Knowledge Type: Clinical Articles

The Therapeutic Guidelines: Antibiotic has recently updated their recommendations for the prevention of infective endocarditis.

Infective endocarditis refers to infection of the endocardial surfaces of the heart and is typically of bacterial origin. While a healthy endocardium is resistant to bacterial colonisation, infection can occur when endocardial injury coincides with bacteraemia. Endocardial injury may be related to turbulent flow (e.g. due to diseased valves), mechanical trauma (e.g. during insertion of intravascular catheters), or intravenous drug abuse (i.e. due to the repeated injection of particulate matter). The bacteraemia required for the development of infective endocarditis may be the result of oral flora introduced into the bloodstream (i.e. during dental procedures or daily oral hygiene activities) or from an established, distant source of infection.

While infective endocarditis is a relatively uncommon condition, it is associated with high morbidity and mortality. Therefore, antibiotic prophylaxis may be appropriate for certain individuals prior to procedures with a high risk of bacteraemia.

Key updates to the guidelines:

• Ventricular assist devices (VADs) added to the list of conditions warranting prophylaxis
• Clindamycin is no longer recommended for endocarditis prophylaxis prior to dental procedures
• Antibiotics with enterococcal activity should be considered for institutions with high rates of endocarditis following transcatheter aortic valve implantation (TAVI) or cardiac implantable electronic device (CIED) procedures using an inguinal approach.

Ventricular assist devices

Ventricular assist device-related infections have been reported to occur in between 18% and 59% of patients after implantation. This can include bloodstream infection, relapsing bacteraemia, sepsis, and endocarditis. When endocarditis occurs in these patients, the mortality rate has been reported to be 50%.

Due to this high risk and poor outcomes, VADs are now included among the conditions for which prophylaxis is recommended.

Clindamycin

Clindamycin is no longer recommended for endocarditis prophylaxis for dental procedures as it is associated with a higher frequency of severe adverse drug reactions (ADR) compared to other antibiotics.

A UK study looking at antibiotic prophylaxis found that clindamycin was associated with 13 fatal and 149 non-fatal ADR reports per million prescriptions. The majority of serious events were related to Clostridioides difficile infection. In contrast, amoxicillin was associated with zero fatal and 22.62 non-fatal ADR reports per million prescriptions.

Where endocarditis prophylaxis is indicated prior to dental procedures, amoxicillin is the first-line option. Cefalexin can be used for patients who have experienced a non-severe penicillin hypersensitivity reaction. For patients who have had a severe penicillin hypersensitivity reaction, doxycycline or azithromycin are the recommended alternatives.

Consideration must still be given to the potential for these alternative agents to cause adverse reactions. For example, doxycycline can cause oesophageal irritation and ulceration, and azithromycin can prolong the QT interval.

Enterococcal activity

A large international cohort study found high rates of postoperative infective endocarditis following TAVI. This study found Enterococcus spp. to be the most commonly isolated species in patients presenting with early peri-procedural infective endocarditis. While this pattern has not been observed in Australia, the updated guidelines recommend considering antibiotics with enterococcal activity in centres with high infection rates following TAVI and cardiac device implantation using an inguinal approach.

First and second generation cephalosporins do not have enterococcal activity. However, amoxicillin and ampicillin are active against enterococci. Oral doses should be administered 60 minutes before the procedure, intramuscular doses 30 minutes before, and intravenous doses 60 minutes before. Vancomycin or teicoplanin could be considered alternatives for patients with penicillin hypersensitivity. These agents should be administered in addition to any standard surgical prophylaxis required.

Conclusion

The current recommendations from the Therapeutic Guidelines: Antibiotic for the prevention of infective endocarditis are shown in Table 1. Prophylaxis is recommended for patients undergoing one of the procedures listed in column A if they also have a condition listed in column B.

Table 1. Indications for antibiotic prophylaxis for infective endocarditis (adapted from eTG)

Procedures requiring prophylaxis (Column A)	Conditions for which prophylaxis is recommended (Column B)
Dental procedures (involving manipulation of the gingival or periapical tissue, or perforation of the oral mucosa )	Prosthetic cardiac valve
Dermatological or musculoskeletal procedures (involving infected skin, skin structures or musculoskeletal tissues)	Prosthetic material used for cardiac valve repair
Respiratory tract or ear, nose and throat procedures (only for tonsillectomy or adenoidectomy; or invasive respiratory tract or ear, nose and throat procedures to treat an established infection).	Previous infective endocarditis
Genitourinary or gastrointestinal tract procedures (only if surgical antibiotic prophylaxis is required, or for patients with an established infection)	Ventricular assist devices
	Congenital heart disease (involving unrepaired cyanotic defects or repaired defects with residual defects at or adjacent to the site of a prosthetic patch or device)
	Rheumatic heart disease

 

 

Pruritus is a common and distressing symptom in patients receiving palliative care. The itch-scratch cycle can compromise skin integrity, increasing the risk of infection. People with advanced, life-limiting illness often already have fragile skin. This can be due to a range of factors such as reduced blood flow, nutritional deficiencies, medications, immobility, and age-related changes.

There are many potential causes of itch in this population, including:

• Dry skin;
• Uraemia related to advanced kidney disease;
• Cancer;
• Opioid analgesics; and
• Comorbid conditions unrelated to the life-limiting illness.

Itch may also be related to cholestasis due to biliary obstruction, intrahepatic disease, or adverse drug effects.

The pathogenesis of pruritus in cholestasis is not entirely understood. It is thought that impaired bile flow leads to the accumulation of pruritogenic substances. These substances may then interact with sensory nerve fibres in the skin, producing the sensation of itch. Substances that may be acting as pruritogens include bile acids, endogenous opioids, and lysophosphatidic acid (LPA).

Cholestatic itch can be treated with biliary drainage. However, this may not be appropriate for all patients with a life-limiting illness. Where systemic drug treatment is required, the Therapeutic Guidelines recommend the following therapies:

• Rifampicin 150mg orally at night (maximum of 600mg daily); or
• Sertraline 50mg daily (maximum of 100mg daily).

These first-line agents are interesting as they are not traditionally thought of as anti-itch medications. Their use in this setting would be considered off-label.

Rifampicin

Rifampicin is an antibiotic that is typically reserved for the treatment of infections due to mycobacteria or methicillin-resistant Staphylococcus aureus (MRSA) and for the prevention of meningitis and epiglottitis. However, it may also be effective in relieving itch in cholestatic pruritus.

One of the proposed mechanisms for this involves the phospholipid, LPA. This molecule is involved in many physiologic and pathologic processes, some of which can lead to the production of pruritogenic interleukins. While LPA is primarily produced intracellularly for the purposes of cell membrane synthesis, it is its extracellular production that is thought to be important in pruritus. When LPA is produced extracellularly, autotaxin is the rate-limiting enzyme involved. Therefore, inhibition of autotaxin could relieve pruritus by reducing the production of LPA.

Rifampicin is a potent agonist of the pregnane X receptor (PXR). Activation of this receptor has been shown to reduce autotaxin expression on hepatocytes. Other theories on the action of rifampicin relate to changes in the intestinal microbiome which may influence the reabsorption of pruritogens.

A Cochrane review found that rifampicin may relieve cholestatic pruritus in palliative care patients, although the certainty of evidence is very low. Rifampicin was associated with a significant reduction in pruritus compared to placebo, with a mean difference of −42.00 (95% confidence interval: −87.31 to 3.31).

Rifampicin therapy does carry a risk of hepatitis. Therefore, caution is required when used in patients with cholestatic conditions. Serum aminotransferases should be monitored at regular intervals.

