurement of an elevated concentration of nitric oxide in exhaled breath has the potential to detect eosinophilic airway inflammation (such as in asthma or eosinophilic bronchitis) and predict a favorable response to inhaled steroids in persons with chronic cough.
In the context of general ACE inhibitor and angiotensin receptor blocker (ARB) therapy, laboratory monitoring of renal function and serum potassium is essential. Potassium retention may become problematic, particularly if the patient is receiving potassium supplements or a potassium-sparing diuretic.
Treatment and Management
Acute Management of Angioedema
The acute management of ACE inhibitor-induced angioedema focuses on airway protection and discontinuation of the offending agent. Published studies present conflicting evidence regarding the efficacy of bradykinin 2 receptor antagonists (such as icatibant) and C1INH protein in the treatment of ACE inhibitor-induced angioedema. Fresh frozen plasma infusion can be utilized for acute attacks in settings where newer modalities are not available.
Management of Chronic Cough
Any patient with chronic unexplained cough who is taking an ACE inhibitor should undergo a trial period off the medication, regardless of the timing of the onset of cough relative to the initiation of ACE inhibitor therapy. Failure to observe a decrease in cough after 1 month off the medication argues strongly against ACE inhibitors as the etiology. In most instances, a safe alternative is available; angiotensin receptor blockers do not cause cough and are the next recommended line of therapy for patients intolerant to ACE inhibitors due to cough or angioedema.
If the cough persists despite discontinuation of the ACE inhibitor, treatment is often empirical and targeted at the most likely cause(s) as determined by history, physical examination, and possibly pulmonary function testing:
Postnasal drainage: Therapy depends on the presumed etiology (infection, allergy, or vasomotor rhinitis) and may include systemic antihistamines, decongestants, antibiotics, nasal saline irrigation, and nasal pump sprays with glucocorticoids, antihistamines, or anticholinergics.
Gastroesophageal reflux: Antacids, histamine type 2 (H2) receptor antagonists, and proton pump inhibitors are used to neutralize or decrease the production of gastric acid. Dietary changes, elevation of the head and torso during sleep, and medications to improve gastric emptying or impede the flow of refluxate (e.g., alginates) are additional therapeutic measures.
Cough-variant asthma: This typically responds well to inhaled glucocorticoids and intermittent use of inhaled beta-agonist bronchodilators.
Eosinophilic bronchitis: This condition is successfully treated with inhaled glucocorticoids.
Switching to Alternative Cardiovascular Therapies
When ACE inhibitors must be discontinued due to cough or angioedema, ARBs are the preferred substitute. ARBs block the effects of angiotensin II on the angiotensin type 1 receptor—the receptor subtype responsible for virtually all the adverse biologic effects relevant to angiotensin II on cardiac remodeling.
Patients who are intolerant to ACE inhibitors because of hyperkalemia or renal insufficiency are likely to experience the same side effects with ARBs. In patients who are intolerant to both ACE inhibitors and ARBs, the combined use of hydralazine and isosorbide dinitrate (H-ISDN) may be considered as a therapeutic option. However, adherence with this combination has generally been poor because of the large number of tablets required and the high incidence of adverse reactions.
Drugs, Doses, and Practical Considerations
Angiotensin Receptor Blockers (ARBs)
Multiple ARBs are available for the treatment of HFrEF, but three—losartan, valsartan, and candesartan—have been extensively evaluated in this setting. ARBs should be initiated at the appropriate starting doses and can be uptitrated every 3 to 5 days by doubling the dose. As with ACE inhibitors, blood pressure, renal function, and potassium should be reassessed within 1 to 2 weeks after initiation and followed closely after changes in dose.
Clinical trial data supports the efficacy of specific ARBs in ACE inhibitor-intolerant patients:
Candesartan: Significantly reduced all-cause mortality, cardiovascular death, or hospital admission in the CHARM-Alternative trial. It reduced all-cause mortality irrespective of background ACE inhibitor or beta blocker therapy.
Valsartan: Showed similar findings to candesartan in the small subgroup of patients not receiving an ACE inhibitor in the Val-HeFT trial.
