Prescribing ACE inhibitors: time to reconsider old habits

Prescribers in New Zealand are highly reliant on cilazapril as their “go-to” ACE inhibitor, but this prescribing is out of step with many other countries where cilazapril is infrequently used, such as Australia and the United Kingdom. Guidelines that recommend use of an ACE inhibitor support the use of any medicine in this class as they are regarded as having similar benefits and risks. High rates of cilazapril use could lead to problems if supply issues were to develop.

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Key practice points:

In New Zealand, approximately 60% of people taking angiotensin-converting enzyme (ACE) inhibitors are prescribed cilazapril. The high use of cilazapril in New Zealand, and low use internationally, leaves New Zealand vulnerable to supply issues.
Consider the range of subsidised ACE inhibitors and whether an ACE inhibitor other than cilazapril could be prescribed when initiating treatment:
- The benefits and risks associated with ACE inhibitors are similar across the class
- Most ACE inhibitors can be taken as once-daily tablets
- Contraindications, cautions and medicines interactions are similar for all ACE inhibitors

Approximately half a million people in New Zealand are prescribed an angiotensin-converting enzyme (ACE) inhibitor, and of these, approximately 60% are prescribed cilazapril, making it the ninth highest prescribed medicine by number of prescriptions in New Zealand.^{1, 2} The high prescribing rates of cilazapril in New Zealand are likely to originate in historical subsidy decisions and successful marketing by the manufacturer.¹ Even though a range of ACE inhibitors are now subsidised, familiarity means cilazapril remains a favoured choice for many clinicians when prescribing an ACE inhibitor. However, the high rates of use in New Zealand increases exposure to supply issues, particularly as cilazapril is used infrequently or not at all in other countries such as Australia and the United Kingdom.^{1, 3} If supply issues were to develop, large numbers of patients would need to be switched to an alternative ACE inhibitor. ACE inhibitors widely used overseas that are subsidised in New Zealand include perindopril and lisinopril.^{3, 4}

ACE inhibitors are generally prescribed in primary care for:

Hypertension; either an ACE inhibitor, angiotensin receptor blocker (ARB), calcium channel blocker (CCB) or thiazide diuretic are recommended as first-line options^*. An ACE inhibitor is preferred for patients with, or at high risk of, diabetes or with chronic kidney disease.⁵
Heart failure with reduced ejection fraction; an ACE inhibitor is typically initiated alongside a diuretic and beta blocker.^{6, 7} ACE inhibitors may be used in some patients with heart failure with preserved ejection fraction, e.g. patients with concurrent hypertension.
Following a myocardial infarction in order to reduce the risk of heart failure, re-infarction and cardiovascular mortality; lisinopril and quinapril are approved for this indication.^{8, 9}
Diabetic nephropathy¹⁰; this is an unapproved indication.

^* In people of African or Caribbean ethnicity, a thiazide diuretic or CCB are recommended as first-line options as evidence suggests ACE inhibitors are less effective in these population groups.⁵

ACE inhibitors subsidised in New Zealand are: cilazapril, enalapril, lisinopril, perindopril and quinapril (Table 1). Captopril is available in an oral liquid formulation subsidised for children aged ≤ 12 years. Subsidised combination formulations of cilazapril or quinapril with a diuretic are also available.

If guidelines recommend prescribing an ACE inhibitor, any of these options can be used as ACE inhibitors are generally recommended as a class, without specifying individual medicines.^{6, 8, 11} In fact, there is more evidence in support of ACE inhibitors such as enalapril, lisinopril and perindopril, rather than cilazapril, as these are the medicines used in clinical trials which form the basis of guideline recommendations.^{5, 12}

No differences between adverse effects

There is no evidence of any difference in effectiveness or rates of adverse effects between ACE inhibitors when used for heart failure or hypertension. The available research has found that differences are not statistically significant, findings are not consistent or patient risk factors that affect morbidity and mortality have not been taken into account.^13–17

Other factors which can influence prescribing decisions, such as medicines interactions, contraindications, and dose reductions in renal impairment, are similar for all members of the ACE inhibitor class.⁹

Titration and dosing are similar

Most of the subsidised ACE inhibitors are available in three tablet sizes, allowing for titration and adjustments to dosing (Table 1). All ACE inhibitors require titration to effect over the same timeframe.⁹

Once-daily medicines are recommended where possible to make dosing and adherence simpler for patients. Once-daily dosing is possible with any of the subsidised ACE inhibitors, although quinapril and enalapril are usually dosed twice daily in patients with chronic heart failure and quinapril may be dosed twice daily in some patients with hypertension.⁹

Combination tablets containing quinapril are available in two different doses, allowing for greater flexibility in dosing of the ACE inhibitor component of a combination tablet, compared to one fixed dose available for cilazapril combination tablets.

