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Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs)

ACE inhibitors and ARBs, a cornerstone in the prevention and treatment of cardiovascular disease

ACE inhibitors and ARBs act by blocking RAAS with beneficial effects on patients with cardiovascular risk factors only (hypertension, diabetes) and with several heart diseases (heart failure, coronary artery disease). When indicated, they should be started at low dose and increased gradually to reach the target dose. ACE inhibitors and ARBs share indications, contraindications and most side effects (except cough, more frequent with ACE inhibtors). Monitoring of the renal function and serum potassium is needed to reduce the incidence of renal insufficiency and hyperkalaemia during treatment, particularly when initiated or uptitrated.



The activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the development and progression of cardiovascular disease, especially in arterial hypertension, heart failure and coronary artery disease.  ACE inhibitors are the most used and studied type of RAAS blocker and their benefits are due to their neurohormonal modulatory effects, which have vasodilatory, anti-inflammatory, plaque-stabilizing, antithrombotic and anti-proliferative effects.

ARBs have similar pharmacological properties to ACE inhibitors but may be better tolerated as coughing is not a frequent adverse effect. As ARBs are more expensive and have not shown any additional clinical benefits over ACE inhibitors, they are usually considered as an alternative for ACE inhibitors intolerant patients.

ACE inhibitors and ARBs share most indications and contraindications:

  • Indications for ACE inhibitors/ARBs
    • Hypertension (HTN), alone or in combination with diuretic or calcium-channel blocker
    • Heart failure or asymptomatic left ventricular dysfunction
    • Secondary prevention of coronary artery disease
    • Diabetes mellitus and diabetic nephropathy
  • Contra-indications for ACE inhibitors/ARBs
    • Severe aortic stenosis
    • Severe hyperkalaemia
    • Symptomatic hypotension
    • Renovascular hypertension (bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney)
    • Pregnancy
    • Angio-oedema
  • ACE inhibitors/ARBs are not contraindicated, but should be used with caution for:
    • Moderate renal insufficiency (serum creatinine <3 mg/dL)
    • Mild hyperkalaemia (K+ <5.5 mEq/L)
    • Asymptomatic hypotension
  • Practical tips & tricks on when and how to change from ACE inhibitors to ARBs
    • When RAAS blockade is indicated, ACE inhibitors should be used as first-line treatment
    • There are currently no compelling indications for the use of ARBs routinely as first-line treatment
    • The combination of ACE inhibitors/ARBs is contraindicated in the vast majority of patients
    • When RAAS blockade is needed but ACE inhibitors are not well tolerated due to a persistent dry cough, ARBs can be considered as an alternative (ARBs should be avoided as an alternative to ACE inhibitors in patients who develop severe renal insufficiency or hyperkalaemia as adverse effects of this treatment)
    • In case of a switch from ACE inhibitors to ARBs, it seems reasonable to stop ACE inhibitors and start ARBs the following day at an equivalent dose.

 

Drug Indications Dose Dose adjustments Comments
ACE inhibitors
Ramipril HF, HTN Start: 2.5 mg oral QD
Target dose: 5 mg BID
CrCl < 40ml/min: start 1.25 mg QD,
max 5 mg/daycaution in elderly and hepatic impairment
Check renal function, electrolytes and drug interactions:
  • Potassium-sparing diuretics, potassium supplements or salt substitutes may lead to an increase in serum potassium and serum creatinine.
  • Non-steroidal anti-inflammatory drugs use may lead to increased risk of renal impairment and loss of antihypertensive effect.
  • Start at low doses and increase gradually (after at least 2 weeks) until the target dose is achieved.
Monitor renal function and serum potassium closely.
Common adverse effects:
dry cough, hypotension, deterioration of renal function, hyperkalaemia.
Captopril  HF Start: 6.25 mg oral TID Target dose: 50 mg TID  CrCl > 50 ml/min: 75-100% of the normal dose
CrCl 10-50ml/min: 25-50%
CrCl < 10ml/min: 12.5%
HTN Start: 12.5 mg oral BID Target dose: 25-50 mg TIDMax 450 mg/day
Enalapril  HF, HTN Start: 2.5 mg oral BID Target dose: 10-20 mg BID CrCl 30-80ml/min: start 5 mg/day
CrCl 10-30ml/min: start 2.5 mg/day
Lisinopril   HF Start: 2.5-5.0 mg oral QD Target dose: 20-35 mg QD CrCl 31-80ml/min: start 5-10 mg/day
CrCl 10-30ml/min: start 2.5-5 mg/day
CrCl < 10ml/min: start 2.5 mg/day
HTN 10-20 mg oral QD Max: 80 mg QD
Perindopril  HF Start: 2.5 mg oral QDMax: 5mg QD CrCl > 60ml/min: start 5 mg/day
CrCl 31-60ml/min: start 2.5 mg/dayCrCl 15-30ml/min: start 2.5 mg alternate days
CrCl < 15ml/min: start 2.5 mg/day on the dayof dialysis
HTN Start: 2.5-5 mg QD Target dose: 10 mg QD
Trandolapril  HF Start: 2.5 mg oral QD
Max: 5mg QD
CrCl > 60ml/min: start 5 mg/day
CrCl 31-60ml/min: start 2.5 mg/dayCrCl 15-30ml/min: start 2.5 mg alternate days
CrCl < 15ml/min: start 2.5 mg/day on the dayof dialysis
HTN Start: 2.5-5 mg QD
Target dose: 10 mg QD
ARBs
Candesartan  HF, HTN Start: 4-8 mg oral QD
Target dose: 32 mg QD
if renal or hepatic impairment:
start 4 mg/day
 Check renal function, electrolytes and drug interactions:
  • Potassium-sparing diuretics, potassium supplements or salt substitutes may lead to increases in serum potassium and in serum creatinine.
  • Non-steroidal anti-inflammatory drugs use may lead to increased risk of renal impairment and loss of antihypertensive effect
Start at low doses and gradually increase (after at least 2 weeks) until the target dose is achieved. 

Monitor renal function and serum potassium closely after drug initiation and uptitration.

Common adverse effects:hypotension, deterioration of renal function, hyperkalaemia
Losartan  HF Start: 50 mg oral QD
Target dose: 150 mg QD
CrCl < 20ml/min: 25 mg QD
caution if hepatic impairment
HTN 50-100 mg oral QD
Valsartan HF start: 40 mg oral Bid
target dose: 160 mg Bid
if mild-moderate hepatic impairment: max dose 80 mg/day
HTN >80-160mg QD

References


De Sutter J, Mendes M, Franco OH. Chapter 19 Cardioprotective drugs. In: Gielen S, De Backer G, Piepoli MF, Wood D, editors. The ESC Textbook of Preventive Cardiology. 2nd ed. United Kingdom: Oxford University Press, 2016.

Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Eur Heart J 2016; 37: 2315–2381.

De Lorenzo A. Chapter 8: Drugs used in acute cardiovascular care. In: Bueno H, Vrancks P, Bonnefoy E. The Acute Cardiovascular Care Association clinical decision-making toolkit.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

The ESC Prevention of Cardiovascular Disease programme is supported by AMGEN, AstraZeneca, Ferrer, and Sanofi and Regeneron in the form of educational grants.