Heart Failure – MEDICATIONS

Medications indicated

1. Angiotensin converting enzyme inhibitor (ACEI)
   • all patients with CHF (if not tolerated use angiotensin II receptor blocker)
2. beta blocker
   • patients with systolic failure; COPD is not a contraindication (bisoprolol, carvedilol, metoprolol, nebivolol)
3. frusemide:
   • symptoms of fluid overload
4. spironolactone:
   • add on if symptom control inadequate
5. digoxin:
   • consider for atrial fibrillation, or as add on therapy for sinus rhythm with severe chF inadequately controlled with the above

1. Medications (contraindicated or caution):
   – verapamil and diltiazem
   – NSAIDs or cyclo-oxygenase-2 inhibitors
   – corticosteroids
2. Vaccinations: influenza, pneumococcal
3. Device therapy for patients with moderate or severe CHF
   – cardiac resynchronisation therapy (eg. if QRs is greater than 120 ms)
   – implantable cardioverter defibrillator.

Drugs used in heart failure with reduced left ventricular ejection fraction

Drug	Indications	Mechanism	Adverse effects	Precautions
ACE inhibitors	First-line therapy when LVEF <40%	Reduces sodium reabsorption  Reduces aldosterone	Hypotension  Worsening renal function  Hyperkalaemia Chronic cough  Angioedema	Previous angioedema  Other drugs that increase potassium
Angiotensin receptor antagonists (sartans)	If intolerant of ACE inhibitors	Reduces vasoconstriction  Reduces sodium reabsorption  Reduces aldosterone	Hypotension  Worsening renal function  Hyperkalaemia	Other drugs that increase potassium
Beta blockers	First-line therapy when LVEF <40%	Reduces sympathetic activity  Has antiarrhythmic effects  Reverses remodelling	Hypotension  Bradycardia  Fatigue  Bronchospasm  Impotence  Worsening heart failure  Masking hypoglycaemia	2nd and 3rd degree heart block  Asthma  Chronic obstructive pulmonary disease – exclude significant reversibility
Aldosterone antagonists	If symptomatic despite ACE inhibitor and beta blocker and LVEF <40%	Is a weak diuretic  Reduces effects of aldosterone	Hyperkalaemia  Worsening renal function  Hypotension  Gynaecomastia (spironolactone)	Other drugs that increase potassium
Sacubitril with valsartan	Heart failure LVEF <35%  In place of ACE inhibitor or angiotensin receptor antagonist	Causes vasodilation  Reduces sympathetic activity  Enhances diuresis	Angioedema  Hypotension	Previous angioedema  A 36-hour ACE inhibitor washout is an absolute requirement before starting
Diuretics	Relief of congestive symptoms	Reduces retention of sodium and water	Renal dysfunction  Hypokalaemia  Worsened gout	Other drugs that lower potassium
Ivabradine	Heart rate 77 beats/min or higher despite beta blocker, or intolerant to beta blocker Sinus rhythm	Reduces heart rate in sinus rhythm	Visual disturbances (phosphenes) Headache Bradycardia Atrial fibrillation	3rd degree atrioventricular block Sinoatrial blockStop if atrial fibrillation developsProlonged QT syndrome
Digoxin	Heart failure in sinus rhythm with symptoms despite ACE inhibitor, beta blocker, aldosterone antagonist, diureticAtrial fibrillation	Is a weak positive inotrope Reduces heart rate Increases vagal tone	Bradycardia Digoxin toxicity	Narrow therapeutic range requires monitoring Interacting drugs Impaired renal function

	Daily starting dose	Daily target maintenance dose
ACE inhibitors
Captopril	6.25 mg x3	25–75 mg x2
Enalapril	2.5 mg	10–20 mg x2
Fosinopril	5–10 mg	20–40 mg
Lisinopril	2.5 mg	20–40 mg
Perindopril arginine	2.5 mg	5–10 mg
Perindopril erbumine	2 mg	4–8 mg
Quinapril	5 mg	20–40 mg
Ramipril	2.5 mg	5–10 mg
Angiotensin receptor inhibitors
Candesartan	4–8 mg	32 mg
Valsartan	40 mg x2	160 mg x2
Losartan	50 mg	150 mg
Beta blockers
Bisoprolol	1.25 mg	10 mg
Carvedilol	3.125 mg	25 mg x2
Metoprolol extended release	23.75 mg	190 mg
Nebivolol	1.25 mg	10 mg
Aldosterone antagonists
Eplerenone	25 mg	50 mg
Spironolactone	25 mg	50 mg
Neprilysin inhibitor/angiotensin receptor antagonist
Sacubitril with valsartan	49/51 mg	97/103 mg