Table 1: Subsidised ACE inhibitors, available tablet strength and recommended doses⁹

	Cilazapril	Enalapril	Lisinopril	Perindopril	Quinapril
Tablet strength	0.5 mg 2.5 mg 5.0 mg	5 mg 10 mg 20 mg	5 mg 10 mg 20 mg	2 mg 4 mg	5 mg 10 mg 20 mg
ACE inhibitor + diuretic combination tablets	cilazapril 5 mg + hydrochlorothiazide 12.5 mg				quinapril 10 mg + hydrochlorothiazide 12.5 mg quinapril 20 mg + hydrochlorothiazide 12.5 mg
Starting dose^*
In patients with hypertension	0.5–1.0 mg, once daily	5 mg, once daily	2.5–10 mg, once daily	2–4 mg, once daily	2.5–10 mg, once daily
In patients with heart failure	0.5 mg, once daily	2.5 mg, once daily	2.5 mg, once daily	2 mg, once daily	2.5 mg, twice daily
Typical maintenance dose^*
In patients with hypertension	2.5–5 mg, once daily	20 mg, once daily	20 mg, once daily	4–8 mg, once daily	20–40 mg, daily in one or two divided doses
In patients with heart failure	5 mg, once daily	10 mg, twice daily^**	20 mg, once daily	4 mg, once daily	10 mg, twice daily^**

^* Starting and maintenance doses depend on the condition being treated and the patient’s response to treatment. All ACE inhibitors are titrated at the same rate. Lower doses are recommended for patients with renal impairment for most ACE inhibitors, and lower initial doses for older patients; see NZF for further details: www.nzf.org.nz/nzf_1240

^**Can be once daily if tolerated

In order to reduce reliance on cilazapril, clinicians are encouraged to initiate patients on an ACE inhibitor other than cilazapril.

All ACE inhibitors require a low starting dose with titration to effect over a number of weeks, with the same rate of titration regardless of which ACE inhibitor is prescribed.⁶ Consider lower initial dosing in patients at increased risk of adverse effects, such as older, frail people.

The same contraindications apply to all ACE inhibitors. They are contraindicated in pregnancy (as are ARBs) and can cause fetal malformations from exposure in the first trimester.⁹ In females of childbearing age, discuss contraception options and whether another treatment option may be more appropriate, e.g. a CCB for patients with hypertension. There is limited data on the use of ACE inhibitors in breast-feeding.⁹ ACE inhibitors should not be used in patients with a known hypersensitivity, e.g. a previous episode of angioedema while using an ACE inhibitor (see “Adverse effects” below)^*.⁹

The same risks of medicine interactions apply to all ACE inhibitors, and there is no reason to favour one over another on the basis of co-prescribed medicines.⁹

In patients with renal impairment, lower initial and maximum doses are recommended for all ACE inhibitors; see NZF for details: www.nzf.org.nz/nzf_1240.

In patients with hepatic impairment, the pharmacodynamic response and blood levels of ACE inhibitors may be altered. ACE inhibitors should be initiated at low doses with careful monitoring in these patients.¹⁸

^* Patients who experience angioedema while using an ACE inhibitor may be able to use an ARB without a recurrence of angioedema (see: “Could this patient take an angiotensin receptor blocker (ARB) instead of an ACE inhibitor?”)

