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Q&A 296.3

When can a combination of angiotensin converting enzyme inhibitors with angiotensin II receptor antagonists be used in patients with heart failure?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

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Date prepared: June 2014

Summary

□ Overall, studies show that the addition of an ARB to the combination of an ACE inhibitor and a beta-blocker in patients with heart failure failed to reduce all-cause mortality or cardiovascular mortality and is associated with an excessive risk of adverse effects. Although the combination significantly reduced the risk of heart failure hospitalisation, this may be offset by the increased risk of hospitalisation for all causes.

□ There are only a limited amount of data on combining an ARB with an ACE inhibitor without a beta-blocker.

□ The risk of adverse events, in particular renal dysfunction, hyperkalaemia and hypotension increases with combination therapy involving the addition of an ARB to a regimen that includes an ACE inhibitor. In addition, patients are more likely to stop taking this combination. For most patients with heart failure, use of an ARB added to a regimen that includes an ACE inhibitor poses considerable safety risks whilst the benefits are uncertain.

□ Therefore, benefits of using a combination of an ARB and ACE inhibitor are only thought to outweigh risks in a select group of heart failure patients in whom aldosterone antagonists are unsuitable.

□ The MHRA issued a Drug Safety Update on combination use of medicines from different classes of renin-angiotensin system (RAS) blocking agents. This followed reviews on the safety of this combination that were published by the European Medicines Agency’s Committee’s for Pharmacovigilance Risk Assessment (PRAC) and Medicinal Products for Human Use (CHMP). The MHRA advise that combination use of medicines from two classes of RAS blocking agents (ACE-inhibitors, ARBs, or aliskiren) is not generally recommended. Neither is the triple combination of an ACE-inhibitor, ARB, and a aldosterone antagonist or other potassium-sparing diuretic recommended. However it is acknowledged that some patients with heart failure may have a medical need for treatment with an ACE-inhibitor and an ARB. In these cases candesartan or valsartan would be used as they are licensed as add-on therapy to ACE-inhibitors for people with symptomatic heart failure who require such a combination despite optimal therapy. Healthcare professionals are advised to review the treatment of all patients currently taking a combination of RAS blocking agents at a routine appointment and 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). They should consider monitoring patients when combination use is started and on a monthly basis thereafter, and also after changing dose and during intercurrent illness.

Background

This Q&A is the second of a series of Q&A’s on the rationale and evidence for combining angiotensin converting enzyme inhibitors with angiotensin II receptor antagonist.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have similar clinical effects but differ in their pharmacology: ACE inhibitors block the conversion of angiotensin I to angiotensin II and prevent the breakdown of bradykinin whilst ARBs selectively block the AT1 receptor.(1) Excessive amounts of angiotensin II leads to vasoconstriction and increased aldosterone secretion causing further sodium and water retention, while bradykinin, acting on receptors in the vascular endothelium, promotes release of vasodilators including nitric oxide.(2) The pharmacology of ACE inhibitors and ARBs is represented in Figure 1.

An ACE inhibitor alone may not fully block the renin-angiotensin system. The continued production of angiotensin II is incompletely understood but may be associated with alternate synthesis pathways (see fig 1).(1-3) Therefore by utilising the combination of an ACE inhibitor and an ARB you would expect to gain a more complete blockade of the renin-angiotensin system. The question is: in practice does this translate into an improved clinical outcome for the patient?

Figure 1: Interaction of ACE inhibitors and ARBs with renin-angiotensin system (RAS).(1)

Candesartan, losartan and valsartan are the ARB’s so far to have been granted marketing authorisation for heart failure. (4) Losartan is not licensed to be used with an ACE inhibitor (4;5) whilst candesartan is licensed as add-on therapy to an ACE inhibitor, a combination which can also be used with a beta-blocker. (4;6) Valsartan is licensed as add-on therapy to ACE inhibitors when beta-blockers cannot be used. Triple combination with a beta blocker, valsartan and an ACE inhibitor is not recommended due to the increased risk of adverse effects and lack of clinical benefit seen in clinical trials. (4;7)

SIGN guidance recommends the addition of candesartan to an ACE inhibitor and a beta-blocker for patients heart failure with left ventricular systolic dysfunction who remain symptomatic.(8) At the time that this guidance was written in 2007, candesartan was the only ARB licensed to be used with an ACE inhibitor for heart failure and there have since been developments regarding the evidence around the benefits and risks of combining an ACE inhibitor with an ARB for the treatment of heart failure. When should a combination of an ACE inhibitor and an ARB be used to treat patients with heart failure?