Sertraline

Sertraline is a selective serotonin reuptake inhibitor (SSRI) that may be used off-label for the management of cholestatic pruritus. Its mechanism of action in pruritus may be related to the role that serotonin plays in nociception and perception of pruritus. As sertraline inhibits the reuptake of serotonin, it may modify itch signalling.

In a study by Ataei et al., the efficacy of sertraline and rifampicin were compared in patients with cholestatic pruritus. Patients were randomised to receive either sertraline 100mg daily or rifampicin 300mg daily. A similar reduction in pruritus scores was seen in each group (-46% for sertraline vs -43% for rifampicin). However, sertraline was considered safer than rifampicin regarding hepatobiliary enzyme levels. This study had some limitations, including the small sample size and the single-blind design.

Sertraline is generally well tolerated. More commonly experienced adverse effects include nausea, diarrhoea, insomnia, and dizziness.

Colestyramine

Pruritus due to partial biliary obstruction is a registered indication for colestyramine. However, it is not currently recommended by the Therapeutic Guidelines in the palliative care setting. This is due to limited evidence to support its use in this population as well as poor tolerance.

Colestyramine is a bile acid sequestrant. It combines with bile acids in the intestine to form insoluble complexes that are excreted in the faeces. Preventing the reabsorption of bile acids results in a continuous, but incomplete, removal of bile acids from the enterohepatic circulation.

Colestyramine is presented as powder that must be mixed with water, juice or highly fluid food before administration. The usual dose for the relief of itch is 4g (one sachet) once or twice daily.

Constipation is the most commonly reported adverse event. This is often mild and easily managed, although severe cases have occurred. In rare cases, this may be accompanied by faecal impaction or haemorrhoids. Other common adverse effects include abdominal pain, dyspepsia, nausea, and anorexia

Colestyramine can reduce the absorption of other orally administered drugs. To avoid this issue, other oral medicines should be taken at least one hour before or four hours after colestyramine.

General measures

General skincare measures are important and may avoid the need for systemic drug therapy. The following measures are recommended for all patients with pruritus and are particularly valuable for patients with dry skin:

• Generous use of emollients twice a day, particularly after bathing
  • Options include aqueous cream, glycerine 10% in sorbolene, and paraffin ointment (liquid paraffin 50% + white soft paraffin 50%)
• Bathe using warm water and gently pat skin dry
• Avoid soap and shampoos
  • Soap substitutes can be used, e.g. aqueous cream, or soap-free washes
  • Dispersible oils may be preferred if the skin is very dry
• Avoid scratching, keep fingernail and toenails short, consider use of cotton gloves and socks at night.

The product information documents for paracetamol are being updated to include warnings of high anion gap metabolic acidosis. Metabolic acidosis is a pathological process or condition that leads to a reduction in blood pH.

There are three major mechanisms that can produce metabolic acidosis:

• Increased acid generation
  • Lactic acidosis
  • Ketoacidosis
  • Ingestions or infusions (e.g. toxic alcohols, chronic paracetamol use)
• Loss of bicarbonate
  • Severe diarrhoea
  • Complication following urinary diversion surgery
  • Proximal (type 2) renal tubular acidosis (RTA)
• Reduced renal acid excretion
  • Renal failure
  • Distal (type 1) RTA and type 4 RTA

There are also two distinct types of metabolic acidosis: high anion gap metabolic acidosis (HAGMA) and normal anion gap metabolic acidosis (NAGMA). Calculation of the anion gap can be used to distinguish between the two.

Anion gap

For electrical charge to be neutral, the total number of positive charges (from cations) must equal the total number of negative charges (from anions). However, not all ions are easy to measure. Therefore, the anion gap equation uses only the dominant cations (i.e. sodium +/- potassium) and the dominant anions (i.e. chloride and bicarbonate). The rest of the ions in the blood can be considered “unmeasured”.

Anion gap = (Na⁺ + K⁺) – (Cl^– + HCO₃^–)

The anion gap is, therefore, the difference between measured cations and measured anions in the blood (which can be used to evaluate the presence of unmeasured anions).

The typical adult reference ranges for these measured ions is shown below:

• Sodium 135 to 145 mmol/L
• Potassium 3.5 to 5.2 mmol/L
• Chloride 95 to 110 mmol/L
• Bicarbonate 22 to 32 mmol/L.

The normal anion gap is often quoted as 8-16 mmol/L (or 4-13 mmol/L if potassium is excluded from the equation). This figure largely represents unmeasured anions like organic acids and negatively charged plasma proteins, such as albumin.

In both HAGMA and NAGMA there is a reduction in bicarbonate. This can be due to increased use of bicarbonate as a buffer, reduced bicarbonate production, or increased loss. However, as electrochemical neutrality must be maintained, there is always a corresponding increase in anions (either chloride or unmeasured anions). If it is the chloride level that increases, a normal anion gap would be seen. However, if it is unmeasured anions that increase, the anion gap increases.

Calculation of the anion gap can be useful to help identify the cause of metabolic acidosis and, therefore, the most appropriate treatment.

Paracetamol and HAGMA

Metabolic acidosis is associated with paracetamol overdose. However, metabolic acidosis can also occur during chronic therapy when therapeutic doses are used. This may also be referred to as pyroglutamic acidosis as it is related to a buildup of pyroglutamic acid.

Pyroglutamic acid (also known as 5-oxoproline) is an intermediate in glutathione metabolism. Glutathione is present in most cells, where it functions as an antioxidant. The γ-glutamyl cycle is responsible for the synthesis and degradation of glutathione, and can be summarised in the following steps:

• Glutathione utilisation
  • Glutathione donates its γ-glutamyl group to amino acids via the enzyme γ-glutamyl transpeptidase (GGT).
  • This forms γ-glutamyl amino acids and cysteinylglycine.
• Transport and conversion
  • γ-glutamyl amino acid is transported into the cell and converted to pyroglutamic acid by γ-glutamyl cyclotransferase.
• Recycling
  • Pyroglutamic acid is converted to glutamate by 5-oxoprolinase.
  • Glutamate then combines with cysteine (via γ-glutamylcysteine synthetase) to form γ-glutamylcysteine.
• Glutathione resynthesis
  • γ-glutamylcysteine combines with glycine (via glutathione synthetase) to regenerate glutathione.

5-oxoprolinase, the enzyme responsible for breaking down pyroglutamic acid, operates at low capacity. Therefore, pyroglutamic acid will accumulate when its rate of production is high.

There are many factors that can interrupt this cycle, including inherited enzyme defects and acquired deficiencies in cellular glutathione and cysteine. Prolonged use of paracetamol can cause depletion of both glutathione and cysteine which may disrupt this cycle.

Risk factors

There are many other factors that increase the risk of metabolic acidosis during prolonged paracetamol use, including:

• Malnutrition;
• Infection;
• Antibiotics;
• Renal failure; and
• Pregnancy.

These risk factors are common, and it has been suggested that the incidence of this condition may be under-reported.

Flucloxacillin, in particular, has been highlighted as the antibiotic more likely to contribute to this condition. This antibiotic can inhibit 5-oxoprolinase, thereby promoting the accumulation of pyroglutamic acid. Caution is advised when flucloxacillin and paracetamol are co-administered, especially when the maximum paracetamol dose is used and where other risk factors for HAGMA exist.

Ciprofloxacin is another antibiotic that may impair this pathway, along with the anticonvulsant vigabatrin.

Presentation

Pyroglutamic acidosis has a fatality rate of around 20%. Prompt recognition is essential as the condition is reversible if the causative agents are ceased.