• ACE inhibitors and angiotensin receptor antagonists
  • first-line therapy in heart failure with reduced ejection fraction and asymptomatic left-ventricular dysfunction. 
  • results in a 3.8% absolute reduction (20% relative) in death, with reductions in myocardial infarction and hospitalisation for heart failure.
  • Beneficial effects occur early and continue long term, in all age groups. 
  • ACE inhibitors reduce the maladaptive effects of chronic renin– angiotensin–aldosterone system activation, including sodium and water retention, vasoconstriction, and cardiac hypertrophy and fibrosis. 
  • Studies of angiotensin receptor antagonists (sartans) have not shown a consistent reduction in mortality, therefore considered as a second choice, indicated only in patients intolerant of ACE inhibitors.
  • Treatment should begin soon after diagnosis, at the lowest dose. 
  • Up-titration is recommended if the blood pressure is 90 mmHg systolic or above, and is limited by symptoms rather than the measured blood pressure. 
  • If symptomatic hypotension occurs, other vasodilators should be reduced or stopped first and, provided the patient is not congested, diuretics should be reduced or ceased before reducing the ACE inhibitor dose.
  • A minor worsening of renal function (up to 30% reduction in estimated glomerular filtration rate (eGFR)) is generally acceptable. 
  • A small rise in potassium can be expected, but the ACE inhibitor dose should be halved if the potassium concentration exceeds 5.5 mmol/L. If an ACE inhibitor induces a chronic cough, a change to a sartan may be appropriate after other causes of cough have been excluded such as pulmonary oedema or underlying lung disease.

• Beta blockers
  • another important first-line therapy for heart failure with reduced ejection fraction. 
  • Given with ACE inhibitors, they are associated with a 4.3% absolute reduction (24% relative reduction) in all-cause mortality and comparable reductions in hospital admissions for patients in sinus rhythm.
  • Beta blockers reduce myocardial oxygen demand, protect from ischaemia, have antiarrhythmic effects and reduce sudden cardiac death. 
  • Only beta blockers that have been shown to be effective in heart failure should be used
    • Bisoprolol
    • Carvedilol
    • extended-release metoprolol
    • nebivolol – if the patient is over 70 years old (as this drug has only been evaluated in the elderly).
  • All patients with heart failure with reduced ejection fraction should be given beta blockers. Start soon after an ACE inhibitor, once the patient is clinically stable and euvolaemic. 
  • At first the symptoms of heart failure may worsen so the smallest dose should be used. 
  • Aim to titrate up to the target dose or as high as tolerated. Heart rate, blood pressure and symptoms of congestion should be reviewed after each up-titration.
• contraindications to beta blockers:
  • Absolute contraindications second or third degree atrioventricular block.
    • If these occur, a pacemaker or cardiac resynchronisation therapy should be considered to enable continuation of therapy. 
  • Asthma is only a relative contraindication. 
  • Chronic obstructive pulmonary disease should be assessed with lung function tests before deciding not to give beta blockers. 
  • If there is no significant airway reversibility, the patient should be able to tolerate beta blockers. 
  • Usually the impact of beta blocker therapy on lung function tests is minimal and without clinical relevance.22
  • The dose should be reassessed if clinical deterioration occurs or the heart rate is under 50 beats per minute. 
  • As with ACE inhibitors, asymptomatic hypotension does not require a change of therapy. 
  • If symptomatic, consider reducing other vasodilators first, or the dose of any diuretic if there is no congestion, before deciding to reduce the dose of beta blocker. 
  • Bisoprolol and metoprolol have a less vasodilating effect and may be better tolerated if the blood pressure is borderline, however the additional vasodilating effects of carvedilol may offset the early worsening of heart failure.

