December-45-6-36pp-V6 (1) Desember 2022

December 2022
Volume 45 Number 6
AN INDEPENDENT REVIEW
nps.org.au/australian-prescriber
CONTENTS
EDITORIAL
The end of NPS MedicineWise 186

D Rigby
ARTICLES
Administration of medicines 188

to children: a practical guide
L Smith, C Leggett, C Borg
Coronary artery disease 193

in women
N Montarello, WP Chan
Diuretics in the management 200

of chronic heart failure:
when and how
JS Magdy, J McVeigh, P Indraratna
Blood pressure elevations 205

in hospital
AA Mangoni, EA Jarmuzewska, GM
Gabb, P Russell
FEATURE
Medicinal mishap 208

Osteonecrosis of the jaw and denosumab
Latest news 210

Wither Australian Prescriber?
NEW DRUGS 211
Asciminib for chronic myeloid leukaemia

Decitabine/cedazuridine for chronic
myelomonocytic leukaemia,
myelodysplastic syndromes
Elasomeran/imelasomeran for prevention
of COVID-19
Mecasermin for primary insulin-like growth
factor-1 deficiency
Pemigatinib for cholangiocarcinoma
Selinexor for multiple myeloma
VOLUME 45 : NUMBER 6 : DECEMBER 2022
EDITORIAL
The end of NPS MedicineWise

Deborah Rigby The National Prescribing Service was established An example of partnership is Choosing Wisely
Advanced practice in 1998, by the Department of Health and Family Australia, launched in 2015. This is a key social
pharmacist, DR Pharmacy
Services, to improve health outcomes by supporting movement involving NPS MedicineWise working
Consulting
the quality use of medicines (QUM).1 The establishment with health professional colleges, societies and
Adjunct associate professor,
of an independent, not-for-profit organisation working associations to address low-value and unnecessary
School of Pharmacy,
University of Queensland, alongside government was considered progressive healthcare practices.
Brisbane and insightful policy. Over the next 24 years the With a multidisciplinary view, the Prescribing
organisation, now known as NPS MedicineWise, built Competencies Framework was developed. This
a trusted reputation for providing national leadership, describes prescribing expectations for all prescribers
Keywords
drug policy, health education, behaviour change and resources to support and also curriculum design for medical, pharmacy and
professional education, QUM and medicines safety in Australia. allied health courses.3
quality use of medicines In March 2022, the Federal Government’s budget NPS MedicineWise’s MedicineInsight program
included a redesign of the Quality Use of Diagnostics, provides important insight into real-world prescribing
Aust Prescr 2022;45:186-7 Therapeutics and Pathology Program. Some functions practices, supporting quality improvement in
https://doi.org/10.18773/ of NPS MedicineWise would shift to the Australian primary care and postmarket surveillance of
austprescr.2022.075 Commission on Safety and Quality in Health Care, medicines. Its reach at a local level also enables
while others would be subject to new contestable evaluation of the impact of NPS MedicineWise
funding arrangements. programs. NPS MedicineWise has delivered over
These unexpected changes to the role and funding $1.1 billion in direct savings for the Pharmaceutical
of NPS MedicineWise have led to a decision to end Benefits Scheme and Medicare Benefits Schedule,
its operations in December 2022. It is therefore time representing a twofold net return on investment
to reflect on the impact of the organisation and its for the government.4
people, celebrate the achievements and look to the Consumers are at the centre of every program
future of QUM and medicines safety in Australia. and resource created by NPS MedicineWise. Their
The fundamental role of NPS MedicineWise is voice is present across every step of program
stewardship of the QUM objectives of the National needs assessment, design, delivery and evaluation.
Medicines Policy.2 Early evidence-based strategies Innovative programs including Be MedicineWise
embraced the ethos of QUM with clinical audit and Week, Good Medicine Better Health, Medicines Line
feedback, educational visiting and newsletters. and Adverse Medicine Events Line, mass audience
Publications grew to include NPS News, RADAR, campaigns such as Antibiotic Resistance Fighter,
and, from 2002, Australian Prescriber, possibly the and the MedicineWise app have made a substantial
most widely read medical journal in Australia. As the contribution to the health literacy of consumers to
impact, reach and credibility of NPS MedicineWise enable Australians to make better decisions about
evolved, its range of initiatives grew. their medicines and health.
A critical strength of NPS MedicineWise programs was A subsidiary, VentureWise, was established in 2015,
behavioural intervention. When NPS MedicineWise to extend QUM activities, beyond those supported
was first established, some were suspicious that it by government funding, to other areas of the
was an arm of government set up to save money. health system. This was a strategic decision to raise
However, over time, the organisation built trust, revenue to build equity and financial stability for
respect and credibility through well-designed NPS MedicineWise.
interventions, with an evidence-based approach and In 2018, the Department of Health undertook a review
being mindful of the complexity of prescribing and to provide clarity and guidance on NPS MedicineWise
medication management. governance, performance, transparency and
One of the principles of QUM is partnership. accountability.5 The review acknowledged the high
NPS MedicineWise therefore worked collaboratively quality and valued resources used in the delivery of
with member organisations, other associations the programs to support the Quality Use of Medicines
and government to ensure its programs were and Diagnostics, but made recommendations for
grounded in issues important to consumers and improvement. NPS MedicineWise accepted the
other stakeholders. recommendations in principle. It committed to
186 This article is peer-reviewed © 2022 NPS MedicineWise

EDITORIAL
enhancements to deliver efficient, flexible and accompanied by competitive tendering for program
innovative QUM programs, while VentureWise was delivery and design.6 As funding for NPS MedicineWise
wound up in 2020. will therefore end on 31 December 2022, the board of
The policy change announced in March 2022, to cease directors had little choice but to close the organisation.7
funding for NPS MedicineWise, was met with dismay The legacy of NPS MedicineWise must drive the
and disappointment across the health sector. A future direction of QUM stewardship in Australia.
change of government led to a rapid review to assess NPS MedicineWise had a remarkable record of
the appropriateness of the proposed redesign of the excellence, innovation and engagement, particularly
Quality Use of Diagnostics, Therapeutics and Pathology with primary care and consumers. The imperative
Program.6 This desktop review occurred without much for an independent, evidence-based QUM voice in
stakeholder consultation. When it reported in August Australia remains more important than ever.
2022, the review identified several risks in the proposal.
However, it supported moving QUM stewardship Conflicts of interest: Deborah Rigby was a Director of
functions to a standards-based organisation, NPS MedicineWise from 2008 to 2020.
REFERENCES
1. Weekes LM, Mackson JM, Fitzgerald M, Phillips SR. National 6. Deloitte Touche Tohmatsu. Rapid review of proposed Quality
Prescribing Service: creating an implementation arm for Use of Diagnostic, Therapeutics and Pathology Program
national medicines policy. Br J Clin Pharmacol 2005;59:112-6. budget measure, August 2022. https://www.health.gov.au/
https://doi.org/10.1111/j.1365-2125.2005.02231.x resources/publications/rapid-review-of-proposed-quality-
2. Weekes LM, editor. Improving use of medicines and medical use-of-diagnostic-therapeutics-and-pathology-program-
tests in primary care. Springer Singapore; 2020. budget-measure [cited 2022 Nov 1]
https://doi.org/10.1007/978-981-15-2333-5 7. NPS MedicineWise to cease operations after 24 years
3. NPS MedicineWise. Prescribing competencies framework: [media release]. 2022 Sept 14. NPS MedicineWise; 2022.
embedding quality use of medicines into practice. 2nd ed. https://www.nps.org.au/media/nps-medicine-wise-to-
Sydney: NPS MedicineWise; 2021. https://www.nps.org.au/ cease-operations-after-24-years [cited 2022 Nov 1]
prescribing-competencies-framework [cited 2022 Nov 1]
4. Weekes LM, Blogg S, Jackson S, Hosking K.
NPS MedicineWise: 20 years of change. J Pharm Policy Pract
2018;11:19. https://doi.org/10.1186/s40545-018-0145-y
5. Department of Health and Aged Care. Review of the
Quality Use of Medicines Program’s delivery by the
National Prescribing Service Limited (NPS MedicineWise),
December 2019. https://www.health.gov.au/sites/default/
files/documents/2022/04/review-of-the-quality-use-of-
medicines-program-s-delivery-by-nps-medicinewise.pdf
[cited 2022 Nov 1]
Full text free online at nps.org.au/australian-prescriber 187

ARTICLE
Administration of medicines to children:

a practical guide
Lucinda Smith
Senior pharmacist1
SUMMARY
Catherine Leggett
Medicines information Getting children to take medicines can be difficult. There is no ‘one-size-fits-all’ approach.
manager1
When selecting medicines for children, it is important to consider the child’s age, swallowing
Corey Borg
Senior pharmacist1
ability, ease of administration and accessibility of the product.
Ask the child, parent or caregiver about their preference for formulations and flavours.
1
Medicines Information
Service, SA Pharmacy, There are different ways to alter the taste, aftertaste and mouth feel of medicines, which may help
Women’s and Children’s
improve palatability.
Hospital Campus, SA
Health, Adelaide Pharmacists or medicines information services can assist with advice on suitable formulations or
methods of administration.
Keywords
drug formulation, oral
administration, paediatrics, Introduction However, liquid formulations are not without risk and
palatability, patient safety,
Giving medicines to infants and children can be can result in over- or underdosing, particularly in the
taste following cases:
challenging. Children may refuse to take medicines
for many reasons, such as fear, taste, embarrassment • Small volumes are required to be measured.
Aust Prescr 2022;45:188–92 or inconvenience. Although smaller volumes may be preferable,
https://doi.org/10.18773/ the use of more concentrated liquids may
This problem is compounded by a lack of suitable
austprescr.2022.067 create an additional risk, particularly with drop
formulations for paediatrics, restricting prescribing
options and posing safety concerns. There is also formulations that are marketed for adult use, but
limited information for parents and caregivers may sometimes be given to children (e.g. tramadol
on how to give medicines to children, with 100 mg/mL).3 Their use can more easily result
most information coming from experience and in 10-fold dosing errors, such as measuring 1 mL
anecdotal reports. instead of 0.1 mL. This can be minimised by
providing carers with an oral syringe marked with
Choosing the right formulation the correct dose and appropriate counselling.4
There is a well-recognised lack of suitable paediatric
• Multiple formulations of the same active
formulations available,1 contributing to an increased
ingredient are available. For example, paracetamol
risk of dosing errors and difficulties in administration.
oral liquids are available in concentrations of
When selecting medicines for children, it is important
24 mg/mL, 48 mg/mL, 50 mg/mL and 100 mg/mL.
to consider factors such as the child’s age, swallowing
When discussing medicines for children, it is
ability, ease of administration and accessibility of
important for carers, clinicians and pharmacists
suitable formulations of the product. Understanding
to include instructions with the dose by weight
the characteristics of each formulation can assist
(e.g. mg or micrograms) and dose by volume.
with choosing the most appropriate medicine for
a child. Oral liquids may contain excipients such as colourings,
solvents and preservatives at concentrations that may
Oral liquids not be suitable for children.5 For example, furosemide
Oral liquids are the preferred formulation for younger (frusemide) oral solution contains 12.7% ethanol,
children as they are easier to swallow2 and allow for which is typically considered insignificant in adults.
flexible dosing based on the child’s age and weight. However, it exceeds the maximum allowed ethanol
Liquids may also be mixed with different flavours at content of 0.5% for children younger than six years
the time of administration to help mask the taste and of age, limiting the use of the proprietary furosemide
smell of a medicine. (frusemide) product in this age group.6

ARTICLE
Oral liquids often contain sugars to help improve Most tablets are intended to be swallowed whole,
palatability. It is important to consider the effects of but some immediate-release preparations may be
sugar on teeth, particularly with chronic medicines. chewed, crushed, or halved or quartered using a tablet
To minimise dental cavities, consider sugar-free cutter.5 Caution should be taken when manipulating
formulations and encourage children to brush their tablets as this may result in a small portion of the
teeth after taking a dose.7 dose being lost. This is particularly significant when
giving medicines with a narrow therapeutic index.
Solid dosage forms Additionally, most tablets are not formulated to be
If an oral liquid is not available, alternative oral palatable, so crushing or dispersing them may impact
formulations may be suitable. If a solid dosage form a child’s willingness to take the medicine.
requires manipulation (chewing, crushing, dispersing,
halving or breaking) to facilitate administration, Modified-release tablets
particular drug properties should be considered: Modified-release tablets should be swallowed whole,
• palatability as chewing or crushing them may damage the
modified-release formulation, causing toxicity by
• physiochemical (e.g. acid labile or light sensitive)
releasing the total amount of medicine at once.11
• hazardous (e.g. irritant, cytotoxic)
• drug release kinetics (e.g. modified release, Capsules
enteric coating). Some children may find capsules easier to swallow
than tablets. However, capsules cannot be halved,
Tablets which limits their dose flexibility.
Tablets are a suitable alternative to oral liquids, Most capsules are formulated to be swallowed whole.
particularly when medicines are unpalatable.8 Some hard capsules (filled with powder or coated
However, a child’s ability to swallow tablets must granules) may be opened and their contents mixed
be considered. There is no established age at which or sprinkled in food or drinks. Similarly, some soft
children are able to swallow tablets, as it is a skill that capsules (filled with liquids or semisolids) may be
must be learned.9 Several resources are available for chewed (e.g. colecalciferol).5
caregivers to assist with teaching children to swallow
tablets or capsules (see Box). Some children may be Oro-dispersible tablets
able to swallow tablets from a young age, although Oro-dispersible dosage forms, including tablets,
most children are usually at least 8–10 years of age wafers and films, are formulated to disperse rapidly
before they can routinely take tablets.10 If prescribing once placed on the tongue. Alternatively, they can
or dispensing for a child, the child or carer should be dispersed in a small volume of liquid before
always be asked if they would prefer tablets or administration. These preparations may be useful in
oral liquids. children, as they do not need to be swallowed whole
Tablets are more accessible with easier storage and or crushed.5
transport options than those for oral liquids. However, Oro-dispersible medicines are commonly formulated
tablets have limited dose flexibility, decreasing the with additive flavours to help mask the taste. Due
ability to prescribe weight-based doses.5 to their delicate composition, it may be difficult to
half or quarter these dosage forms, limiting their
dose flexibility.
Box Useful resources ‘Making the medicine go down’

There are some common ‘Dos & Don’ts’ for
Society of Hospital Pharmacists of Australia. Don’t rush administering medicines to children, which
to crush. 4th ed. [Booklet] depend on the type of formulation (Table 1). These
NPS MedicineWise. How to give medicines to children suggestions are also outlined in a consumer-friendly
Royal Children’s Hospital, Melbourne. How to give leaflet (see Fig.).12
medications to children. [Pamphlet]
Taste
Royal Children’s Hospital, Melbourne. Teaching children
how to swallow tablets and capsules Taste is a powerful deterrent for children and is
thought to have evolved as a safeguard against
Medicines for Children. Helping your child to swallow
tablets ingesting toxic substances.13 The unpleasant taste of
a medicine can be improved by mixing it with various