Answer

Heart failure is characterised by abnormal fluid retention and volume regulation. Excessive angiotensin II and aldosterone levels contribute to the worsening of this condition via vasoconstriction and sodium retention increasing the preload and afterload. (2) It has been postulated that combining an ACE inhibitor and an ARB may provide benefit. In 2010 NICE reviewed the evidence for the use of ACE inhibitors and ARBs in patients with chronic heart failure. They recommend seeking specialist advice and to consider adding either; an aldosterone antagonist (also known as mineralocorticoid receptor antagonist), an ARB licensed for heart failure or hydralazine in combination with a nitrate, if a patient remains symptomatic despite optimal therapy with an ACE inhibitor and a beta-blocker. (9) The European Society of Cardiology (ESC) advocates the use of ARBs in patients with heart failure and a left ventricular ejection fraction (LVEF) ≤40% who remain symptomatic despite optimal treatment with an ACE inhibitor and beta-blocker who are unable to tolerate an aldosterone antagonist.(10)

The MHRA issued a Drug Safety Update in 2014 on the combination use of medicines from different classes of renin-angiotensin system (RAS) blocking agents. (11) This was based on a review by the Pharmacovigilance Risk Assessment Committee (PRAC) at the European Medicines Agency (EMA) which looked at the risk of combining different classes of medicines that act on the renin-angiotensin system (ACE-inhibitors, ARBs, or aliskiren). (12) The review was initiated due to concerns that these combinations could increase the risk of hyperkalaemia, hypotension and renal failure compared to their use as monotherapies. (13) In particular, there was concern that the combinations might not lead to the anticipated benefits and therefore risk may outweigh benefits. The review found that the risk was likely to be greater than the benefits and the PRAC advised against combining medicines from any two of these classes. The triple combination of an ACE-inhibitor, ARB, and an aldosterone antagonist or other potassium-sparing diuretic is also not recommended. [MHRA] Healthcare professionals are advised to review the treatment of all patients currently taking a combination of RAS blocking agents at a routine appointment and carefully consider if combination use is appropriate (11). PRAC advised that if such a combination is considered absolutely necessary, it should be used under a specialist’s supervision with close monitoring of kidney function, fluid and electrolyte balance and blood pressure. This recommendation includes the licensed use of candesartan or valsartan as add on therapy to ACE inhibitors in patients with symptomatic heart failure who require such a combination despite optimal therapy. The Committee for Medicines Products for Human Use (CHMP) at the EMA have endorsed the PRAC recommendation based on a detailed review of the available data, which includes clinical trials and meta-analyses, as well as expert advice. They added that benefits were thought to outweigh risk only in a selected group of patients with heart failure in whom other treatments (aldosterone antagonists) were unsuitable.(14) The European Society of Cardiology (ESC) guidelines (10) are considered to be consistent with this recommendation whereas other guidelines (8;9) may not have been updated to reflect the MHRA and CHMP recommendations.

Adding ARBs to the combination of ACE inhibitor and beta-blocker therapy

The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial (n=2548)) provided evidence for the benefit of combination therapy.(15) Patients with New York Heart Association (NYHA) Class II-IV Chronic Heart Failure (CHF) and a left ventricular ejection fraction 40% or less who were already established on an ACE inhibitor were selected (55% of patients were already taking beta-blockers). In addition to their usual prescription, they were randomised to receive either placebo (n=1272) or candesartan 4mg or 8mg daily titrated upwards to a target dose of 32mg/day from 6 weeks onwards (n=1276). The median duration of follow-up was 41 months and the annual event rates were 14.1% in the candesartan group and 16.6% in the placebo group. The study found that the composite primary endpoint of cardiovascular death or hospitalisation for worsening chronic heart failure occurred less frequently in the candesartan treated group (38%) compared to the placebo group (42%) (p=0.011). Other outcomes such as cardiovascular deaths were 24% in the candesartan group compared with 27% in the placebo group (p=0.029) and hospitalisation for chronic heart failure 24.2% vs. 28% respectively (p=0.014). These beneficial effects of candesartan support the evidence that angiotensin II continues to be produced despite chronic ACE inhibitor treatment. However, combining candesartan and an ACE inhibitor increased the incidence of renal dysfunction and hyperkalaemia. Discontinuations due to adverse events were greater in the candesartan group (n=309 (24%)) than the placebo group (n= 233 (18%) (p=0.0003).

