Synonyms: ACE inhibitors, ACEIs, ACEs

This family of drugs inhibits the conversion of angiotensin I to angiotensin II by inhibiting angiotensin-converting enzyme (ACE). Angiotensin II has various functions including:

• Promoting vasoconstriction - through stimulation of the sympathetic nervous system, and the release of aldosterone and vasopressin.
• Renal changes - some of which are through the actions of aldosterone (with salt and water retention) and others which may be caused directly, e.g. renal vasoconstriction.
• Cardiac and vascular remodelling - through the actions of growth factors and increased afterload.

This leads to hypertension and the complications of hypertension, such as left ventricular hypertrophy. Angiotensin-converting enzyme (ACE) inhibitors induce vasodilatation which will improve cardiac output (by reducing afterload) and enhance the renal excretion of salt and water. Most ACE inhibitors are pro-drugs which are metabolised in the liver to active metabolites. All are excreted by the kidney, and need careful titration in renal impairment¹

Under normal circumstances ACE also inactivates bradykinin and thus ACE inhibition is associated with increased levels of bradykinin and this is thought to underly the ACE inhibitor- associated cough.

Indications

• Hypertension: recommended first-line antihypertensive in diabetics and younger (<55 years) patients with hypertension, and second-line for other patients if blood pressure (BP) is not adequately controlled on thiazide or a calcium-channel blocker (or if these drugs are not tolerated or are contra-indicated).² See separate article Management of Hypertension.
• Heart failure: (particularly in patients with left ventricular dysfunction); reduces both mortality and hospital admissions in these patients.^3,4 More recently data are emerging that ACE inhibitors are also beneficial in patients with heart failure and normal left ventricular systolic function.^5,6 See separate article Heart Failure Management.
• Post-myocardial infarction (MI): ACE inhibitors reduce ischaemic events, mortality and hospital admissions (heart failure or further MI) in this group of patients.³ There is good evidence to suggest that they should be started early.⁷
• Diabetic nephropathy: as well as lowering BP, ACE inhibitors reduce the rate of albumin excretion in normotensive diabetic patients (types 1 and 2),⁸ and there is reduced mortality (all causes).^9,10,11
• Non-diabetic renal disease: ACE inhibitors can lower urinary protein excretion in patients with proteinuria and slow progression to renal failure (evidence for white populations only) - hence they are indicated for most patients with chronic renal disease.¹²

Stroke Prevention (unlicensed indication) - evidence exists that both ramipril,¹³ and perindopril (the latter when in combination with diuretic indapamide)^14,15 reduce the number of strokes occurring in high-risk patients whose BP is not elevated.

Contra-indications

• Pregnancy (maternal and fetal hypotension, fetal defects, oligohydramnios)^16,17,18,19 - some manufacturers say only second and third trimesters^20,21,22
• Haemodynamically significant renal artery stenosis (may cause progressive renal failure).¹⁶
• Hypersensitivity to ACE.^{16,17,18,19,20,21,22}
• Hereditary and idiopathic angio-oedema.²⁰
• Breast-feeding.^16,17,18,19

Cautions

• Renal impairment, renovascular disease (beware in patients with known atherosclerosis who may have silent renal artery stenosis). Reduce and monitor frequently.
• Aortic stenosis.²²
• Hyperkalaemia.
• Beware a very rapid fall of BP in volume-depleted patients, patients with hyponatraemia, on low-salt diets, on dialysis or in heart failure.

Important interactions

Avoid the following if possible, or monitor frequently:

• Non-steroidal anti-inflammatory drugs (NSAIDs) - increased risk of renal failure.
• Heparin, potassium-saving diuretics or potassium supplements, ciclosporin, and epoetin - Increased risk of hyperkalaemia.
• Lithium - increased serum levels of lithium.

Common problems

(For a full list of side-effects see individual drugs).

• Impaired renal function - especially in patients with already poor renal function or renal artery stenosis - ensure regular monitoring (see 'Monitoring', below).
• Hyperkalaemia (stop or reduce potassium supplements and potassium-saving diuretics before starting ACE inhibitors).
• First-dose hypotension - minimise this by stopping or reducing loop diuretics for 24 hours before starting and give a small trial dose, and/or take tablet immediately at bedtime. Consider initiation under specialised supervision.²³
• Persistent dry cough (in up to 10%) - consider switching to angiotensin-II receptor antagonists.

Initiation

• Always check U&E and creatinine before starting.
• Assess the patient for likely problems - consider whether ACE inhibitors may be better started in hospital, e.g. in patients with high risk of first-dose hypotension, hyperkalaemia or renal failure:²³
• If on high-dose diuretics (>80 mg furosemide/day) - reduce or stop diuretics, if possible a day or two before starting ACE inhibitor, to reduce the risk of first-dose hypotension. If this is not possible - monitor BP for 2 hours post-dose.
  
