Cautions and Monitoring

Medications

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Identifying precautions and contraindications of common cardiac medications

Examples of precautions or contraindications to commonly prescribed medications are shown in the tables below. NB. Refer to a comprehensive reference such as the Australian Medicines Handbook or treatment product information for a full description of all precautions and contraindications.

Table 1: ACEI/ARB/ARNI precautions and contraindications

ACEI/ARB/ARNI: Precautions	Considerations
Bilateral renal artery stenosis (unstented)[#australian-medicines-handbook-2015]	Increased risk of acute renal failure[#australian-medicines-handbook-2015]
Renal impairment[#preston-cl-ed..-stockleys-drug-interactions-online] and hyperkalaemia	Renal impairment may worsen, with an increased risk of hyperkalaemia Monitor carefully and consider a lower initial dose[#australian-medicines-handbook-2015] A mild increase in creatinine (up to 30%) may be acceptable if this is stable and the patient has a high level of need for an ACEI/ARB
History of angioedema[#national-prescribing-service.-2011,#micromedex-healthcare-series-internet-database,#kaplan-nm.-2014]	ARBs may be trialled in patients with a history of angioedema associated with ACEI treatment Closely monitor due to the possibility of cross-sensitivity particularly when administering the first dose[#australian-medicines-handbook-2015]
Unstable coronary syndromes and severe aortic stenosis[#national-prescribing-service.-2004]	Caution to avoid systemic hypotension, reduced renal function, and coronary hypoperfusion[#australian-medicines-handbook-2015] Requires specialised medical supervision[#national-prescribing-service.-2004]
Pregnancy	Contraindicated due to risk of foetal abnormalities[#national-prescribing-service.-2011,#micromedex-healthcare-series-internet-database], and lack of data (ARNI)[#australian-medicines-handbook-2015]
Dehydration	Increases the risk of hypotension, falls, and acute renal impairment

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor, ARNI = angiotensin receptor neprilysin inhibitors

Table 2: Beta-blocker precautions and contraindications

Beta-blockers: Precautions	Considerations
Decompensated HF[#national-prescribing-service.-2011]	Should not be initiated during acute decompensation as may cause symptomatic hypotension, and worsening of HF symptoms due to withdrawal of sympathetic drive and bradycardia.[#national-prescribing-service.-2000]
Airway diseases (e.g., asthma).	May be used in COPD Asthma requires a risk-benefit evaluation. Beta1-selective beta-blockers such as bisoprolol, atenolol or metoprolol, may be preferred, although beta1-selectivity may be lost at higher doses [#mcmurray-jj-adamopoulos-s-anker-sd-et-al.-2012] Verapamil may be considered as an alternative in patients with asthma.
Symptomatic bradycardia (<50 bpm)[#national-prescribing-service.-2011]	May further decrease heart rate[#australian-medicines-handbook-2015]
Second- or third-degree atrioventricular heart block [#australian-medicines-handbook-2015,#preston-cl-ed..-stockleys-drug-interactions-online,#national-prescribing-service.-2011]	Contraindicated (without a pacemaker)[#australian-medicines-handbook-2015,#national-prescribing-service.-2004]
Diabetes[#australian-medicines-handbook-2015]	Beta-blockers may mask signs of hypoglycaemia (tachycardia, tremor), and increase incidence and severity of hypoglycaemic episodes[#australian-medicines-handbook-2015] Beta1-selective beta-blockers (e.g. bisoprolol, metoprolol) may be considered especially if at risk of hypoglycaemia

COPD = chronic obstructive pulmonary disease; HF = heart failure

Table 3: Calcium channel blockers, statins and nitrates precautions and contraindications