Signs and symptoms may include:

• Reduced consciousness;
• Kussmaul breathing (rapid, deep breathing);
• Nausea and vomiting;
• High anion gap;
• Low bicarbonate levels (often < 10 mmol/L);
• Hypokalaemia; and
• Severe deterioration of kidney function.

Treatment

Treatment of paracetamol-induced HAGMA involves cessation of paracetamol and any other causative agent (i.e. any medication that can inhibit enzymes involved in the γ-glutamyl cycle).

Supportive measures, such as intravenous fluids and respiratory support, may be sufficient for the management of mild cases. A sodium bicarbonate infusion may be considered for patients with more severe disease (i.e. serum pH < 7.1).

As glutathione depletion is thought to be key in the pathogenesis of this condition, administration of N-acetylcysteine (NAC) may also be considered. A recently published systematic review found that NAC was associated with a lower fatality rate (11% with NAC vs 24% without). Case reports have also shown that haemodialysis may hasten the removal of pyroglutamic acid.

Reports in Australia

In the past ten years, the Therapeutic Goods Administration (TGA) has received 96 reports of metabolic acidosis in patients taking paracetamol. While many of these patients were taking multiple medications, paracetamol was the only suspected medicine involved in 32 of these reports.

Demographics of reports to the TGA:

• 7% related to children (< 17 years);
• 41% occurred in people aged 18-64;
• 26% in people > 64 years
• 57% related to females and 36% to males.

The patient age was unknown for 26% of the reports and gender was not specified in 6% of cases.

Summary

Pyroglutamic acid accumulation is a rare cause of metabolic acidosis and may occur in association with chronic therapeutic use of paracetamol. Risk factors are common in hospitalised patients, and it is thought to be an underdiagnosed condition. Awareness is essential as untreated cases can progress to severe acidosis.

Patients presenting with HAGMA in association with paracetamol are typically women with chronic illness and malnutrition. The co-administration of flucloxacillin is thought to be a significant contributing factor.

The possibility of paracetamol as a causative agent should be considered in patients with HAGMA who are taking long-term paracetamol, particularly if additional risk factors exist.

Angiotensin-converting enzyme (ACE) inhibitors are used in the management of many conditions, including hypertension, heart failure, myocardial infarction, and diabetic nephropathy. Around 30% of individuals are intolerant to these medications, most commonly due to symptomatic hypotension or the development of a persistent dry cough. Angioedema is a less frequent but potentially serious adverse effect associated with this class.

Angioedema is characterised by non-pitting oedema of subcutaneous or submucosal tissues. It often affects the face, lips, tongue and throat. Where angioedema affects the bowel wall, gastrointestinal symptoms, may also be present. While some cases are mild and self-limiting, airway involvement can be life-threatening.

There are many potential causes of angioedema, including:

• Allergic reactions;
• Genetic disorders (e.g. hereditary angioedema);
• Acquired disorders (e.g. B cell lymphoproliferative disorders);
• Autoimmune disorders;
• Certain infections; and
• Medications (via allergic and non-allergic mechanisms).

Medication-induced angioedema

Allergic causes of angioedema are related to mast cell degranulation and may also be referred to as histaminergic angioedema. This may be accompanied by other signs and symptoms of mast cell mediator release, e.g. urticaria, flushing, generalised pruritus, and hypotension. Allergic angioedema may also be accompanied with anaphylaxis. In general, mast-cell mediated angioedema begins within minutes of exposure to an allergen, peaks within a few hours, and resolves in 24 to 48 hours.

In contrast, symptoms of non-allergic angioedema tend to develop over a more prolonged period. These reactions are related to activation of the kallikrein-kinin cascade (a key regulatory system involved in the maintenance of blood pressure, haemostasis, inflammation, and renal function). Bradykinin, a potent vasodilator produced in this cascade, increases vascular permeability and contributes to angioedema. Non-allergic angioedema is typically not associated with urticaria, bronchospasm, or other symptoms of allergic reactions.

ACE inhibitors

All medications in the ACE inhibitor class are associated with non-allergic angioedema. This is an infrequent adverse event, with an estimated incidence of around 0.1-0.42%. However, as ACE inhibitors are widely prescribed, they represent a significant cause of non-allergic angioedema.

One small Australian study found that 32% of patients presenting to the emergency department with angioedema were taking an ACE inhibitor. While causation was not confirmed in this study, the attributable risk factor for ACE inhibitors in patients with ACE-inhibitor-associated angioedema is thought to be 80%.

Bradykinin accumulation is thought to be the cause as ACE inhibitors block bradykinin degradation. Symptoms of ACE inhibitor-associated angioedema typically affect the face, lips, tongue, and upper airway. Gastrointestinal involvement is less common but may present with abdominal pain, vomiting, or diarrhoea.

Angioedema can occur at any stage during ACE inhibitor therapy. Around half of all cases occur in the first month of treatment. However, a first presentation can occur after months or years of therapy without incident. This variability can lead to the ACE inhibitor being overlooked as the causative agent.

Before the cause is correctly identified, patients may experience multiple episodes of angioedema with long symptom-free periods. If administration of the ACE inhibitor continues, the episodes will usually get worse. Patients with mild initial presentations can go on to develop life-threatening angioedema. Therefore, early recognition is crucial to prevent serious events.

Risk factors

While ACE inhibitors can cause angioedema on their own, combination with other medications may increase the risk.

Medications associated with a heightened risk include:

• Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin);
• Mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus, sirolimus); and
• Neprilysin inhibitors (i.e. sacubitril – combination contraindicated by manufacturer).

Other factors that may increase the risk of ACE inhibitor-induced angioedema include:

• Smoking;
• History of ACE inhibitor-induced cough (~9x increased risk); and
• African American background (~4x increased risk).

Management

As ACE inhibitor-induced angioedema is mediated by bradykinin rather than histamine, it often does not respond to standard treatments used for histaminergic angioedema. However, initial management may still include these therapies, as distinguishing between the two forms can be challenging at presentation.

The primary management of ACE inhibitor-induced angioedema is airway management (if required) and discontinuation of the drug. Mild cases may not require treatment. However, patients should be monitored for several hours in case of symptom progression. Antihistamines are sometimes used to relieve symptoms, although their efficacy in this setting is likely limited.

Angioedema caused by ACE inhibitors typically resolves within 24-72 hours. Some patients may experience recurrent episodes in the weeks to months after discontinuing the ACE inhibitor due to lingering effects of the discontinued drug. However, if the angioedema persists, alternative causes should be considered.

When a patient presents with angioedema and is taking an ACE inhibitor, discontinuation is generally recommended even if the cause is unclear. This is because continuing the ACE inhibitor puts the patient at risk of more frequent and severe episodes.

Alternatives

Patients who experience angioedema attributed to an ACE inhibitor should not be rechallenged with any other ACE inhibitor in the future. A history of ACE inhibitor-induced angioedema is also listed as a contraindication for the angiotensin receptor neprilysin inhibitor, sacubitril with valsartan.

An angiotensin II receptor blocker (ARB) may be considered as a replacement for the discontinued ACE inhibitor. While angioedema has been reported with ARBs, recent studies suggest that these drugs do not have a higher risk compared with other antihypertensives.

A large registry-based cohort study investigated the safety of ARBs in people with a history of angioedema during ACE inhibitor therapy. The study included over one million users of ACE inhibitors, and angioedema was reported to occur in 0.5% of users. Of the individuals who experienced angioedema during ACE inhibitor therapy, the highest recurrence rate was seen in the group who continued to take an ACE inhibitor (adjusted hazard ratio of 1.45 (95% CI, 1.19 to 1.78)). However, the lowest incidence occurred in patients switched to an ARB (adjusted hazard ratio, 0.39; 95% CI, 0.30 to 0.51).