ARTICLE Administration of medicines to children: a practical guide
flavoured syrups or cordials (Table 2).6,7 However, the Aftertaste

child’s taste preferences must be considered before The aftertaste of a medicine is a difficult issue to
mixing with flavours. Liquorice, peppermint and navigate, particularly if it prevents a child from
coconut flavours may taste reasonable to adults but accepting subsequent doses.13,14 When administering
may be disliked by children.14 a medicine, try and avoid the tongue, aiming oral
Mixing medicines with a small amount of food or liquids towards the back of the mouth against the
liquid is unlikely to cause drug–food interactions, cheek. Alternatively, consider swapping to a capsule
even with medicines recommended to be given on an or tablet formulation, which can be swallowed whole.
empty stomach (e.g. flucloxacillin). A small reduction Some children may find it more palatable to take a
in absorption of the medicine will pose less of a medicine via a straw or follow with a cold drink to
problem than that created by a child refusing to take lessen the aftertaste.
the medicine at all.
Mouth feel
The mouth feel of a medicine may also be a deterrent
Table 1 C
ommon recommendations and precautions for for some children. To improve the feel of oral liquids,
administering medicines to children consider diluting in water or a flavoured drink to
reduce their viscosity.13,14 To combat the grittiness of
Recommendations Precautions
crushed tablets or granules, try mixing with thick or
Oral liquids, suspensions and elixirs gelatinous foods such as jelly, custard or spreads.
Use metric measures, such as a medicine Do NOT use everyday utensils, such as Advice for prescribers
syringe or cup teaspoons or tablespoons
When prescribing medicines for children, some
Count oral drops on a spoon before Do NOT administer drops directly from practical considerations include:
administering the bottle into the child’s mouth
• minimising the dosing frequency where appropriate
Mix oral liquids with a small amount of Do NOT mix the medicine in large volumes (e.g. prescribing cefalexin 12-hourly (twice a day)
water or juice
rather than six-hourly (four times a day))
If the medicine is available in multiple Do NOT mix the medicine with a child’s
• avoiding medicines that are known to be less
flavours, ask the child for their preference essential foods (e.g. milk or formula),
palatable (e.g. flucloxacillin is known to be bitter,
as the altered taste may cause future
aversion to the essential foods so using cefalexin as an alternative)
• using alternative routes of administration,
Tablets, capsules and solid dosage formulations
especially for children who cannot tolerate oral
Place the tablet in the middle of the Do NOT mix with honey in children fluids (e.g. using a rectal paracetamol formulation
tongue and follow with a large volume younger than one year of age due to the rather than an oral formulation).
of liquid potential risk of infant botulism
Try drinking a small amount of liquid from Do NOT give large volumes (i.e. aim for
Conclusion
a bottle or using a straw one mouthful)
Try halving or quartering tablets Do NOT break modified-release, cytotoxic There are several techniques and strategies that can
or hazardous medicines
be used to improve the palatability and acceptance
Crush tablets between two spoons and Do NOT crush modified-release, cytotoxic of medicines by children. Often, there is no single
mix with a small amount of soft food or hazardous medicines solution, and instead, there are many strategies that
such as yoghurt, cold custard, fruit puree may be implemented by the parent or caregiver.
or jam
Further guidance may be obtained from the local
Try dispersing the tablet in a small pharmacist or medicines information service.
volume of liquid (water or juice)
Acknowledgements: Sean Turner (Director of
Check with a pharmacist if the tablets
can be crushed or the capsules opened
Pharmacy), David Ellis (Senior specialist pharmacist
(Manufacturing and Psychiatry)) and Lynn Costi
Encourage parents and caregivers to
(Senior pharmacist, Medicines Information Service),
teach children how to swallow tablets.
SA Pharmacy, Women’s and Children’s Hospital Campus,
There are several resources to assist with
teaching children to swallow solid dosage SA Health.
forms (see Box)
Conflicts of interest: none declared
190 Full text free online at nps.org.au/australian-prescriber

ARTICLE
Fig. Suggestions for administering medicines to children12
General
Try cold treats like an ice cream or Try mixing with fatty foods like peanut butter Have the child’s favourite drink
ice blocks to numb the tastebuds or chocolate to coat the tastebuds ready to follow the medicine
Tablets/capsules Liquids
Try cutting the tablet in halves Try using an oral syringe, aiming towards the
before swallowing it* back of the mouth against the inner cheek
Avoid the tongue
Try crushing the tablet or opening the capsule and sprinkling Try mixing the medicine into a small amount
the contents on foods such as yoghurt or custard* of fruit juice before drinking†
Try crushing the tablet or opening the capsule and sprinkling Try pouring the medicine in a small cup
the contents in a small amount of fruit juice* and drinking with a straw
* Not all tablets and capsules can be altered. Confirm with your local pharmacist.
† The entire drink must be consumed to ensure the full dose has been taken.
Adapted from reference 12
Table 2 T
astes and masking flavours
Taste of the medicine Examples* Flavour to mask the taste of the medicine
Sour Multivitamins (e.g. vitamin C) Cherry, lemon, lime, mandarin, orange, strawberry, raspberry, pineapple
Bitter Antibiotics Cherry, chocolate, liquorice, strawberry, peach, coffee, mint, lemon, lime, raspberry,
Paracetamol tutti-frutti, orange, cinnamon
Corticosteroids
Sweet Lactulose Caramel, lemon, orange, vanilla, bubble-gum

Sorbitol
Salty Iron supplements Banana, caramel, cream, chocolate, grape, vanilla, raspberry, orange, cinnamon, nut,
Antihistamines butter, butterscotch, maple
Macrogol laxatives
Oral rehydration solutions
Any Spreadable yeast extract, peanut butter, jam, honey, apple sauce, custard, ice cream
* Common examples are based on patient reports, although any drug may be considered ‘bad’ tasting depending on subjective taste preferences.

ARTICLE Administration of medicines to children: a practical guide
REFERENCES
1. Schirm E, Tobi H, de Vries TW, Choonara I, 7. Allen LV Jr. Basics: excipients used in nonsterile
De Jong‑van den Berg LT. Lack of appropriate compounding, Part 2. Int J Pharm Compd 2019;23:393-6.
formulations of medicines for children in the community. 8. Baguley D, Lim E, Bevan A, Pallet A, Faust SN. Prescribing
Acta Paediatr 2003;92:1486-9. https://doi.org/10.1111/ for children - taste and palatability affect adherence to
j.1651-2227.2003.tb00837.x antibiotics: a review. Arch Dis Child 2012;97:293-7.
2. Nunn T, Williams J. Formulation of medicines for children. https://doi.org/10.1136/archdischild-2011-300909
Br J Clin Pharmacol 2005;59:674-6. https://doi.org/10.1111/ 9. Tse Y, Vasey N, Dua D, Oliver S, Emmet V, Pickering A, et al.
j.1365-2125.2005.02410.x The KidzMed project: teaching children to swallow tablet
3. Bauters T, Claus B, Willems E, De Porre J, Verlooy J, medication. Arch Dis Child 2020;105:1105-7. https://doi.org/
Benoit Y, et al. What’s in a drop? Optimizing strategies 10.1136/archdischild-2019-317512
for administration of drugs in pediatrics. Int J Clin Pharm 10. Nunn T, Williams J. Formulation of medicines for children.
2012;34:679-81. https://doi.org/10.1007/s11096-012-9670-y Br J Clin Pharmacol 2005;59:674-76. https://doi.org/10.1111/
4. Yin HS, Dreyer BP, van Schaick L, Foltin GL, Dinglas C, j.1365-2125.2005.02410.x
Mendelsohn AL. Randomized controlled trial of a pictogram- 11. Sansom LN. Oral extended-release products. Aust Prescr
based intervention to reduce liquid medication dosing errors 1999;22:88- 90. https://doi.org/10.18773/austprescr.1999.072
and improve adherence among caregivers of young children. 12. CHEO ED Outreach. Making meds taste better. 2014 [Poster].
Arch Pediatr Adolesc Med 2008;162:814-22. https://doi.org/ https://outreach.cheo.on.ca/pharmacy/making-meds-taste-
10.1001/archpedi.162.9.814 better [cited 2022 Nov 1]
5. van Riet-Nales DA, Schobben AF, Vromans H, Egberts TC, 13. Mennella JA, Roberts KM, Mathew PS, Reed DR. Children’s
Rademaker CM. Safe and effective pharmacotherapy in perceptions about medicines: individual differences and
infants and preschool children: importance of formulation taste. BMC Pediatr 2015;15:130. https://doi.org/10.1186/
aspects. Arch Dis Child 2016;101:662-9. https://doi.org/ s12887-015-0447-z
10.1136/archdischild-2015-308227
14. Mennella JA, Beauchamp GK. Optimizing oral medications
6. Chan DS. Stability issues for compounding for children. Clin Ther 2008;30:2120-32. https://doi.org/
extemporaneously prepared oral formulations for pediatric 10.1016/j.clinthera.2008.11.018
patients. Int J Pharm Compd 2001;5:9-12.

ARTICLE
Coronary artery disease in women

Natalie Montarello
SUMMARY Cardiology advanced
trainee1
Cardiovascular disease is the leading global cause of death in women but remains Wai Ping (Alicia) Chan
underdiagnosed and undertreated. Cardiologist1
Health professionals play an important role in improving the heart health of Australian women. Royal Adelaide and The
1
Routine heart health checks should be offered to all women 45 years of age and older and to all Queen Elizabeth Hospitals,
Aboriginal and Torres Strait Islander women 30 years of age and older. Central Adelaide Local
Health Service, South
Cardiovascular risk assessment in women must include traditional and sex-specific risk factors, Australia
including their pregnancy history and early-onset menopause.
Women with pregnancy-related hypertensive and metabolic disorders have an increased long- Keywords
term cardiovascular risk and require close monitoring. cardiovascular disease,
cardiovascular risk,
Women with acute coronary syndrome may not experience classical chest pain. More often, they menopause, myocardial
experience cardiovascular events in the absence of obstructive coronary disease and have poorer infarction with non-
cardiovascular outcomes. obstructed coronary
arteries
The recognition of sex-specific differences and more sex-specific trials are key to improving
clinical outcomes.
Aust Prescr 2022;45:193–9
https://doi.org/10.18773/
Introduction is 3.8 times more likely than in other Australian austprescr.2022.065
Cardiovascular disease, which encompasses heart women.5 Positively, the mortality rates of coronary
disease, stroke and peripheral vascular disease, artery disease have been declining in Australia in recent
is the leading cause of illness and death in women decades. From 2006 to 2016, the rate fell by 46% for
women (from 78 to 44 per 100,000 population) and by
worldwide. Biological and physical differences, such
40% for men (from 135 to 84 per 100,000 population).5
as a smaller body surface area, smaller coronary vessel
Further, between 2001 and 2016, the prevalence of
size and sex hormone-mediated factors in women, are
acute coronary events (myocardial infarction and
exacerbated by sociocultural factors and contribute
unstable angina) in Australian women fell by 57% (from
to differences in the prevalence, presentation and
465 to 215 events per 100,000).5 However, the rates of
natural history of cardiovascular disease between the
decline are lower in women under the age of 55 years,
sexes. Women with cardiovascular disease experience
with a rise in strokes and myocardial infarcts.1
delays in diagnosis, are less likely to be treated in
line with guidelines and standards, and have higher Cardiovascular risk factors
complication rates and worse outcomes than men.
Various traditional and sex-specific risk factors
Women are significantly under-represented in clinical
increase the risk of cardiovascular disease in women.
trials, and sex-specific diagnostic and management
strategies are not included in current clinical guidelines. Traditional risk factors
Traditional risk factors are more often under-
Epidemiology
recognised and undertreated in women than in
Three out of every 10 female deaths in Australia are due
men and affect the risk of cardiovascular disease
to cardiovascular disease, including coronary artery
differently between the sexes (Box 1).4,6-18
disease.1 It is estimated that between the ages of 45
and 64 years, one in nine women will develop some Sex-specific risk factors
form of cardiovascular disease, which increases to one Several female-specific risk factors increase the risk of
in three women after the age of 65 years.2-4 Indigenous cardiovascular disease in women.
Australian women are particularly at risk, often at
a younger age. In 2016, indigenous women aged 25 Hormonal contraceptives
years and older experienced an acute coronary event Combined hormonal contraceptives are associated
in the form of myocardial infarction or unstable with a 12-fold increase in the risk of acute myocardial
angina at a rate of 617 per 100,000 population. This infarction in women with hypertension19 and should
© 2022 NPS MedicineWise This article is peer-reviewed 193

ARTICLE Coronary artery disease in women
Box 1 Traditional cardiovascular risk factors in women

Menopause
Following menopause, the risk of cardiovascular
Hypertension disease rises substantially. This is possibly related to
The impact of hypertension on the risk of developing ischaemic heart disease seems a sharp, sustained increase in low-density lipoprotein
consistent across the sexes.6 cholesterol around the time of the final menstrual
Although sex differences in the incidence of hypertension have not been found,6 period.25 Lower concentrations of oestrogen and
hypertension is undertreated in women,7 leading to heart failure with preserved higher concentrations of androgen contribute to this
ejection fraction.8 increased risk.26 Premature menopause increases
Dyslipidaemia the risk of cardiovascular disease before the age of
The ratio of total cholesterol to high-density lipoprotein cholesterol is more powerfully 60 years.27
associated with acute myocardial infarction in women than in men.4
Menopausal hormone therapy
Diabetes
Randomised controlled trials have not shown any
Diagnosis occurs at a higher body mass index, older age and more advanced stage of
benefit in primary or secondary prevention with the
disease progression in women than in men.
use of hormone replacement therapy. Oestrogen use
Obesity results in a small but significantly increased risk of
The Framingham Heart Study showed that the excess risk of cardiovascular disease from cardiovascular events, particularly in women starting
obesity was 64% in women versus 46% in men.9 therapy 20 or more years after menopause or at
Smoking least from 70 years of age.28 In women with acute
Tobacco use confers a 25% increase in the risk of developing coronary artery disease myocardial infarction, menopausal hormone therapy
compared to that in men.10 should be discontinued.29
Systemic inflammation and auto-immune disorders Other hormonal factors