Precautions & contraindication	Considerations
Calcium channel blockers: Verapamil and diltiazem can both slow heart rate	Monitor heart rate closely Verapamil and diltiazem have problematic and often unrecognised drug interactions (e.g., with statins), which require careful consideration[#australian-medicines-handbook-2015] In patients taking beta-blockers, avoid verapamil (unless advised by cardiologist) and use diltiazem with caution
Statins: Myalgia is common with statin medications (5-15%); however, myopathy is rare Statins, particularly simvastatin, have some problematic drug interactions[#australian-medicines-handbook-2015]	Statin-induced myalgias can often be ameliorated by changing to another statin or lowering the dose Mild transient increases in ALT and AST are common and rarely of significance. Significant increases in liver enzymes (3-4 times normal) are rarer but require cessation of the statin. Pravastatin is renally excreted and thus should be used in lower doses in patients with impaired renal function.[#australian-medicines-handbook-2015]
Nitrates: Concomitant use of erectile dysfunction medicines (sildenafil or tadalafil) may dangerously reduce BP in patients taking nitrates[#australian-medicines-handbook-2015]	Nitrate patches should be left off for at least 8 hours a day to maintain effectiveness Isosorbide mononitrate tablets should always be taken as a single daily dose[#australian-medicines-handbook-2015]

Precautions & contraindication

Considerations

Calcium channel blockers:

Verapamil and diltiazem can both slow heart rate

Monitor heart rate closely

Verapamil and diltiazem have problematic and often unrecognised drug interactions (e.g., with statins), which require careful consideration[#australian-medicines-handbook-2015]

In patients taking beta-blockers, avoid verapamil (unless advised by cardiologist) and use diltiazem with caution

Statins:

Myalgia is common with statin medications (5-15%); however, myopathy is rare

Statins, particularly simvastatin, have some problematic drug interactions[#australian-medicines-handbook-2015]

Statin-induced myalgias can often be ameliorated by changing to another statin or lowering the dose

Mild transient increases in ALT and AST are common and rarely of significance.

Significant increases in liver enzymes (3-4 times normal) are rarer but require cessation of the statin.

Pravastatin is renally excreted and thus should be used in lower doses in patients with impaired renal function.[#australian-medicines-handbook-2015]

Nitrates:

Concomitant use of erectile dysfunction medicines (sildenafil or tadalafil) may dangerously reduce BP in patients taking nitrates[#australian-medicines-handbook-2015]

Nitrate patches should be left off for at least 8 hours a day to maintain effectiveness

Isosorbide mononitrate tablets should always be taken as a single daily dose[#australian-medicines-handbook-2015]

ALT = alanine transaminase; AST = aspartate aminotransferase;

Table 4: Antiplatelet precautions and contraindications

Antiplatelet	Precautions & Contraindications	Considerations
Aspirin	Active GI bleeding or a history of allergy or bronchospasm with aspirin[#australian-medicines-handbook-2015] Concomitant warfarin therapy is a precaution, but not a contraindication	Patients with allergies or who experience bronchospasm when taking aspirin may be referred to an immunologist for aspirin desensitisation Take formulations as recommended, i.e., dissolve dispersible aspirin in at least half a glass of water; swallow enteric-coated aspirin whole and do not cut or crush Low-dose aspirin (i.e., 100mg-150mg daily) is less likely than high-dose aspirin or other NSAIDs to cause renal impairment, and is generally considered safe to use with ACEI/ARBs and diuretics with appropriate monitoring
Clopidogrel	Potential interaction with proton pump inhibitors (PPIs) such as omeprazole	Approximately 30% of patients are non-responders due to an inability to convert clopidogrel to its active metabolite Patients who have had a thrombotic event on clopidogrel should therefore be switched to prasugrel or ticagrelor
Ticagrelor	May cause dyspnoea and bradycardia[#australian-medicines-handbook-2015]	Use with caution in patients with severe respiratory disease or who are at high risk of heart block Ticagrelor has a higher rate of bleeding than clopidogrel
Prasugrel	Increased bleeding risk in those >75 years old[#australian-medicines-handbook-2015]	The recommended dose in those aged >75 years of age is 5mg daily[#australian-medicines-handbook-2015] due to increased bleeding risk, although this dose has not been shown to be effective in clinical trials Prasugrel has a higher rate of bleeding than clopidogrel
Glycoprotein 2b/3a inhibitors e.g., abciximab, tirofiban	Avoid in those at high risk of bleeding	Most of the evidence of benefit is from trials where patients were not prescribed two antiplatelet agents These medications play an important role in patients with ongoing symptoms who cannot access PCI quickly (e.g., in rural and remote settings)