Summary

While ACE inhibitor-induced angioedema is infrequent, this adverse effect is potentially serious. Prompt recognition and management is essential to improve patient outcomes and prevent progression to life-threatening complications. ACE inhibitors may be overlooked as the cause of angioedema due to the highly variable timing of the initial event. Discontinuation of the ACE inhibitor is recommended for all patients with ACE inhibitor-associated angioedema. Alternative therapies, such as ARBs, may be considered in these patients.

The management of coronavirus disease 2019 (COVID-19) continues to evolve as new therapies become available and new virus variants emerge. A recently published meta-analysis, including data from over 166,000 patients, examined the efficacy of antivirals in mild to moderate COVID-19. The analysis provides insights into the effectiveness of therapies in reducing hospital admissions.

This study ranked the following from most to least effective in reducing hospital admission:

• Nirmatrelvir + ritonavir (OR_SC 0.15 (95% CI 0.07 to 0.32)) – moderate certainty
• Remdesivir (OR_SC 0.25 (95% CI 0.07 to 0.77)) – moderate certainty
• Systemic corticosteroids (OR_SC 0.43 (95% CI 0.20 to 0.90)) – low certainty
• Molnupiravir (OR_SC 0.66 (95% CI 0.44 to 0.92)) – low certainty

Abbreviations: OR_SC, odds ratio compared with standard care; CI, credible interval

The study authors concluded that nirmatrelvir + ritonavir and remdesivir probably reduce admission to hospital, while systemic corticosteroids and molnupiravir may reduce admission to hospital. Evidence to support a mortality benefit for these agents compared to standard care is inconsistent.

Choice of therapy

The National COVID-19 Clinical Evidence Taskforce provides information on the management of COVID-19 in the Australian context. While this resource is no longer being updated, it will remain online until it no longer reflects the evidence or recommended practice.

Antivirals that target the virus that causes COVID-19 are intended to reduce the risk of severe illness and are prescribed to patients with risk factors for developing serious complications.

Risk factors for disease progression include:

• Older age (> 65 years, or > 50 years for Aboriginal and Torres Strait Islander people);
• Diabetes requiring medication;
• Obesity (BMI >30 kg/m²);
• Renal failure;
• Cardiovascular disease, including hypertension;
• Respiratory compromise, including COPD, asthma requiring steroids, or bronchiectasis; and
• Immunocompromising conditions (i.e. primary or acquired immunodeficiency or immunosuppressive therapy).

Where antivirals are considered necessary, treatment should be initiated as soon as possible after symptom onset.

Nirmatrelvir + ritonavir (Paxlovid®)

Paxlovid® is the preferred oral treatment for COVID-19, unless contraindications are present. This product contains nirmatrelvir tablets co-packaged with ritonavir tablets.

Nirmatrelvir inhibits the main protease of the SARS‑CoV‑2 virus, preventing viral replication. Ritonavir is included to increase nirmatrelvir levels by inhibiting its metabolism.

The approved indication is:

• COVID-19 in adults ≥18 years who do not require initiation of supplemental oxygen due to COVID-19 and are at increased risk of progression to hospitalisation or death.

Administration

The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet). These tablets should be taken together every 12 hours for five days. Failure to correctly take nirmatrelvir with ritonavir will result in subtherapeutic plasma levels of nirmatrelvir.

No dose adjustment is required for mild renal impairment (eGFR 60 to < 90 mL/min/1.73m²). For patients with moderate impairment (eGFR 30 to < 60 mL/min/1.73m²), the nirmatrelvir dose should be reduced to 150 mg (taken with ritonavir 100 mg) every 12 hours for 5 days. Paxlovid® is currently contraindicated in severe renal impairment as data for appropriate dosing is not yet available. Its use is also contraindicated in severe hepatic impairment, although no dose adjustment is required in mild to moderate hepatic impairment.

It is recommended that the tablets be swallowed whole without regards to food. However, studies suggest that administering nirmatrelvir + ritonavir as an oral suspension does not alter its pharmacokinetic parameters. The guidelines advise that nirmatrelvir + ritonavir tablets can be crushed or split and mixed with food or liquid, where necessary. Alternatively, they may be administered via a nasogastric tube, as indicated.

Adverse effects

Common adverse effects include taste disturbance, headache, diarrhoea, and nausea.

Nirmatrelvir and ritonavir are both metabolised by CYP3A4, and this contributes to many clinically significant drug interactions. Coadministration with medicines that induce this enzyme may reduce the concentration and efficacy of the antiviral. Use with strong CYP3A4 inducers is contraindicated as this may be associated with loss of virologic response and potential resistance. Paxlovid® may also increase the levels of medications that are metabolised by CYP3A. Use is contraindicated with medicines that are highly dependent on CYP3A for clearance and for which elevated levels may result in serious or life-threatening events.

The interactions of ritonavir can be difficult to predict, as it inhibits and induces CYP3A4 and other CYP enzymes. It also inhibits P‑glycoprotein and is a strong inducer of UGTs (which mediate glucuronidation). A full medication history should be taken before initiating therapy, ensuring that complementary and over-the-counter products are included.

Many medications are contraindicated with Paxlovid®, including:

• Drugs that may result in serious or life-threatening reactions, e.g. amiodarone, flecainide, colchicine, simvastatin, diazepam, and sildenafil.
• Drugs that may result in loss of virologic response and potential resistance, e.g. apalutamide, carbamazepine, phenytoin, rifampicin, St John’s wort.

The product information should be consulted for comprehensive advice on drug interactions.

Molnupiravir (Lagevrio®)

Molnupiravir has provisional approval for the treatment of adults with COVID-19 who do not require initiation of oxygen due to COVID-19 and who are at increased risk for hospitalisation or death.

Molnupiravir inhibits viral replication following incorporation into viral RNA. It is less effective than nirmatrelvir + ritonavir and is not routinely recommended for the treatment of COVID-19. Molnupiravir is only recommended if an oral agent is required and the nirmatrelvir + ritonavir combination is contraindicated.

Administration

The recommended dose is 800 mg (four 200 mg capsules) taken orally every 12 hours for five days. Doses may be taken with or without food.

Adverse effects

Diarrhoea, nausea, and dizziness were the most commonly reported adverse events in clinical trials. These were of mild to moderate severity. No serious drug-related adverse events were reported.

Molnupiravir is not a substrate of any major drug metabolising enzymes or transporters and is considered unlikely to cause drug interactions.

Remdesivir (Veklury®)

Remdesivir is an intravenously administered agent that may also be considered for patients with mild to moderate disease, as well as more severe cases where ventilation is not required.

The approved indications are for the treatment of COVID-19 in:

• Adults and paediatric patients (at least 4 weeks of age and weighing at least 3 kg) who have pneumonia due to SARS-CoV-2, and who require supplemental oxygen; and
• Adults and paediatric patients (weighing at least 40 kg) who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19.

Remdesivir is metabolised to remdesivir triphosphate (an adenosine analogue). This pharmacologically active form is then incorporated into viral RNA, preventing its replication. Remdesivir is used in both outpatient and hospital settings and treatment should begin within seven days of symptom onset.

Administration:

Remdesivir is administered daily via IV infusion. For adults and patients >40kg, the usual dose is 200mg on day 1, then 100mg on subsequent days. The usual treatment duration is three days for patients who do not require supplemental oxygen, and 5-10 days for patients with pneumonia who do need supplemental oxygen.

Remdesivir is supplied as a powder for injection. The powder is reconstituted with water for injection and then further diluted with 0.9% sodium chloride. The final volume is typically 250mL, although a volume of 100mL may be used for patients with severe fluid restrictions. The infusion should run over 30-120 minutes.

