MHRA Drug Safety Update (June 2014): Combination use of medicines from different classes of renin-angiotensin system blocking agents is associated with an increased risk of hyperkalaemia, hypotension, and impaired renal function and is therefore not recommended as routine practice.

• Combination use of medicines from two classes of RAS blocking agents (ACE inhibitor (ACEi), Angiotensin Receptor Blocker (ARB) or direct renin inhibitors (aliskiren)) is not recommended
• The combination of an ACEi and an ARB is not recommended for the management of primary hypertension
• Prescribers are advised not to give patients with diabetic nephropathy an ACEi with an ARB since they are particularly prone to developing hyperkalaemia
• The combination of aliskiren with an ACEi or ARB is contraindicated in patients with kidney impairment (estimated glomerular filtration rate [eGFR] < 60 mL/minute/1.73 m²) or diabetes
• Combination therapy with ACEi and ARBs may be initiated only by specialists for patients with resistant proteinuria which is unresponsive to either medication alone.

Patients with heart failure:

• The benefits of combination use may outweigh the risks in a selected group of people with heart failure for whom other treatments are unsuitable. Some patients with heart failure may have a medical need for treatment with an ACEi and an ARB. Candesartan and valsartan are licensed as add-on therapy to ACEi for people with symptomatic heart failure who require such a combination despite optimal therapy. Specialist guidance should be sought
• The triple combination of an ACEi, ARB, and a mineralocorticoid receptor antagonist or other potassium-sparing diuretic is not recommended.

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.

Monitoring of drugs acting on the renin-angiotensin system:

• Measure serum potassium concentrations and eGFR before starting ACEi, ARBs and direct renin inhibitors. Repeat these measurements between 1 and 2 weeks after starting, after each dose increase, and regularly during intercurrent illness or if concomitant drug treatment is modified; thereafter renal function should be monitored regularly (e.g. annually).
• Healthcare Commission audit standards advise 6 monthly monitoring of renal function in patients with heart failure. Consider monitoring these parameters monthly in patients taking a combination of medication acting on the renin-angiotensin system.
• Following introduction or a dose increase, if either the eGFR decrease from pre-treatment baseline is less than 25% or the serum creatinine increase from baseline is less than 30% do not modify the dose; repeat the test in 1–2 weeks. If the eGFR change is 25% or more, or the change in serum creatinine is 30% or more stop drug, and investigate cause of deterioration in renal function, such as volume depletion or concurrent medication (for example, NSAIDs). If no explanation, consider investigation for renal artery stenosis. Do not discontinue for lesser changes in eGFR/creatinine, some change is expected. If no cause for the deterioration in renal function is found, stop the medication or reduce the dose to a previously tolerated lower dose, and add an alternative antihypertensive medication if required.
• Do not routinely offer a drug that blocks or inhibits the renin–angiotensin to people with CKD if their pre-treatment serum potassium concentration is greater than 5.0 mmol/litre.
• Concurrent prescription of drugs known to promote hyperkalaemia (e.g. NSAIDs or potassium sparing diuretics) is not a contraindication to the use these agents, but be aware that more frequent monitoring of serum potassium concentration may be required. Use the lowest effective dose of spironolactone and ACEi or ARB if co-administration is considered essential.
• If serum potassium concentration increases to 6.0 mmol/litre or more, stop drugs known to promote hyperkalaemia and check diet as a cause for raised potassium (e.g. 'LoSalt' intake). If hyperkalaemia persists the ACEi or ARB should be stopped. Modest stable hyperkalaemia may be preferable to discontinuing a valuable therapy.

All patients who have indications for ACEi or ARBs are at higher risk of acute kidney injury (AKI), therefore consideration should be given to stopping these drugs temporarily during an acute illness that increases the risk of AKI (for example, diarrhoea, vomiting and other conditions leading to dehydration or shock).

2.5.5.1 Angiotensin-converting enzyme inhibitors

Doses of ACEi should be titrated up until target doses are reached. In heart failure it is important that ACEi are titrated up to their target dose (or maximum tolerated), as advised by NICE.

Patients discharged from hospital following an acute coronary syndrome, post MI have usually been started on ACEi and beta-blockers, however the doses are usually suboptimal and need up-titrating. Following an infarct with significant damage to the left ventricle it is important that the ACEi is up-titrated first. Doses can be increased every 2 weeks in accordance with the BNF dosing regimen. The beta-blocker needs up-titrating with similar time intervals. Up-titrate agents one at a time.