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; GI = gastrointestinal; NSAIDs = non-steroidal anti-inflammatory drugs; PCI = percutaneous coronary intervention; PPI = proton pump inhibitor

Table 5: Anticoagulants and thrombolytics precautions and contraindications

Anticoagulants & thrombolytics	Precaution & Contraindication	Considerations
Unfractionated heparin	Heparin induced thrombocytopenia and thrombosis syndrome (HITTS) [#australian-medicines-handbook-2015] Patients taking warfarin or other anticoagulants Raised INR due to liver disease	Although rare, HITTS can be catastrophic All patients should have platelets monitored daily and if platelets reduce by 30-50% perform HITTS screening blood test HITTS is less common with enoxaparin than with heparin.
Low molecular weight heparin (LMWH)	HITTS.[#australian-medicines-handbook-2015] Patients taking warfarin or other anticoagulants such as apixaban, dabigatran, rivaroxaban or edoxaban Raised INR due to liver disease	LMWH (e.g., enoxaparin) is predominantly renally excreted and should be avoided in those with CrCl <30mL/min[#australian-medicines-handbook-2015] In those with a CrCl of 30-50mL/min, consider using unfractionated heparin
Thrombolytics	There are numerous precautions particularly in any condition that increases the risk of bleeding, especially intracranial haemorrhage[#national-prescribing-service.-2000]	If accessible within a short time frame, PCI is preferable to thrombolysis [#barras-ma-duffull-sb-atherton-jj-green-b.-2008]

Anticoagulants & thrombolytics

Precaution & Contraindication

Considerations

Unfractionated heparin

Heparin induced thrombocytopenia and thrombosis syndrome (HITTS)
[#australian-medicines-handbook-2015]

Patients taking warfarin or other anticoagulants

Raised INR due to liver disease

Although rare, HITTS can be catastrophic

All patients should have platelets monitored daily and if platelets reduce by 30-50% perform HITTS screening blood test

HITTS is less common with enoxaparin than with heparin.

Low molecular weight heparin (LMWH)

HITTS.[#australian-medicines-handbook-2015]

Patients taking warfarin or other anticoagulants such as apixaban, dabigatran, rivaroxaban or edoxaban

Raised INR due to liver disease

LMWH (e.g., enoxaparin) is predominantly renally excreted and should be avoided in those with CrCl <30mL/min[#australian-medicines-handbook-2015]

In those with a CrCl of 30-50mL/min, consider using unfractionated heparin

Thrombolytics

There are numerous precautions particularly in any condition that increases the risk of bleeding, especially intracranial haemorrhage[#national-prescribing-service.-2000]

If accessible within a short time frame, PCI is preferable to thrombolysis
[#barras-ma-duffull-sb-atherton-jj-green-b.-2008]

CrCl = creatinine clearance; HITTS = heparin-induced thrombocytopenia and thrombosis syndrome; INR = international normalised ratio; LMWH = low molecular weight heparin; PCI = percutaneous coronary intervention

Drug interactions with other medications and substances

Identification of drug interactions is particularly important when initiating new medicines, (including antibiotics), in elderly patients, those with renal impairment, and those taking medicines with frequent drug interactions. See Table 6 below for ACS interacting medications.

Heart failure

Many patients with chronic heart failure are prescribed multiple medications increasing the likelihood for drug interactions. The common combination of ACEIs and beta-blockers for example usually has an additive hypotensive effect. While such interactions should be considered and monitored, using these medicines concomitantly is often fundamental to HF treatment. See Table 7 below for heart failure interacting medications.

Other substances

Foods such as grapefruit juice, herbal medicines such as St John's Wart, and non-prescription and illicit medicines should be checked for interactions. Consult with a pharmacist to assist with interpretation of potential and risk of medication interactions.

