Download Pharmacological Management of Chronic Heart Failure with Left

Pharmacological Management of
Chronic Heart Failure
with
Left Ventricular Systolic
Dysfunction (LVSD)
in adults in primary care
Prepared by:
Rizwana Iqbal, Medicines Management Pharmacist, NHS Sheffield CCG
Dr A Al-Mohammad, Consultant Cardiologist, Sheffield Teaching Hospitals NHS FT
Version 2
Reviewed and updated: March 2016
Approved by APG: March 2016
Review date: March 2019
Glossary
Acronym/Term
LVSD
Left ventricular systolic dysfunction
ACE inhibitors
Angiotensin converting enzyme inhibitors
AIIRA
Angiotensin II receptor antagonist
BB
Beta-blocker
AA
Aldosterone antagonist
eGFR
Estimated Glomerular Filtration Rate
NYHA
New York Heart Association
bpm
beats per minute
MHRA
Medicines & Healthcare products
Regulatory Agency
Note:
The doses in this guideline are locally recommended and may differ from those in the
SPC.
LVSD Guidelines March 2016 Version 2
First Produced September 2013
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Summary of guidance
The pharmacological management of chronic heart failure with LVSD is covered in this
guideline. The guideline is targeted at health care professionals in primary care but is
also applicable to secondary care clinicians.
The guideline takes into account NICE clinical guideline 108 and NICE technology
appraisal on ivabradine 267 Nov 2012.
Diagnosis
The basis for historical diagnosis of heart failure with LVSD should be reviewed and
only patients whose diagnosis is confirmed via an echocardiogram or specialist
assessment should be managed in accordance with this guidance.
See NICE CG108 for more detailed information on diagnosis.
Pharmacological Management of LVSD
The management of LVSD can be divided into separate stages1.
1st line – Both ACE inhibitors and beta-blockers; alternative first line agents are
AIIRAs or hydralazine with nitrate
2nd line – Addition of aldosterone antagonists or AIIRAs or hydralazine with
nitrate
3rd line – Addition of digoxin or ivabradine
Angiotensin Converting Enzyme (ACE) inhibitors

ACE inhibitors are offered to all patients with heart failure due to LVSD

They reduce heart failure symptoms, significantly reduce hospitalisation rate,
mortality rate and improve exercise tolerance.

ACE inhibitor therapy is usually, but not necessarily initiated before beta-blocker is
introduced.

Start at a low dose and up titrate it to the maximum tolerated dose (see Table 1).
LVSD Guidelines March 2016 Version 2
First Produced September 2013
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Table 1 Sheffield Formulary Licensed ACE inhibitors for LVSD 2.4
Drug
Initial
Dose
Increment
titrations
Maximum
Dose
Monitoring at initiation,
after up titration and 6
monthly once stable
Ramipril
1.25mg
OD/BD
1.25 mg OD/BD
up to the dose of 5
mg/day and then at
2.5 mg OD/BD at 1
to 2 week intervals
10 mg increments
at intervals of at
least 2 weeks
Increased gradually
over 2-4 weeks
10mg OD
U & Es, eGFR
35mg OD
U & Es, eGFR
10- 20 mg
BD
U & Es, eGFR
Lisinopril 2.5mg
OD
Enalapril
2.5mg
OD

The up titration should be continued unless systolic pressure falls below 100
mmHg. Sometimes, the physician may decide to go beyond that limit.

The creatinine can rise whilst up titrating these agents. A rise in the creatinine
following a single up titration step of over 30% is a sign that further up titration is
not advisable. Consider potential reasons for this change; further U&Es after 2
weeks is advisable as a minimum.

Blood biochemistry (urea, creatinine and electrolytes) should be measured after
initiation and at each dose increment.

If patient is intolerant to ACE inhibitor then use an AIIRA (see below)
Angiotensin II receptor antagonists (AIIRAs)

AIIRAs are usually indicated as an alternative to ACE inhibitors for patients
intolerant of ACE inhibitors (for example, because of cough).