These more commonly affect women and cause endothelial dysfunction and the
Early menarche (<12 years of age), young age at
acceleration of atherosclerosis, resulting in an increased risk of cardiovascular disease.11
first birth, a history of miscarriage, stillbirth, preterm
Sedentary lifestyle birth, low-birthweight babies and hysterectomy are
The increase in the risk of cardiovascular disease risk is greater in women (particularly independently associated with an increased risk of
older women) as they are more sedentary than men.12,13 cardiovascular disease in later life.30 This is possibly
Psychosocial mediated by increased systemic inflammation30
Physical and psychological abuse affects 15–71% of women and contributes to depression.14,15,16 and endothelial dysfunction, which accelerate
Increased substance abuse including tobacco and alcohol in women who report partner atherosclerosis.31 Polycystic ovarian syndrome is
violence independently contributes to an increased cardiovascular risk.17,18 associated with a heightened risk of cardiovascular
disease, specifically coronary artery disease.32
The clustering of insulin resistance, obesity and
be avoided in this subgroup. Progestogen-only metabolic syndrome, which leads to type 2 diabetes,
contraceptives should be considered in women with dyslipidaemia and hypertension, may be causal.33
an increased risk of acute myocardial infarction. Prior
Cancer radiotherapy and chemotherapy
use of hormonal contraceptives does not increase the
risk of subsequent cardiovascular disease.20 Radiation can cause coronary endothelial injury
leading to a pro-inflammatory state, the rupture
Pregnancy-related disorders of vessel walls, platelet aggregation, thrombosis
Hypertensive and metabolic disorders of pregnancy and the replacement of damaged intima by
are also independently associated with an increased myofibroblasts, resulting in vessel stenosis and
risk of maternal cardiovascular disease.21 These atherosclerosis.34 Women with a history of breast
include gestational hypertension, pre-eclampsia, cancer receiving radiotherapy show a relative 7.4%
eclampsia and placental abruption. Early onset (<34 increase in the risk of cardiovascular events with
weeks) and severe degrees of pre-eclampsia confer a each gray of radiation exposure.35 Furthermore, for
particularly increased risk of maternal cardiovascular reasons that are unclear, women treated with mantle
disease in later life,22 potentially due to resultant or mediastinal radiation for Hodgkin lymphoma have
endothelial dysfunction, which persists for many a significantly higher cardiovascular event rate and
years after an affected pregnancy and is linked to mortality compared to those in men, highlighting
atherosclerosis.23 Women with gestational diabetes the need for increased surveillance.36 Reduced
have an increased risk of subsequent cardiovascular cardiovascular-specific survival has also been
disease, and more than 50% will go on to develop reported in women treated with radiation for cervical
chronic type 2 diabetes mellitus.24 and uterine cancers.37

ARTICLE
Cardiovascular risk assessment Box 2 Coronary artery disease in women compared to men
Cardiovascular risk should be assessed differently in
men and women (Box 2). The Framingham Risk Score Presentation
underestimates the risk of cardiovascular disease in Similar to men, where most experience central chest pain, but onset is more often
women.38 The Reynolds Risk Score39 is best suited for at rest
women.40 This 10-year cardiovascular risk prediction Atypical symptoms more frequent, including pain in the upper back, arms and jaw,
algorithm for women older than 45 years of age and diaphoresis, dyspnoea, indigestion, nausea, dizziness, fatigue and palpitations
includes two additional risk variables. These are the Absence of chest pain more often in acute coronary syndrome
high-sensitivity C-reactive protein concentration and a Ischaemia and myocardial infarction more often in the setting of non-obstructive
parental history of premature coronary artery disease coronary artery disease
before 60 years of age (Table). Takotsubo syndrome a common cause of myocardial infarction
No sex-specific risk factors are included in any Diagnosis

available primary prevention risk assessments. Further Reynolds Risk Score more accurate than the Framingham Risk Score
research that promotes the incorporation of female- Better prognostic information from CT coronary angiography than from functional testing
specific risk factors in this algorithm would improve Coronary angiography used less often after positive exercise stress test results
the accuracy of cardiovascular risk assessment
in women. Treatment
Statins used less in angina and after myocardial infarction
Types of coronary artery disease Similar coronary stent use
There are differences between men and women Less frequent coronary artery bypass grafting
across different types of coronary artery disease.
Coronary artery disease

Obstructive coronary artery disease generally
Table Reynolds Risk Score for cardiovascular risk in women39
manifests similarly in women and men, with the
most common symptom being central chest pain. Risk factor Measure
In women, there is a greater likelihood of chest pain
Age years
onset at rest, during sleep or when under mental
stress. Women also more frequently present atypically Systolic blood pressure mmHg
with pain in the upper back, arms, neck and jaw, Diabetes mellitus  Yes  No
as well as presenting with dyspnoea, diaphoresis,
Current smoker  Yes  No
indigestion, nausea, palpitations, dizziness and
weakness.41 Furthermore, the proportion of women High-density lipoprotein cholesterol mmol/L
aged 55 years and younger presenting with acute
Total cholesterol mmol/L
coronary syndrome without chest pain is significantly
greater than the proportion of men (19% vs 13.7%).42 High-sensitivity C-reactive protein mg/L
As a result, they are at a greater risk of being Parental history of premature coronary artery disease aged  Yes  No
discharged home with evidence of acute coronary <60 years
syndrome compared to men.43
The Reynolds Risk Score is an online calculator that uses a risk prediction algorithm
Women with coronary artery disease also more to predict the 10-year cardiovascular event risk, for myocardial infarction, ischaemic
frequently develop symptomatic heart failure than stroke, coronary revascularisation and cardiovascular mortality (<5% = low risk, 5–9% =
moderate risk, 10–19% = moderate-to-high risk, ≥20% = high risk).40
men. This may be due to the impact of co-existent
hypertension, an important risk factor for coronary
artery disease, which leads to a greater incidence of
left ventricular hypertrophy that is less responsive condition or coronary stenosis is not diagnosed,
to antihypertensive therapy in women, resulting in many women are mistakenly presumed to not have
diastolic dysfunction and heart failure with preserved heart disease and are not treated, which increases
ejection fraction.44 their risk of adverse cardiac events. A comprehensive
meta-analysis has revealed an overall estimated
Ischaemia with non-obstructive coronary incidence of all-cause mortality or myocardial
artery disease infarction of 0.98 per 100 person-years in patients
Ischaemia with non-obstructive coronary disease is a with non-obstructive coronary disease compared
condition due to coronary microvascular dysfunction with 0.2 per 100 person-years in a similarly matched
or epicardial vascular spasm. It is more common in general population. In addition, 50% of patients with
women, especially at 45–65 years of age.45 If this non-obstructive coronary disease will experience

repeated episodes of ischaemic chest pain, similar Diagnosis of cardiovascular disease

to those with obstructive coronary artery disease,
Women are not referred as often as men for
further underscoring the importance of the condition.
appropriate diagnostic and therapeutic procedures for
Functional coronary angiography is needed to
cardiovascular disease.55 A biased view that coronary
evaluate macroscopic resistance, coronary flow
artery disease preferentially affects men may lead to
reserve and microvascular resistance to confirm the
underestimation of its severity in women, resulting in
diagnosis that is otherwise missed on routine non-
lower rates of invasive testing and intervention.56.57
invasive testing.46
Such biases may be more extreme in younger patients
Myocardial infarction with non-obstructive due to a lower incidence of coronary artery disease in
coronary artery disease younger women.58 Clinicians may also be concerned
Myocardial infarction with non-obstructive coronary about the safety of invasive procedures in women.59
artery disease (MINOCA) is roughly three times more Women have higher risks of bleeding and vascular
common in women than in men.47 This is based on complications following percutaneous coronary
a pooled analysis of 10 studies that recruited both intervention and surgery, which may lead to a greater
patients with MINOCA and myocardial infarction reluctance to intervene.60,61
with obstructive coronary artery disease (MI-CAD).48
Risk assessment
Furthermore, approximately 25% of patients
The presence of diabetes, smoking habits and a family
with MINOCA have ongoing angina, equivalent
history of premature coronary artery disease are risk
to the prevalence in patients with MI-CAD.47 The
factors of cardiovascular disease.62 In the presence
pathophysiology is unknown in approximately a
of these factors, the risk is greater in women than
quarter of MINOCA cases. Processes involving the
in men.56,63,64
epicardial vessels and coronary microvascular disease,
which prevent an increase in myocardial blood flow Non-invasive testing
in response to an increased oxygen demand, may be
Stress tests, involving either exercise or drugs to
responsible. There may also be an overlap with mild
mimic the effects of exercise, are used primarily for
forms of Takotsubo syndrome.49
the diagnosis and risk stratification of obstructive
Takotsubo syndrome coronary artery disease. Exercise testing is associated
Takotsubo syndrome accounts for 7.5% of cases of with a higher false-positive rate of diagnosis in women
acute myocardial infarction in women, with 90% of than in men due to a lower pre-test probability of
cases occurring in postmenopausal women aged the disease.65 Exercise echocardiography is often
50–75 years.50-52 It is triggered by emotional or preferred to stress nuclear imaging or CT coronary
physical stress, which is associated with enhanced angiography in women because of concerns about
sympathetic activity. Patients present with chest pain radiation exposure, particularly to the breasts.
and ECG changes characteristic of acute coronary However, CT coronary angiography may provide
syndrome but without angiographically obstructive greater prognostic information than that provided
coronary artery disease. These patients have by functional stress testing in women. Men appear
reversible left ventricular ballooning. Cardiac arrest to derive similar prognostic value from both types
occurs in 5.9% of patients.53 of tests.66
Spontaneous coronary artery dissection Invasive testing

In at least 25% of women aged 60 years or younger, Some studies have shown sex-based differences in
spontaneous coronary artery dissection causes the use of coronary angiography, which may reflect
acute myocardial infarction, with conventional risk physicians’ failure to refer women with positive
factors often being absent. It is the most common exercise stress test results,67 leading to poorer patient
cause of myocardial infarction associated with outcomes. In one study, women with a positive
pregnancy, primarily occurring in the third trimester exercise stress test result were more likely than men
or postpartum.54 The risk of recurrence is substantial to have no further cardiac evaluation (62% vs 38%).
with a pathological process independent of At three years, this difference was associated with
atherosclerotic disease. While strategies to prevent a higher incidence of acute myocardial infarction or
spontaneous coronary artery dissection include death in non-revascularised women (14.3% vs 6% per
avoiding hormonal therapy and future pregnancies, year in men).68 Other studies, however, have shown
there is currently a lack of evidence that allows for similar rates of coronary angiography following acute
treatment guidelines to be established. myocardial infarction.69

ARTICLE
Cardiovascular disease treatment consider heart disease as the main threat to women’s
The management of cardiovascular disease in women health. Even women themselves often view cancer as
must take into account sex-specific factors including a greater health threat. This may explain why women
the size of coronary vessels, bleeding risk and less often fill scripts for statins after myocardial
hormonal status, as well as potential pharmacokinetic infarction compared to men.72 To date, there is no
evidence to support that statins are safer in men than
and pharmacodynamic differences.
in women. A large meta-analysis suggested that statin
Revascularisation use to prevent major cardiovascular events has similar
Compared to men, women are nearly as likely effectiveness in women and men,73 and thus a poorer
to undergo percutaneous coronary angioplasty outcome in women is likely due to current practice.
but less likely to undergo coronary artery bypass
grafting.70 It is unclear whether this represents bias Conclusion
or appropriate treatment given the higher mortality
in women following coronary artery bypass grafting Current guidelines for the diagnosis, investigation
linked to increased comorbidities including smaller and treatment of cardiovascular disease do not
coronary vessels. discriminate between the sexes and are derived from
male-dominant studies. Women remain more likely to
Cardiovascular pharmacotherapy experience delays in diagnosis and are less likely to
In younger women, dual antiplatelet therapy results receive guideline-directed care.
in an increased risk of heavy menstrual bleeding and
Attention to the differing contributions of traditional
anaemia and needs close monitoring. Discussions
risk factors such as the presence of diabetes,
about contraception use are important, as statins
physicians’ compliance with established guidelines
and ACE inhibitors are contraindicated in pregnancy.
for the management of hyperlipidaemia, and a focus
Prescribing may differ in women based on their
on lifestyle factors are fundamental to reducing the
reproductive age, other hormonal treatments and use
risk of cardiovascular disease in women. In addition,
of contraceptives.
recognising the importance of sex-specific risk
Women with cardiovascular disease are more likely factors, such as hypertensive and metabolic disorders
to receive nitrates, calcium channel blockers and of pregnancy, are vital to improving outcomes.
sedatives and less likely to receive aspirin and statins
While sex-specific cardiovascular research has
than men,71 likely reflecting the higher prevalence of
increased significantly in recent years, this has not
non-atherosclerotic cardiovascular disease. Statin use
translated into changes in guideline-recommended
after acute myocardial infarction is also significantly
care, nor has it improved clinical outcomes for
lower in women than in men. This is partly physician
women. Fundamentally, cardiovascular disease in
driven and may be appropriate when myocardial
women remains understudied, underdiagnosed
infarction is due to MINOCA, which is more commonly
and undertreated. Until this is addressed, women
encountered in women. However, low statin use in
will continue to experience disproportionally high
women with MI-CAD may be related to a reduced
cardiovascular morbidity and mortality.
awareness among physicians of the risks of recurrent
heart disease in women and a reduced likelihood to Conflicts of interest: none declared
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Chest 2007;132:809-16. https://doi.org/10.1378/chest.07-0608 https://doi.org/10.7326/0003-4819-120-7-199404010-00005
51. Wedekind H, Moller K, Scholz KH. [Tako-tsubo 69. Krumholz HM, Douglas PS, Lauer MS, Pasternak RC.
cardiomyopathy. Incidence in patients with acute coronary Selection of patients for coronary angiography and coronary
syndrome]. Herz. 2006;31:339-46. German. https://doi.org/ revascularization early after myocardial infarction: is there
10.1007/s00059-006-2822-x evidence for a gender bias? Ann Intern Med 1992;116:785-90.
52. Sy F, Basraon J, Zheng H, Singh M, Richina J, Ambrose JA. https://doi.org/10.7326/0003-4819-116-10-785
Frequency of Takotsubo cardiomyopathy in postmenopausal 70. Bertoni AG, Bonds DE, Lovato J, Goff DC, Brancati FL.
women presenting with an acute coronary syndrome. Sex disparities in procedure use for acute myocardial
Am J Cardiol 2013;112:479-82. https://doi.org/10.1016/ infarction in the United States, 1995 to 2001. Am Heart J
j.amjcard.2013.04.010 2004;147:1054-60. https://doi.org/10.1016/j.ahj.2003.11.019
53. Gili S, Cammann VL, Schlossbauer SA, Kato K, D’Ascenzo F, 71. Daly C, Clemens F, Lopez Sendon JL, Tavazzi L, Boersma E,
Di Vece D, et al. Cardiac arrest in takotsubo syndrome: results Danchin N, et al. Gender differences in the management and
from the InterTAK Registry. Eur Heart J 2019;40:2142-51. clinical outcome of stable angina. Circulation 2006;113:490-8.
https://doi.org/10.1093/eurheartj/ehz170 https://doi.org/10.1161/CIRCULATIONAHA.105.561647
54. Elkayam U, Jalnapurkar S, Barakkat MN, Khatri N, Kealey AJ, 72. Peters SAE, Colantonio LD, Zhao H, Bittner V, Dai Y,
Mehra A, et al. Pregnancy-associated acute myocardial Farkouh ME, et al. Sex differences in high-intensity statin
infarction: a review of contemporary experience in 150 cases use following myocardial infarction in the United States.
between 2006 and 2011. Circulation. 2014;129:1695-702. J Am Coll Cardiol 2018;71:1729-37. https://doi.org/10.1016/
https://doi.org/10.1161/CIRCULATIONAHA.113.002054 j.jacc.2018.02.032
55. Seils DM, Friedman JY, Schulman KA. Sex differences 73. Fulcher J, O’Connell R, Voysey M, Emberson J, Blackwell L,
in the referral process for invasive cardiac procedures. Mihaylova B, et al; Cholesterol Treatment Trialists
J Am Med Womens Assoc (1972). 2001;56:151-4, 160. Collaboration. Efficacy and safety of LDL-lowering therapy
56. Woodward M. Cardiovascular disease and the female among men and women: meta-analysis of individual
disadvantage. Int J Environ Res Public Health 2019;16:1165. data from 174,000 participants in 27 randomised trials.
https://doi.org/10.3390/ijerph16071165 Lancet 2015;385:1397-405. https://doi.org/10.1016/
57. Bönte M, von dem Knesebeck O, Siegrist J, Marceau L, S0140-6736(14)61368-4
Link C, Arber S, et al. Women and men with coronary heart
disease in three countries: are they treated differently?
Womens Health Issues 2008;18:191-8. https://doi.org/
10.1016/j.whi.2008.01.003
58. Zheng X, Dreyer RP, Hu S, Spatz ES, Masoudi FA, Spertus JA,
et al. Age-specific gender differences in early mortality
following ST-segment elevation myocardial infarction in
China. Heart 2015;101:349-55. https://doi.org/10.1136/
heartjnl-2014-306456
59. Hvelplund A, Galatius S, Madsen M, Rasmussen JN,
Rasmussen S, Madsen JK, et al. Women with acute coronary
syndrome are less invasively examined and subsequently
less treated than men. Eur Heart J 2010;31:684-90.
https://doi.org/10.1093/eurheartj/ehp493

