Titration to maximum tolerated doses of ACE inhibitors (ACEIs), Angiotensin receptor blockers (ARBs), beta-blockers and mineralocorticoid receptor antagonists (MRAs) is recommended to reduce morbidity and mortality in left ventricular systolic HF.

Titration of medicines can be challenging as individuals with HF frequently have multiple co-morbidities, numerous medications and often move between acute and primary health-care sectors.

Other difficulties that may impact upon titration include:

• Lack of a clear, patient-specific titration plan
• Poor communication of medication plan between acute and primary care
• Difficulty in managing adverse effects associated with increasing doses
• Patient adherence issues due to the changing medication regimen

Nursing and pharmacy support can play an important role in enhancing treatment by supporting patient adherence and optimising evidence-based treatment by using tools such as a Heart failure medication titration plan. Medication titration plans should be completed by the patient’s treating healthcare team and outline a suggested schedule of titration, target doses for HF medicines, required monitoring, and management of common adverse effects.

• Blood pressure and pulse should be reviewed prior to each dose adjustment
• Aim to achieve recommended target dose for heart failure medications. However, if a patient is unable to tolerate the target dose, continue at the maximum tolerated dose as this may still be beneficial
• Start at a low dose and progressively increase to the recommended target dose or to the maximum tolerated dose
• Intervals between dose titration vary from 1 to 4 weeks, depending on the patient and medication. As a guideline, the dose can usually be doubled every 2 weeks
• Generally, only titrate one medicine at a time; however, patients do not have to be maximised on an ACEI or ARB before initiating a beta-blocker[#hunt-sa-abraham-wt-chin-mh-et-al.-2009]
• If adverse effects arise, consider whether these are likely to be transient, such as dizziness, in which case it is prudent to re-attempt an increase in dose at a later stage
• Optimisation of medications may take a longer time to achieve in some patients
• Patients over 75 years old with co-morbidities are more likely to experience adverse effects
• Diuretics, such as furosemide (frusemide) may be used in a flexible manner to achieve the minimum effective dose
• Ensure that clinicians involved with a patient's exercise program are aware of any ongoing medicine dose titration as this may impact upon the exercise regime. See Cardiac medications that impact upon exercise response

Management of potential adverse effects, such as hypotension and worsening renal function, when titrating first line HF medicines is outlined in the heart failure medication titration problem solving guidelines.  Practice points for dosing and titration of ACEI, ARB, ARNI; beta-blockers, mineralocorticoid receptor antagonist (MRA) and diuretics is described below.

ACE inhibitors (ACEIs), ARBs, and ARNI titration tips

• Avoiding hypotension
  • Prior to up-titration of ACEI /ARB/ARNI, ensure systolic BP is >90mmHg and that the patient is not symptomatically hypotensive or has a significant postural drop in BP.
  • ACEI or ARBs should be commenced at a low dose as they are associated with significant first-dose hypotension. To avoid excessive first dose hypotension, consider decreasing the dose of any diuretics or temporarily stopping diuretic agents 24 hours prior to ACEI/ARB commencement, if clinically appropriate.
  • Initiation of ARNI (sacubitril/valsartan) will be dependent on the patient’s pre-existing ACEI or ARB dose (but is never more than 49/51 mg twice daily). Consider a lower initial dose (24/26mg twice daily) in patients at risk of hypotension, the elderly, or those with any degree of renal impairment or moderate liver impairment.
  • Patients with an activated renin angiotensin system, such as those receiving high doses of diuretics, are at increased risk of hypotension. Correct sodium or volume depletion before initiating ARNI and adjust the dose of diuretics as required.
• ARBs are generally reserved as an alternative for patients who experience ACEI mediated adverse effects, such as a cough[#national-prescribing-service.-2008].
• ARNI (sacubitril/valsartan) should not be administered together with an ACEI or ARB, and a wash-out period of at least 36 hours is required when switching from ACEI therapy.
• Check electrolytes, creatinine and urea 1 week after commencing or adjusting the dose (i.e. titration). Monitor potassium regularly as ACEIs, ARBs and ARNIs may increase serum levels. The concomitant use of potassium supplements and potassium-sparing diuretics (other than MRAs) is rarely indicated and increases the risk of hyperkalaemia.

Beta-blockers titration tips

• Beta-blockers should be started at the lowest dose and titrated slowly to the target dose as they are associated with hypotension, fatigue, and potential worsening of HF symptoms.
• Prior to up-titration of beta-blockers, ensure that:
  • Systolic BP is >90mmHg;
  • Heart rate is >55 beats per minute (bpm);
  • There is no evidence of decompensation such as peripheral oedema, new pulmonary crackles, wheezes or ascites
  • The patient is not experiencing excessive fatigue or lethargy

Mineralocorticoid receptor antagonists (MRAs) titration tips

• Renal function and potassium levels must be checked prior to initiation and after dose changes of MRAs, as they may cause hyperkalaemia and renal dysfunction.
• MRA Monitoring: While guidelines vary the following tips will assist with safe titration:
  • Baseline serum potassium is <5mmol/L and eGFR is>30mL/min
  • Renal function and potassium should be rechecked 1 week after commencing treatment or when adjusting dose, monthly for 6 months and then 6 monthly thereafter once dosing is stable
  • eGFR caution: An eGFR may overestimate renal function for some individuals (such as those with low body weight below 50kg).  Where an eGFR may not be accurate a calculated CrCl using the Cockcroft-Gault formula may assist in  dosing. However, for patients with fluctuating creatinine levels, formulas are not accurate and MRA initiation and titration may not be advised.

Diuretics

• Diuretics may be used in a flexible manner, but the dose should be carefully monitored to ensure it is sufficient to provide symptom relief due to fluid retention while avoiding volume depletion, hypotension, electrolyte disturbances and renal impairment.
• A diuretic dose increased beyond 3 days (to manage worsening HF symptoms) requires medical review and blood chemistry.
• A decreased diuretic dose requires assessment of fluid status and may require blood chemistry 3-7 days post dose reduction.
• Fluid overload is suspected when an increase of 2kg or more above stable body weight for 2 days occurs.
• Dehydration is suspected when weight loss exceeds 2kg over 2 consecutive days, in the presence of dizziness, postural hypotension, dry mucosa or low skin turgor.