Dose adjustment is not required for patients with renal impairment (including those on dialysis) or hepatic impairment.

Adverse effects

Common adverse effects include nausea, vomiting, headache, rash, increased aminotransferases, and prolonged prothrombin time (PT). While prolonged PT has been observed in clinical trials, no difference has been reported in the incidence of bleeding events compared to placebo.

Hypersensitivity reactions (including infusion-related and anaphylactic reactions) have been associated with remdesivir. Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnoea, wheezing, angioedema, rash, nausea, vomiting, diaphoresis, and shivering. Slower infusion rates (up to 120 minutes) may reduce the risk of these events. Remdesevir must only be administered in settings where there is immediate access to medications to treat a severe infusion or hypersensitivity reaction and access to an emergency medical response.

Table 1. Comparison of COVID-19 antiviral agents.

Drug	Route	Timing of initiation	Comments
Remdesivir	IV	≤7 days	30-120 minute infusion
Nirmatrelvir + ritonavir	Oral	≤5 days	1st line oral agent Many drug interactions + contraindications
Molnupiravir	Oral	≤5 days	Less effective

Summary

If an antiviral is considered appropriate for COVID-19, therapy should be promptly initiated following diagnosis. Where an oral agent is required, nirmatrelvir + ritonavir is preferred as it is more effective than molnupiravir. Remdesivir remains a valuable option for reducing the risk of hospitalisation. However, as it requires IV administration, its use in the community is limited.

INTRODUCTION:

Migraine headaches impose a substantial level of pain and disruption to a person’s quality of life. (Malmberg-Ceder, Soinila et al. 2022) Common triggers for migraine included physical activity, poor sleep hygiene, physical and mental fatigue, and emotional anxiety and stress. (Aderinto, Olatunji et al. 2024)

The age-adjusted prevalence of migraine is observed to be 21% in women, which is twice the rate of 10.7% seen in men (Burch, Rizzoli et al. 2021) and the economic burden is substantial. Starting from 2020 as a baseline, over the next 10 years migraine is predicted to have a in health-care costs of AU$1.67 billion, or AU$1313 per person. There could also be AU$68.13 billion loss to the GDP.(Tu, Liew et al. 2020)

Historically, acute migraine treatment has involved triptans as the leading clinical option. Preventive treatments include propranolol, metoprolol, amitriptyline and anti-epileptics such as sodium valproate and topiramate (Zobdeh, Ben Kraiem et al. 2021) as well as botulinum toxin.  (Kępczyńska and Domitrz 2022).

More recently a new class of drugs, the calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs), have become available as an effective preventative treatment for chronic migraine. (Ray, Dalic et al. 2024) In Australia eptinezumab, fremanezumab, galcanezumab and erenumab are available. The first three act directly against CGRP whilst erenumab acts against the CGRP receptor. (de Vries, Villalón et al. 2020). They are collectively referred to as CGRP antagonists. (AMH, 2025).

Briefly, the pathophysiology of migraine involves the triggering of the trigeminovascular system. Divisions of the trigeminal nerve innervate the face and as well as the meninges, which also includes intracranial blood vessels and the dura. These nerve branches release calcitonin-gene related peptide (CGRP), which acts as a potent vasodilator of cerebral and dural vessels, leading to neurogenic inflammation, and CGRP facilitates pain transmission from trigeminal vessels to the CNS.(Pescador Ruschel and De Jesus 2025)

Proof of concept for the role of CGRP has been demonstrated by the venous infusions of CGRP which results in migraine-like headaches. (de Vries, Villalón et al. 2020). Calcitonin gene-related peptide is reported to be most potent known vasodilator of both cerebral and peripheral blood vessels. (ACOG. 2022)

It is important to note that CGRP monoclonal antibodies (mAbs), due to their molecular size, exhibit only 0.1% presence in the brain as they are unable to cross the blood-brain barrier. Therefore, their mechanism of action primarily involves the trigeminal network located outside the brain. (Edvinsson and Warfvinge 2019). Two studies using radiolabelled mAbs have confirmed that these drugs act mainly peripherally, due to their large size.(Labastida-Ramírez, Caronna et al. 2023)

USE IN LACTATION:

For lactating mother’s, the current approved product information for erenumab (Aimovig) in eMIMS (2025) states:

“It is not known whether Aimovig is present in human milk. There are no data on the effects of Aimovig on the breastfed child or the effects of Aimovig on milk production. Because drugs are excreted in human milk and because of the potential for adverse effects in nursing infants from Aimovig, a decision should be made whether to discontinue nursing or discontinue Aimovig, taking into account the potential benefit of Aimovig to the mother and the potential benefit of breast feeding to the infant.”

However, a more forensic analysis of the pharmacokinetics of CGRP drugs, understood as the timeline of the drug’s absorption, bioavailability, distribution, metabolism and excretion, is important in assessing the suitability of administering these drugs to pregnant and lactating mothers. (Ernstmeyer and Christman 2023)

THE RESEARCH:

Erenumab (Aimovig), a biosynthetic immunoglobulin G monoclonal antibody (mAb), is a large protein molecule with a weight of 150,000 Da. (Bussiere, Davies et al. 2019, Kothari, Wanjari et al. 2024).

Because of the size of erenumab, presentation via maternal milk to a newborn infant faces a number of physical barriers.

First, erenumab (and other mAbs) must cross the mammary epithelium from maternal blood into milk. A review of the research by LaHue, Anderson et al. (2020) of 155 women using the mAbs certolizumab, rituximab or natalizumab across 30 studies reported that “a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections.”

These researchers applied the relative infant dose (RID), a metric comparing the infant and maternal drug dose, where <10% is generally considered safe, and found that certolizumab and rituximab were present in maternal milk at <1%.

A second “barrier’ is the digestion of a mAb in the infants GIT. A study of the IgG1 mAb palivizumab presence in neonatal intestinal fluid found a variably level of destruction of 50%. (Sah, Lueangsakulthai et al. 2020) As a guide to understanding the poor GI abruption, “native” IgG is only 0.01% absorbed intact from the GIT. (Anderson 2021)

Other “barriers” to infant exposure include the extent to which the drug is bound by maternal plasma proteins, the degree of drug ionisation, lipid solubility and most pertinently, the molecular weight of the drug, which for CGRP drugs is 150,000 Da. (Hotham and Hotham 2015).

Once a CRGP drug enters the infant GIT there are added impediments to the drug entering its bloodstream. These include the infant gut immune barrier (GIB) (Daneman and Rescigno 2009), as well as infant acidic denaturing. (Tashima 2021). 

The implications of this low rate of infant GI tract absorption of mAbs is readily demonstrated by another mAb, natalizumab, for which there is considerable pharmacokinetic data.

Natalizumab is given at a 300mg dose and, according to the official information, will achieve an average patient plasma concentration of 110mg/L. Applying the aforementioned 0.01% GIT absorption and an estimated volume of distribution of 0.25L (Anderson 2021), the infant would be exposed to a concentration of approximately 0.04% of the mother’s serum level.

This is a trivial level when measured against the WHO Working Group of experts of drug use during breastfeeding, who consider an infant: maternal ratio of less than 10% to be safe.

Indeed, many medicines enter breast milk, but usually the amount received by the infant is less than 10% of the maternal dose.(Amir, Pirotta et al. 2011)

In summary, Rayhill (2022) has noted: “The large size of monoclonal antibodies could theoretically reduce the degree that these medications are expressed in breast milk, although this has not been adequately studied.”

