Cilazapril must be switched now – how to avoid ‘rocking the boat’

Tom is a 64-year-old Māori man who currently takes cilazapril 5mg once daily for hypertension, atorvastatin 20mg once daily for cardiovascular disease risk, vildagliptin + metformin (Galvumet 50mg/1000mg) one tablet twice daily and empagliflozin 25mg once daily for type 2 diabetes, and allopurinol 300mg once daily for gout prevention. You had previously advised him to please consult with you the next time he needs a repeat prescription for cilazapril as it needs to be changed to an alternative medicine. He has had a blood test in preparation for the visit (Table 1).

When you first met Tom in 2018, he had recurrent, disabling gout flares, type 2 diabetes, and high cardiovascular disease risk, none of which were being treated pharmacologically. He was fatalistic that no one in his family had lived past age 60 due to coronary heart disease, and he was not keen on taking medicines.

Since then, he has come to terms with the need to take medicines to prevent gout flares and their long-term sequelae, and to reduce his cardiovascular and renal risk factors. He has also been implementing lifestyle changes.

Tom is delighted with how he feels and likes to see his laboratory results change from “red” (abnormal) to “black” on the portal. He no longer gets gout flares, although he tells you he had “twinges” one hot weekend in November when he was helping his son build a deck. He does not report any cough. He previously wanted to delay switching cilazapril as he was worried about “rocking the boat”.

Losartan may offset the serum uric acid-increasing effects of other medicines

People taking cilazapril need to be switched to an alternative ACE inhibitor or an angiotensin receptor blocker (ARB) by mid-2023. At such time, cilazapril will become delisted due to the potential for supply issues. It may be important to reassure people that this change is not due to any concerns regarding cilazapril’s effectiveness or any newly discovered adverse effects.

There is no exact alternative to cilazapril. Most ACE inhibitors are similar and essentially interchangeable as their differences are small. Most ACE inhibitors and ARBs are similar in effectiveness, but there are some prescribing considerations and possible interpatient variability in tolerability. In addition, most ACE inhibitors can be taken once daily for hypertension, but some should be taken twice daily for heart failure, which may influence the choice of medicine. It can be helpful to ask the person what they would prefer and consider adherence.

Historically, ACE inhibitors had the greater evidence base over ARBs, with the latter prescribed if the person didn’t tolerate an ACE inhibitor. However, early studies did not allow a direct comparison between ACE inhibitors and ARBs. Subsequent meta-analyses showed no significant difference in the primary outcomes of acute myocardial infarction, heart failure, stroke or composite cardiovascular events between treatment groups, but fewer reports of adverse effects from ARBs.^1,2

Many clinicians now prefer to start a person directly on an ARB to avoid potential side effects of ACE inhibitors, as these result in reluctance to take medicines and may lead to non-adherence and inequitable outcomes.

The most common adverse effect of ACE inhibitors is cough, which can occur in 5–20 per cent of people up to two years after initiation. If cough occurs, a change to an ARB is warranted. Cough associated with ARBs is approximately 65–75 per cent lower than with ACE inhibitors.

Angio-oedema is a rare but serious adverse effect of ACE inhibitors, with an incidence of 0.3 per cent (of which 20 per cent is severe), whereas the incidence with ARBs is much lower at approximately 0.1 per cent. Angio-oedema may also present atypically, with less acute, localised or mild symptoms, intermittent abdominal pain, or isolated limb swelling. This may occur years after initiation.

Losartan is an alternative to consider if the person has gout. Losartan is the only ARB (or ACE inhibitor) that has a demonstrated uricosuric effect. However, this is subject to pharmacogenomic variation, with resultant serum uric acid (SUA) lowering of up to 20 per cent. Even allowing for variation, losartan may offset the SUA-increasing effects of other medicines, such as thiazides, when used as an add on (but not replacement) for allopurinol or other gout preventers.

Although there is some variation between individual studies, the overall evidence for renal protection in people with hypertension and pre-existing albuminuria is not significantly different between ACE inhibitors and ARBs.^3–6 However, diabetic nephropathy is currently only an approved use for losartan, not candesartan, in people with type 2 diabetes in Aotearoa New Zealand.

An additional consideration is that empagliflozin reduces the baseline risk of progression to end-stage kidney disease by approximately one-third. This is such a large effect compared with ACE inhibitors and ARBs that any difference between the classes would not be clinically relevant if empagliflozin is being taken.

In heart failure with reduced ejection fraction, the guidance is for an angiotensin receptor–neprilysin inhibitor as first-line therapy, with an ACE inhibitor or ARB if ARNIs are not tolerated.⁷ An important consideration when changing agents is that the treatment targets for ACE inhibitors and ARBs in heart failure differ from those in hypertension, as the dose is titrated to the maximum tolerated rather than to a blood pressure target. Further, close monitoring is required to avoid decompensation.