Monitoring for adverse effects

Monitoring patients for the development of adverse effects is recommended during initiation of treatment and after adjusting doses of ACE inhibitors (Table 2). After the maximum tolerated dose has been reached, the frequency of monitoring can be reduced, guided by the condition being treated, co-morbidities and the patient’s risk of developing hypotension or renal impairment.¹¹ For example, patients with heart failure may require follow-up after two weeks if their clinical condition changes, but patients with stable hypertension and a stable medicine regimen may only require follow-up every six months or more.⁷

Table 2: Recommended monitoring for patients taking ACE inhibitors^{19, 20}

Monitoring recommended	Prior to initiation	One to two weeks after dose adjustments or changing ACE	After titration to maximum tolerated dose
Measure blood pressure			Depending on patient characteristics; at least annually
Ask patients about symptoms of hypotension or adverse effects
Request tests for: Creatinine Electrolytes

A dry, irritating cough is the most common adverse effect associated with the use of any ACE inhibitor. In a meta-analysis of approximately 200,000 people taking enalapril, the incidence of cough was 11%, with 3% of people withdrawing from treatment due to cough.²¹ Clinical trials have found rates of cough were two and half times higher in people of Asian ethnicity compared to European ethnicity.²¹ In patients who find the cough problematic, temporarily withdrawing treatment and then re-challenging with the same or another ACE inhibitor is an option, but in practice patients are often switched to an ARB (See: “Could this patient take an angiotensin receptor blocker (ARB) instead of an ACE inhibitor?”).

A decline in renal function is associated with the use of ACE inhibitors and ARBs. Blocking the effects of angiotensin-II, either through the use of ACE inhibitors or ARBs, reduces glomerular pressure and causes a reduction in glomerular filtration rate due to dilation of the efferent (post-glomerular) blood vessels.²² Some degree of increase in serum creatinine is likely, however, changes may resolve with continued treatment and withdrawing the ACE inhibitor is not always necessary (Table 3). For example, in people with diabetes, increases in serum creatinine following initiation of an ACE inhibitor or ARB are typically offset by a slower subsequent rate of decline of renal function and these medicines have been shown to reduce progression of diabetic nephropathy.²³ Most patients will not have increases in serum creatinine that necessitate withdrawal of treatment. In the United Kingdom, for example, only approximately 2% of people initiating an ACE inhibitor or ARB had an increase of creatinine levels of 30% or more in the two months after initiation.²⁴

Combined use of ACE inhibitors or ARBs with other medicines which influence renal function, such as non-steroidal anti-inflammatory medicines (NSAIDs) or diuretics, can increase the risk of acute kidney injury.

For further information on avoiding the risk of acute kidney injury when prescribing ACE inhibitors or ARBs, see: Avoiding the triple whammy in primary care: ACE inhibitor/ARB + diuretic + NSAID bpac^NZ, May 2018

The use of ACE inhibitors can increase serum potassium levels. Monitoring potassium levels is recommended, with management depending on the extent of change. In clinical trials, 1–5% of people using an ACE inhibitor had their serum potassium level increase to > 5.5 mmol/L.^{25, 26} A typical increase is around 0.1–0.2 mmol/L, which does not require intervention.²² To minimise the risk of hyperkalaemia while taking an ACE inhibitor, advise patients to avoid other medicines which cause an elevation of potassium levels, such as NSAIDs, and salt substitutes high in potassium, e.g. Lo Salt.⁶

Angioedema is a rare but potentially serious adverse effect which can be fatal. It can occur at any time, including in patients who have been taking ACE inhibitors for years.²¹ Clinical trials have found angioedema occurs in approximately 0.3% of people, with approximately 20% of these cases being life-threatening and affecting the upper respiratory tract and larynx.²¹ Patients who develop angioedema should stop taking an ACE inhibitor immediately; most patients can be cautiously switched to an ARB (see: “Could this patient take an angiotensin receptor blocker (ARB) instead of an ACE inhibitor?”).⁶

Table 3: An example of testing and monitoring for adverse effects in patients taking ACE inhibitors for heart failure; thresholds for intervention may differ in local guidance ^{6, 20}

Decision point	Extent of increase		Action
Prior to reducing dose or withdrawing treatment consider other causes of increased creatinine or potassium levels, such as other medicines or foods which influence potassium levels or renal function, or re-testing potassium as haemolysis can cause higher readings²⁷
Mild creatinine or potassium elevation	Creatinine	> 50% to < 100% higher than baseline (before an ACE inhibitor was initiated) OR > 266 micromol/L to < 310 micromol/L	Reduce the dose of ACE inhibitor by half
Mild creatinine or potassium elevation	Potassium	Above reference range but <5.9 mmol/L	Reduce the dose of ACE inhibitor by half
Moderate to severe creatinine or potassium elevation	Creatinine	>100% above baseline level OR > 310 micromol/L	Discontinue ACE inhibitor treatment Consider discussing treatment options with a nephrologist or cardiologist
Moderate to severe creatinine or potassium elevation	Potassium	> 5.9 mmol/L