ARTICLE
Diuretics in the management of chronic

heart failure: when and how
Joseph S Magdy
Cardiology advanced SUMMARY
trainee1
Conjoint associate lecturer2 Heart failure is an increasingly prevalent condition resulting in recurrent hospitalisations and
James McVeigh significant mortality and morbidity.
Nurse practitioner1 The management of heart failure has evolved, and multiple drugs have an established mortality
Praveen Indraratna benefit in heart failure with reduced ejection fraction.
Consultant cardiologist1
Conjoint lecturer2 Although the focus should be on ensuring that patients are treated with the maximum
tolerated doses of these guideline-directed therapies, diuretics continue to play a key role in the
1
Department of Cardiology, management of clinical congestion in all forms of heart failure.
Prince of Wales Hospital,
Sydney Clinicians play a key role in heart failure management. Familiarity with the role of diuretics and
2
Prince of Wales Clinical their dosing and monitoring is critical.
School, UNSW Sydney
Introduction nocturnal dyspnoea), an elevated jugular venous

Keywords pressure, hepatic enlargement and tenderness,
Heart failure affects approximately 2% of the
congestive heart failure,
adult Australian population, and the prevalence is peripheral oedema, pulmonary oedema and the
mineralocorticoid receptor
antagonists, thiazides increasing.1 The natural history of the condition is formation of ascites. In patients with heart failure
characterised by episodes of acute decompensation, and clinical congestion, diuretics are first-line therapy
with significant associated mortality.2 Heart failure to improve symptoms. While they may not have
Aust Prescr 2022;45:200–4
can be classified as heart failure with reduced ejection an established mortality benefit, diuretics were
https://doi.org/10.18773/
fraction (HFrEF), and heart failure with preserved used as background therapy in most patients in the
austprescr.2022.069
ejection fraction (HFpEF). HFrEF is characterised pivotal trials that showed the survival benefit of the
by impaired contractility of the left ventricular aforementioned heart failure therapies.1 The aim of
myocardium with a left ventricular ejection fraction using diuretics is to achieve euvolaemia. Once this is
(LVEF) below 50%. HFpEF is characterised by diastolic achieved, the diuretic dose should be reduced to the
dysfunction that limits the filling of the left ventricle, lowest effective dose or potentially discontinued.
although the LVEF remains greater than 50%. Loop diuretics are the most frequently used diuretics
The management of HFrEF has evolved over the due to their rapid onset and efficacy.3 Acting on
last two decades and multiple drug classes have an the sodium–potassium–chloride symporter of the
established mortality benefit, including angiotensin ascending limb of the loop of Henle, loop diuretics
receptor–neprilysin inhibitors, ACE inhibitors, beta promote the excretion of sodium and chloride, as
blockers, mineralocorticoid receptor antagonists well as potassium.2 Furosemide (frusemide) is the
and sodium-glucose co-transporter 2 (SGLT2) most commonly used first-line therapy, which is
inhibitors. The primary aim is to establish patients
typically started at a dose of 20–40 mg once daily in
on the maximum tolerated doses of these guideline-
the outpatient setting. Patients who are furosemide
directed medical therapies, all of which reduce heart
(frusemide)-naïve typically have greater diuresis
failure-related mortality. However, patients with
when the drug is started. If there is no response,
hypervolaemia should also be treated with diuretics
the dose should be increased to reach the required
for symptom relief. When euvolaemia is achieved,
threshold of diuresis.4 The typical total daily dose for
diuretic therapy should be reduced or stopped where
maintenance ranges between 40 mg and 240 mg.
possible to prioritise these mortality-reducing drugs.
In the setting of advanced renal failure, daily doses
Principles of diuretic therapy up to 500 mg may be needed, and liaison with the
In heart failure, the abnormal cardiac filling and treating nephrologist is recommended. To optimise
resultant high venous pressures can lead to the typical the effect, it is recommended to divide the daily dose
symptoms and signs of ‘clinical congestion’, including into morning and midday doses if more than 80 mg is
dyspnoea (particularly orthopnoea and paroxysmal required in a day.

ARTICLE
Although furosemide (frusemide) is the only loop prescribing and is generally dispensed from hospitals.
diuretic on the Pharmaceutical Benefits Scheme While it may be dosed daily in the acute setting, in the
(PBS), there are other drugs in the class with differing non-acute environment, doses of metolazone can be
pharmacological properties, including bumetanide. reduced to 2.5–5 mg once weekly.
The oral bioavailability of bumetanide is high
(approximately 80–90%), while that of furosemide
Monitoring and adverse effects
of diuretics
(frusemide) varies. As such, a direct conversion is
not consistently reliable, although in general, oral Given the potential for renal dysfunction and
furosemide (frusemide) 40 mg is considered to be electrolyte imbalance (particularly hypokalaemia and
equivalent to oral bumetanide 0.5–1 mg.2 Some hyponatraemia, the latter especially with thiazide
clinicians favour the use of bumetanide for its higher diuretics), regular monitoring is required. Monitoring
oral bioavailability over furosemide (frusemide) in the of electrolytes (particularly sodium and potassium),
setting of significant peripheral oedema, as bowel wall urea and creatinine should be performed 1–2 weeks
oedema may limit absorption.5 A recent systematic after starting or adjusting diuretic doses, and
review, however, did not show a significant benefit eventually every six months in the long term.1
over furosemide (frusemide).6 Given that furosemide Abnormal potassium concentrations are associated
(frusemide) contains a sulfonamide moiety, it carries with increased mortality in heart failure.1,3 Diuretics, as
a potential risk of cross-reactivity in the setting of well as the other heart failure therapies, can change
sulfonamide allergies.7 Etacrynic acid (which does not potassium concentrations. Dietary measures are
contain the sulfonamide moiety) is an alternative loop helpful in addressing both low and high potassium
diuretic for patients with sulfonamide allergies. concentrations and should be used. Increasing the
dose of mineralocorticoid receptor antagonists can
Refractory congestion and sequential also be used to mitigate the hypokalaemia induced
nephron blockade
by diuretics, if not already at the maximum tolerated
If congestion persists despite adequate dosing of dose. Occasionally, potassium supplementation may
loop diuretics, clinicians should consider ‘sequential be required with close monitoring.
nephron blockade’, the addition of diuretics that
Hyponatraemia is frequent, occurring in up to 20%
exert their effects at successive components of the
of patients hospitalised with heart failure, and is also
nephron. However, it should be noted that sequential
associated with higher mortality in heart failure.1,3
nephron blockade is a potent combination. While
The presence of hyponatraemia should prompt an
the combination can be more effective, it carries an
assessment of fluid status. Hyponatraemia is usually
increased risk of renal dysfunction and electrolyte
dilutional in the setting of hypervolaemia, which may
imbalance and so should be used cautiously,
respond to fluid restriction. Occasionally it is due
particularly in elderly patients. This approach
to diuretics, particularly thiazides and thiazide-like
includes the concurrent use of thiazide diuretics and
diuretics, and if the patient is not hypervolaemic, the
mineralocorticoid receptor antagonists. Thiazides
clinician should reconsider the need for diuretics.1
act more distally in the nephron, by blocking
the sodium–chloride co-transporter in the distal Hyperuricaemia is common among patients with
convoluted tubule.2 Thiazide-like diuretics, which heart failure. Prescribers should be aware of the
lack the benzothiadine backbone in their molecular risk of gout exacerbations associated with diuretics,
structure, also act on the same transporter but have a particularly thiazides.1
longer elimination half-life.8 The addition of thiazides Clinicians must also be aware of the rare complication
may help overcome diuretic resistance, which can of ototoxicity with loop diuretics, typically with high-
arise from prolonged use of a loop diuretic and dose intravenous therapy or in the setting of impaired
the resultant nephron remodelling and increased renal function. Concurrent use of other potentially
sodium reabsorption.9 ototoxic drugs, such as aminoglycosides, also
A readily available thiazide is hydrochlorothiazide, increases the risk.10
which can be started at 12.5–25 mg per day, and Prescribers should also be mindful of the potential for
increased up to a total of 50 mg per day. Several interactions with other heart failure therapy. Diuretic
thiazide-like diuretics can also be used, including doses may need to be reduced to mitigate the risk
indapamide, metolazone and chlortalidone, without of adverse effects of hypotension and hypovolaemia
strong evidence for the superiority of one drug.4 when starting beta blockers, renin–angiotensin system
Some clinicians favour the potent diuretic metolazone blockade or SGLT2 inhibitors.11
in the setting of refractory congestion, although Primary care physicians play a key role in titrating
it is a highly specialised drug with restrictions on diuretics, particularly following hospitalisation, when

ARTICLE Diuretics in the management of chronic heart failure: when and how
early outpatient follow-up has been shown to reduce They should be started at low doses (e.g. 12.5 mg
readmissions.12 The doses of diuretics are often daily), particularly in the setting of diabetes or renal
increased during admissions for exacerbations of impairment. International guidelines recommend
heart failure, and patients are instructed to follow up up-titration over 1–2 months to 25–50 mg daily,3
with their GPs in the week following discharge for although the risk of hyperkalaemia is higher when
further titration. On follow-up, assessments of body the dose of spironolactone or eplerenone is 50 mg
weight, fluid status, renal function and electrolytes and above.
should be performed to ensure that a patient is Mineralocorticoid receptor antagonists should be
euvolaemic. Once euvolaemia is established, the goal avoided or used cautiously in patients with stage IV–V
is to ensure a patient’s body weight remains stable chronic kidney disease or a potassium concentration
at their dry weight, by ensuring compliance with fluid above 5 mmol/L. With each dose adjustment,
restrictions and gentle adjustments in the dose of electrolytes and renal function should be checked at
diuretics. Should a patient become hypovolaemic, 1–2 weeks and then monthly for three months, before
then clinicians should reduce the dose of diuretics eventually stretching out to every six months. If the
until the body weight returns to baseline. While exact estimated glomerular filtration rate (eGFR) reduces
dose alterations must be individualised, furosemide by more than 30% or potassium concentration rises
(frusemide) doses are often reduced by 40 mg above 5.5 mmol/L, the mineralocorticoid receptor
(although the adjustments are greater in the setting of antagonist should be reduced and may need to be
high-dose diuretics). Follow-up at 1–2 weeks following stopped altogether if the potassium concentration
a dose adjustment is crucial. rises above 6 mmol/L. Spironolactone can also
Clinicians can trial stopping diuretics in patients cause gynaecomastia and, if this occurs, it may be
with heart failure who are stable on optimal therapy, substituted with eplerenone.1 However, eplerenone
have not been recently hospitalised due to heart is only listed on the PBS for HFrEF, specifically after
failure, and are receiving a dose of up to 80 mg acute myocardial infarction.
furosemide (frusemide). The dose can gradually be
reduced, and patients should be closely monitored for Sodium-glucose co-transporter 2
rebound hypervolaemia.13 inhibitors
SGLT2 inhibitors have shown benefits for both
Diuretics in renal dysfunction HFrEF and HFpEF. Dapagliflozin or empagliflozin
Renal impairment often coexists with heart failure are recommended in all patients with HFrEF
and is an independent predictor of mortality.3 already receiving optimal treatment with an ACE
However, acute increases in creatinine during diuretic or angiotensin receptor–neprilysin inhibitor, a beta
treatment are common and do not necessitate a blocker and a mineralocorticoid receptor antagonist,
reduction in the dose, particularly if congestion irrespective of the presence of diabetes.3 Dapagliflozin
is present.4 Data suggest that these increases in has recently been included on the PBS for the
creatinine in response to diuresis are usually transient treatment of HFrEF, improving patient access to
and do not worsen outcomes. Moreover, in patients the drug.
with pre-existing renal impairment, a higher dose
Although it is not thought to be the primary
of diuretics is required to exert the same effect.
mechanism responsible for their benefits in terms
Diuretics form part of the treatment of cardiorenal
of cardiovascular death and heart failure-related
syndromes by improving ventricular filling and
hospitalisation, SGLT2 inhibitors have diuretic and
reducing renal venous pressures, thereby enhancing
natriuretic properties, giving them an added benefit
renal perfusion.14
of reducing congestion.3 If a patient is euvolaemic on
Mineralocorticoid receptor starting SGLT2 inhibitors, the prescriber can consider
antagonists reducing the dose of diuretics. A reversible reduction
Mineralocorticoid receptor antagonists are one of in the eGFR by up to 30% often occurs after starting
the proven pillars of therapy for HFrEF. Despite SGLT2 inhibitors and should not lead to premature
being classed as potassium-sparing diuretics, their discontinuation.3 The evidence in favour of SGLT2
benefit occurs through neurohormonal modulation inhibitors in HFpEF is also evolving, and they are
and effects on ventricular remodelling rather than currently recommended in HFpEF guidelines.16
diuresis itself.15 In the kidneys, aldosterone antagonists Clinicians should be mindful of the adverse effects
modulate the expression and activity of sodium of SGLT2 inhibitors. While there are conflicting data
and potassium channels in the distal nephron.2 about a possible increased urinary tract infection
Spironolactone and eplerenone doses are identical. risk, the risk of fungal genital infection is increased