Losartan: In the ELITE-II trial, losartan did not improve survival in elderly HF patients compared to captopril, but it was significantly better tolerated. In the HEAAL trial, high-dose losartan (150 mg daily) was superior to low-dose losartan (50 mg daily) for the composite outcome of death or admission for HF over 4.7 years of follow-up. Although there were more side effects with the high dose, these adverse events infrequently led to discontinuation of therapy.
Management of Hyperkalemia
If potassium retention occurs during RAAS inhibition and is not responsive to the discontinuation of potassium supplements or potassium-sparing diuretics, a reduction in the dose of the ACE inhibitor may be required. Alternatively, the addition of a potassium-binding agent (e.g., patiromer) can be considered to allow therapy to continue.
Bradykinin-Mediated Angioedema Therapies
For prophylaxis of hereditary angioedema (HAE) attacks, approved options include infusion of plasma-derived C1INH protein, a monoclonal anti-plasma kallikrein antibody (lanadelumab), and a small-molecule plasma kallikrein inhibitor (berotralstat). Older, less expensive preventative options include attenuated androgens, which stimulate production of functional C1INH. The antifibrinolytic agent 8-aminocaproic acid may be used for preoperative prophylaxis but is contraindicated in patients with thrombotic tendencies or arterial atherosclerosis.
For the treatment of an acute attack of HAE, administration of plasma-derived or recombinant C1INH protein, a bradykinin 2 receptor antagonist (icatibant), or a kallikrein inhibitor (ecallantide) may be utilized. Treatment of the underlying autoimmune disease or malignancy is indicated for acquired C1INH deficiency.
Guideline Recommendations
Guidelines recommend ARBs for symptomatic and asymptomatic patients with an ejection fraction (EF) less than 40% who are intolerant to ACE inhibitors for reasons other than hyperkalemia or renal insufficiency (Class I indication). Both ACE inhibitors and ARBs are generally recommended for all patients with HFrEF, independent of symptom burden, and should be titrated to the doses proven to provide clinical benefit or to the maximally tolerated dose.
In the management of ST-elevation myocardial infarction (STEMI), ACE inhibitors should be prescribed unselectively to all hemodynamically stable patients (systolic pressure >100 mmHg) due to a reduction in ventricular remodeling and subsequent risk of heart failure. The maximum benefit is observed in high-risk patients, such as those with an anterior infarction, prior infarction, or globally depressed LV function. ACE inhibitors should be continued indefinitely in patients with clinically evident heart failure, reduced global LV function, large regional wall motion abnormalities, or hypertension. ARBs should be administered to STEMI patients who are intolerant of ACE inhibitors and who have either clinical or radiologic signs of heart failure.
For patients with chronic coronary syndromes (CCS), ACE inhibitors (or ARBs in cases of intolerance) are recommended for the treatment of patients with co-existing hypertension, LVEF <40%, diabetes mellitus (DM), or chronic kidney disease (CKD), unless contraindicated (e.g., severe renal impairment, hyperkalemia). However, routine administration of ACE inhibitors or ARBs to ischemic heart disease (IHD) patients who have normal LV function and have achieved blood pressure and LDL goals on other therapies does not reduce the incidence of events and is therefore not cost-effective.
Prognosis and Follow-Up
The inability to tolerate the initiation or dose titration of neurohumoral antagonists due to hypotension, worsening heart failure, or progressive renal insufficiency is a poor prognostic marker and may be a cardinal manifestation of transition to an advanced heart failure phenotype.
Data from large registries in the United States and Europe suggest that guideline-directed medical therapy for patients with HFrEF is frequently underutilized and underdosed, leaving considerable room for quality improvement. Prospective trials of high-dose versus low-dose RAAS inhibitors consistently favor the higher dose, demonstrating lower rates of death and heart failure hospitalization in the higher-dose groups. In the absence of symptoms suggesting hypotension (such as fatigue and dizziness), pharmacotherapy may be uptitrated every 2 weeks in stable ambulatory patients as tolerated.
Special attention should be directed to women, racial minorities, the elderly, and patients with diabetes or chronic kidney disease, as registries have shown these populations are less likely to receive evidence-based pharmacologic and interventional therapies, resulting in poorer clinical outcomes and quality of life.