Valsartan has also been studied in combination with an ACE inhibitor. The Valsartan Heart Failure Trial (Val–HeFT) randomised 5,010 patients with heart failure (NYHA Class II-IV) already receiving standard heart failure therapy (93% of patients were on an ACE inhibitor and 35% were receiving beta-blockers) to receive either valsartan, target dose 160mg bd (n=2511) or placebo (n=2499). (16) The mean follow up period was 2 years. Mortality was similar in the two treatment groups (19.7% vs. 19.4%, p=0.80) but the combined end point of mortality and morbidity was significantly reduced in the combination group (28.8%) compared with those receiving standard treatment (32.1%, p=0.009). The predominant benefit in terms of combined end point was reduction in hospitalisation for worsening heart failure in those receiving combination therapy compared to placebo (13.8% vs. 18.2%, p40%. Seven studies (all double-blind, randomised controlled parallel group trials that reported mortality/morbidity and lasted at least 4 weeks) randomised a total of 8260 patients (20% females, mean age 63, LVEF 27%) who took an ARB plus ACE inhibitor or ACE inhibitor plus placebo for a mean duration of 101 weeks. Two of the large trials described earlier contributed the vast majority of the data for this analysis; CHARM-Added (candesartan) and Val-HeFT (valsartan).(15;16) There were no differences between combination therapy and ACE inhibitor therapy in the rates of total mortality, cardiovascular mortality and non-cardiovascular mortality. Combined therapy with an ARB plus ACE inhibitor reduced the risk of hospitalisation for heart failure (RR 0.81 [95% CI 0.74 to 0.89]; ARR=4.4%; NNT=23) but this was offset by a non-significant increase in hospitalisation for other causes (RR 1.07 [95% CI 0.98 to 1.18]). The risk of MI was reduced with combination therapy (RR 0.64 [95% CI 0.44 to 0.92]; ARR=2.0%; NNT=50) but the risk of stroke was not [this was only reported in one study, CHARM-Added]. However, more patients had to stop taking the combination due to adverse effects (RR 1.34 [95% CI 1.19 to 1.51]; ARI=3.7%; NNH=27). This review, --considered the risks and benefits of using a combination of ARB’s and ACE inhibitors in heart failure and suggests that there is no overall benefit.

A number of meta-analyses have been published between 2004 and 2013 and there is considerable overlap due to the same studies being included in these analyses (18-22). Therefore the findings in these, as would be expected, are highly consistent with the findings reported in the Cochrane review. One meta-analyses is particularly relevant as it specifically included studies which evaluated the combination of ACE inhibitors plus ARB’s vs. ACE inhibitors as monotherapy in patients with heart failure (19). Eight trials (n=18,061) were included and, as expected given that the principal studies were the same, findings were consistent with the Cochrane Review. There was no difference between the combination and ACE inhibitors as monotherapy with respect to overall mortality, hospitalisation for any reason and fatal/non-fatal MI. Hospital admissions due to heart failure were fewer in the combined therapy group (RR 0.81 [95% CI 0.72 to 0.91]) but there was no difference between the groups with respect to hospitalisation for any reason (RR 0.92 [95% CI 0.82 to 1.05]), including for fatal or non-fatal MI. There was insufficient data for the rates of revascularisation and stroke. Patients taking combination therapy had a higher risk of worsening renal function (RR 1.91 [95% CI 1.40 to 2.60]), symptomatic hypotension (RR 1.57 [95% CI 1.44 to 1.71]) and hyperkalaemia (RR 1.95 [95% CI 0.85 to 4.48]). Patients taking combination therapy were also more likely to discontinue due to adverse effects; (RR 1.21 [95% CI 1.07 to 1.37]).