Table 6: ACS interacting medications

Medicine/drug class	Interacting medication	Risk	Considerations & Recommendations
Simvastatin	+Amiodarone	Amiodarone inhibits the metabolism of simvastatin	Reduce simvastatin dose to 20mg or change to another statin
Verapamil or diltiazem	+Beta-blockers	Additive effects on slowing HR	Avoid combining, or monitor HR closely
Clopidogrel	+PPIs e.g., omeprazole.	PPIs may reduce metabolism of clopidogrel to its active metabolite	Inconsistent trial data as to whether this interaction exists. There may be differences in the interaction potential within the PPI class of medicines
Aspirin, clopidogrel, ticagrelor, prasugrel	+Warfarin, dabigatran, rivaroxaban, apixaban.	Doubling of bleeding risk	Avoid combination or where not possible (e.g., high-risk MI patients with mechanical valve or intracardiac thrombus), use combination for shortest time possible Reduce risk by ensuring BP control, cessation of smoking, and PPI cover where appropriate
Clopidogrel	+PPI e.g., omeprazole	PPIs may reduce metabolism of clopidogrel to its active metabolite	Inconsistent trial data as to whether this interaction exists. There may be differences in the interaction potential within the PPI class of medicines
Statins	+Fibrates e.g., fenofibrate, gemfibrozil	Increased risk of myalgia	Risk is small and usually outweighed by benefits in patients requiring this combination (if combination required, use fenofibrate not gemfibrozil)

HR = heart rate; MI = myocardial infarction; PPI = proton pump inhibitor References: [#australian-medicines-handbook-2015,#mims-online.-mims-australia,#indiana-university.-department-of-medicine.-clinical-pharmacology]

Table 7: Heart failure interacting medications

Medication	Interacting medication	Potential risk	Considerations and recommendations
ACEIs & ARBs	+Loop diuretic	Increased risk of renal impairment [#australian-medicines-handbook-2015,#preston-cl-ed..-stockleys-drug-interactions-online] When initiating there is an increased risk of severe hypotension due to volume depletion[#australian-medicines-handbook-2015]	Closely monitor renal function and be very cautious in patients with hypovolaemia[#australian-medicines-handbook-2015] Monitored closely during a hospital admission, however carefully consider treatment combination for outpatients Consider: withholding loop diuretic (or reduce dose) for at least 24 hours before starting, and begin with a low dose of ACEI, giving the first dose of ACEI/ARB in the evening under medical supervision [#australian-medicines-handbook-2015] Seek specialist advice in fluid-overloaded patients before withholding a diuretic as they may be at risk of decompensation
Beta-blockers	+Other medicines that reduce BP, cardiac contractility and conduction [#australian-medicines-handbook-2015]	May cause additive hypotension, HF or bradyarrhythmia [#australian-medicines-handbook-2015]	Monitor BP, cardiac function and heart rate closely[#australian-medicines-handbook-2015]
MRA	+ACEI or ARB +Digoxin	Increased risk of hyperkalaemia [#national-prescribing-service.-2011] Spironolactone may increase digoxin concentration and potential toxicity[#australian-medicines-handbook-2015,#kaplan-nm.-2014]	MRA + ACI or ARB combination is common and requires monitoring of electrolytes and renal function vigilantly[#national-prescribing-service.-2011] (See Titrating medications in systolic heart failure) Monitor digoxin levels and potential adverse effects of digoxin during concomitant use [#australian-medicines-handbook-2015,#micromedex-healthcare-series-internet-database]
NSAID*	+ACEI + diuretic MRA	Acute renal failure[#mims-online.-mims-australia] Increased risk of hyperkalaemia [#australian-medicines-handbook-2015]	Avoid this combination but if it is essential to co-administer, closely monitor renal function, serum potassium and signs of HF [#national-heart-foundation-of-australia-and-the-cardiac-society-of-2011] Monitor electrolytes vigilantly[#australian-medicines-handbook-2015]

* NSAIDs including the selective COX-2 inhibitors, e.g., celecoxib
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; HF = heart failure; MRA = mineralocorticoid receptor antagonist; NSAID = non-steroidal anti-inflammatory drug

Adverse drug reactions in heart failure

Adverse drug reactions (ADR) refer to undesirable drug effects, excessive therapeutic effects, or allergic reactions to a medicine.[#australian-pharmaceutical-formulary-and-handbook.-2015]