• Aldosterone antagonists
  • improve survival across the full spectrum of heart failure with reduced ejection fraction. 
  • There is an 11% absolute reduction (30% relative) in mortality in severe heart failure, a 7.6% absolute reduction (37% relative) in mortality and cardiovascular hospitalisation in mild heart failure, and a 2.3% absolute reduction (15% relative) in death in patients with heart failure after myocardial infarction.
  • Aldosterone antagonists block the adverse effects of aldosterone activation, which includes sodium and water reabsorption, and cardiovascular fibrosis. 
  • These drugs are markedly underused and should be added to ACE inhibitors and beta blockers in all patients who remain symptomatic.
  • Serious hyperkalaemia can occur, especially with underlying renal impairment. Serum potassium should be closely monitored, at one week and one, two and three months after starting or increasing the dose, then every three months to 12 months, and then four monthly thereafter. 
  • The starting dose can be halved if diabetes or renal impairment is present 
  • The dose should be halved if potassium exceeds 5.5 mmol/L, and ceased if it is more than 6.0 mmol/L. Gynaecomastia can occur in men, but is less common with eplerenone than with spironolactone.

• Sacubitril with valsartan
  • Sacubitril with valsartan is a new combination which was shown to be superior to enalapril in a large head-to-head trial, with an absolute reduction of cardiovascular death and heart failure hospitalisation of 4.7% (20% relative reduction).
  • Sacubitril is a neprilysin inhibitor.
    • It inhibits the degradation of vasoactive peptides including natriuretic peptides, thereby enhancing their beneficial effects such as vasodilation and diuresis. 
  • The combination reduces sympathetic tone, aldosterone and myocardial fibrosis and hypertrophy.
  • Sacubitril with valsartan can replace an ACE inhibitor or sartan if symptoms persist despite optimal medical therapy.
  • This combination may become first-choice therapy in the future, given its efficacy. 
  • However, currently it should be used when a patient has been stabilised on an ACE inhibitor, beta blocker and aldosterone antagonist.
  • Previous angioedema (due to any cause) is a contraindication. 
  • A 36-hour ACE inhibitor washout period is an absolute requirement to reduce the risk of angioedema. 
  • The combination lowers the blood pressure more potently and therefore can cause hypotension. 
  • This improves over time, but can be addressed by reducing the dose of other vasodilators or halving the starting dose of sacubitril with valsartan.

• Other drugs
  • Other therapies can be added to the essential drugs for heart failure (beta blockers, ACE inhibitors and aldosterone antagonists). They can also be considered secondary choices if the first-line drugs are not tolerated.

• Diuretics
  • Loop diuretics are used by most patients at some stage for symptomatic control of heart failure. 
  • They should be used in addition to ACE inhibitors and beta blockers in patients with heart failure with reduced ejection fraction if there is associated symptomatic congestion. 
  • Diuretics can often be reduced as doses of neurohormonal blockers are increased.
  • A small dose of a thiazide or a potassium-sparing diuretic can be added to furosemide (frusemide) or bumetanide for a short period. 
  • This has a synergistic diuretic effect for patients with peripheral oedema resistant to treatment with a loop diuretic. 
  • Renal function and potassium need to be closely monitored.

• Ivabradine
  • A raised resting heart rate is a marker of cardiovascular risk.28 Ivabradine reduces heart rate by inhibiting the sinus node, and results in a 5% absolute reduction (18% relative) in the risk of either cardiovascular mortality or heart failure hospitalisations.
  • It is used in heart failure with sinus rhythm when the left ventricular ejection fraction is less than 35% as an add-on to an ACE inhibitor, aldosterone antagonist and maximally tolerated beta blocker if the heart rate is at least 77 beats per minute.
  • It can be used if the patient cannot tolerate a beta blocker.
  • Ivabradine can only be used in sinus rhythm. 
  • It does not affect blood pressure, intracardiac conduction or myocardial contractility. It may cause visual symptoms, including flashing lights, which are not associated with retinal damage, and which usually resolve spontaneously. Stop ivabradine if atrial fibrillation develops.

• Digoxin
  • Digoxin is useful for symptomatic control of heart failure in sinus rhythm, but only after therapy with an ACE inhibitor, beta blocker, aldosterone antagonist and diuretic has been optimised. 
  • It is a weak positive inotrope and increases vagal tone. In atrial fibrillation digoxin slows the heart rate by reducing atrioventricular nodal conduction.
  • Digoxin does not improve survival, but can reduce hospitalisations associated with heart failure and improves symptoms.
  • It should be used at a low dose in sinus rhythm, aiming for a serum digoxin of 0.5–0.9 nanogram/mL measured at least six hours after oral dosing.
  • Digoxin toxicity may result from deteriorating renal function or dehydration, with symptoms most commonly including nausea, vomiting and drowsiness.
  • Digoxin may also be useful for rate control in the treatment of atrial fibrillation in heart failure.