A clinical audit on the safe and effective use of ACE inhibitors is available from: Safe and effective use of ACE inhibitors bpac^NZ, Audits

Where appropriate, clinicians are encouraged to consider switching patients from cilazapril to another ACE inhibitor to reduce risks associated with supply. However, changing from cilazapril may not always be appropriate, e.g. in a patient with heart failure who is stabilised on treatment. Switching is also unadvisable in patients who are unable to be monitored following the change, patients at greater risk of adverse effects, e.g. frail people at risk of falls, and patients who are highly distressed about the change.

When changing treatment, patients can discontinue one ACE inhibitor and initiate a different ACE inhibitor at a comparable dose (Table 1) the following day. Although ACE inhibitors are regarded as clinically equivalent, individual patients may respond differently. Patients should be followed up one to two weeks after initiating a new ACE inhibitor; assess blood pressure, creatinine and electrolytes and enquire about symptoms of adverse effects, such as hypotension or cough.²⁰

Patient information sheets for subsidised ACE inhibitor and ARB medicines are available from the NZF: www.nzf.org.nz/nzf_70421

Could this patient take an angiotensin receptor blocker (ARB) instead of an ACE inhibitor?

Angiotensin receptor blockers block the binding of angiotensin II to angiotensin type 1 (AT1) receptors.⁹ In New Zealand, losartan and candesartan are fully subsidised ARBs and both can be prescribed without restriction in primary care (Table 4); Special Authority criteria were removed from candesartan on 1 July, 2018.

A simple rule of thumb is ACE inhibitor first, switch to an ARB if intolerable adverse effects develop

Despite both ARBs and ACE inhibitors being designed to affect angiotensin signalling, guidelines recommend that patients with heart failure, hypertension or who have had a myocardial infarction should use an ACE inhibitor in preference to an ARB. This is because clinical trial evidence shows that ACE inhibitors provide better outcomes than ARBs and because more clinical trials have been conducted using ACE inhibitors. For patients with chronic kidney disease or diabetic nephropathy, ARBs are an equally effective alternative to ACE inhibitor treatment.^{8, 10, 11}

An ARB and ACE inhibitor should not be used in combination for patients with hypertension, following a myocardial infarction or with diabetic nephropathy.^{8, 10, 11} For some patients with chronic heart failure an ACE inhibitor and ARB are used in combination, however, this regimen would typically be initiated in secondary care.⁶

Patients are much less likely to experience cough with an ARB

A common adverse effect of ACE inhibitors is the development of cough. This is thought to occur due to increases in bradykinin levels with ACE inhibition, which does not occur when ARBs are used.²¹ The incidence of cough in patients taking ARBs is approximately 65–75% lower than in patients taking ACE inhibitors.^{32, 33} Other than a reduced incidence of cough with ARBs, the overall rate of adverse effects in clinical trials of ACE inhibitors or ARBs is the same.³⁴

Monitoring is the same as for patients taking ACE inhibitors

Like ACE inhibitors, ARBs are associated with changes in renal function and the same monitoring advice for measuring serum creatinine and electrolytes in patients taking ACE inhibitors applies for patients being treated with ARBs.⁸ Angioedema is also a rare adverse effect associated with ARB use, but occurs approximately half as often compared to patients taking ACE inhibitors.³⁵ If patients have previously experienced angioedema while taking an ACE inhibitor, an ARB could be initiated with caution; available evidence suggests approximately 10% or fewer patients who have angioedema while taking an ACE inhibitor have a recurrence of angioedema while taking an ARB.³⁶

Choosing an ACE inhibitor or ARB

ACE inhibitor first-line

Conditions where an ACE inhibitor should be used first-line, with an ARB as a second-line option for patients who develop adverse effects

Either ACE inhibitor or ARB first-line

Conditions where evidence and guidelines suggest either medicine class can be used first-line

Heart failure^{* 6}
Following a myocardial infarction^{8, 28}
Hypertension, including people with type 2 diabetes^{29, 30}

