For your patients living with heart failure, time is essential

All patients with heart failure with reduced ejection fraction (HFrEF), regardless of their symptoms have a poor prognosis. Within three years, 34% of patients with mild to moderate heart failure (NYHA class I and II) die. ¹

As a General Practitioner, the majority of patients you will see with HFrEF will be mildly symptomatic (NYHA Class II).² Just one heart failure hospitalisation will put patients at up to a six-times greater risk of death vs patients who had not been hospitalised for HFrEF (post hoc analysis).³

Health-Related Quality of Life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities.⁴

There are an estimated 75,000 adults in New Zealand with heart failure (HF) 2018/19.⁵ Maori are at a 1.81 times greater risk of Heart Failure than non-Maori while Pacific Islanders are at a 1.92 times greater risk of Heart Failure than non-Pasifika.⁵

Research has shown that patients with heart failure visited their General Practitioner on average 12 times over a year and 3 of those visits were specifically for heart failure.⁶

Tane 64, had been on his beta-blocker, ACEi and diuretic since being diagnosed 18 months ago with HFrEF. He has not been troubled by any apparent side effects of his medication in this time. His left ventricular ejection fraction (LVEF) had been 33% upon initial diagnosis but has not been re-tested due to difficulty accessing ECG services especially since the COVID-19 pandemic.

At Tane’s last visit he complained of feeling a little fatigued and now 4 weeks later he is still fatigued and now not able to do as much in the garage without having to stop for a rest.

A patient like Tane can be significantly affected by their disease with regards social capacity and emotional health. Three quarters struggle to perform daily activities, more than half report difficulty with recreational pastimes and hobbies and about two thirds report symptoms that are consistent with depression.^7-9 Health-Related Quality of Life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities.⁴

But the need for urgency is driven by the mortality figures for patients like Tane. Even though they were receiving optimal heart failure therapy, patients like Tane in the PARADIGM-HF study were still at risk of death.

• 16.5% of ACEi patients died due to cardiovascular causes.¹⁰
• 7.4% of ACEi patients experienced sudden cardiac death.¹⁰
• 4.4% of ACEi patients died due to worsening heart failure.¹⁰

Just one HF hospitalisation put patients at up to six times greater risk of death vs patients who had not been hospitalised for HFrEF.³

In the case of Tane who is already on a Beta-Blocker, ACEi, MRA and a diuretic the Guidelines suggest that his ACEi should be replaced with an ARNI (Angiotensin Receptor Neprilysin Inhibitor) i.e., ENTRESTO^®.

What is ENTRESTO^®

ENTRESTO^® an ARNI (Angiotensin Receptor Neprilysin Inhibitor) replaces the ACEi/ARB in HFrEF therapy. 13 ENTRESTO® contains valsartan an ARB (Angiotensin Receptor Blocker), and sacubitril a neprilysin inhibitor:¹³

What replacing the ACEi with ENTRESTO^® (sacubitril/valsartan) will mean for Tane?

Replacing Tane’s ACEi therapy with ENTRESTO^® reduces the relative risk of CV death and time to first HF hospitalisation by an additional 20% compared to ACEi therapy alone – an absolute risk reduction of 4.7% (p <0.001).¹¹

Time to first HF hospitalisation or cardiovascular death.¹¹

Furthermore, replacing the ACEi with ENTRESTO^® will improve Tane’s quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).12

The effect of ENTRESTO^® on physical and social activities compared with enalapril was equivalent to a difference of 9 years of ageing. ⁴

KCCQ Overall Score Entresto vs enalapril Health Related Quality of Life Outcome in PARADIGM-HF¹²

For patients currently on an ACEi, a 36-hour washout period is required to reduce the potential risk of angioedema. This is not required if replacing an ARB.¹³

What is the dosage regimen for ENTRESTO^®?

This is a simple one or two step titration in patients with HFrEF. The recommended starting dose if already on standard ACEi is one tablet of 49 mg/51 mg twice daily, double every 2-4 weeks to the target dose. The target dose for ENTRESTO^® is one tablet of 97 mg/103 mg twice daily.¹³

A reduced starting dose of ENTRESTO^® of one tablet of 24 mg/26 mg taken twice daily is recommended for:

• ACEi/ARB naive patients,¹³
• those with severe renal impairment, moderate hepatic impairment^,13
• those with low systolic blood pressure (SBP ≥100 to 110 mmHg),¹³
• those ≥ 75 years old.¹³

What monitoring is needed for patients switched to ENTRESTO^®?

ENTRESTO^® has a safety and tolerability profile generally similar to that of an ACEi. It is however recommended that patients be reviewed two weeks after being switched to ENTRESTO^®.¹³ Patients switched to ENTRESTO^® should have their blood pressure, renal function, potassium levels and volume status monitored.¹³

What are the Special Authority Requirements?