PREGNANCY IMPLICATIONS:

The positive implications associated with a putative low foetal concentration are supported by a 2021 analysis of WHO pharmacovigilance date for erenumab, galcanezumab and fremanezumab when given during pregnancy and lactation. (Noseda, Bedussi et al. 2021) The researchers reported that there were “no specific maternal toxicities, patterns of major birth defects or increased reporting of spontaneous abortion…”

There are various case reports of erenumab given during pregnancy. For example, Vig, Garza et al. (2022) referenced a case of a woman who used erenumab for migraine through her pregnancy with no harm to her child.

In another report of three pregnancies with gestational exposure to erenumab, two women ceased erenumab during the first trimester with no adverse sequalae for their babies.

One woman ceased erenumab 1 month before conception and experienced a first trimester spontaneous abortion due to gestational trophoblastic neoplasia, however a subsequent pregnancy was uneventful. No plausible drug-related explanation could be offered by the authors for the spontaneous abortion. (Bonifácio, de Carvalho et al. 2022)

An updated safety analysis on erenumab, galcanezumab, fremanezumab and eptinezumab use in pregnancy by  Noseda, Bedussi et al. (2023) “ showed no signals of foeto-maternal toxicity according to VigiBase® safety reports.”

A case series and literature review by Elosua-Bayes, Alpuente et al. (2024) focused on the periconceptional period of CGRP therapies that were ceased prior to conception. They reported that “database reviews revealed 63 spontaneous abortions, eight premature births, and seven birth defects among 286 World Health Organization and 65 European Medicines Agency cases. These rates align with untreated population rates.”

They concluded that “CGRP-mAbs use in the periconceptional period does not lead to clinically significant increase in pregnancy-related pathology or adverse effects on newborns within our case series and the literature reviewed.”

A reasonable explanation for foetal safety is that mAbs likely do not cross the blood brain barrier secondary to their molecule size. (de Vries, Villalón et al. 2020).

In contrast to these positive reports, Rayhill (2022) advise that CGRP mAbs should be ceased 5-6 months pre-conception due to their long half-life and a lack of safety data.

EFFICACY:

All four CGRP therapies have been reported to possess long-term safety, making them “effective and well-tolerated for the prevention of migraines.” (Muddam, Obajeun et al. 2023)

Summarising the current research, Oliveira, Gil-Gouveia et al. (2024) reported that “Most studies reported on monoclonal antibodies targeting CGRP (anti-CGRP mAbs), that overall prove to be effective in decreasing monthly migraine days by half in about 27.6–61.4% of the patients. Conversion from chronic to episodic migraine was seen in 40.88% of the cases, and 29–88% of the patients stopped medication overuse.”

CONCLUSION:

Based upon the preceding literature review, the use of erenumab and other CGRP medications in lactation is an option that can be positively considered by a clinician when balancing the maternal benefits against potential foetal harms. However caution is necessary because longer-term studies are still required, (Burch, Rizzoli et al. 2021) notably in its cardiovascular impact, since CGRP has protective properties in cardiovascular disease. (González-Hernández, Marichal-Cancino et al. 2016).

Their use in pregnancy currently has contradicting research findings.   (Elosua-Bayes, Alpuente et al. 2024) (Moisset, Demarquay et al. 2024)

The Heart Foundation and the Cardiac Society of Australia and New Zealand have released the new Australian clinical guideline for diagnosing and managing acute coronary syndromes 2025. This new guideline replaces National Heart Foundation of Australia & Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of acute coronary syndromes 2016.

Acute coronary syndrome (ACS) includes acute myocardial infarction (AMI) and unstable angina. Around 160 Australians experience an acute coronary event each day and these events remain a leading cause of morbidity and mortality.

The new guideline contains updated evidence-based recommendations and practical advice that is intended to improve patient outcomes overall and reduce disparities in care for people experiencing ACS across Australia.

Changes relating to pharmacotherapy include new recommendations and guidance on secondary prevention measures, as follows:

• More detailed advice on post-discharge care (e.g. medicines and adherence strategies, vaccinations, mental health screening);
• Treatment algorithms to enable more tailored prescribing of antiplatelet and anticoagulation therapies;
• A new recommended treatment target for low density lipoprotein cholesterol (LDL-C) of <1.4 mmol/L and a reduction of at least 50% from baseline; and
• New recommendations on select medicines, including beta blockers and the PCSK9 inhibitors, alirocumab and evolocumab.

Vaccinations

Viral respiratory infections are a well-documented trigger for AMI. Various mechanisms have been proposed for this increased risk. The systemic inflammatory response to a viral infection may destabilise atherosclerotic plaques. These plaques contain inflammatory cells that can be activated by several cytokines present in a pro-inflammatory state. This can lead to activation of the coagulation cascade, thereby increasing the risk of AMI. Hypoxaemia associated with severe respiratory infections can also increase the risk of AMI. The reduced oxygen supply, coupled with the increased metabolic needs during systemic inflammation, can create an imbalance in oxygen supply and demand.

One study conducted in patients with angiographically confirmed AMI found a 17-fold increased risk of AMI within seven days of a respiratory infection. Other studies looking at individual viruses found an elevated risk for influenza, respiratory syncytial virus, and COVID-19.

The relationship between viral infections and cardiovascular events suggests that vaccination could play a role in preventing AMI in patients with cardiovascular disease. Evidence for the benefits of vaccination in this setting is particularly strong for influenza. Vaccination against influenza has also been shown to reduce the risk of further cardiac complications following ACS. The evidence demonstrates that influenza vaccination is safe and effective when administered within 72 hours of an invasive coronary procedure or hospitalisation for AMI.

The benefits of vaccination in these patients likely go beyond prevention of cardiovascular events. People with cardiovascular disease are at higher risk of severe viral infection, making preventative measures particularly important.

The guidelines recommend:

• Annual influenza vaccination
• Pneumococcal vaccination per the immunisation schedule
• RSV vaccination for patients with coronary artery disease (CAD) who are 60 years of age or older.
• Consideration of additional doses of COVID-19 vaccine for all patients with chronic cardiac conditions.

Antiplatelet therapy

Some of the recommendations for antiplatelet therapy have been updated. The recommended duration for dual antiplatelet therapy (DAPT) in patients discharged following an ACS is now:

• High ischaemic and/or low bleeding risk
  • DAPT for 6-12 months.
  • P2Y₁₂ inhibitor preferred over aspirin for continuation of long-term therapy.
  • Long-term (>12 months) DAPT may be considered for patients who remain at high ischaemic and low bleeding risk.
• Low ischaemic risk and/or high bleeding risk
  • DAPT may be ceased at 1-3 months, with single antiplatelet therapy continued.
• Indication for long-term oral anticoagulant therapy (e.g. atrial fibrillation)
  • Continue anticoagulant and DAPT for 1-4 weeks, then cease aspirin.
  • Cease antiplatelet therapy at 6-12 months and continue anticoagulant alone.

Available P2Y₁₂ receptor inhibitors are:

• Clopidogrel;
• Prasugrel; and
• Ticagrelor.

The choice of P2Y₁₂ receptor inhibitor will depend on different patient factors. Ticagrelor and prasugrel are considered more potent than clopidogrel and are also associated with less interpatient variability. Clopidogrel is preferred for older adults with higher bleeding risk. Some patients may prefer the convenience of once daily dosing with clopidogrel and prasugrel, compared to ticagrelor which is taken twice a day.

Gastroprotection

A proton pump inhibitor (PPI) is recommended for patients receiving DAPT who have a high risk of gastrointestinal bleeding and for patients receiving triple antithrombotic therapy.

Available PPIs are:

• Esomeprazole;
• Lansoprazole;
• Omeprazole;
• Pantoprazole; and
• Rabeprazole.