Investigate whether a symptom of an ADR is being treated with another medication (such as using a cough suppressant caused by an ACEI)
Advise patients to report adverse effects, such as dizziness, to their GP or appropriate healthcare professional.
ADRs often limit potential dose increases of ACEIs, ARBs, beta-blockers and MRAs that are recommended to reduce morbidity and mortality in left ventricular systolic HF. Where a patient is unable to tolerate the Recommended target doses for heart failure medications, the maximum tolerated dose should be continued.
The management of potential adverse effects of titrating HF medicines, such as hypotension and worsening renal function, are outlined in the Heart failure medication titration problem solving guidelines.
Where any potential ADR is identified, the reaction and consequent recommendations and actions should be appropriately documented in the patient records as part of the medication review. For further information see Adverse drug reactions and heart failure.
Note that medications can significantly influence an individual’s physiological response to exercise. For further information refer to the Exercise response to cardiac medications.

Medications to avoid in ACS and heart failure

There are many medications that should be avoided or used with caution in ACS as they may directly increase the risk of cardiovascular events. Table 8 summarises medication combinations to avoid in ACS. Similarly, some medications may worsen heart failure, such as non-steroidal anti-inflammatory drugs (NSAIDs). For more information specific to heart failure, see Potentially harmful drugs to avoid in heart failure.

Table 8: Medication combinations to avoid in ACS

Avoid	Interacting medication	Risk	Considerations and recommendations
NSAIDs (ibuprofen) and COX-2 inhibitors (celecoxib, meloxicam)	Aspirin ACEIs, beta-blockers, calcium channel blockers and other anti-hypertensives	NSAIDS, meloxicam and celecoxib increase the risk of MIs (risk is small primarily due to COX-2 inhibition) NSAIDS and COX-2 inhibitors increase BP that reduces antihypertensive benefits of other medicines and increases MI risk	Avoid and consider paracetamol +/- codeine
Tricyclic antidepressants e.g., amitriptyline	Beta-blockers	Tricyclic antidepressants oppose the effects of beta-blockers by increasing heart rate and workload of the heart and decreasing diastolic filling time and thus myocardial perfusion	Avoid tricyclic antidepressants or use lowest recommended dose
HRT that contains oestrogen		Oestrogen slightly increases MI risk and thus should be avoided in ACS	Consider alternatives for osteoporosis prevention

Avoid

Interacting medication

Risk

Considerations and recommendations

NSAIDs (ibuprofen) and COX-2 inhibitors (celecoxib, meloxicam)

Aspirin

ACEIs, beta-blockers, calcium channel blockers and other anti-hypertensives

NSAIDS, meloxicam and celecoxib increase the risk of MIs (risk is small primarily due to COX-2 inhibition)

NSAIDS and COX-2 inhibitors increase BP that reduces antihypertensive benefits of other medicines and increases MI risk

Avoid and consider paracetamol +/- codeine

Tricyclic antidepressants e.g., amitriptyline

Beta-blockers

Tricyclic antidepressants oppose the effects of beta-blockers by increasing heart rate and workload of the heart and decreasing diastolic filling time and thus myocardial perfusion

Avoid tricyclic antidepressants or use lowest recommended dose

HRT that contains oestrogen

Oestrogen slightly increases MI risk and thus should be avoided in ACS

Consider alternatives for osteoporosis prevention

ACEI = angiotensin-converting enzyme inhibitor; ACS = acute coronary syndrome; COX-2 = cyclo-oxygenase 2; MI = myocardial infarction; HRT = hormone replacement therapy; NSAIDS = non-steroidal anti-inflammatory drugs. References [#australian-medicines-handbook-2015,#mims-online.-mims-australia]

Medication monitoring

Common medications used to treat ACS and heart failure that require intermittent monitoring of electrolytes, renal function and physiological parameters are outlined below.