A Special Authority application can be made by any relevant practitioner and approvals are valid for 12 months.¹⁵

Patients must meet all the following criteria:¹⁵

• Patient has heart failure and is in NYHA/WHO functional Class II, III or IV

• Patient has a documented Left Ventricular Ejection Fraction (LVEF) of less than or equal to 35%

• An ECHO is not reasonably practical, and in the opinion of treating practitioner the patient would benefit from treatment

• Patient is receiving concomitant optimal standard chronic heart failure therapy

References

1. Ahmed A. Am J Cardiol 2007;99:549–53.

2. Taylor JC et al, 2016. Australian Family Physician; 45 (11): 823-827.

3. Okumura N et al. Circulation 2016; 133: 2254–2262.

4. Chandra A et al. JAMA Cardiol. 2018 Jun; 3(6): 498–505

5. Ministry of Health - https://minhealthnz.shinyapps.io/nz-health-survey-2018-19-annual-data-explorer/_w_80c5789b/_w_dcec3768/#!/explore-indicators

6. Britt H et al. General practice activity in Australia 2014–2015. BEACH, November 2015

7. Calvert MJ et al. Eur J Heart Fail 2005;7: 243–51.

8. Moser DK et al. Heart Lung 2010;39: 378–85.

9. Cowie MR et al. ESC Heart Failure 2014;1:110–45.

10. Desai AS et al. Eur Heart J 2015; 36: 1990-1997.

11. McMurray JJ et al. N Eng J Med 2014; 371(11): 993-1004.

12. Lewis EF et al. Circ Heart Fail. 2017;10:e003430. DOI: 10.1161/CIRCHEARTFAILURE.116.003430

13. ENTRESTO New Zealand Data Sheet.

14. Vardeny O et al. JACC Heart Fail 2014; 2: 663–70

15. Pharmaceutical Schedule – Pharmac www.pharmac.govt.nz.

16. Atherton JJ et al. Heart, Lung and Circulation 2018; 27: 1123–1208

Abbreviations

ACEi – Angiotensin Converting Enzyme inhibitor, NYHA – New York Heart Association, ARB – Angiotensin Receptor Blocker, HF – Heart Failure, LVEF – Left Ventricular Ejection Fraction, ECHO - Echocardiogram, HFrEF – Heart Failure with reduced Ejection Fraction MRA - mineralocorticoid receptor antagonists

Minimum Prescribing Information
PRESCRIPTION MEDICINE. Entresto® 24mg/26mg, 49mg/51mg, 97mg/103mg (sacubitril/valsartan) film coated tablets. Consult full Data Sheet before prescribing, available from www.medsafe.govt.nz. Entresto is fully funded under Special Authority Criteria, please refer to www.pharmac.health.nz.

Indication: Treatment of chronic heart failure (NYHA Class II-IV) with reduced ejection fraction. Contraindications: Hypersensitivity to sacubitril, valsartan, or excipients. ACE inhibitors (ACEi). Do not administer within 36 hours of switching from or to an ACEi. Angioedema related to previous ACEi or ARB therapy. Use with aliskiren in Type 2 diabetes (T2D). Severe hepatic impairment, biliary cirrhosis and cholestasis. Pregnancy. Precautions: Caution switching from ACEi or while co-administering with aliskiren in T2D (see Contraindications). Should not be co-administered with an ARB. May cause symptomatic hypotension, especially in those ≥75 years old, renal disease and systolic BP <112 mmHg or patients with an activated RAAS. Initiation not recommended in systolic BP <100 mmHg. Monitor BP when initiating therapy or during dose titration. If hypotension occurs, dose adjustment of diuretics, antihypertensives, and consider treatment of other causes of hypotension. If hypotension persists, consider dose reduction or temporary interruption. Correct sodium and/or volume depletion before starting treatment. May be associated with decreased renal function; assess renal function before initiation and during treatment. Monitor serum creatinine, and down-titrate or interrupt if a clinically significant decrease in renal function develops. May increase urea and creatinine levels in patients with renal artery stenosis. Not recommended with end-stage renal disease. Should not be initiated and consider discontinuation if the serum potassium level is >5.4 mmol/L. Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors, dosage reduction or interruption may be required. Caution with medications known to raise potassium levels. If clinically significant hyperkalaemia occurs, consider adjusting the dose of concomitant medications. If angioedema occurs, immediately discontinue, and provide appropriate therapy and monitoring until complete and sustained resolution; black patients or patients with a prior history of angioedema may be at higher risk. Caution in NYHA Class IV or in moderate hepatic impairment or with AST/ALT >2X ULN. Use in lactation not recommended. Use contraception during treatment and for 1 week after last dose. Interactions: Aliskiren in T2D, ACEi/ARB. Caution with statins, sildenafil, lithium, potassium-sparing diuretics including mineralocorticoid antagonists, potassium supplements, or salt substitutes containing potassium, NSAIDs including selective COX-2 Inhibitors, frusemide, inhibitors of OATP1B1/B3, OAT3 or MPR2 and metformin. Dosage: Target dose one tablet of 97 mg/103 mg twice daily. Starting dose one tablet of 49 mg/51 mg twice daily. Starting dose one tablet of 24 mg/26 mg taken twice daily recommended for ACEi/ARB naive patients, those with severe renal impairment, moderate hepatic impairment, and in those ≥ 75 years old. Double every 2-4 weeks to the target dose. Adverse effects: Very common (≥ 10%): Hyperkalaemia, hypotension, renal impairment. Common (1 to 10%): Cough, dizziness, renal failure, diarrhoea, hypokalaemia, fatigue, headache, syncope, nausea, asthenia, orthostatic hypotension, vertigo. Uncommon (0.1 to 1%): Angioedema, dizziness postural. Unknown: Hypersensitivity (including rash, pruritus, and anaphylaxis).

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