Profound first-dose hypotension may occur when ACEi are introduced to patients with heart failure who are already taking a high dose of a loop diuretic (e.g. furosemide 80 mg daily or more). Temporary withdrawal of the loop diuretic reduces the risk, but may cause severe rebound pulmonary oedema. Therefore, for patients on high doses of loop diuretics, the ACEi may need to be initiated under specialist supervision. An ACEi can be initiated in the community in patients who are receiving a low dose of a diuretic or who are not otherwise at risk of serious hypotension; nevertheless, care is required and a very low dose of the ACEi is given initially.

ACEi should be initiated under specialist supervision and with careful clinical monitoring in those with severe heart failure or in those:

• receiving multiple or high-dose diuretic therapy (e.g. more than 80 mg of furosemide daily or its equivalent);
• receiving concomitant ARB or aliskiren;
• with hypovolaemia;
• with hyponatraemia (plasma-sodium concentration below 130 mmol/litre);
• with hypotension (systolic blood pressure below 90 mmHg);
• with unstable heart failure;
• receiving high-dose vasodilator therapy;
• known renovascular disease.

Enalapril

• Tablets 2.5mg, 5mg, 10mg, 20mg (£0.81 = 10mg daily)

Indications

• Hypertension
• Heart failure

Lisinopril

• Tablets 2.5mg, 5mg, 10mg, 20mg (£0.72 = 5mg daily)

Indications

• Hypertension
• Heart failure
• Renal complications of diabetes mellitus
• Prophylaxis after myocardial infarction

Dose

• Hypertension:
  • initially 10mg once daily;
  • if used in addition to diuretic or in cardiac decompensation or in volume depletion, initially 2.5–5mg once daily;
  • usual maintenance dose 20mg once daily; maximum 80mg once daily
• Heart failure (adjunct), initially 2.5mg once daily under close medical supervision; increased in steps no greater than 10mg at intervals of at least 2 weeks up to maximum 35mg once daily if tolerated
• Renal complications of diabetes mellitus, initially 2.5–5mg once daily adjusted according to response; usual dose range 10–20mg once daily

Ramipril

• Capsules 1.25mg, 2.5mg, 5mg, 10mg (£0.99 = 5mg daily)

Indications

• Hypertension
• Heart failure
• Prophylaxis of cardiovascular events
• Prophylaxis after myocardial infarction

Dose

• Hypertension, initially 1.25–2.5mg once daily, increased at intervals of 2–4 weeks to maximum 10 mg once daily; if used in addition to diuretic
• Heart failure (adjunct), initially 1.25mg once daily under close medical supervision, increased gradually at intervals of 1–2 weeks to maximum 10mg daily if tolerated (preferably taken in 2 divided doses)
• Prophylaxis after myocardial infarction (started at least 48 hours after infarction), initially 2.5mg twice daily, increased after 3 days to 5mg twice daily
• Prophylaxis of cardiovascular events, initially 2.5mg once daily, increased after 1–2 weeks to 5mg once daily, then increased after a further 2–3 weeks to 10mg once daily

Perindopril arginine

Following national guidance from NHS England, perindopril arginine is not recommended for use due to significant extra costs and no evidence of clinical advantage. Click here for more information. Prescribers should not initiate perindopril arginine for any new patient. Click the following link for a patient information leaflet to support deprescribing.

Perindopril erbumine

• Tablets 2mg, 4mg, 8mg (£0.92 = 4mg daily)

Indications

• Secondary prevention of stroke or TIA

2.5.5.2 Angiotensin-II receptor antagonists

Angiotensin-II receptor antagonists (ARBs) can be used for those patients who suffer from unacceptable side effects when using ACEi. ARBs have many similar properties to ACEi. However, unlike ACEi, are less likely to cause the persistent dry cough which can complicate ACEi therapy. They are therefore a useful alternative for patients who have to discontinue an ACEi because of persistent cough. Note that cough is common in patients with chronic heart failure, many of whom have smoking-related lung disease. Cough is also a symptom of pulmonary oedema which should be excluded when a new or worsening cough develops. Care should therefore be taken when attributing 'worsening cough' as a side effect of ACE inhibitor treatment.