Table 9: Monitoring requirements for medications used for ACS

Medication	Monitor	Action
ACEI/ARB	K+, Cr, BP	Cease if K+ >5.5mmol/L; creatinine >130% of baseline; or systolic BP is <100mgHg
Beta-blockers	Cr, BP, HR	Atenolol/bisoprolol: renally cleared. Reduce/cease if heart rate <50 bpm or systolic BP is <100mgHg
*Clopidogrel/ticagrelor/prasugrel**	HR*, Hb	Advise patient to report black stools or vomiting
Unfractionated heparin	BP, Hb, APTT, Plt, Bleeding	APTT initially 4-6 hourly, then daily Platelets daily
LMWH (Renally cleared)	Cr, Plt, Bleeding	Monitor via anti-Xa levels Monitor if there is obesity, renal impairment or prolonged therapy. Seek specialist advice for dosing In patients with low platelets where HITTS cannot be ruled out, consider a HITTS screen
Aspirin	Bleeding	Patients to report any signs of haematemesis or melaena Peak flow monitoring is recommended for asthmatics as bronchoconstriction may occur in 20% of cases
Glycoprotein 2a/3b inhibitors	Plt, Bleeding	Consider possibility of HITTS in thrombocytopaenic patients also taking heparin
Verapamil & diltiazem	Cr, BP, HR	Verapamil is renally cleared
Statins	Cr, Cholesterol	Consider dose reduction in renal impairment

*ticagrelor only; CEI= angiotensin-converting enzyme inhibitor; APTT = activated partial thromboplastin time; ARB = angiotensin receptor blocker; BP = blood pressure; Cr = creatinine; Hb = haemoglobin; HITTS = heparin-induced thrombocytopenia and thrombosis syndrome; HR = heart rate; K+ = potassium; LMWH = low-molecular weight heparin; Plt = platelets

Monitoring of heart failure medicines

The Monitoring of heart failure medicines table provides a quick reference of recommendations and intervals for monitoring of MRAs, ACEIs /ARBs, diuretics, digoxin and beta-blockers.

The rationale for monitoring commonly used HF medications are summarised below:

ACEIs/ARBs: Combining an ACEI and loop diuretic increases risk of hypotension and renal impairment. Check electrolyte, renal function and blood pressure including postural BP drop
Beta-blockers: There is an increased risk of hypotension so requires BP and heart rate monitoring
MRAs: Combining an MRA with ACEI or ARB increases the risk of hyperkalaemia and therefore requires vigilant electrolyte monitoring, as well as monitoring of renal function
Diuretics: Renal function, electrolytes, BP, and daily weight should be carefully monitored to ensure the diuretic dose is sufficient to provide fluid retention symptom relief while avoiding volume depletion, hypotension, electrolyte disturbances or renal impairment. Patients should be aware of signs of fluid overload and dehydration, see Fluid management in heart failure
Digoxin: Digoxin serum levels should be monitored, where appropriate. A level of 0.5-0.8ng/mL has been suggested for patients in sinus rhythm as there has been an observed trend towards worsened outcomes at a higher level[#colucci-ws.-2014]

References

Australian Medicines Handbook 2015. Adelaide: Australian Medicines Handbook Pty Ltd. 2015.

australian-medicines-handbook-2015
Preston CL (Ed.). Stockley’s Drug Interactions Online. London: Pharmaceutical Press.

preston-cl-ed..-stockleys-drug-interactions-online
National Prescribing Service. (2011). Improving treatment of systolic heart failure.75.

national-prescribing-service.-2011
Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.

micromedex-healthcare-series-internet-database
Kaplan NM. Major side effects of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. UpToDate. July 2014.

kaplan-nm.-2014
National Prescribing Service. (2004). A step-wise approach to heart failure management. 36.

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National Prescribing Service. (2000). Medication review for your patients with heart failure.

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McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787-1847.

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Barras MA, Duffull SB, Atherton JJ, Green B. Individualized compared with conventional dosing of enoxaparin. Clin Pharmacol Ther 2008;83:882-8.

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MIMS Online. MIMS Australia.

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Indiana University. Department of Medicine. Clinical Pharmacology. P450 Drug Interaction Table: Abbreviated "Clinically Relevant" Table.

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NHFA CSANZ Heart Failure Guidelines Working Group: Atherton JJ, Sindone A, De Pasquale CG, et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the Prevention, Detection, and Management of Heart Failure in Australia 2018. Heart Lung Circ. 2018;27(10):1123-208.

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Australian pharmaceutical formulary and handbook. 23rd ed. Canberra: Pharmaceutical Society of Australia. 2015.

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Colucci WS. Overview of the therapy of heart failure due to systolic dysfunction. UpToDate. October 2014.

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