ARTICLE
3–5-fold.17 SGLT2 inhibitors can also result in A self-care written strategy encourages weight
hypovolaemia and euglycaemic ketoacidosis.17 Due to monitoring, adherence to drugs, fluid management
their mild diuretic effect, reducing or stopping loop and physical activity, and alerts patients to the early
or thiazide diuretics should be considered if a patient signs and symptoms of congestion. Rapid weight
is euvolaemic. Patients should also be instructed to gain (e.g. 2 kg over two days) is likely to be related
withhold their SGLT2 inhibitors perioperatively and to hypervolaemia and should prompt patients to
during ‘sick days’.17 consult with their GP or other supervising healthcare
professional. In motivated and competent patients,
Carbonic anhydrase inhibitors
a flexible diuretic plan can enable patients to safely
There is renewed interest in the use of acetazolamide titrate diuretic doses in response to hypervolaemia.
for acute decompensated heart failure. Acetazolamide For example, a patient is recommended to take
is a carbonic anhydrase inhibitor, which inhibits 40 mg furosemide (frusemide) if their body weight
the reabsorption of sodium and bicarbonate in increases by more than 2 kg over two days.
the proximal tubule. The randomised, placebo-
Exercise programs should be considered for patients
controlled Acetazolamide in Acute Decompensated
with heart failure. There is good-quality evidence
Heart Failure with Volume Overload trial included
supporting the role of exercise in improving physical
hospitalised patients with acute decompensated
fitness, quality of life and hospital admissions in the
heart failure who were also receiving intravenous
heart failure population.1 Regular, moderate-intensity
loop diuretics. In this trial, the addition of intravenous
exercise has well-demonstrated safety and efficacy
acetazolamide resulted in a greater incidence of
and is recommended for all patients with heart failure.
successful early decongestion, without increasing
the rate of adverse events.18 This promising finding Nurse-led clinics have been shown to improve
offers another potential drug to assist in the challenge survival, reduce hospitalisations and reduce the time
of achieving decongestion in decompensated heart required to achieve optimal doses of therapy.1 If oral
failure, although it should be noted that the use of diuretics are insufficient, intravenous administration
SGLT2 inhibitors was a contraindication and that the may be suitable and can be provided in the outpatient
drug was administered intravenously in this trial. setting, either by the local heart failure service or the
Further evidence is required to determine whether treating GP (particularly in the rural setting), thereby
there is a role for oral acetazolamide in the primary avoiding hospital admissions.
care setting.
Conclusion
Non-pharmacological fluid
management
While the aim of heart failure management should
In patients with congestive heart failure, a 1.5 L fluid
be the initiation and up-titration of guideline-
restriction can be considered on the basis of biological
directed medical therapies with a proven mortality
plausibility, although the supporting evidence is
benefit, diuretics still play an important role in the
lacking.1 In patients without clinical congestion, fluid
management of symptomatic congestion in all
restriction is not recommended.
forms of heart failure. When euvolaemia is achieved,
Self-management is a key component of the diuretics may be stopped or flexibly used in
management of heart failure, and heart failure action conjunction with a heart failure action plan in selected
plans should be instituted where possible. Numerous patients, allowing for further up-titration of the proven
practical clinical resources are available for patients, guideline-directed therapies. Furosemide (frusemide)
including the NPS MedicineWise program on heart is typically the first-line diuretic. Combinations of
failure, which was developed in collaboration with the diuretics can result in significant clinical improvement,
Heart Foundation and provides a succinct outline of although prescribers should be cognisant of
the goals in heart failure and how to achieve them. possible additive adverse events such as electrolyte
The program also offers a practical guide to assist abnormalities, renal impairment and hypovolaemia.
GPs in the up-titration of heart failure medicines.
An understanding of dosing, monitoring and adverse
The Heart Foundation’s ‘Heart Failure Resources for
events is critical for GPs managing heart failure.
Patients’ also offers a range of practical resources for
patients to assist with self-management. Conflicts of interest: none declared

ARTICLE Diuretics in the management of chronic heart failure: when and how
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15. Vizzardi E, Regazzoni V, Caretta G, Gavazzoni M, Sciatti E,
https://doi.org/10.1016/j.jacc.2019.12.059
Bonadei I, et al. Mineralocorticoid receptor antagonist
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HYPERTENSIONAHA.114.05122

ARTICLE
Blood pressure elevations in hospital

Arduino A Mangoni1,2
SUMMARY Elzbieta A Jarmuzewska3
Genevieve M Gabb4,5,6,7
Long-term hypertension control in the community significantly reduces cardiovascular risk. Patrick Russell8
However, the benefit of controlling acute elevations of blood pressure in hospitalised patients 1
Discipline of Clinical
is unclear. Pharmacology, College of
In-hospital elevations of blood pressure are relatively common and might not reflect poorly Medicine and Public Health,
Flinders University, Adelaide
controlled blood pressure before admission. The measurement of blood pressure in hospital
patients significantly differs from the best practice recommended for primary care and outpatients.
2
Department of Clinical
Pharmacology, Flinders
Recent observational studies suggest that the pharmacological treatment of acute, asymptomatic, Medical Centre, Southern
in-hospital elevations of blood pressure may have no benefit. However, it may increase the risk of Adelaide Local Health
Network
in-hospital and post-discharge complications.
3
Formerly Department of
Pending the development of robust inpatient measurement protocols, acute blood pressure Internal Medicine, Polyclinic
elevations in hospitalised patients should not routinely require antihypertensive treatment in IRCCS, Ospedale Maggiore,
the absence of symptoms or acute end-organ damage. Rather, such elevations should facilitate University of Milan, Italy
follow-up of blood pressure and other cardiovascular risk factors after discharge. 4
Acute and Urgent Care,
Royal Adelaide Hospital,
Central Adelaide Local
Introduction A more recent study captured information regarding Health Network
Long-term control of hypertension in patients living pre-admission and in-hospital blood pressure control 5
Faculty of Health and
in the community effectively reduces cardiovascular in a cohort of 14,915 older adults admitted for non- Medical Sciences, University
cardiac reasons within the US Veterans Administration of Adelaide
morbidity and mortality. There is a substantial
Health System. Nearly half of the patients with 6
Division of Medicine,
evidence base informing national and international
uncontrolled blood pressure during admission had Cardiac and Critical Care,
hypertension management guidelines.1-3 However, Flinders Medical Centre,
the evidence is less clear for a benefit from rapid well-controlled blood pressure before admission.7 It is
Adelaide
control of acute, asymptomatic, uncomplicated currently unknown whether these observations can be 7
College of Medicine and
elevations of blood pressure. In the hospital setting, extrapolated to Australia. Public Health, Flinders
elevation of blood pressure may trigger calls for University, Adelaide
Measurement
urgent assessments by medical emergency teams.4,5 8
Department of Internal
A critical issue in relation to in-hospital blood pressure Medicine, Royal Adelaide
Current hypertension guidelines do not address
elevations is how blood pressure is measured in Hospital, Central Adelaide
asymptomatic in-hospital blood pressure elevations
hospital. The methods used are likely to differ from Local Health Network
or recommendations regarding their diagnosis,
current recommendations designed for primary care
management and follow-up.1-3
and outpatient settings. For example, the methods Keywords
Epidemiology and causes of for clinic blood pressure measurement emphasise blood pressure,
in-hospital hypertension the importance of repeated readings (typically cardiovascular risk,
hypertension, in-hospital
Acute elevations of blood pressure during an three) taken in a standardised fashion in a quiet
blood pressure elevations
admission to hospital are common. However, there environment.1-3 Out-of-office measurements (24-hour
are currently no published data on the epidemiology ambulatory blood pressure monitoring, or home
of asymptomatic blood pressure elevations in blood pressure monitoring) are also important in the Aust Prescr 2022;45:205–7
Australian hospitals. accurate diagnosis of hypertension.1-3,8 https://doi.org/10.18773/

austprescr.2022.068
One international review reported a prevalence A study in a UK hospital highlighted why inpatient
of in-hospital hypertension of 24–87%, however it blood pressure measurement may be unreliable.
included studies published between 1982 and 2009 Blood pressure was measured once only (96% of
which might not reflect current inpatient populations. measurements), an incorrect cuff size was used
Furthermore, the definition of in-hospital hypertension (36%), and staff and patients were conversing during
varied across the studies, including a history of the measurement (41%).9 This study casts doubt on
hypertension on admission and various thresholds for the use of these measurements as a justification for
systolic and diastolic blood pressure according to clinic starting or increasing antihypertensive treatment for
or ambulatory blood pressure monitoring criteria.6 inpatients who are asymptomatic.
© 2022 NPS MedicineWise This article is peer-reviewed 205

ARTICLE Blood pressure elevations in hospital
In addition to the method of measurement, factors chest pain, severe headache, confusion, blurred vision,
contributing to the high prevalence of in-hospital nausea and vomiting, severe anxiety, dyspnoea,
blood pressure elevations include uncontrolled pain, seizures and reduced consciousness. Papilloedema is
noise, anxiety and disrupted sleep patterns. There a hallmark of malignant hypertension and can be seen
may also be an interruption to the regular doses taken on examination of the optic fundi.
by patients already on antihypertensive drugs.10
Outcomes
Physicians’ attitudes towards Observational studies published since 2018 have
in-hospital hypertension reported the effect on clinical end points of starting or
A few studies have examined the attitude of doctors increasing antihypertensive treatment in hospital. One
towards treatment. In a survey of 181 US hospital study reported that 14% of older patients admitted
residents, most (79%) regarded controlling blood for non-cardiac reasons were discharged with new
pressure in hospital as important or very important, or intensified antihypertensive treatment. Among
and decisions regarding blood pressure lowering those who started treatment, 29% received renin–
should be based on current national guidelines (66%). angiotensin system inhibitors, 42% beta blockers, 27%
Many residents (44%) considered drugs should be calcium-channel blockers, 11% thiazide diuretics and
started or adjusted if the systolic blood pressure 12% other antihypertensives. More than half (52%)
was mildly high (140–159 mmHg) and that patients of the patients whose treatment was intensified had
with in-hospital blood pressure elevations should well-controlled blood pressure before admission. The
be discharged on the antihypertensive regimen probability of antihypertensive intensification was 25%
prescribed in hospital (91%).11 for patients with moderately elevated blood pressure
and 42% for those with severe elevations.7
In another survey, about a third of hospital doctors
would transfer an asymptomatic patient to an In another study, patients discharged with a new
intensive care unit because of high blood pressure or intensified antihypertensive regimen were more
even in the absence of target organ damage. The likely to be readmitted (hazard ratio (HR) 1.23, 95%
average blood pressure that would prompt the confidence interval (CI) 1.07–1.42, number needed
transfer was 210/117 mmHg for house officers and to harm (NNH) 27, 95% CI 16–76) or experience
193/110 mmHg for other hospital doctors.10 serious adverse events within 30 days (HR 1.41, 95%
CI 1.06–1.88, NNH 63, 95% CI 34–370). In secondary
In Australia, the wide adoption of set criteria for
analyses, new or intensified inpatient treatment was
calling rapid medical emergency teams to respond to
associated with an increased risk of cardiovascular
specific alterations of vital parameters4,5 might lead
events within 30 days of discharge (HR 1.65, 95% CI
hospital doctors to treat acute elevations of blood
1.13–2.40).15
pressure even in absence of symptoms or acute end-
organ damage. However, as previously discussed, The association between inpatient treatment initiation
there is no available information regarding the or intensification and specific end points was studied
incidence and the treatment of acute, asymptomatic in 22,834 adults admitted with non-cardiac diagnoses
blood pressure elevations by Australian hospital at 10 hospitals in the USA. At least one hypertensive
medical emergency teams. reading was recorded in 78% of patients. Of these,
33% were treated mainly with oral antihypertensives.
Management After controlling for patient and blood pressure
Studies of in-hospital blood pressure elevations have characteristics, treatment was associated with an
primarily reported the acute effects of treatment on increased risk of in-hospital acute kidney injury (odds
the blood pressure rather than clinical outcomes. ratio (OR) 1.36, 95% CI 1.21–1.52) and myocardial injury
For example, in a study of medical inpatients with (OR 2.23, 95% CI 1.56–3.20). By contrast, there were no
asymptomatic hypertension, hydralazine or labetalol significant differences in the risk of in-hospital stroke,
given orally or intravenously acutely reduced blood length of stay, myocardial infarction within 30 days and
pressure in 85% of patients. In 22% the systolic blood pressure control one year after discharge.16
blood pressure was reduced by at least 25% within A cohort study matched 4219 patients admitted
six hours.12 Such an acute and excessive reduction without a primary cardiovascular diagnosis who
in blood pressure could decrease cerebral and received antihypertensive drugs on an as-needed
myocardial perfusion. This approach should be basis, in addition to scheduled antihypertensives,
avoided except in particular circumstances such as with 4219 patients who only received scheduled
hypertensive emergencies with end-organ damage antihypertensives. The former group had an increased
(e.g. aortic dissection or acute renal failure).13,14 Clinical risk of an abrupt lowering of systolic blood pressure
features of hypertensive emergencies may include by more than 25% within one hour of administration