• Hydralazine plus isosorbide dinitrate
  • High-dose hydralazine is an arterial vasodilator
  • Isosorbide dinitrate is predominantly a venodilator. 
  • The combination can be used with a beta blocker if the patient is intolerant of ACE inhibitors and sartans. Specialist advice should be sought.

Devices

• An implantable cardioverter defibrillator should be considered for primary or secondary prevention of ventricular arrhythmias if left ventricular ejection fraction is 35% or less to reduce the risk of sudden death and all-cause mortality.
• This may be implanted alone, or may be combined with cardiac resynchronisation therapy (or biventricular pacing) if the QRS duration on the ECG is prolonged at 130 milliseconds or above with left bundle branch block morphology. 
• This reduces mortality and heart failure hospitalisations and improves symptoms. 

Heart failure with preserved ejection fraction

• Compared to those with a reduced ejection fraction, patients with heart failure with preserved ejection fraction are older, more likely to be female and to have hypertension, atrial fibrillation, diabetes or obesity. 
• The mechanism probably relates to a combination of pathophysiological processes including increased myocardial stiffness, abnormal myocardial relaxation and increased arterial stiffness.
• No drug has been shown to improve survival, however recent data suggest that in a subset of patients with heart failure and preserved ejection fraction, aldosterone antagonists may improve clinical outcomes.
• Sacubitril with valsartan was found to be beneficial in a phase II study.
• The combination is therefore currently under evaluation for heart failure with preserved ejection fraction.
• Diuretics should be used judiciously and over-diuresis avoided. 
• Treatment should focus on aggressive control of concurrent conditions particularly hypertension. 
• Atrial fibrillation should be managed according to guidelines, using a rate control strategy and anticoagulation initially, with a trial of rhythm control for persistent symptoms. 
• Myocardial ischaemia, obesity and anaemia should be addressed. Exercise training can improve quality of life. 

Withdrawal of treatment

• Substantial improvements in symptoms are seen after starting drug therapy and often patients will feel back to normal. 
• Left ventricular ejection fraction can sometimes return to normal or close to the normal range. 
• Drugs that confer a survival benefit, in particular ACE inhibitors and beta blockers, should not be stopped, as this may lead to a recurrence of heart failure.
• Diuretics and digoxin (in sinus rhythm) may be reduced and stopped if the patient remains stable.
• When the goals of treatment move to palliation and symptom control, ACE inhibitors, beta blockers and aldosterone antagonists should be continued if possible, as they improve symptoms. 
• Down-titration of doses may be needed if hypotension or issues with renal function and electrolytes occur. 
• Statins and digoxin if not being used for atrial fibrillation can be withdrawn. Deactivation of an implantable cardioverter defibrillator should be considered in a patient entering the palliative phase of their illness, or in a patient making an informed end-of-life decision.
• This decision should be undertaken by the patient, their family, GP and specialist.

Drugs to avoid

• Many drugs have been shown to exacerbate heart failure.
• salt and water retention
  • Non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors should be avoided as they cause salt and water retention and impair renal function. 
  • Corticosteroids result in salt and water retention. 
• negative inotropic effect
  • Non-dihydropyridine calcium channel blockers (verapamil and diltiazem)
    • should be strictly avoided in heart failure with reduced ejection fraction due to their negative inotropic effect. 
• pro-arrhythmic potential
  • Antiarrhythmic drugs (except beta blockers and amiodarone)
  • tricyclic antidepressants have
• increase the risk of heart failure.
  • Pioglitazone 
  • dipeptidyl peptidase 4 (DPP 4) inhibitors
• Non-potassium sparing diuretics can contribute to digoxin toxicity by causing hypokalaemia, and digoxin concentrations can be increased by amiodarone and spironolactone.
• Potential drug–drug interactions occur with various complementary therapies, including St John’s wort, black cohosh and grapefruit juice. These should be avoided.