Candesartan

• Tablets 2mg, 4mg, 8mg, 16mg, 32mg (£1.07 = 8mg daily)

Indications

• Hypertension
• Heart failure

Losartan

• Tablets 12.5mg, 25mg, 50mg, 100mg (£0.88 = 50mg)

Indications

• Hypertension

Valsartan

• Capsules 40mg, 80mg, 160mg (£12.24 = 160mg twice daily)

Indications

• Prophylaxis after myocardial infarction- for patients intolerant of ACE inhibitors and showing signs of heart failure

Dose

• Treatment should be initiated at 20mg twice daily and titrated first to 40mg twice daily and then 80mg twice daily, and to a target dose of 160mg twice daily over the next few weeks

Sacubitril/ valsartan

• Tablets sacubitril 24mg/ valsartan 26mg (£45.78)
• Tablets sacubitril 49mg/ valsartan 51mg (£91.56)
• Tablets sacubitril 97mg/ valsartan 103mg (£91.56)

Indications

• Sacubitril valsartan is recommended in accordance with NICE TA388 as an option for treating symptomatic chronic heart failure with reduced ejection fraction, only in people:
  • with New York Heart Association (NYHA) class II to IV symptoms and
  • with a left ventricular ejection fraction of 35% or less and
  • who are already taking a stable dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor-blockers (ARBs).
• Prior treatment with an ACE inhibitor or ARB is a pre-requisite in accordance with NICE TA388 however treatment must be stopped prior to initiation of sacubitril valsartan.

Dose

• The initial dose is one tablet of 49mg/51mg twice daily, except in the situations described below. The dose should be doubled at 2-4 weeks to the target dose of one tablet of 97mg/103mg twice daily, as tolerated by the patient.
• A lower starting dose of 24mg/26mg may be required for patients who were taking a low dose of ACE inhibitor or ARB, patients with, low systolic blood pressure (SBP), or renal impairment (see manufacturer's information for further details)
• Treatment should not be initiated in patients with serum potassium level >5.4mmol/l or with SBP <100 mmHg

Notes

1. To avoid accidental prescribing of concomitant ACEi or ARB it is recommended that sacubitril/valsartan is prescribed using the generic name.
2. Sacubitril valsartan should be used in accordance with NICE TA388 (April 2016).
3. Treatment with sacubitril valsartan should be initiated by a heart failure specialist. Following dose titration and once the patient is stabilised on treatment by the specialist heart failure team, ongoing management and monitoring of the patient may be performed in primary care. Initial clinical assessment, monitoring and prescribing will remain the responsibility of the specialist heart failure team until the patient is stabilised on treatment.
4. Sacubitril valsartan should not be co-administered with an ACE inhibitor or an ARB. Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor, sacubitril/valsartan must not be started for at least 48 hours after discontinuing ACE inhibitor therapy. A washout period is not needed if switching from an ARB to sacubitril valsartan.
5. Following stabilisation on a maximum tolerated dose, patients should be monitored in line with the NICE clinical guideline on chronic heart failure management.

2.5.5.3 Renin inhibitors

Aliskiren

Following national guidance from NHS England, aliskiren is not recommended for use because more cost-effective products are available. Click here for more information. Prescribers in primary care should not initiate aliskiren for any new patient. In exceptional circumstances, consultants may undertake a trial of aliskiren for patients with resistant hypertension.

Patients who are currently prescribed aliskiren in primary care should not have their prescriptions stopped without a review by a specialist.

The combination of aliskiren with ACE inhibitors or ARBs has been associated with serious adverse cardiovascular and renal outcomes and is not recommended; the combination is strictly contraindicated in people with kidney impairment (eGFR less than 60mL/min per 1.73m²) or diabetes. Any use of aliskiren (either as monotherapy or in combination with other medicines) is no longer recommended in any patient with severe renal impairment (eGFR less than 30mL/min/1.73m²). Refer to guidance at the top of the page and the following MHRA Drug Safety Updates:

• MHRA Drug Safety Update (May 2009): Aliskiren (Rasilez▼): risk of angioedema and renal dysfunction
• MHRA Drug Safety Update (March 2012): Aliskiren (Rasilez▼): risk of cardiovascular and renal adverse reactions
• MHRA Drug Safety Update (June 2014): Combination use of medicines from different classes of renin-angiotensin system blocking agents: risk of hyperkalaemia, hypotension, and impaired renal function – new warnings