Conclusion

The risk/benefit ratio of adding an ARB to an ACE inhibitor in NYHA Class II-IV heart failure patients is made clearer by recent meta-analyses, publications and recommendations from European Medicines Agencies. (3;12-14;21;23) The current thinking is that, for most patients with heart failure, ARB’s added to ACE inhibitors pose considerable safety risks whereas the benefits are uncertain. In addition, a safer and possibly more effective combination is available since the risk-benefit profile is thought to be much more acceptable for the aldosterone antagonists in combination with ACE inhibitors. Benefits of using a combination of ARB’s and ACE inhibitors are only thought to outweigh risks only in a selected group of patients with heart failure in whom aldosterone antagonists are unsuitable. For these patients in whom a combination of ARB’s and ACE inhibitors is considered absolutely necessary, the combination should only be used under a specialist’s supervision with close monitoring of kidney function, fluid and salt balance and blood pressure. This includes the licensed use of candesartan or valsartan as add on therapy to ACE inhibitors.

Limitations

There is limited information available for combination ARB and ACE inhibitor therapy in heart failure patients. Studies were often small and were excluded from the review due to potential for bias, lack of placebo control arm and use of surrogate outcome measures and whether the combination was truly useful was not clear from the studies. The data from the ValHeFT study should be interpreted with caution because background therapy was not controlled and patients were only stratified at randomisation by the absence or presence of beta-blockers but not ACE inhibitors. In the meta-analyses, prespecified endpoints of mortality and morbidity as well as study design and population varied between the trials.

It was outside of the scope of this Q&A to discuss the rationale and evidence for combining ACE inhibitors with aldosterone antagonists such as spironolactone or eplerenone. This combination has not been associated with an increased risk of renal failure or hypotension (although the risk of hyperkalaemia is increased) (23). This combination is therefore considered to have a more acceptable relative benefit versus risk profile over the combination of an ACE inhibitor and an ARB for heart failure.

References

(1) Chiaventone K, Ou N. Cardiovascular Update: The role of combination ACE inhibitors and angiotensin II receptor blockers. Pharm Times 2004;(Dec).

(2) Opie.l.H, Gersh.B.J. Ace Inhibitors, ARBs, and Aldosterone Antagonists. In: Elsevier and Saunders, editor. Drugs for the Heart. Philadelphia; Pennsylvania: 2005.

(3) Heran.B.S, Musini.V.M, Bassett.K et al. Angiotensin receptor blockers for heart failure. Cochrane Database of Systematic Reviews 2012; Issue 4(Art. No.: CD003040).

(4) BMJ Group, RCPCH Publications Ltd, Royal Pharmaceutical Society of Great Britain. Heart Failure. British National Formulary (online). London: RCPCH Publications, 2014.

(5) Summary of Product Characteristics (SmPC); COZAAR 12.5 mg, 25 mg, 50 mg and 100 mg Film-Coated Tablets. Date of revision of the text: March 2014. Merck Sharp & Dohme Limited Accessed via: .uk on 29/5/2014.

(6) Summary of Product Characteristics (SmPC); Amias Tablets. Date of revision of the text: 21/11/2013. Takeda UK Ltd Accessed via: .uk on 29/5/2014.

(7) Summary of Product Characteristics (SmPC); Diovan 160mg Capsules. Date of revision of the text: 02/11/2012. Novartis Pharmaceuticals UK Ltd Accessed via: .uk on 29/5/2014

(8) Management of Chronic Heart Failure: A national clinical guideline. Number 95. Scottish Intercollegiate Guidelines Network Accessed via: on 22/05/2014

(9) Chronic heart failure: The management of chronic heart failure in adults in primary and secondary care. Clinical Guideline No.108. NICE/Royal College of Physicians Accessed via:

(10) McMurray JJV, Adamopoulos.S., Anker.S.D. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012; 33:1787-1847.

(11) MHRA. Combination use of medicines from different classes of renin-angiotensin system blocking agents. Drug Safety Update 2014; 7(11):A1.

(12) PRAC recommends against combined use of medicines affecting the renin-angiotensin (RAS) system. European Medicines Agency Accessed via on 29/05/2014.

(13) de Leeuw.P.W. Dual renin-angiotensin system blockage. Br Med J 2012; 344:e656.

(14) Combined use of medicines affecting the renin-angiotensin system (RAS) to be restricted - CHMP endorses PRAC recommendation. European Medicines Agency Accessed via: on 29/05/2014.

(15) McMurray JJV, Ostergren J, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. The Lancet 2003; 362:767-771.

(16) Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345(23):1667-1675.

(17) Pfeffer MA, McMurray JJV, Velazquez EJ et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349(20):1893-1906.