Some patients with LVSD may have a medical need for treatment with an ACE
inhibitor and AIIRA. There is some evidence that the benefits of this combination
may outweigh the risks (hyperkalaemia, hypotension, impaired renal function) in a
selected group of people with LVSD5. The combination should be initiated under
specialist supervision with frequent assessment of the renal profile and serum
potassium levels.
LVSD Guidelines March 2016 Version 2
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
Candesartan and valsartan are licensed as an add-on therapy to ACE inhibitor
when such a combination is required despite optimal therapy MHRA June 2014.
Table 2 Licensed AIIRAs in LVSD 2
Drug
Initial Dose
Dose titration
Maximum
Dose
Candesartan
2-4 mg OD
Increased
gradually at
least 2 weekly
intervals
32 mg OD
Monitoring at
1, 4, 8 and 12
weeks
initiation & 3
monthly once
stable
U & Es, eGFR
Valsartan
20-40 mg OD
Increased
gradually at
least 2 weekly
intervals
160 mg BD
U & Es, eGFR
Losartan
12.5mg once
daily
12.5mg OD
weekly
increments
150mg daily
U & Es, eGFR
Beta-blockers (BB)

BB are proven to reduce heart failure morbidity and mortality in LVSD.

BB should be given to all patients with heart failure due to LVSD, including older
adults and to patients with:
-

Peripheral vascular disease (PVD),
Erectile dysfunction,
Diabetes mellitus,
Interstitial pulmonary disease
Chronic obstructive pulmonary disease (COPD) with no reversibility.
BB licensed for use in heart failure due to LVSD should be initiated in patients with
symptomatic heart failure due to LVSD, usually after ACE inhibitor therapy (even if
rendered asymptomatic with diuretic and ACE inhibitor).
 Start at a low dose and up titrate the BB to the maximum tolerated dose.
LVSD Guidelines March 2016 Version 2
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
Each increment of a BB could be associated with a transient increase in pulmonary
congestion. This may be overcome by pre-warning the patient, and at times by a
transient increase in the dose of the loop diuretic for 2-3 days.

It is ideal if the heart rate is kept at around 55 bpm. However, it is uncommon for
the up titration to continue when the heart rate reaches 60 bpm or below. Similarly,
while the physician may exceed this limit, it is customary not to persevere with the
up titration if the systolic BP is at 100 mmHg or below.

In addition, the patient should have a 12 lead ECG at the outset of the BB therapy;
if there is left bundle branch block, bi-fascicular block or 1st degree AV block, it will
then be favourable to get an ECG performed after each up titration.

If a patient with heart failure due to LVSD is already taking a BB for a concomitant
condition, then the BB should be switched to one of the licensed BB.
Table 3 Beta-blockers licensed for the treatment of heart failure in the UK 2
Drug
Initial Dose
Increment
titrations
Maximum
Dose
Monitoring
Bisoprolol
1.25 mg OD
Weekly by 1.25
mg up to 5mg
OD then every 4
weeks by 2.5 mg
OD
10 mg OD
Pulse, BP,
U & Es, eGFR
(after up titration)
Carvedilol
(Avoid in
COPD &
PVD)
3.125 mg BD
Weekly to 6.25
mg BD, 12.5 mg
BD, then 25 mg
BD
< 85kg:
25 mg BD
Pulse, BP,
U & Es, eGFR
(after up titration)
Nebivolol
(licensed in
patients 70
years and
over)3
1.25 mg od
Increased at
intervals 0f 1-2
weeks to 2.5mg
od, then 5mg od
10 mg OD
> 85kg:
50 mg BD
Pulse, BP,
U & Es, eGFR
(after up titration)
Titration of BB and ACE inhibitors
Clinical judgement is used by the clinician when initiating either a BB first or an ACE
inhibitor. Both can be up titrated simultaneously. However it does not usually matter
which one to up titrate first unless the patient has tachy-arrhythmias when preference
should be given to BB; or is hypertensive when preference is given to ACE inhibitor.
Otherwise it would be appropriate to alternate between the two agents during the up
LVSD Guidelines March 2016 Version 2
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titration process. Patients should be reviewed within 2 weeks of any change in their
dose or type of heart failure medication 14.
It is important that both ACE inhibitors and BB are given at the highest possible
doses for patients with heart failure due to LVSD 9. However, if the patient is
intolerant of these high doses then lower doses need to be accepted. Moreover,
having a high dose of one without the other at all is inferior to having both
agents at low doses.
Aldosterone antagonist (AA)
The introduction of an AA results in significant reduction of both morbidity and
mortality. The specialist’s opinion should be sought prior to the introduction of AA.
Suitable for patients:
 with NHYA class II onwards
 symptomatic despite adequate up titration of both the ACE inhibitor & BB
There is a risk of potentially fatal hyperkalaemia when spironolactone is used in
combination with ACE inhibitors or AIIRAs 12:

DO NOT USE:
 in patients on ACE inhibitor who have a serum creatinine of 200 micromol/L;
 if serum creatinine rises to 220 micromol/L and on both ACE inhibitor & AA
withdraw or reduce dose.