Chronic kidney disease³¹
Diabetic nephropathy^{* 10}

^* Unapproved indication for ARB

Table 4: Subsidised ARBs, available tablet sizes and recommended doses⁹

		Losartan	Candesartan
Tablet strength		12.5 mg, 25 mg, 50 mg, 100 mg Also losartan 50 mg + hydrochlorothiazide 12.5 mg	4 mg, 8 mg, 16 mg, 32 mg
Starting dose^*	In patients with hypertension	25–50 mg, once daily	4–8 mg, once daily
Starting dose^*	In patients with heart failure	12.5 mg, once daily	4 mg, once daily
Typical maintenance dose^*	In patients with hypertension	50 mg, once daily	8 mg, once daily
Typical maintenance dose^*	In patients with heart failure	150 mg, once daily	32 mg, once daily

^* Starting and maintenance doses depend on the condition being treated and the patient’s response to treatment; lower doses are recommended for patients with hepatic or renal impairment, and lower initial doses for patients aged over 75 years; see NZF for further details: www.nzf.org.nz/nzf_1240

References

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Chitnis AS, Aparasu RR, Chen H, et al. Effect of certain angiotensin-converting enzyme inhibitors on mortality in heart failure: a multiple-propensity analysis. Res Social Adm Pharm 2012;8:145–56. http://dx.doi.org/10.1016/j.sapharm.2011.03.001
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Published: 7 September 2018 | Updated: 20 September 2018

What's changed?

20 September 2018 Table 1 additional footnote on dosing for Enalapril and Quinapril

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Sharyn Willis, Medical Advisor, bpacnz 20 Sep 2018 13:32

We have had an email from Andrew Orange, Chief Pharmacist, Cook Islands.

“Thank you for the article on ACE inhibitors – it has lots of good information, is timely for us and the suggestion to reduce the use of cilazapril is a good one. In the Cook Islands, we have enalapril as our only ACE-I listed on our Essential Medicines List.  I note that your article recommends bd dosing of enalapril in heart failure.  However, the medicine datasheet advises that once daily dosing may be utilised, and there is at least one clinical trial (Am J Cardiol 1989; 63: 17D-21D) that shows once daily dosing of enalapril in heart failure to be no different from bd dosing over 48 weeks, up to a 20mg/day dose.  Note also that the elimination half-life of enalapril is longer than that for cilazapril, which is recommended to be dosed once daily.

Given all this, I’d be interested to know the rationale for BPAC recommending bd dosing of enalapril in heart failure when once daily dosing seems entirely feasible and would be a lot simpler for patients.”

Our response to Andrew:
You are correct that the medicines datasheet includes the advice that enalapril can be “given in a single dose or two divided doses, as tolerated by the patient”. We agree once daily dosing is more convenient for many people and is likely to improve adherence. The question for clinicians really has to be what is best for the patient in front of them. Our table includes examples of “typical” doses and as noted in the footnote these may vary with the condition being treated and the patient’s response.  
We generally base our medicine dosing recommendations on the New Zealand Formulary. Their advice for dosing of enalapril in heart failure is to start with a low once daily dose and gradually increase over 2-4 weeks to a target dose of 10 mg twice daily, as tolerated. The dose can be increased to a maximum of 20 mg twice daily if required, again if tolerated by the patient. 
This advice is consistent with most current international guidelines on heart failure management, e.g. those from Canada, United States and Europe, which all recommend twice daily dosing for enalapril, largely based on older trials that have used this dosing regimen and achieved favourable clinical endpoints. N.B The 2018 National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guideline for heart failure does not include specific dosing recommendations for enalapril or other ACE inhibitors. There is a lack of evidence on whether once daily dosing is as effective as twice daily dosing – the study you refer to being one of only a few which addresses this issue. 
Overall, it is a balance between trying to achieve good clinical outcomes based not only on trial evidence which informs clinical guidance, but also on the patient’s clinical condition, how they tolerate the medicine and their preference for when they take their medicines.

Franz Hubmann 26 Sep 2018 10:59

The Editor 26 Sep 2018 11:11

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Prescribing ACE inhibitors: time to reconsider old habits

Key practice points:

Use of cilazapril in New Zealand is very high compared to other countries

ACE inhibitors are prescribed for a variety of indications

There are a range of subsidised ACE inhibitors

No differences between adverse effects

Titration and dosing are similar