For people with concurrent heart failure with reduced ejection fraction, empagliflozin reduces the risk of cardiovascular death or hospitalisation for heart failure by 25 per cent, and that of any heart failure hospitalisations by 30 per cent.⁸ So, again, any differences between ACE inhibitors and ARBs would not be clinically significant if empagliflozin is being taken. However, these people may require closer monitoring during a medication change.

Below are the suggested cilazapril switching strategies for people with hypertension.

Blood pressure satisfactory, stable person – switch as per Table 2, and monitor blood pressure in case of increased or decreased effect.

Blood pressure not optimal – and/or 24-hour ambulatory blood pressure monitoring shows no night dip or not maintaining 24-hour control:

• consider perindopril (longer half-life), or
• use increased dose of another agent, or
• switch to two agents – for example, add thiazide-like medicine (chlortalidone or indapamide) or a calcium channel blocker (amlodipine or felodipine), or
• give the ACE inhibitor or ARB at night – if the person is confident (>8/10) they will take the night dose, otherwise keep administering it in the morning.

Systolic blood pressure <120mmHg or <130mmHg in an older, frail person; postural hypotension; or low sodium or high potassium levels – if no heart failure, trial a lower-dose equivalent at first, and titrate depending on clinical situation. Remember ACE inhibitors and ARBs can rarely cause hyponatraemia or hyperkalaemia.

Concurrent gout – losartan is the preferred choice due to its slight uricosuric effect (up to 0.055mmol/L or approximately 20 per cent SUA lowering). This is subject to significant interpatient variation, and usual urate-lowering therapy must be continued.

Triple whammy (ACE inhibitor/ARB plus diuretic plus NSAID) – consider whether a calcium channel blocker (amlodipine or felodipine) can be used instead of the thiazide diuretic if NSAIDs are indicated.

Stable heart failure – take caution with switching in case of destabilisation. Treat to the maximum tolerated dose, not to a blood pressure target. Close follow-up is required, and consult with someone experienced in heart failure management if you are concerned.

Remember, do not use an ACE inhibitor and ARB concurrently due to an increased risk of adverse events, including renal impairment, and no demonstrated improvement in clinical outcome.

An ARB is preferred for people of African or Caribbean ethnicity with type 2 diabetes, due to a risk of angio-oedema with ACE inhibitors. A calcium channel blocker is recommended if there is no diabetes and only hypertension.

A change of agent to a similar dose in a stable patient is unlikely to cause adverse effects such as cough, angio-oedema or electrolyte disturbance. However, it is possible for some interpatient variability, and people should be advised to report any signs of gastrointestinal disturbance, nausea, swelling, headache, dizziness or rash.

A change in dose or agent requires baseline renal function tests and electrolytes, repeated at one to two weeks and at three months. The stability of electrolyte levels, and whether they are low or high normal, would influence the frequency of monitoring.

Do not increase the dose if potassium is elevated. Titrate upwards slowly at a minimum of every two weeks, provided serum creatinine does not rise above 30 per cent from baseline, and estimated glomerular filtration rate does not drop more than 25 per cent. A small increase in creatinine is not unexpected with up-titration of doses or a change in agent. Several studies indicate this may be due to a reduction in hyperfiltration (pre-renal success).

Check blood pressure at baseline and at two to four weeks (two weeks for heart failure). Some people may require a few checks at each dose before increasing due to natural variations in blood pressure.

Tom’s blood pressure has been stable and less than 130/80mmHg since taking cilazapril 5mg daily. He hasn’t developed an ACE inhibitor-induced cough, so one option could be to swap to another ACE inhibitor. However, as he has concurrent gout and his SUA level is just above the target of 0.36mmol/L, and he had some gout twinges when he was dehydrated, he may benefit more from changing to losartan.

You advise him that losartan may only lower his SUA level by approximately 10–20 per cent, and it is not a “gout drug”, so he should continue allopurinol as well. Tom agrees to this, and you prescribe him losartan 100mg daily. You tell him he can swap straight over after he runs out of cilazapril.

You reassure him that some people experience slight light-headedness after the first dose, although this is unlikely for him as the dose is similar to cilazapril 5mg. Any light-headedness should resolve, but you tell him to contact you if it doesn’t, or if he experiences a rash or gastrointestinal upset. You remind Tom about the importance of hydration to avoid gout, and because of concurrent empagliflozin. You then take the opportunity to refresh his sick day plan.

As Tom has had very stable renal function, and his electrolytes are mid-range, there is unlikely to be any significant changes to his laboratory results. Therefore, you give him a laboratory form for a repeat creatinine, electrolytes and SUA level in four weeks, and he agrees to call in for a blood pressure check with the medical centre assistant.

This case study does not represent an identifiable person

Penny Clark is a pharmacist prescriber at NorthCare, Hamilton