ARTICLE
(OR 2.05, 95% CI 1.56–2.71), acute kidney injury in asymptomatic patients admitted for non-cardiac
(OR 1.24, 95% CI 1.09–1.42), ischaemic stroke (OR 8.5, reasons provides no clinical benefit. It is, however,
95% CI 1.96–36.79), death (OR 2.36, CI 1.26–4.41), and associated with an increased risk of in-hospital and
prolonged hospitalisation (4.7 vs 2.9 days). Ischaemic post-discharge complications.
events were more frequent with abrupt blood A significant problem in investigating in-hospital
pressure reductions and more doses of as-needed blood pressure elevations and their management
drugs. Notably, 93% of the as-needed drugs were is the lack of robust protocols for inpatient blood
given intravenously, with hydralazine (53%) and pressure measurement. A more robust assessment
labetalol (43%) being the most common drugs.17 would facilitate diagnosis and risk stratification, as well
The results of these observational studies, primarily as the planning of appropriately designed intervention
conducted in the USA, suggest that proactively studies assessing the efficacy and safety of specific
managing asymptomatic in-hospital blood pressure drugs and post-discharge follow-up strategies. Only
elevations does not confer clear benefits. Treatment then can the clinical significance of asymptomatic
may be associated with significant adverse outcomes, in-hospital blood pressure elevations be appropriately
at least in the short term. determined in Australia and worldwide.
At present, it appears that acute blood pressure
Conclusion elevations in asymptomatic hospitalised patients do
not routinely require drug treatment. The criteria used
There is overwhelming evidence of the benefit by hospital medical emergency teams require review
of identifying and treating hypertension in the and revision, in relation to blood pressure elevations
community. However, little is known about the without alterations in other vital parameters, to
clinical significance of common, asymptomatic and prevent unnecessary and potentially dangerous
short-term blood pressure elevations in hospitalised antihypertensive treatment.
patients. This is compounded by the variability of Blood pressure elevations in hospital should prompt
how blood pressure is measured in hospital, the lack consideration of post-discharge assessments to
of consideration for an individual patient’s overall check the blood pressure and the need for starting
cardiovascular risk and the absence of evidence about long-term treatment. In this context, a clear
drug treatment and follow-up strategies. communication with GPs is essential to appropriately
Recent studies, albeit with the limitations of plan investigations and management.
observational data, suggest that the as-needed use,
Conflicts of interest: none declared
initiation, or intensification of antihypertensive drugs
REFERENCES
1. Gabb GM, Mangoni AA, Anderson CS, Cowley D, Dowden JS, Golledge J, et al. 10. Weder AB. Treating acute hypertension in the hospital: a lacuna in
Guideline for the diagnosis and management of hypertension in adults - 2016. the guidelines. Hypertension 2011;57:18-20. https://doi.org/10.1161/
Med J Aust 2016;205:85-89. https://doi.org/10.5694/mja16.00526 HYPERTENSIONAHA.110.164194
2. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Dorairaj P, et al. 11. Neal Axon R, Garrell R, Pfahl K, Fisher JE, Zhao Y, Egan B, et al. Attitudes
2020 International Society of Hypertension global hypertension practice and practices of resident physicians regarding hypertension in the inpatient
guidelines. Hypertension 2020;75:1334-57. https://doi.org/10.1161/ setting. J Clin Hypertens (Greenwich) 2010;12:698-705. https://doi.org/10.1111/
HYPERTENSIONAHA.120.15026 j.1751-7176.2010.00309.x
3. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 12. Gaynor MF, Wright GC, Vondracek S. Retrospective review of the use of
2018 ESC/ESH Guidelines for the management of arterial hypertension. as-needed hydralazine and labetalol for the treatment of acute hypertension
Eur Heart J 2018;39:3021-104. https://doi.org/10.1093/eurheartj/ehy339 in hospitalized medicine patients. Ther Adv Cardiovasc Dis 2018;12:7-15.
4. Concord Medical Emergency Team (MET) 2 Study Investigators. Outcomes https://doi.org/10.1177/1753944717746613
following changing from a two-tiered to a three-tiered hospital rapid response 13. van den Born BH, Lip GYH, Brguljan-Hitij J, Cremer A, Segura J, Morales E,
system. Aust Health Rev 2019;43:178-187. https://doi.org/10.1071/AH17105 et al. ESC Council on hypertension position document on the management of
5. Bergmeir C, Bilgrami I, Bain C, Webb GI, Orosz J, Pilcher D. Designing a more hypertensive emergencies. Eur Heart J Cardiovasc Pharmacother 2019;5:37-46.
efficient, effective and safe Medical Emergency Team (MET) service using https://doi.org/10.1093/ehjcvp/pvy032
data analysis. PLoS One 2017;12:e0188688. https://doi.org/10.1371/ 14. Burton TJ, Wilkinson IB. The dangers of immediate-release nifedipine in the
journal.pone.0188688 emergency treatment of hypertension. J Hum Hypertens 2008;22:301-2.
6. Axon RN, Cousineau L, Egan BM. Prevalence and management of https://doi.org/10.1038/sj.jhh.1002324
hypertension in the inpatient setting: a systematic review. J Hosp Med 15. Anderson TS, Jing B, Auerbach A, Wray CM, Lee S, Boscardin WJ, et al.
2011;6:417-22. https://doi.org/10.1002/jhm.804 Clinical outcomes after intensifying antihypertensive medication regimens
7. Anderson TS, Wray CM, Jing B, Fung K, Ngo S, Xu E, et al. Intensification among older adults at hospital discharge. JAMA Intern Med 2019;179:1528-36.
of older adults’ outpatient blood pressure treatment at hospital discharge: https://doi.org/10.1001/jamainternmed.2019.3007
national retrospective cohort study. BMJ 2018;362:k3503. https://doi.org/ 16. Rastogi R, Sheehan MM, Hu B, Shaker V, Kojima L, Rothberg MB. Treatment
10.1136/bmj.k3503 and outcomes of inpatient hypertension among adults with noncardiac
8. Head GA, McGrath BP, Mihailidou AS, Nelson MR, Schlaich MP, Stowasser M, admissions. JAMA Intern Med 2021;181:345-52. https://doi.org/10.1001/
et al. Ambulatory blood pressure monitoring in Australia: 2011 consensus jamainternmed.2020.7501
position statement. J Hypertens 2012;30:253-66. https://doi.org/10.1097/ 17. Mohandas R, Chamarthi G, Bozorgmehri S, Carlson J, Ozrazgat-Baslanti T,
HJH.0b013e32834de621 Ruchi R, et al. Pro re nata antihypertensive medications and adverse outcomes
9. Holland M, Lewis PS. An audit and suggested guidelines for in-patient blood in hospitalized patients: a propensity-matched cohort study. Hypertension
pressure measurement. J Hypertens 2014;32:2166-70; discussion 2170. 2021;78:516-24. https://doi.org/10.1161/HYPERTENSIONAHA.121.17279
https://doi.org/10.1097/HJH.0000000000000306

MEDICINAL MISHAP
Osteonecrosis of the jaw and denosumab

Alastair N Goss Case Medication-related osteonecrosis of the jaw is a well-
Emeritus Professor of Oral documented severe complication of dental extractions
and Maxillofacial Surgery, The patient was an 87-year-old female with
hypothyroidism, cardiovascular disease and gastro- in patients on the oral bisphosphonates. It has been
University of Adelaide
oesophageal reflux disease. Her regular treatments assumed that the risk with denosumab is similar to
were thyroxine, apixaban and esomeprazole. She had that with bisphosphonates.2 This is incorrect. In the
Keywords 2022 update of its position paper, the American
bisphosphonates, also been diagnosed as having osteoporosis and had
received one injection of denosumab. Association of Oral and Maxillofacial Surgeons
denosumab, medication-
related osteonecrosis of the has stated that the risk is a magnitude higher for
The left mandibular premolars were decayed so
jaw, osteoporosis denosumab than the oral bisphosphonates.3 The risk
the patient was referred to an oral and maxillofacial
is 0.3%.
surgeon for extraction of teeth 34 and 35. This
Aust Prescr 2022;45:208–9 extraction was performed seven months after her Minimising the risks of these two serious
https://doi.org/10.18773/ denosumab injection. Bone turnover measured by complications requires opposing actions. To avoid
austprescr.2022.066 serum C-terminal telopeptide was 176 pg/mL, which vertebral fractures denosumab should not be delayed,
is within the range for postmenopausal women. Initial whereas to avoid medication-related osteonecrosis
healing had occurred when the patient was reviewed of the jaw, time is needed for a return to the normal
one week after surgery. bone turnover to allow wound healing.
The woman presented again 11 weeks after the

extractions with pain, swelling and exposed bone.
She had been given another injection of denosumab
10 days after the extraction.
Fig. Stage 2 medication-related
Medication-related osteonecrosis of the jaw was osteonecrosis of the jaw
diagnosed. This was treated conservatively with
chlorhexidine mouth rinses, analgesics and a short
course of cephalosporin for the soft tissue infection.
The C-terminal telopeptide was low at 116 pg/mL.
Symptoms persisted for six months after the last
denosumab injection. X-rays showed a sequestrum
(Fig.). As the C-terminal telopeptide was by then
returning to normal (230 pg/mL), the sequestrum
was removed under local anaesthesia and the wound
primarily closed. One month later, when the area was
healed, the denosumab was recommenced.
Comment
Despite having no clear guidelines to favour
denosumab, it has substantially replaced the oral
bisphosphonates as the first-line treatment for
osteoporosis in Australia.1 Denosumab is effective
when given as a six-monthly 60 mg subcutaneous
injection and has few adverse reactions. The
main concern medically is that, if denosumab is
discontinued or the injection is substantially delayed,
there is a risk of vertebral fracture. This means
effectively that, once started, the patient must remain
on denosumab or another antiresorptive drug for the Note sequestrum
rest of their life.

MEDICINAL MISHAP
Conclusion and recommendations Box Recommendations for dental care in patients treated
with denosumab4,5
Medication-related osteonecrosis of the jaw can
occur following oral surgery if denosumab is Risk factors
recommenced before bony healing of the socket. If Factors include being female, aged over 70 years, having comorbidities, and taking
antiresorptive drugs for over four years.
there is uncertainty about bone turnover, it should be
measured at the time of the extraction.3 Communication
The Box shows evidence-based recommendations Prescribers, dentists and patients should communicate with each other.
drawn from a prospective trial of 546 patients Determination
taking denosumab for osteoporosis, who had 1082 Determine dental health, the need for extractions, and presence of implants. Dentist to
dental extractions, and another study of 13 patients consider alternative treatment.
who developed osteonecrosis.4,5 Besides dental
Timing
extractions, another risk group is patients with dental
Wait until six months after last injection for extractions.
implants that sometimes lose integration during
Measure fasted C-terminal telopeptide if not sure of bone turnover.
antiresorptive treatment.
Delay next dose of denosumab for one month after extraction until bone healing
Conflicts of interest: none declared has occurred.
Avoid excessive delay or discontinuation of denosumab.
REFERENCES
1. Drug Utilisation Sub-Committee. Denosumab for 4. Smith S, Finn B, Goss AN. Medication-related osteonecrosis
osteoporosis. October 2020. Updated 2021 Mar 16. of the jaws: a single centre, Far North Queensland case
https://www.pbs.gov.au/info/industry/listing/participants/ series. Aust Dent J 2022;67:168-71. https://doi.org/10.1111/
public-release-docs/2020-10/denosumab-for-osteoporosis- adj.12905.
october-2020 [cited 2022 Nov 1] 5. Goss A. Evidence based guidelines for patients on
2. Ebeling PR, Seeman E, Centre J, Chen W, Chiang C, antiresorptive medication for osteoporosis requiring dental
Diamond T, et al. Position statement on the management extractions. Aust Dent Assoc News Bulletin 2021;515:22-4.
of osteoporosis, February 2021. Sydney: Healthy Bones
Australia; 2021. https://healthybonesaustralia.org.au/
wp-content/uploads/2021/02/HBA-Position-Statement-on-
Osteoporosis-25-02-21.pdf [cited 2022 Nov 1]
3. Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER,
Ward BB, Kademani D. American Association of Oral and
Maxillofacial Surgeon’s position paper on medication-related
osteonecrosis of the jaw. 2022 Update. J Oral Maxillofac Surg
2022;80:920-43. https://doi.org/10.1016/j.joms.2022.02.008

LATEST NEWS
Wither Australian Prescriber?

John Dowden Australian Prescriber was first published by expressed support for Australian Prescriber and more
Editor in Chief, the Department of Health in 1975.1 In 2002, the than 8000 health professionals signed an open letter
Australian Prescriber
Department of Health outsourced the publication to the Minister of Health and Aged Care in favour of
Aust Prescr 2022;45:210 to the National Prescribing Service,2 now known as the journal.
https://doi.org/10.18773/ NPS MedicineWise. Following recent changes to its There is clearly much goodwill for Australian
austprescr.2022.076 funding, NPS MedicineWise will cease all operations Prescriber to continue but, at the time of writing,
by 31 December 2022. This creates some uncertainty the outlook is unclear. At present, the plan is for
about the future of Australian Prescriber. the Department of Health and Aged Care to find a
The need for an independent journal of therapeutics new publisher for Australian Prescriber through a
was reaffirmed in the first Policy on the Quality Use competitive tendering process.
of Medicines in 1992.3 In turn, that policy became Currently, it is unknown who the new publisher will be
part of the National Medicines Policy.4 It is therefore and when it will take over. Sadly, it is known that the
important to sustain the publication of independent entire editorial team will be made redundant, along
information about medicines. with all the other employees of NPS MedicineWise,
Australian Prescriber has fared well in the reviews of before Christmas. However, the team and the
NPS MedicineWise.5,6 The recent rapid review of the independent Editorial Executive Committee have
budget decision affecting NPS MedicineWise reported already prepared articles for publication in 2023.
a need ‘…to allocate outstanding NPS MedicineWise It is therefore hoped that any interruption to the
functions, most notably ongoing preparation and publication of Australian Prescriber will be brief.
publication of Australian Prescriber’.6 Around the time
of this review, over 30 specialist colleges and societies To be continued…
REFERENCES
1. Executive Editorial Board. Towards better prescribing. 5. Department of Health. Review of the Quality Use of
Aust Prescr 1975;1:3. Medicines Program’s delivery by the National Prescribing
2. Phillips S. The National Prescribing Service and Australian Service Limited (NPS MedicineWise), December
Prescriber. Aust Prescr 2002;25:26-7. https://doi.org/ 2019. https://www.health.gov.au/sites/default/files/
10.18773/austprescr.2002.027 documents/2022/04/review-of-the-quality-use-of-
3. Commonwealth Department of Health, Housing and medicines-program-s-delivery-by-nps-medicinewise.pdf
Community Services. A policy on the quality use of [cited 2022 Nov 1]
medicines. Canberra: Australian Government Publishing 6. Deloitte Touche Tohmatsu. Rapid review of proposed Quality
Service; 1992. Use of Diagnostic, Therapeutics and Pathology Program
4. Australian Government Department of Health and Ageing. budget measure, August 2022. https://www.health.gov.au/
National Medicines Policy 2000. Canberra: Commonwealth resources/publications/rapid-review-of-proposed-quality-
of Australia; 1999. https://www.health.gov.au/resources/ use-of-diagnostic-therapeutics-and-pathology-program-
publications/national-medicines-policy [cited 2022 Nov 1] budget-measure [cited 2022 Nov 1]