See table 4 for dose and titration. Spironolactone should be used unless the
patient cannot tolerate due to gynaecomastia.

Patients with heart failure taking an AA should have blood potassium and
creatinine levels monitored for signs of hyperkalaemia and/or deteriorating renal
function.

If hyperkalaemia is a problem then the dose of the AA should be halved and
biochemistry rechecked. (For doses less than 25mg please advise patient to use a
tablet cutter).

Once biochemistry and dose are stable, repeat biochemistry, checking for
hyperkalaemia and deteriorating renal function, every 6 months or 3 months if
receiving ACE inhibitor or AIIRA.
LVSD Guidelines March 2016 Version 2
First Produced September 2013
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Table 4 Aldosterone antagonists licensed for the treatment of LVSD.2
Drug
Initial Dose
Doses for
impaired renal
function or low
BP
Maximum Dose
Spironolactone 25mg OD
12.5mg OD /
alternate days
50mg OD
U&Es, eGFR
Eplerenone
12.5mg OD /
alternate days
50mg OD
U&Es, eGFR
25 mg OD
(preferred if there is
painful
gynaecomastia)
Monitoring at 1, 4,
8 and 12 weeks
initiation & 6 monthly
once stable or 3
monthly if Rx with
ACEI/AIIRA
Hydralazine with Nitrate

Started under specialist supervision

This combination had been shown to reduce mortality in patients with heart failure,
improve survival and additional outcomes when added to other evidence-based
treatments in African-Americans with NYHA class III or IV HF6.
Suitable in patients:
 who are intolerant of both ACE inhibitors and AIIRA or with advanced chronic
kidney disease without renal replacement therapy;
 As second line therapy in patients of Afro-Caribbean origin with NYHA class III-IV.
Table 5 Hydralazine with nitrate licensed for LVSD 2
Drug
Hydralazine
Initial Dose
25mg TDS
Maximum Dose
Commonly
50mg TDS
Rarely up to 75mg
TDS
Monitoring
BP
10-20 mg
BD
N/A
BP
(Must have BP>110mgHg)
Isosorbide mononitrate
(ISMN)
LVSD Guidelines March 2016 Version 2
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Ivabradine


Started under specialist supervision
Ivabradine is recommended as a treatment option for treating chronic heart failure
for people with:
 NYHA class II to IV stable chronic heart failure with systolic dysfunction and
 who are in sinus rhythm with a heart rate of 75 bpm or more and
 who are given ivabradine in combination with standard therapy including BB
therapy, ACE inhibitors and AA, or when BB therapy is contraindicated or not
tolerated and
 with a left ventricular ejection fraction of 35% or less.
Ivabradine should only be initiated by secondary care after a stabilisation period
of 4 weeks on optimised standard therapy with ACE inhibitors, BB and AA.