All PPIs have similar safety and efficacy. However, there are some differences in their potential to cause drug interactions. For example, esomeprazole and omeprazole inhibit CYP2C19 and may increase the plasma levels of medications that are substrates of this enzyme (e.g. warfarin, citalopram, diazepam).

Lipid-modifying therapy

A reduction in LDL-C of 1.0 mmol/L can reduce the risk of AMI, stroke, coronary revascularisation and vascular death. Statins are the first-line lipid-modifying agents. They have established efficacy and a low rate of serious adverse effects.

The guidelines recommend the initiation of statin therapy prior to hospital discharge following ACS. If the patient was already on lipid-lowering therapy, this should be reviewed with consideration of intensifying therapy. Statin therapy should be continued indefinitely at the highest tolerated dose, unless contraindicated or the patient is not tolerant.

Available statins are:

• Atorvastatin;
• Fluvastatin;
• Pravastatin;
• Rosuvastatin; and
• Simvastatin.

All statins are associated with a reduced risk of cardiovascular events. However, it is the extent of LDL-C reduction that is important, and this is determined by the potency of the statin and the dose used. High-potency statins, such as atorvastatin and rosuvastatin, are preferred following an ACS.

One other consideration when selecting a statin is the potential for drug interactions. Fluvastatin, pravastatin and rosuvastatin are associated with fewer interactions compared to atorvastatin and simvastatin.

Additional non-statin therapies are often required to achieve target lipid levels. Medications that may be added to statin therapy include:

• Ezetimibe;
• PCSK9 inhibitors. This class includes alirocumab, evolocumab, and inclisiran. These medications are administered by subcutaneous injection every 2-4 weeks (alirocumab and evolocumab) or up to six-monthly (inclisiran); or
• Icosapent ethyl (for elevated triglyceride levels).

Beta blocker therapy

The guidelines recommend the use of a beta blocker for patients with ACS and left ventricular (LV) impairment. In this cohort, they are associated with a reduced risk of recurrent AMI. Their efficacy in patients with preserved ejection fraction is less clear.

For patients with confirmed LV impairment, the guidelines recommend use of a beta blocker with proven benefit in heart failure with reduced ejection fraction. This includes bisoprolol, carvedilol, metoprolol, and nebivolol.

Renin-angiotensin antagonist therapies

Angiotensin converting enzyme (ACE) inhibitors are associated with a reduced risk of early mortality and further cardiovascular events following AMI. Angiotensin receptor blockers (also known as sartans) exhibit similar effects to ACE inhibitors. However, angiotensin receptor–neprilysin inhibitors (i.e. sacubitril + valsartan) have not demonstrated any benefit in this population.

Adjunct medications

The new version of the guidelines also contains recommendations regarding colchicine and semaglutide. These medications were not included in the previous version of the guidelines.

Colchicine

Colchicine may reduce the risk of recurrent ischaemic events in ACS by reducing the persistent inflammation that occurs in these patients. Studies have evaluated doses ranging from 0.5 mg to 1.0 mg per day. A recent meta-analysis suggests that doses at the lower end of this range may be effective in reducing recurrent ischaemic events. Higher doses are associated with an increased risk of gastrointestinal adverse events and may not offer any additional benefits. However, colchicine was not associated with a significant reduction in all-cause mortality or cardiovascular death. Further research is required to clarify the role of colchicine post-ACS.

The most common side effects are gastrointestinal, e.g. diarrhoea, nausea, vomiting, and abdominal pain. Colchicine is metabolised by CYP3A4 and is a substrate of P‑glycoprotein. Therefore, combination with CYP3A4 inhibitors (e.g. amiodarone, ciclosporin, ticagrelor, grapefruit juice) or P‑ glycoprotein inhibitors (e.g. carvedilol, clarithromycin, verapamil) may increase colchicine concentration. This can lead to increased adverse effects and is particularly important to consider in patients with renal impairment.

Semaglutide

For people with ACS who are overweight or obese, a glucagon-like peptide-1 (GLP-1) receptor agonist may improve outcomes. The SELECT trial demonstrated that the cardiovascular benefits associated with semaglutide in people with diabetes were also seen in patients without diabetes.

The SELECT trial enrolled people without diabetes who were overweight or obese and had pre-existing cardiovascular disease (defined as previous AMI or stroke, or symptomatic peripheral arterial disease). Participants were randomly assigned to receive weekly semaglutide or placebo. Semaglutide was found to be superior to placebo in reducing the incidence of non-fatal AMI and stroke as well as death from cardiovascular causes.

Semaglutide is not currently subsidised on the Pharmaceutical Benefits Scheme (PBS) for people without diabetes.

Further information

The Heart Foundation provides a range of useful resources for healthcare professionals and free access to the MyHeart MyLife support program for patients.

 

The Australian Institute of Health and Welfare (AIHW) recently released the report, Injury among women 2022-23. This report shows that unintentional falls are the leading cause of injury hospitalisation and death for women.

In the year 2022-23, falls injuries in women were responsible for:

• 122,826 hospitalisations;
• 57% of injury hospitalisations; and
• 3,437 deaths.

While males are more likely to be injured and hospitalised across most causes, falls are one of the few exceptions. The rate of falls in males is reported to be 730 per 100,000, while the rate in females is around 770 per 100,000. The AIHW reports that the death rates for falls is currently the highest of the last decade.

The increasing incidence of falls may be related to population ageing. In Australia, women represent an increasing proportion of older adults. Factors that increase the risk of falls in older adults include musculoskeletal decline, osteoporosis, and cognitive decline. Dementia increases the risk of falls almost three-fold due to effects on balance and gait control. Research also suggests that medications are a significant contributing factor to falls.

Effect of medications on falls risk

The impact that medications play in falls is difficult to quantify. One study looking at elderly patients admitted to hospital with hip fractures found that medications were a likely contributing factor in 41% of cases.

Polypharmacy is an important consideration, with studies finding a significant increase in falls risk for patients taking more than four medications. As the population ages and chronic disease management becomes more complex, the prevalence of polypharmacy has risen in Australia.

Some medications have been identified as being of particularly high risk of causing falls. These are sometimes referred to as fall-risk increasing drugs (FRIDs), and they appear to be more strongly related to falls than polypharmacy alone. Medications classified as FRIDs include many medicines that act on the central nervous system, i.e. sedatives and hypnotics, neuroleptics and antipsychotics, antidepressants, and opioids.

There is a range of ways in which a medication may increase the risk of falls, including:

• Sedation;
• Cognitive impairment;
• Orthostatic hypotension;
• Muscle weakness; and
• Impaired vision or balance.

Some medications may contribute to falls via multiple mechanisms. For example, anticholinergics can cause sedation, cognitive impairment, and visual disturbances. Drug interactions may also increase a person’s falls risk by amplifying adverse effects. This could be due to additive effects (e.g. increased sedation when a benzodiazepine is combined with an opioid) or due to changes in serum levels as a result of altered metabolism.

Anticholinergic medications are well known for their additive effects. There are many tools available that attempt to quantify the overall anticholinergic effect of a medication regime. The anticholinergic cognitive burden (ACB) scale categorises drugs into three levels:

• Level 1 – drugs with low anticholinergic effect that may still contribute to overall burden (e.g. atenolol, digoxin)
• Level 2 – Drugs with moderate anticholinergic effect that may produce noticeable cognitive effects (e.g. carbamazepine, pethidine)
• Level 3 – Drugs with high anticholinergic activity and a greater risk of cognitive impairment (e.g. clozapine, paroxetine)

The ACB scale can be used to score a patient’s overall risk of anticholinergic adverse effects. A score of greater than three is considered significant, with the risk further increasing as the score increases.

