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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 2|Page 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 3|Page 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 First Produced September 2013 4|Page 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 First Produced September 2013 5|Page 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 First Produced September 2013 6|Page 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 7|Page 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 First Produced September 2013 8|Page 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 LVSD Guidelines March 2016 Version 2 First Produced September 2013 9|Page 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 10 | P a g e 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 LVSD Guidelines March 2016 Version 2 First Produced September 2013 11 | P a g e 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 LVSD Guidelines March 2016 Version 2 First Produced September 2013 12 | P a g e