The starting dose of ivabradine is 5 mg twice daily.
The maintenance dose should not exceed 7.5 mg twice daily.
Carefully monitor patients for bradycardia or its symptoms (e.g., dizziness, fatigue,
hypotension) MHRA June 2014.
Only increase the dose to 7.5 mg twice daily after 3 to 4 weeks of treatment and if
the 5 mg dose is well tolerated but insufficient. Carefully monitor the effect of a
dose increase on heart rate.
Down-titrate the dose if resting heart rate decreases persistently below 50 bpm or
if the patient experiences symptoms of bradycardia. The dose can be down-titrated
to 2.5 mg twice daily if necessary.
Stop ivabradine treatment if the resting heart rate remains below 50 bpm or
symptoms of bradycardia persist.
Digoxin
Digoxin is recommended for:
 worsening or severe heart failure due to LVSD despite ACE inhibitor, beta-blocker
and diuretic therapy.
 patients with atrial fibrillation and any degree of heart failure7.
Diuretics
In patients with heart failure due to LVSD in the presence of congestion, use a loop
diuretic such as
o furosemide 40 mg od or bd, OR
o bumetanide 1 mg od or bd
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The diuretics should be titrated according to need. The dose can be reduced but,
ideally, do not stop the diuretics once the other HF-LVSD treatments are maximised
and the patient if free from fluid overload.
The diuretic dose may need to be increased according to the patients' needs. If not
responding, seek specialist opinion with regards to admission for intravenous therapy
or for sequential diuretics therapy
ECG monitoring
Please note the ECG is part of the monitoring tasks that the GP should
undertake.
Patients, who have bundle branch block, should have an ECG every 6 months to
detect prolongation of the QRS complex. The latter is one of the criteria for
considering patients for the lifesaving cardiac resynchronisation therapy (CRT) 13, 15.
Those who have heart failure and do not have bundle branch block and who are
stable, should have an annual ECG to detect the development of prolonged QRS
complexes and thus the development of bundle branch block.
The GP should state on the request form that the ECG is to detect bundle branch
block and prolonged QRS complexes. If these are found, the patient should be
referred to the specialist.
Antiplatelet and statin
Antiplatelet and statins are not routinely indicated for LVSD; however, they should be
prescribed for patients with the combination of heart failure and symptomatic
atherosclerotic arterial disease (including coronary heart disease). See local
guidelines for further information 10,11.
Guideline Prepared by:
Rizwana Iqbal
Medicines Management Pharmacist, NHS Sheffield CCG
Dr A Al-Mohammad, MD, FRCP(E), FRCP(L), FESC
Consultant Cardiologist, Sheffield Teaching Hospitals NHS Foundation Trust
First approved by APG:
Reviewed and updated (Version 2):
Version 2 approved by APG:
Review date:
September 2013
March 2016
March 2019
March 2019 or on update of NICE guidance
LVSD Guidelines March 2016 Version 2
First Produced September 2013
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References
1. NICE-CG 108, Chronic heart failure - Management of chronic heart failure in adults in
primary and secondary care, 2010. https://www.nice.org.uk/Guidance/CG108
2. BNF 68, sections 2.5 (September –March 2015)
3. Summary of product characteristics Nebivolol
http://www.medicines.org.uk/emc/medicine/22624
4. The Sheffield Formulary available from
http://www.intranet.sheffieldccg.nhs.uk/Medicines%20Management/medicinesprescribing/sheffield-formulary.htm
5. MHRA Drug Safety Update June 2014
https://www.gov.uk/drug-safety-update/combination-use-of-medicines-from-different-classesof-renin-angiotensin-system-blocking-agents-risk-of-hyperkalaemia-hypotension-andimpaired-renal-function-new-warnings
https://www.gov.uk/drug-safety-update/ivabradine-carefully-monitor-for-bradycardia
6. Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure
http://www.nejm.org/doi/full/10.1056/NEJMoa042934
7. NICE – CG180, Atrial fibrillation
http://www.nice.org.uk/guidance/cg180/chapter/1-recommendations
8. NICE TA 207, November 2012
http://www.nice.org.uk/guidance/ta267
9. NICE Quality Standard 9 statement 3. Medication for chronic heart failure due to LVSD
https://www.nice.org.uk/guidance/qs9/chapter/Quality-statement-3-Medication-for-chronicheart-failure-due-to-left-ventricular-systolic-dysfunction
10. Antiplatelets in the prevention and treatment of cardiovascular disease
http://www.intranet.sheffieldccg.nhs.uk/Downloads/Medicines%20Management/prescribing%2
0guidelines/Sheffield%20guidelines%20antiplatelets%20for%20CVD_April2015.pdf
11. Lipid Modification Guidelines
http://www.intranet.sheffieldccg.nhs.uk/Downloads/Medicines%20Management/prescribing%2
0guidelines/Sheffield%20Lipid%20Guidelines%202015%20with%20appendix.pdf
12. MHRA Drug Safety Update February 2016
https://www.gov.uk/drug-safety-update/spironolactone-and-renin-angiotensin-system-drugs-inheart-failure-risk-of-potentially-fatal-hyperkalaemia
13. NICE TA314 Implantable cardioverter defibrillators and cardiac resynchronisation therapy
for arrhythmias and heart failure
https://www.nice.org.uk/guidance/ta314
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14. NICE Quality Standard 9 statement 4 Review after changes in medication
https://www.nice.org.uk/guidance/qs9/chapter/Quality-statement-4-Review-after-changes-inmedication
15. NICE Quality Standard 9 statement 5 Review of people with stable chronic heart failure
https://www.nice.org.uk/guidance/QS9/chapter/Quality-statement-5-Review-of-people-withstable-chronic-heart-failure
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