Combination use of medicines from different classes of renin-angiotensin system blocking agents: risk of hyperkalaemia, hypotension, and impaired renal function—new warnings

New warnings due to risk of hyperkalaemia, hypotension, and impaired renal function have been agreed following an EU-wide review.

Article date: June 2014

The renin-angiotensin hormone system (RAS) controls blood pressure and the volume of fluids in the body. Medicines that have an inhibitory action on the RAS (RAS blocking agents) are used to treat high blood pressure and congestive heart failure. Some are also used to reduce protein loss through the urine in certain kidney disorders. RAS blocking agents fall into three classes: angiotensin-receptor blockers (ARBs, sometimes known as sartans), angiotensin-converting enzyme inhibitors (ACE-inhibitors), and direct renin inhibitors (aliskiren is the only direct renin inhibitor currently marketed in the UK).

Combination use review

An EU review recently concluded that combination use of medicines from two classes of RAS blocking agents is not recommended. The review identified evidence from large clinical trials such as ONTARGET,1 ALTITUDE, 2 and VA NEPHRON-D 3 and from meta-analyses such as Makani 2013. 4 These studies showed that combination use was associated with an increased risk of hyperkalaemia, hypotension, and impaired renal function compared with using either class of RAS blocking agent alone. No significant benefits of combination use were seen in patients who did not have heart failure.

Heart failure

There is some evidence that the benefits of combination use may outweigh the risks in a selected group of people with heart failure for whom other treatments are unsuitable.5 Candesartan and valsartan, both ARBs, are the only two RAS blocking agents licensed as add-on therapy to ACE-inhibitors for people with symptomatic heart failure who require such a combination despite optimal therapy.

The triple combination of an ACE-inhibitor, ARB, and a mineralocorticoid receptor antagonist or other potassium-sparing diuretic is not recommended.

Diabetic nephropathy

Prescribers are advised that patients with diabetic nephropathy should not be given an ARB with an ACE-inhibitor as they are already prone to developing hyperkalaemia.

Contraindications

As previously reported, combining aliskiren and an ACE-inhibitor or ARB is strictly contraindicated in people with kidney impairment (estimated glomerular filtration rate [eGFR] < 60 mL/minute/1.73 m2) or diabetes (see the Drug Safety Update article from March 2012).

Advice for healthcare professionals:

  • Combination use of medicines from two classes of RAS blocking agents (ACE-inhibitors, ARBs, or aliskiren) is not recommended.
  • In particular, prescribers are advised not to give patients with diabetic nephropathy an ACE-inhibitor with an ARB since they are particularly prone to developing hyperkalaemia.
  • The combination of aliskiren with an ACE-inhibitor or ARB is contraindicated in patients with kidney impairment or diabetes.

Patients with heart failure

  • Some patients with heart failure may have a medical need for treatment with an ACE-inhibitor and an ARB. Candesartan and valsartan are licensed as add-on therapy to ACE-inhibitors for people with symptomatic heart failure who require such a combination despite optimal therapy.
  • The triple combination of an ACE-inhibitor, ARB, and a mineralocorticoid receptor antagonist or other potassium-sparing diuretic is not recommended.

Patients currently taking a combination of RAS blocking agents

  • Review the treatment of all patients currently taking a combination of RAS blocking agents at a routine appointment. Carefully consider if combination use is appropriate.
  • If combination use is considered absolutely necessary, it must be carried out under specialist supervision and with close monitoring of blood pressure, renal function, and electrolyte levels (particularly potassium). Consider monitoring patients when combination use is started and on a monthly basis thereafter, and also after changing dose and during intercurrent illness.

Article citation: Drug Safety Update volume 7 issue 11, June 2014: A1.

  1. Yusuf S, et al. N Engl J Med 2008; 358: 1547-59.

  2. Parving HH, et al. N Engl J Med 2012; 367: 2204-13.

  3. Fried LF, et al. N Engl J Med 2013; 369: 1892-1903.

  4. Makani H, et al. BMJ 2013; 346: f360.

  5. McMurray JJ, et al. Eur Heart J 2012; 33:1787-847.

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