NEW DRUGS
New drugs
while 76 took bosutinib, another tyrosine kinase
Asciminib inhibitor, 500 mg once daily. The median follow-up
was 14.9 months with the molecular response being
Approved indication: chronic myeloid leukaemia assessed at 24 weeks. There was a major molecular Aust Prescr 2022;45:211–2
Scemblix (Novartis) response in 25% of the patients taking asciminib and https://doi.org/10.18773/
20 mg and 40 mg film-coated tablets 13.2% of the bosutinib group.3 This advantage for austprescr.2022.070
asciminib was still present when the patients were First published
Tyrosine kinase inhibitors are the mainstay of 12 October 2022
reviewed at 96 weeks.
treatment for chronic myeloid leukaemia.1 However,
patients may develop resistance to treatment and A higher dose of asciminib has been tried in patients
some patients do not respond to tyrosine kinase with the T315I mutation. In this open-label trial, 52
inhibitors because they have a genetic mutation previously treated patients with chronic myeloid
(T315I). As resistance may be related to the binding leukaemia were given asciminib 200 mg twice daily.
site on the tyrosine kinase molecule, there has been a Among the evaluable patients, 40.8% (20/49) had a
search for drugs that use an alternative binding site. major molecular response by 24 weeks. At 96 weeks
there was a response in 46.9% (23/49).4
Asciminib is a tyrosine kinase inhibitor with a different
binding site. It has also been called a STAMP inhibitor In the phase III trial, 5.8% of the patients stopped
(as it specifically targets the ABL myristoyl pocket). asciminib because of adverse effects compared
with 21.1% of the bosutinib group.3 A common
Depending on the dose, asciminib tablets are taken
adverse effect is myelosuppression, particularly
once or twice daily without food, as food reduces
thrombocytopenia, and this may require treatment
absorption. While most of the dose will be excreted
to be withheld or stopped. Full blood counts are
unchanged in the faeces, asciminib is also metabolised
required every two weeks for the first three months of
by cytochrome P450 (CYP) 3A4. Its concentrations
treatment. Serum lipase and amylase should also be
will therefore be increased by inhibitors of CYP3A4,
monitored as some patients will develop pancreatitis. The new drug
such as clarithromycin and azole antifungal drugs, commentaries in
Blood pressure should be checked as hypertension
and decreased by inducers, such as rifampicin. Australian Prescriber are
is a common adverse effect. As a few patients will
Asciminib itself is an enzyme inhibitor, so it will raise prepared by the Editorial
develop prolongation of the QT interval, the ECG Executive Committee.
concentrations of substrates of CYP3A4, such as
should be monitored. In the trial using asciminib Some of the views
midazolam and fentanyl, and substrates of CYP2C9,
200 mg twice daily there were hypersensitivity expressed on newly
such as warfarin. Although concentrations of approved products
reactions in 26.9% of the patients.4 As asciminib is
asciminib will be increased, no dose adjustments are should be regarded as
likely to be harmful to the fetus, it should not be used
recommended for patients with liver or kidney disease. preliminary, as there
in pregnancy. may be limited published
An early indication of the efficacy of asciminib came
The evidence for the safety and efficacy of asciminib data at the time of
from a dose-escalation study. This involved 150 publication, and little
patients who had been unable to tolerate tyrosine is currently limited. For example, the Australian
experience in Australia of
kinase inhibitors or who had been previously treated product information states that the safety profile
their safety or efficacy.
with at least two different tyrosine kinase inhibitors. is based on a total of 356 patients. As a molecular However, the Editorial
All the patients had the Philadelphia chromosome response is a surrogate outcome, it is too early to Executive Committee
know if asciminib improves survival. It would also be believes that comments
and 22% had the T315I mutation. Molecular responses
useful to know how asciminib compares to ponatinib made in good faith at
were used to assess efficacy. In the patients without an early stage may still
the T315I mutation who could be evaluated, 37% which is also approved for previously treated patients
be of value. Before new
(37/99) had a major molecular response within and those with the T315I mutation. drugs are prescribed,
six months. A major molecular response was achieved the Committee believes
T manufacturer provided the product information
it is important that more
by 24% (4/17) of the patients with the mutation by
detailed information
12 months.2 REFERENCES
is obtained from the
An open-label phase III trial studied previously treated 1. Li EW, Yeung D, Fuller S. Chronic leukaemias in the manufacturer’s approved
community. Aust Prescr 2020;43:126-30. https://doi.org/ product information,
patients with chronic myeloid leukaemia who were 10.18773/austprescr.2020.034
a drug information
Philadelphia chromosome positive, but did not have 2. Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D,
DeAngelo DJ. Asciminib in chronic myeloid leukemia after centre or some other
a T315I mutation. One group of 157 patients was ABL kinase inhibitor failure. N Engl J Med 2019;381:2315-26. appropriate source.
randomised to receive asciminib 40 mg twice daily https://doi.org/10.1056/NEJMoa1902328
© 2022 NPS MedicineWise Full text free online at nps.org.au/australian-prescriber 211

NEW DRUGS
3. Réa D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E,

Voloshin S, et al. A phase 3, open-label, randomized study of The Transparency Score is explained in New drugs:
asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or
more prior TKIs. Blood 2021;138:2031-41. https://doi.org/ transparency, Vol 37 No 1, Aust Prescr 2014;37:27.
10.1182/blood.2020009984
4. Cortes JE, Hughes TP, Mauro MJ, Hochhaus A, Rea D, At the time the comment was prepared, information
Goh YT, et al. Asciminib, a first-in-class STAMP inhibitor, about this drug was available on the websites of
provides durable molecular response in patients (pts)
with chronic myeloid leukemia (CML) harboring the T315I the Food and Drug Administration in the USA, the
mutation: primary efficacy and safety results from a phase 1 European Medicines Agency and the Therapeutic
trial. Blood 2020;136(Suppl 1):47-50. https://doi.org/10.1182/
blood-2020-139677 Goods Administration.

NEW DRUGS
marrow examination, 60% of the patients responded

Decitabine/cedazuridine to treatment with 21% having a complete response.
The median duration of the complete responses
Approved indication: chronic myelomonocytic was 13.3 months. For all patients, the median overall Aust Prescr 2022;45:213
leukaemia, myelodysplastic syndromes survival was 18.3 months.1 https://doi.org/10.18773/
Inqovi (Otsuka) austprescr.2022.071
A phase III trial also used a crossover design between
35 mg/100 mg tablets oral and intravenous therapy for the first two cycles First published
12 October 2022
Chronic myelomonocytic leukaemia and the followed by the fixed-dose combination. This also
myelodysplastic syndromes are disorders of stem found that each formulation resulted in a similar
cells. As many patients are not eligible for a stem exposure to decitabine. At the time of writing, the full
cell transplant, they are treated with cytotoxic drugs results of the trial are yet to be published. Information
such as azacitidine. Another option, not previously on 133 patients treated for a median of 8.2 months
marketed in Australia, is decitabine. This inhibits DNA shows a complete response in 21%. Some patients
methyltransferase. As abnormal DNA methylation ceased to be dependent on transfusions.
may be involved in myeloid malignancies, decitabine Most patients will have serious adverse effects from
may improve the differentiation of cells and lead to decitabine/cedazuridine. These include neutropenia,
apoptosis of abnormal cells. anaemia, and thrombocytopenia which can lead
Treatment with azacitidine or decitabine can require to haemorrhage. Blood counts must be checked
intravenous infusions for several consecutive regularly as abnormalities will require treatment to
days every month. By combining decitabine with be delayed or reduced. Dose adjustment may also
cedazuridine, oral therapy is now possible. be needed for non-haematological toxicity such as
elevated creatinine or liver enzymes. Less serious,
The oral bioavailability of decitabine is low because
but frequent, adverse effects include fatigue, nausea,
the molecule undergoes first-pass metabolism by the
dizziness, diarrhoea and constipation. Five of the
enzyme cytidine deaminase found in the liver and
80 patients in the phase II trial stopped treatment
gut. Cedazuridine inhibits this enzyme and therefore
because of adverse effects.1
increases the bioavailability of oral decitabine. As
the absorption of decitabine is reduced by food, While decitabine/cedazuridine is easier to administer
the tablet should be taken on an empty stomach. than azacitidine, it is uncertain how the outcomes
The bioavailability of cedazuridine may be affected of treatment compare. Evaluating the combination
by gastric pH so drugs that increase pH should not will be easier when the results of the phase III trial
be taken within four hours. Decitabine is mainly become available.
metabolised while the absorbed portion of the T manufacturer provided the AusPAR and the product
cedazuridine dose undergoes renal elimination. No information
dose modification is recommended for patients with
REFERENCES
mild hepatic impairment or mild to moderate renal
impairment. The effects of more severe impairment 1. Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ,
Wells R, McCloskey J, et al. Oral cedazuridine/decitabine
are unknown. for MDS and CMML: a phase 2 pharmacokinetic/
pharmacodynamic randomized crossover study. Blood
A phase II trial compared patients’ exposures
2020;136:674–83. https://doi.org/10.1182/blood.2019004143
to decitabine when it was given as 20 mg/m2
intravenously and as 35 mg orally in combination with
100 mg cedazuridine. Eighty patients with chronic
myelomonocytic leukaemia or myelodysplastic
syndromes received one formulation for one cycle of
treatment then switched to the other formulation for
the second cycle. The oral formulation was used in The Transparency Score is explained in New drugs:
subsequent cycles. For the fixed-dose combination, transparency, Vol 37 No 1, Aust Prescr 2014;37:27.
the exposure (area under the time–concentration At the time the comment was prepared, information
curve) was 97.6% of that of the intravenous dose.1 about this drug was available on the websites of
The 80 patients in the phase II trial received treatment the Food and Drug Administration in the USA, the
in cycles of five days every 28 days for a median European Medicines Agency and the Therapeutic
of seven cycles. Based on blood counts and bone Goods Administration.

NEW DRUGS
Most people will have adverse effects to a booster

Elasomeran/imelasomeran of elasomeran or the bivalent vaccine. These are
usually mild or moderate and resolve in a few days.
Aust Prescr 2022;45:214 Approved indication: prevention of COVID-19 Approximately 80% will have pain at the injection
https://doi.org/10.18773/ Spikevax bivalent original/Omicron (Moderna) site. There may also be swelling at the injection
austprescr.2022.073 multi-dose vials containing 0.1 mg/mL site and axilla. Erythema was more frequent with
First published the bivalent vaccine (6.9% vs 3.7%). Very common
12 October 2022
Vaccines against SARS‑CoV‑2 became available
systemic effects include headache, fatigue, myalgia
during 2021. However, in November 2021 the
and arthralgia.
Omicron variant of the virus emerged and became
the dominant strain. Several sub-lineages of the While the combination of elasomeran and
Omicron variant subsequently appeared. The vaccines imelasomeran produces neutralising antibodies, the
developed earlier in the pandemic were less effective effectiveness of this bivalent booster is yet to be
against Omicron. Vaccine manufacturers have confirmed. The ongoing study was not designed
therefore needed to develop new products to improve to evaluate effectiveness, but it found that after a
protection. Clinical trials are ongoing, but data have median follow-up of 43 days, 3.2% of those given
been provided to regulatory agencies to enable the bivalent vaccine were infected by SARS‑CoV‑2
emergency or provisional use of the new products. compared with 1.9% of the elasomeran group after a
The provisional approval of elasomeran/imelasomeran median of 57 days. No participants needed hospital
in Australia is for use as a booster dose in adults. admission. While the adverse effects will probably
resemble those of elasomeran, the safety data are
Elasomeran was the main component of a
limited in size and duration. Reporting adverse
messenger RNA (mRNA) vaccine approved in 2021.
events, following a bivalent booster dose, to the
Imelasomeran is also a mRNA vaccine, but is based
Therapeutic Goods Administration is therefore
on the spike protein of Omicron lineages. The two
particularly important.
vaccines are enclosed in lipid nanoparticles to enable
them to enter cells after intramuscular injection. Each
0.5 mL dose contains 25 micrograms of elasomeran
and 25 micrograms of imelasomeran. After entry into
cells the vaccines’ mRNA stimulates the production
of spike proteins. This generates an immune
response which may prevent subsequent infection
with SARS‑CoV‑2.
At present, the evidence for this bivalent vaccine
is based on its immunogenicity in adults. One trial
is studying people who have previously received
two doses and a booster of elasomeran. A group
of 437 adults was given the bivalent vaccine and
377 were given another dose of elasomeran as their
second booster. By 29 days after these boosters,
antibody titres against SARS-CoV-2 had increased in
both groups. There was no difference between the
bivalent vaccine and elasomeran alone in stimulating At the time the comment was prepared, information
antibodies against an ancestral variant of the virus. about this drug was available on the websites of
When considering the Omicron variant, the response the Food and Drug Administration in the USA, the
was greater in the group given the bivalent vaccines European Medicines Agency and the Therapeutic
(geometric mean ratio 1.7). Goods Administration.
214 Full text free online at nps.org.au/australian-prescriber © 2022 NPS MedicineWise

NEW DRUGS
Giving a growth factor can cause hypertrophy of

Mecasermin some tissues. The growth of lymphoid tissue in the
tonsils and adenoids1 can lead to chronic middle
Approved indication: primary insulin-like growth ear effusions, snoring and sleep apnoea. IGF-1 Aust Prescr 2022;45:215
factor-1 deficiency may have a role in cancer so children treated with https://doi.org/10.18773/
Increlex (Ipsen) mecasermin could have an increased risk of benign austprescr.2022.077
vials containing 10 mg/mL solution and malignant neoplasia.
Some children fail to grow as expected because of Headache is a common adverse effect, but can be a
an insensitivity to growth hormone. One cause is a symptom of intracranial hypertension. Fundoscopy
deficiency of insulin-like growth factor-1 (IGF-1), as is recommended particularly if there are other
in Laron syndrome. In affected children, there is an symptoms such as vomiting or altered vision.
abnormality in the growth hormone receptor. As a An echocardiogram is recommended before
result, growth hormone fails to stimulate the synthesis treatment. Valve incompetence and cardiomegaly are
of IGF-1 in the liver. This leads to slow growth and very uncommon adverse effects.
short stature. In untreated patients the final height A European database of children being treated with
can be 4–10 standard deviations below the mean. IGF-1 therapy contained a safety population of 188
Genetic engineering has enabled the production patients. The most frequent serious adverse events
of mecasermin, a recombinant human IGF-1. It has recorded in the database were hypoglycaemia, adeno-
been available overseas for more than 10 years. tonsillar hypertrophy and injection-site reactions.3
Mecasermin is given twice daily by subcutaneous The approval of mecasermin in Australia is restricted
injection. It should be given shortly before or after a to children who have the most severe manifestations
meal to reduce the risk of hypoglycaemia. The half-life of primary IGF-1 deficiency. Other causes of the
of mecasermin is about six hours. It is metabolised deficiency must be excluded before beginning
in the liver and kidneys, but there is no information treatment. Mecasermin is not intended for secondary
about how impairment of these organs might affect forms of IGF-1 deficiency such as hypopituitarism,
the drug’s pharmacokinetics. Doses are based on malnutrition or chronic steroid therapy.
body weight and adjusted according to adverse
REFERENCES
reactions and growth. Treatment continues until
epiphyseal fusion. 1. Chernausek SD, Backeljauw PF, Frane J, Kuntze J,
Underwood LE. Long-term treatment with recombinant
Primary IGF-1 deficiency is a very rare condition. insulin-like growth factor (IGF)-I in children with severe
IGF-I deficiency due to growth hormone insensitivity.
Clinical trials have therefore been small and mostly
J Clin Endocrinol Metab 2007;92:902-10. https://doi.
open label. org/10.1210/jc.2006-1610
2. Backeljauw PF, Kuntze J, Frane J, Calikoglu AS,
One open-label trial of mecasermin has followed Chernausek SD. Adult and near-adult height in patients with
76 children with severe IGF-1 deficiency for up severe insulin-like growth factor-I deficiency after long-term
therapy with recombinant human insulin-like growth factor-I.
to 12 years. In the first year of treatment, growth Horm Res Paediatr 2013;80:47-56. https://doi.org/10.1159/
increased from a baseline of 2.8 cm/year to 000351958
3. Bang P, Polak M, Woelfle J, Houchard A, on behalf of the
8 cm/year. The higher the dose, the faster the EU IGFD Registry Study Group. Effectiveness and safety of
growth. Growth velocities remained above baseline rhIGF-1 therapy in children: the European Increlex® growth
forum database experience. Horm Res Paediatr 2015;83:345-57.
for up to eight years of follow-up.1 There were 21 https://doi.org/10.1159/000371798
children, treated for an average of 10 years, who
reached an adult or new-adult height. They were an
average of 13.4 cm taller than they would have been
without treatment.2
Some of the adverse effects of an insulin-like growth
factor are related to its mechanism of action. For At the time the comment was prepared, information
example, some children will have seizures related about this drug was available on the websites of
to hypoglycaemia.1 Blood glucose monitoring is the Food and Drug Administration in the USA, the
recommended when the dose is changed and when a European Medicines Agency and the Therapeutic
child is unwell or has reduced oral intake. Goods Administration.

