What are some common side effects of angiotensin converting enzyme inhibitors (ACEIs)?

All medications cause side effects, but angiotensin-converting enzyme (ACE) inhibitors are among the better tolerated of the antihypertensive agents.^1-3 A 2003 meta-analysis of 354 randomized double-blind placebo-controlled trials of hypertension treatment with thiazides, beta blockers, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and ACE inhibitors looked at the rate of side effects at the standard dose.¹ The study found that overall 3.9% of patients in the ACE inhibitor group had symptoms (mainly cough) at the standard dose. The other medications caused more symptoms at the standard dose at rates of 7.5% in the beta-blocker group, 8.3% in the CCB group, and 9.9% in the thiazide group. ARBs were the exception with no excess symptoms at the standard dose. Rates of treatment withdrawal due to adverse symptoms (treated minus placebo) were 0.1% for ACE inhibitors and thiazides, 0.8% for beta blockers, zero for CCBs (at half the standard dose), and zero for ARBs at regular doses. The unabridged version of this study gave more detail on symptoms reported for ACE inhibitors. The prevalence of symptoms severe enough for patients taking an ACE inhibitor to stop treatment was 0.1% (95% confidence interval [CI] [-0.3% – 0.6%]) of cases. Out of 38 studies including 4326 patients on ACE inhibitors and 2536 on placebos, the prevalence of symptoms recognized as being caused by the drugs over placebo was:⁴

• Cough 4.1% (95% CI, [3.2 – 5.0])
• Skin rash 1.0% (95% CI, [-0.2 – 2.1])
• Nausea 0.7% (95% CI, [-0.1 – 1.6])
• Dizziness 0.6% (95% CI, [-0.4 – 1.5])
• Fatigue 0.6% (95% CI, [-0.5 – 1.7])
• Abdominal cramps 0.5% (95% CI, [-0.2 – 1.2])

ACE inhibitors increase serum potassium due to their effect on aldosterone. The above 2003 meta-analysis found potassium increased by 4%, or 0.16 mmol/l with ACE Inhibitors (95% CI, [0.08 – 0.23 mmol/l], 15 trials, 20 treatment arms).⁴

Several major hypertension management guidelines recognize that patients may stop treatment with ACE inhibitors due to cough.^3,5-8 They explicitly suggest ARBs as a suitable alternative for people intolerant of ACE inhibitors due to side effects, particularly cough.^3,5-7  In studies, reports of dry, persistent cough varied widely from 5% to 35% of patients taking ACE inhibitors (9.9% in randomized controlled trials and 1.7% in cohort studies).^8,9

A 2014 Cochrane meta-analysis² of eight studies that compared ACE inhibitors to ARBs found a high level of evidence of a slightly lower incidence of withdrawals from studies due to adverse effects for ARBs as compared with ACE inhibitor (risk ratio 0.83, 95% CI [0.74 – 0.93]; absolute risk reduction 1.8%, number needed to treat for an additional beneficial outcome 55 over 4.1 years). This was mainly due to a higher incidence of dry cough with an ACE inhibitor. In the six studies that recorded the specific reason for withdrawal from treatment, 43% (22/51 events) in the ACE inhibitor patients were due to cough.

While the above Cochrane meta-analysis provides important insights into the side effect profile of ACE inhibitors from many studies, the manufacturer also cites the prevalence of side effects in their prescribing information. The prevalence of side effects is largely similar in both sources.

Manufacturer Trials and Recommendations

According to prescribing information, the most common side effects that can occur in more than 1% of patients receiving an ACE inhibitor and at greater rates than placebo in clinical trials were:^10-19

• Cough (4 to 12 in 100)
• Headache (6 in 100)
• Dizziness (4-6 in 100)
• Fatigue or tiredness (2-3 in 100)
• Chest pain (2-3 in 100)
• Rash (2-7 in 100)
• Nausea or vomiting (2 in 100)

Hypotension rarely occurs, but patients may report lightheadedness especially in the first few days of treatment. Manufacturers recommend that if actual syncope occurs, the patient should discontinue the drug until they have spoken to their doctor.^10-19

^References

1. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003; 326 (7404): 1427.
2. Li EC, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev 2014; (8): Cd009096.
3. Powers BJ, Coeytaux RR, Dolor RJ, et al. Updated report on comparative effectiveness of ACE inhibitors, ARBs, and direct renin inhibitors for patients with essential hypertension: much more data, little new information. J Gen Intern Med 2012; 27 (6): 716-729.
4. Law M, Wald N, Morris J. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy. Health Technol Assess 2003; 7 (31): 1-94.
5. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62 (16): e147-239.
6. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults. JAMA 2014; 311 (5): 507-520.
7. Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. Circulation 2015; 131 (19): e435-470.
8. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. Chest 2006; 129 (1 Suppl): 169s-173s.
9. Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med 2008; 148 (1): 16-29.
10. Accupril [package insert]. New York, NY: Parke Davis, Pfizer; 2017.
11. Capoten [package insert]. Spring Valley, NY: Par Pharmaceutical Companies, Inc.; 2012.
12. Vasotec [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2015.
13. Lotensin [package insert]. Parsippany, NJ: Validus Pharmaceuticals LLC; 2014.
14. Altace [package insert]. New York, NY: Pfizer Laboratories; 2017.
15. Aceon [package insert]. North Chicago, IL: Abbot Laboratories; 2011.
16. Moexipril hydrochloride [package insert]. Teva Pharmaceuticals USA Inc; 2016.
17. Fosinopril sodium [package insert]. Miami, FL: Ciplo USA Inc; 2015.
18. Trandolapril [package insert]. Laurelton, NY: Epic Pharma, LLC; 2017.
19. Prinivil [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; 2016.