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Optimising drug combinations for people with heart failure
Optimising drug combinations for people with heart failure
![PHARMACOTHERAPY Heart](/sites/default/files/styles/cropped_image_16_7_/public/2022-10/Pharmacotherapy_Heart_CR_Ali%20Hajiluyi_Unsplash.jpg?itok=DoqEvFVa)
Here at New Zealand Doctor Rata Aotearoa we are on our summer break! While we're gone, check out Summer Hiatus: Stories we think deserve to be read again! This article was first published 12 October 2022.
As our understanding of heart failure has increased, so too has the number of medicines used to treat it. This article summarises the optimisation and cumulative impact of heart failure treatments
- Optimisation of therapy extends life expectancy for those with heart failure.
- For heart failure with reduced ejection fraction (≤35 per cent), those in NYHA class II–IV despite optimal treatment are eligible for sacubitril/valsartan (Entestro).
- Empagliflozin provides benefit to people with heart failure, with or without diabetes, but is currently only funded for some patients with type 2 diabetes.
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Barry is a 52-year-old Māori man who presents for three-monthly review. He is well known to you and has a history of dilated cardiomyopathy with fluid overload and severe left ventricular dysfunction of unknown cause, requiring acute hospital admissions in 2020 and 2021. He also has type 2 diabetes.
Six months ago, you optimised his heart failure medicines (enalapril 10mg twice daily, bisoprolol 10mg once daily, spironolactone 25mg once daily) due to some initial misunderstandings regarding the doses after discharge from hospital in 2021.
Three months ago, you started him on empagliflozin 10mg once daily as he divulged that he could not tolerate metformin without significant diarrhoea. He had stopped the metformin as it affected his job as a farm worker.
He now has excellent self-management strategies for his heart failure, weighing himself daily. He tells you he feels even better, with a significant improvement in managing his daily tasks. However, he is still breathless on exertion at times.
On examination, he does not have any abdominal bloating or peripheral oedema; however, he hasn’t been able to stop furosemide (40mg once daily) without gaining 2kg. His jugular venous pressure is not elevated. The results of further investigations are shown in the table. An echocardiogram in 2021 showed a left ventricular ejection fraction <20 per cent, and he has not yet had a repeat echocardiogram.
Barry asks if there is anything more that can be done.
For Māori, the heart failure mortality rate is more than twice that of non-Māori
On average, 50 per cent of people with heart failure will die within five years.1 For Māori, the heart failure mortality rate is more than twice that of non-Māori (relative risk 2.36).2 Comprehensive treatment can extend this life expectancy.
As our understanding of heart failure has increased, so too has the number of medicines required to extend quality-adjusted life years. From the days of treating symptoms with furosemide, optimal therapy now involves appropriate polypharmacy with at least five medicines.
Heart failure involves activation of the sympathetic nervous system (SNS), resulting in vasoconstriction and increased heart rate, blood pressure and blood volume; as well as activation of the renin–angiotensin–aldosterone system (RAAS), causing vasoconstriction and increased aldosterone levels. This gives a clear rationale for using ACE inhibitors/angiotensin II receptor blockers (ARBs), beta-blockers and spironolactone to inhibit the SNS and RAAS.
The balance to SNS and RAAS activation is the natriuretic peptide system (NPS) – activation of natriuretic peptides results in vasodilation with reduced blood pressure, sympathetic tone and aldosterone levels. In heart failure, enhancing the NPS by inhibiting neprilysin (which is involved in the degradation of natriuretic peptides) is advantageous. Sacubitril is a neprilysin inhibitor used in combination with the ARB valsartan.
In the landmark PARADIGM-HF study comparing sacubitril/valsartan (Entresto) with enalapril, 21 people needed to be treated for 27 months with sacubitril/valsartan instead of enalapril to prevent one death from cardiovascular causes or hospitalisation for heart failure. Approximately 36 people needed to be treated to prevent one death from any cause.3
This provides good evidence to support the use of sacubitril/valsartan in place of monotherapy with an ACE inhibitor (or ARB). Most people in whom sacubitril/valsartan is to be started are already on an ACE inhibitor or ARB. It is imperative to stop the ACE inhibitor 36 hours before starting sacubitril/valsartan. The panel summarises further points to consider when initiating sacubitril/valsartan.
Pharmac Special Authority requirement
The patient has heart failure, and:
- is in NYHA class II, III or IV, and
- has a documented left ventricular ejection fraction ≤35 per cent or an echocardiogram is not reasonable, and the practitioner believes the patient would benefit from treatment, and
- is already receiving optimal standard chronic heart failure treatments.