(18) Dimopoulos K, Salukhe TV, Coats AJS et al. Meta-analyses of mortality and morbidity effects of an angiotensin receptor blocker in patients with chronic heart failure already receiving an ACE inhibitor (alone or with a beta-blocker). Int J Cardiol 2004; 93(2-3):105-111.

(19) Kuenzli.A, Bucher.H.C, Anand.I. Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure. PLoS ONE 2010; 5(4):e9946.

(20) Lee VC, Rhew DC, Dylan M et al. Meta-analysis: Angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med 2004; 141(9):693-704.

(21) Makani.H, Bangalore.S, Desouza.K.A. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials. Br Med J 2013; 346:f360.

(22) Shibata.M.C, Tsuyuki.R.T, Wiebe.N. The effects of angiotensin-receptor blockers on mortality and morbidity in heart failure: a systematic review. Int J Clin Pract 2008; 62(9):1397-1402.

(23) Bangalore.S, Kumar.S, Messerli.F.H. When convesntional heart failure therapy is not enough: Angiotensin receptor blocker, direct renin inhibitor, or aldosterone antagonist? Congestive Heart Failure 2013; 19:107-115.

Quality Assurance

Prepared by

Updated by Sheena Vithlani, London Medicines Information Service (Northwick Park Hospital).

Date Prepared

30th May 2014

Checked by

Alexandra Denby, London Medicines Information Service (Northwick Park Hospital)

Date of check

4th August 2014

Search strategy

• Medline: DRUG THERAPY, COMBINATION/ AND exp HEART FAILURE/ AND (*ANGIOTENSIN RECEPTOR ANTAGONISTS/ OR ANGIOTENSIN-CONVERTING ENZYME INHIBITORS/) [Limit to: English Language and Humans and Publication Year 2012-2014];

• Embase: *DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR/cb [cb=Drug Combination] AND exp HEART FAILURE [Limit to: Human and English Language and Publication Year 2012-2014]

• In-house databases/resources

• NHS Evidence: “heart failure”

Appendix: Summary of published heart failure trials combining an ACE inhibitor with an ARB.

|Patient population |Trial drug combination |Trial points |Primary endpoint |Adverse Drug Reaction (ADR) |Trial conclusion |

|CHARM-added trial (15) |Candesartan up to 32mg/day|N=2548 |Cardiovascular death or unplanned admission |Higher incidence of discontinuation in |The addition of |

| |+ standard HF therapy* |Randomised, double blind, |to hospital for worsening heart failure. |combination group due to renal |candesartan to an ACE |

|Heart failure |(n=1276) |multi-centre, | |dysfunction and hyperkalaemia. |inhibitor leads to a |

|% of NYHA classes in the combination group |or |placebo-controlled study. |37.9% for candesartan group vs. 42.3% for | |further reduction in |

|Class II (24.5%) |placebo plus standard HF |Median follow-up: 41 months|placebo group, p=0.011. | |cardiovascular events.|

|Class III (73.0%) |therapy* (n=1272) | | | | |

|Class IV (2.6%) |*including an ACE | | | | |

| |inhibitor | | | | |

|No statistically significant differences in baseline | | | | | |

|characteristics between the groups | | | | | |

|VALIANT trial (17) |Valsartan up to 160mg bd |N=14,703 |Mortality from any cause. |Higher incidence of discontinuation in |Combining valsartan |

|Myocardial infarction complicated by left ventricular |(n=4909) |Randomised, double-blind, | |the combination group due to drug |with captopril |

|systolic dysfunction, heart failure or both |or |multi-centre study. |19.3% for combination group vs. 19.9% for |related ADRs. |increased the rate of |

|% of Killip classes in the combination group |valsartan up to 80mg bd |Median follow-up: 24.7 |valsartan group and | |adverse events without|

|Class I (28.4%) |+ captopril up to 50mg tds|months |19.5% for captopril group. |9% vs. 5.8% valsartan group and 7.7% |improving survival. |

|Class II (47.9%) |(n=4885) | | |captopril group. | |

|Class III (17.3% |or | |No statistically significant differences | | |

|Class IV (6.4%) |captopril up to 50mg tds | |between the groups. | | |

| |(n=4909) | | | | |

|No statistically significant differences in baseline | | | | | |

|characteristics between the groups | | | | | |

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