NEW DRUGS
possibly hypocalcaemia, seizures and arrhythmias.

Pemigatinib Patients may require a low-phosphate diet and
phosphate-lowering therapy, but these might need
Aust Prescr 2022;45:216 Approved indication: cholangiocarcinoma to be discontinued during treatment breaks to avoid
https://doi.org/10.18773/ Pemazyre (Specialised Therapeutics) hypophosphataemia.
austprescr.2022.078 4.5 mg, 9 mg and 13.5 mg tablets Other very common adverse events during the
Cancers of the bile duct (cholangiocarcinoma) phase II trial included alopecia, dysgeusia, stomatitis,
are relatively rare. Surgery may not be possible nausea and diarrhoea.1 Dry eyes are common and,
and relapse rates are high. Even with combination less frequently, retinal detachment can occur. Regular
chemotherapy, the prognosis is poor. In patients eye examinations are required. Overall, 9% of the
with metastatic disease, survival may be less than patients stopped treatment because of adverse
12 months. events, while many others required dose interruptions
or reductions.
Genetic research has found that some patients have
alterations in the genes for fibroblast growth factor In animal studies, pemigatinib was toxic to the fetus.
receptors (FGFR). These receptors may induce Pregnancy should be avoided and male patients
the proliferation of cancer cells. As the receptors should not father a child while taking pemigatinib.
contain tyrosine kinases, a kinase inhibitor could have Any benefit of pemigatinib appears to be limited
beneficial effects. to patients with abnormalities of FGFR2. Although
Pemigatinib is an inhibitor of FGFR1, 2 and 3. only 2.8% (3/107) of these patients had a complete
A dose of 13.5 mg is taken once daily for 14 days response, the overall response rate may be better
followed by a seven-day break. Food has little effect than the response to second-line chemotherapy.1
on absorption. Most of the dose is metabolised Another trial is investigating how pemigatinib would
by cytochrome P450 (CYP) 3A4 and excreted in compare to chemotherapy as a first-line treatment for
the faeces. Dose reductions are recommended unresectable or metastatic cholangiocarcinoma. At
for patients with severe liver or kidney disease. present, pemigatinib is only provisionally approved
Reductions are also required if inhibitors of CYP3A4, for previously treated patients with abnormalities of
such as itraconazole, cannot be avoided. Inducers of FGFR2. Whether its benefit is sustained, or is reduced
CYP3A4, such as phenytoin, should be avoided and St by the development of resistance to treatment,
John’s wort is contraindicated. Proton pump inhibitors requires further study.
should also be avoided as they reduce pemigatinib T manufacturer provided relevant information
concentrations in some patients. As pemigatinib is an
REFERENCES
inhibitor of P-glycoprotein, doses should be separated
by at least six hours from drugs such as digoxin. 1. Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D,
Al-Rajabi R, et al. Pemigatinib for previously treated, locally
A phase II open-label trial studied pemigatinib in 146 advanced or metastatic cholangiocarcinoma: a multicentre,
open-label, phase 2 study. Lancet Oncol 2020;21:671-84.
previously treated patients with locally advanced or
https://doi.org/10.1016/S1470-2045(20)30109-1
metastatic cholangiocarcinoma. Most (107) of the
patients had alterations of FGFR2. After a median
follow-up of 17.8 months, 35.5% of this group had a
response to treatment. The median duration of the
response was 7.5 months with a median progression-
free survival of 6.9 months. At the time the trial was The Transparency Score is explained in New drugs:
published, median overall survival was 21.1 months.1 transparency, Vol 37 No 1, Aust Prescr 2014;37:27.
Inhibition of FGFR increases serum phosphate At the time the comment was prepared, information
concentrations. In the phase II trial 60% of the about this drug was available on the websites of the
patients developed hyperphosphotaemia.1 This in Food and Drug Administration in the USA and the
turn can cause precipitation of calcium crystals and European Medicines Agency.
216 Full text free online at nps.org.au/australian-prescriber © 2022 NPS MedicineWise

NEW DRUGS
was observed in 26% of the patients. The median

Selinexor progression-free survival was 3.7 months.1
Selinexor in combination with bortezomib and
Approved indication: multiple myeloma Aust Prescr 2022;45:217–8
dexamethasone was studied in the open-label,
Xpovio (Antengene) active-controlled, phase III BOSTON trial. This https://doi.org/10.18773/
20 mg film-coated tablets austprescr.2022.072
randomised 402 patients with multiple myeloma
First published
Exportin-1 is an essential nuclear exporter of many who had previously been treated with one to three
12 October 2022
tumour suppressor proteins, growth regulator proteins lines of therapy, including proteasome inhibitors.
and several classes of messenger RNAs, including In this trial, the median progression-free survival
those of oncogenic proteins. It is overexpressed was 13.9 months in the 195 patients who received
in several cancers including multiple myeloma. the triplet combination, compared with 9.5 months
Selinexor is a selective inhibitor of exportin-1. This in the 207 patients who received bortezomib and
inhibition leads to marked accumulation of the dexamethasone only. The objective response rate was
tumour suppressor proteins and growth regulator also significantly higher in the patients who received
proteins in the nucleus and reduced expression of the triplet combination (76.4% vs 62.3%).2
several oncoproteins, resulting in cell cycle arrest and In the STORM trial, the most common grade 3–4
apoptosis of cancer cells. adverse events were thrombocytopenia (59%, which
Selinexor is indicated in combination with bortezomib then resulted in grade 3 or higher bleeding events
and dexamethasone as a treatment for multiple in six patients), anaemia (44%), hyponatraemia
myeloma in patients who have received at least (22%) and neutropenia (21%). Treatment-emergent
one therapy previously. The drug is also indicated adverse events led to discontinuation in 18% of
with dexamethasone as a treatment for relapsed or the patients and two deaths.1 In the BOSTON trial,
refractory multiple myeloma in patients who have the most frequent grade 3–4 adverse events in
received at least three therapies previously and whose the patients who received the triplet combination
disease is refractory to at least one proteasome were thrombocytopenia (39% vs 17% without
inhibitor, at least one immunomodulatory medicinal selinexor), fatigue (13% vs 1%), anaemia (16% vs
product and an anti-CD38 monoclonal antibody. 10%) and pneumonia (11% vs 11%). Grade 2 or
Selinexor should be swallowed whole with water, higher peripheral neuropathy was less frequent
with or without food, and should not be crushed, with the triplet combination (21% vs 34% without
chewed, broken or divided. For multiple myeloma, selinexor). Treatment-emergent adverse events led to
the dose is based on a 35-day cycle and is given with discontinuation in 21% of the patients and four deaths
bortezomib and dexamethasone. For relapsed or with the triplet combination compared with 16% of
refractory multiple myeloma, selinexor is given with patients and one death without selinexor.2
dexamethasone. Treatment should be continued until Thrombocytopenia, neutropenia, neurological
disease progression or unacceptable toxicity. toxicities, hyponatraemia and infections are all
Selinexor is a substrate of cytochrome P450 (CYP) potential adverse reactions to selinexor that can be
3A4, and so its exposure might be reduced with life-threatening. The drug can also lead to severe
the concomitant use of strong CYP3A4 inducers, gastrointestinal toxicities, fatigue, weight loss,
such as rifampicin, St John’s wort and phenytoin. anorexia, dizziness, tumour lysis syndrome and
The drug’s mean half-life after an 80 mg dose is new onset or exacerbation of cataracts. Patients
6–8 hours. The dose does not need to be adjusted in are advised to avoid driving or operating machines
patients with renal impairment or mild to moderate if they experience dizziness or a confusional state.
hepatic impairment. Most patients will require dose reductions to manage
Selinexor with dexamethasone was studied in the adverse events. Detailed dosage modification
single-arm, open-label phase II STORM trial, which guidelines to manage adverse haematologic and
included 122 patients with triple-class refractory nonhaematologic reactions are provided in the
multiple myeloma. They had previously been Australian product information for selinexor.
treated with bortezomib, carfilzomib, lenalidomide, Based on animal studies, selinexor might impair
pomalidomide, daratumumab, glucocorticoids fertility. Patients are advised to use effective
and an alkylating drug and had disease that was contraceptive options during and for one week after
refractory to at least one proteasome inhibitor, stopping treatment. The drug has not been studied
one immunomodulatory drug and daratumumab. in children or pregnant women. The drug has similar
When assessed by the reduction in myeloma efficacy in patients older than 75 years of age, but
protein concentration, a partial response or better they have a higher incidence of adverse effects.

NEW DRUGS
A once-weekly regimen of selinexor with

dexamethasone alone or with dexamethasone The Transparency Score is explained in New drugs:
and bortezomib is an effective treatment option transparency, Vol 37 No 1, Aust Prescr 2014;37:27.
for patients with multiple myeloma. It has modest At the time the comment was prepared, information
efficacy in patients with triple-class refractory disease. about this drug was available on the websites of
However, patients and clinicians must be mindful of the Food and Drug Administration in the USA, the
the many potential adverse reactions, which should be European Medicines Agency and the Therapeutic
managed appropriately. Goods Administration.
T T manufacturer provided additional useful
information
REFERENCES
1. Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ,
Huff CA, et al. Oral selinexor–dexamethasone for triple-class
refractory multiple myeloma. N Engl J Med 2019;381:727-38.
https://doi.org/10.1056/NEJMoa1903455
2. Grosicki S, Simonova M, Spicka I, Pour L, Kriachok I,
Gavriatopoulou M, et al. Once-per-week selinexor,
bortezomib, and dexamethasone versus twice-per-week
bortezomib and dexamethasone in patients with multiple
myeloma (BOSTON): a randomised, open-label, phase 3
trial. Lancet 2020;396:1563-73. https://doi.org/10.1016/
s0140-6736(20)32292-3

SUBSCRIPTIONS
Correction
Bariatric surgery and medicines [Correction]

Aust Prescr 2022;45:219
https://doi.org/10.18773/austprescr.2022.074
First published 21 October 2022
The article on bariatric surgery and medicines (Aust Prescr 2022;45:162-6) has been corrected.
View corrected article.
In the Figure showing four common procedures in bariatric surgery, the third image from the left
depicting one anastomosis gastric bypass was incorrect. The Figure has now been replaced using the
correct image for this procedure.
SUBSCRIPTIONS
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The end of NPS MedicineWise 186

Administration of medicines 188

Coronary artery disease 193

Diuretics in the management 200

Blood pressure elevations 205

Medicinal mishap 208

Latest news 210

NEW DRUGS 211

Asciminib for chronic myeloid leukaemia

The end of NPS MedicineWise

186 This article is peer-reviewed © 2022 NPS MedicineWise

Full text free online at nps.org.au/australian-prescriber 187

Administration of medicines to children:

188 This article is peer-reviewed © 2022 NPS MedicineWise

Box Useful resources ‘Making the medicine go down’

Full text free online at nps.org.au/australian-prescriber 189

ARTICLE Administration of medicines to children: a practical guide

flavoured syrups or cordials (Table 2).6,7 However, the Aftertaste

190 Full text free online at nps.org.au/australian-prescriber

Fig. Suggestions for administering medicines to children12

Sweet Lactulose Caramel, lemon, orange, vanilla, bubble-gum

Full text free online at nps.org.au/australian-prescriber 191

ARTICLE Administration of medicines to children: a practical guide

192 Full text free online at nps.org.au/australian-prescriber

Coronary artery disease in women

© 2022 NPS MedicineWise This article is peer-reviewed 193

ARTICLE Coronary artery disease in women

Box 1 Traditional cardiovascular risk factors in women

Systemic inflammation and auto-immune disorders Other hormonal factors

194 Full text free online at nps.org.au/australian-prescriber

No sex-specific risk factors are included in any Diagnosis

Coronary artery disease

Full text free online at nps.org.au/australian-prescriber 195

ARTICLE Coronary artery disease in women

repeated episodes of ischaemic chest pain, similar Diagnosis of cardiovascular disease

Spontaneous coronary artery dissection Invasive testing

196 Full text free online at nps.org.au/australian-prescriber

Full text free online at nps.org.au/australian-prescriber 197

ARTICLE Coronary artery disease in women

198 Full text free online at nps.org.au/australian-prescriber

Full text free online at nps.org.au/australian-prescriber 199

Diuretics in the management of chronic

Introduction nocturnal dyspnoea), an elevated jugular venous

200 This article is peer-reviewed © 2022 NPS MedicineWise

Full text free online at nps.org.au/australian-prescriber 201

202 Full text free online at nps.org.au/australian-prescriber

Full text free online at nps.org.au/australian-prescriber 203

204 Full text free online at nps.org.au/australian-prescriber

Blood pressure elevations in hospital

Australian hospitals. accurate diagnosis of hypertension.1-3,8 https://doi.org/10.18773/

© 2022 NPS MedicineWise This article is peer-reviewed 205

ARTICLE Blood pressure elevations in hospital

206 Full text free online at nps.org.au/australian-prescriber

Full text free online at nps.org.au/australian-prescriber 207

Osteonecrosis of the jaw and denosumab

The woman presented again 11 weeks after the

208 This article is peer-reviewed © 2022 NPS MedicineWise

Full text free online at nps.org.au/australian-prescriber 209

Box Useful resources ‘Making the medicine go down’

Fig. Suggestions for administering medicines to children12

Box 1 Traditional cardiovascular risk factors in women