  Other higher-risk patients:
  • High doses of vasodilators.
  • Hypovolaemia.
  • Hyponatraemic (Na <130 mmol/L).
  • Hyperkalaemia.
  • Hypotension (systolic <100 mm Hg).
  • Unstable heart failure.
  • Renal impairment (creatinine >150 μmol/L).
  • Very elderly.
• Start with the lowest dose at bedtime, e.g. 2.5 mg lisinopril; (consider 6.25 mg captopril (shorter acting) for highest-risk patients.
• Titrate the dose up, e.g. at weekly intervals, until a maximum dose is reached or BP target is achieved.

Monitoring

• Monitor renal function, potassium and BP before starting, and regularly during treatment.
• Ideally, monitor creatinine and the required dose, and then every 6 or 12 months thereafter.

Common reasons to stop angiotensin-converting enzyme inhibitors

• Worsening renal function: 20% increase in the serum creatinine level is significant.
• Persistent dry cough: switch to angiotensin-II receptor antagonists.
• Hypotension.
• Hyperkalaemia.

Combination products available

• ACE inhibitor with thiazide diuretic.
• ACE inhibitor with calcium-channel blocker.

Document references

1. No authors listed; Who needs nine ACE inhibitors? Drug Ther Bull. 1995 Jan 19;33(1):1-3.
2. No authors listed, JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005 Dec;91 Suppl 5:v1-52.
3. Flather MD, Yusuf S, Kober L, et al; Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000 May 6;355(9215):1575-81. [abstract]
4. Garg R, Yusuf S; Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995 May 10;273(18):1450-6. [abstract]
5. Shah R, Wang Y, Foody JM; Effect of statins, angiotensin-converting enzyme inhibitors, and beta blockers on survival in patients >or=65 years of age with heart failure and preserved left ventricular systolic function. Am J Cardiol. 2008 Jan 15;101(2):217-22. [abstract]
6. Borghi C, Ambrosioni E; Effects of zofenopril on myocardial ischemia in post-myocardial infarction patients with preserved left ventricular function: the Survival of Myocardial Infarction Long-term Evaluation (SMILE)-ISCHEMIA study. Am Heart J. 2007 Mar;153(3):445.e7-14. [abstract]
7. Pedrazzini G, Santoro E, Latini R, et al; Causes of death in patients with acute myocardial infarction treated with angiotensin-converting enzyme inhibitors: findings from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI)-3 trial. Am Heart J. 2008 Feb;155(2):388-94. Epub 2007 Dec 19. [abstract]
8. No authors listed; Hypertension in type 2 diabetes--targeting angiotensin. Drug Ther Bull. 2005 Jun;43(6):41-5. [abstract]
9. Strippoli GF, Craig M, Deeks JJ, et al; Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ. 2004 Oct 9;329(7470):828. Epub 2004 Sep 30. [abstract]
10. Lovell HG; Angiotensin converting enzyme inhibitors in normotensive diabetic patients with microalbuminuria. Cochrane Database Syst Rev. 2001;(1):CD002183. [abstract]
11. Goede P, Lund-Andersen H, Parving HH, et al; Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008 Feb 7;358(6):580-91. [abstract]
12. Jafar TH, Schmid CH, Landa M, et al; Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med. 2001 Jul 17;135(2):73-87. [abstract]
13. Yusuf S, Sleight P, Pogue J, et al; Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000 Jan 20;342(3):145-53. [abstract]
14. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack, Lancet. 2001 Sep 29;358(9287):1033-41. [abstract]
15. Wennberg R, Zimmermann C; The PROGRESS trial three years later: time for a balanced report of effectiveness. BMJ. 2004 Oct 23;329(7472):968-70.
16. Summary of Product Characteristics - Tritace® (Ramipril) Sanofi-Aventis (Updated 30 September 2003); electronic Medicines Compendium
17. Summary of Product Characteristics - Capoten® Tablets 12.5mg, 25mg, 50mg E. R. Squibb & Sons Limited (Updated June 2005); electronic Medicines Compendium
18. Summary of Product Characteristics - fosinopril sodium tablets 20mg, Actavis UK Ltd. (Updated Dec 2010), electronic Medicines Compendium
19. Summary of Product Characteristics - Accupro® (quinapril) tablets 5mg, 10mg, 20mg & 40mg Pfizer Limited (Updated March 2007); electronic Medicines Compendium
20. Summary of Product Characteristics - Zestril® (lisinopril) 2.5mg, 5mg, 10mg, 20mg and 30mg tablets. AstraZeneca UK Limited (Updated 18 March 2004); electronic Medicines Compendium
21. Summary of Product Characteristics - Innovace® (enalapril), Merck Sharp & Dohme Limited (Updated October 2005); electronic Medicines Compendium
22. Summary of Product Characteristics - Coversyl® (perindopril) Astra Zeneca UK Ltd. (Updated Jan 2010); electronic Medicines Compendium
23. Davies MK, Gibbs CR, Lip GY; ABC of heart failure. Management: diuretics, ACE inhibitors, and nitrates. BMJ. 2000 Feb 12;320(7232):428-31.

Internet and further reading

• Martin U, Coleman JJ; Monitoring renal function in hypertension. BMJ. 2006 Oct 28;333(7574):896-9.
• British National Formulary

Acknowledgements