Do not use sacubitril/valsartan:
- with an ACE inhibitor or another ARB
- in people with severe hepatic impairment
- during pregnancy
- if the serum potassium level is >5.4mmol/L or systolic blood pressure is <100mmHg.
Dosing
Usual initial dosage:
- sacubitril 49mg/valsartan 51mg twice daily if already on an ACE inhibitor or ARB.
Start sacubitril 24mg/valsartan 26mg twice daily if:
- not already on an ACE inhibitor or ARB
- of older age or at risk of hypotension
- eGFR <30ml/min/1.73m2.
Target dosage:
- titrate two to four-weekly to sacubitril 97mg/valsartan 103mg twice daily if tolerated.
Adverse effects*
- During the run-in stage of PARADIGM-HF, 12 per cent of people withdrew due to an adverse event.3
- Hypotension, especially with first dose and age over 75, occurs in over 10 per cent of people (number needed to harm is approximately 17 compared with enalapril).
- Hyperkalaemia, renal impairment and cough as for usual ACE inhibitor use.
- Angioedema – 0.5 per cent compared with 0.2 per cent for enalapril.
* In addition to ACE inhibitor/ARB adverse effects.
Monitoring
- Baseline renal function, electrolytes and blood pressure, and usual monitoring as for ACE inhibitors and ARBs.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin, are the other class of medicines with a significant benefit in heart failure.
To prevent one death from cardiovascular causes or hospitalisation for heart failure, the number needed to treat with empagliflozin instead of placebo is 19 for people with reduced ejection fraction (over 16 months),4 and 31 for people with preserved ejection fraction (over 26 months).5
The mechanism is still unclear, and while some of empagliflozin’s effect may be due to increased diuresis, there also appears to be an effect on brain natriuretic peptide levels. This effect occurs in people with or without diabetes.
At a time when polypharmacy is topical, it is important to recognise that in heart failure, treatment optimisation is the maximisation of dosages and the comprehensive use of medicines which provide mortality and symptomatic benefits (see figure for cumulative mortality benefits). With the increased mortality from heart failure for Māori, this is a crucial area of focus to reduce inequity of outcomes.
Compared with the traditional ACE inhibitor or ARB plus beta-blocker approach, optimisation of heart failure therapy by adding spironolactone and empagliflozin, with sacubitril/valsartan replacing the ACE inhibitor or ARB, will result in an average life extension of 6.3 years in a 55-year-old, five years in a 70-year-old and 1.4 years in an 80-year-old.6
Barry is euvolemic with apparent New York Heart Association (NYHA) class II symptoms. He is on maximal doses of ACE inhibitor, beta-blocker and spironolactone, plus he is on empagliflozin. As his previous echocardiogram showed an ejection fraction of less than 35 per cent, he meets the threshold Special Authority criteria for sacubitril/valsartan. Although he had some clinical improvement on his current medicines, it would be suitable to consider sacubitril/valsartan for symptom improvement, reduction of hospitalisation risk and to increase Barry’s life expectancy.
Barry is keen to proceed. To simplify changing from enalapril to sacubitril/valsartan, you agree he will stop taking his enalapril on Friday evening and start sacubitril/valsartan on Monday morning.
As he is on the maximal dose of the ACE inhibitor, you prescribe the middle dose of sacubitril 49mg/valsartan 51mg. You remind Barry that sacubitril/valsartan needs to be taken twice daily for effectiveness. You ask him to continue watching his salt intake, monitoring his weight and symptoms, and to have a blood test to monitor his serum creatinine and electrolytes in two weeks.
At the return appointment for dose titration, Barry is feeling well with no lightheadedness. His laboratory monitoring is stable, blood pressure is 122/70mmHg (with no postural drop) and heart rate is 60 beats per minute. He is happy to increase to the maximum dose of sacubitril 97mg/valsartan 103mg twice daily and repeat the blood test monitoring in another two weeks.
This case study does not represent an identifiable person
Penny Clark is a pharmacist prescriber at NorthCare, Hamilton. Linda Bryant is a pharmacist prescriber at Newtown Union Health Service and Porirua Union and Community Health Service, Wellington
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- Troughton R. Heart failure: what a GP needs to know in 2020. Research Review Speaker Series 2020.
- Ministry of Health. Cardiovascular disease. August 2018.
- McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371(11):993–1004.
- Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383(15):1413–24.
- Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385(16):1451–61.
- Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet 2020;396(10244):121–28.