One large retrospective study of older adults with mild cognitive impairment or dementia sought to determine whether drugs with different anticholinergic ratings contribute proportionately to the anticholinergic burden. The study found differing levels of risk for patients with the same ACB score. The evidence suggested that patients taking level 2 and level 3 drugs had a higher risk of falls compared to patients with the same ACB score who were only taking level 1 drugs.

Medicines with strong anticholinergic properties are considered potentially inappropriate for older individuals as the risks typically outweigh the benefits. In addition to falls, these medicines are associated with other serious adverse events, including cognitive impairment and delirium.

Some examples of highly anticholinergic medicines and potential alternatives are shown in Table 1.

Table 1. Highly anticholinergic medicines and potential alternatives

Indication	Highly anticholinergic medicines (avoid where possible)	Potential alternatives (no or lower anticholinergic effects)
Allergic rhinitis	Chlorpheniramine Promethazine	Cetirizine Loratadine Intranasal corticosteroids
Major depression	Amitriptyline Doxepin	Sertraline Venlafaxine
Urinary urge incontinence	Solifenacin Oxybutynin	Mirabegron
Psychoses	Chlorpromazine Clozapine	Amisulpride Risperidone Ziprasidone
Pain	Tramadol	Paracetamol
Nausea and vomiting	Cyclizine	Domperidone Metoclopramide

Medication review

As medications are a significant modifiable risk factor for falls, regular review is recommended for older adults. Reviews can be used to identify medications with a high risk of harm or a lack of benefit for the individual patient.

Deprescribing may be considered for some patients identified as high risk, particularly if the harms of the medication outweigh the potential benefits for the patient at their current stage of life.

Medication review and deprescribing have been shown to reduce hospital readmission rates in older adults. Studies highlight the particular benefit that reducing the use of potentially inappropriate medications has in preventing readmission.

Other falls prevention strategies

It is thought that around 40% of falls could be preventable. However, the causes of falls are typically multifactorial. Therefore, addressing multiple risk factors will be more beneficial than relying on a single intervention.

In addition to medication optimisation, other falls prevention strategies may include:

• Exercise – a large review found that exercise of any type may reduce the risk of falls by 23%. The benefits may be even higher for exercise programs combining balance and functional exercises with resistance exercises;
• Home hazard assessment and modification;
• Vision correction;
• Mobility aids; and
• Encouraging the use of non-pharmacological therapies where appropriate, e.g. the Therapeutic Guidelines considers psychological and behavioural interventions as first-line options for the treatment of insomnia.

Falls can have significant outcomes for older adults, including serious injury and loss of independence. Individualised assessment of patient risk factors along with the implementation of appropriate interventions can reduce the risk of falls in older adults.

Dapagliflozin and empagliflozin are sodium-glucose co-transporter 2 (SGLT-2) inhibitors. These medications inhibit SGLT-2 in the renal proximal convoluted tubules.

The SGLT-2 protein is responsible for the resorption of around 90% of the glucose from the glomerular filtrate. This makes SGLT-2 an attractive target for diabetes therapies as inhibition of SGLT-2 increases the amount of glucose removed by the kidneys. As the name suggests, SGLT-2 also transports sodium. Therefore, SGLT-2 inhibitors also increase the amount of sodium that is removed via the kidneys. This produces natriuresis and a mild diuresis that is associated with a moderate and sustained reduction in blood pressure.

Significant improvements in glycaemic control can be achieved with SGLT-2 inhibitors, and these medications were originally only indicated for the management of type 2 diabetes. However, studies have demonstrated cardiorenal protective effects and SGLT-2 inhibitors now also have a place in the management of heart failure and chronic kidney disease (CKD).

Indications

The current approved indications for SGLT-2 inhibitors in Australia are:

• Dapagliflozin
  • Type 2 diabetes – glycaemic control
  • Type 2 diabetes – reduce risk of hospitalisation for heart failure in patients with established cardiovascular disease or risk factors for cardiovascular disease
  • Heart failure – as an adjunct to standard therapy
  • Chronic kidney disease – to reduce the risk of disease progression in patients with proteinuric CKD.
• Empagliflozin
  • Type 2 diabetes – glycaemic control
  • Type 2 diabetes – prevention of cardiovascular death in patients with established cardiovascular disease
  • Heart failure – as an adjunct to standard therapy
  • Chronic kidney disease – to reduce the risk of disease progression.

Studies have demonstrated that the cardiorenal benefits become evident soon after randomisation. The mechanisms responsible for these benefits are not fully understood. However, these effects appear to be independent of glucose lowering and are apparent in patients with and without diabetes.

Some mechanisms that have been suggested include:

• Modulation of the renin-angiotensin-aldosterone (RAAS) system
• Osmotic diuresis and natriuresis to reduce preload;
• Vascular effects, such as improved endothelial function, to reduce afterload;
• Inhibition or reversal of adverse cardiac remodelling; and
• Improved myocardial metabolism to improve cardiac efficiency.

Evidence

Cardiovascular outcomes

The EMPA-REG OUTCOME trial evaluated cardiovascular outcomes of empagliflozin in patients with type 2 diabetes and high cardiovascular risk. Over 7,000 patients were randomised to receive empagliflozin or placebo. The empagliflozin group demonstrated significantly lower rates of death from cardiovascular causes (3.7% vs. 5.9%), hospitalisation for heart failure (2.7% vs 4.1%), and death from any cause (5.7% vs 8.3%).

Similar findings were reported for dapagliflozin in the DECLARE-TIMI trial. This was a larger study with more than 17,000 patients with type 2 diabetes at risk of atherosclerotic cardiovascular disease. Patients randomised to the dapagliflozin group had a lower rate of hospitalisation for heart failure compared to placebo (2.5% vs 3.3%).

The cardiovascular benefits of these studies prompted their investigation in people without diabetes. Studies such as the DAPA-HF and EMPEROR-Reduced trials demonstrated that SGLT-2 inhibitors may provide cardiovascular benefits for patients with heart failure regardless of their diabetes status.

Renal outcomes

In the initial cardiovascular outcomes trial, EMPA-REG OUTCOME, patients in the empagliflozin group were significantly less likely to experience a rapid decline in renal function over a median exposure period of 2.6 years. The potential renal benefits of SGLT-2 inhibitors were further investigated in the following trials:

• CREDENCE
  • Drug – canagliflozin (no longer available in Australia)
  • Population – type 2 diabetes and kidney disease
  • Outcome – 32% lower relative risk of end-stage kidney disease
• DAPA-CKD
  • Drug – dapagliflozin
  • Population – patients with CKD
  • Outcome – hazard ratio for the primary outcome (composite of sustained decline in the eGFR of ≥ 50%, end-stage kidney disease, or death from renal causes) was 0.56 (95% CI: 0.45 to 0.68).
• EMPA-KIDNEY trials
  • Drug – empagliflozin
  • Population – patients with CKD
  • Outcome – hazard ratio for the progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 mL/min/1.73 m², a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) was 0.71 (95% CI: 0.62 to 0.81).

A recently published umbrella review of network meta-analyses provided further support for the use of SGLT-2 inhibitors in CKD. This study compared the safety and efficacy of SGLT-2 inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and non-steroidal mineralocorticoid receptor antagonists (ns-MRA) in patients with CKD. The authors concluded that all three classes of medication are associated with significant reductions in the risk of major cardiovascular events and the progression of CKD compared to placebo. Furthermore, indirect evidence suggests that SGLT-2 inhibitors may be the most attractive option when considering efficacy together with safety.

Adverse effects

As SGLT-2 inhibitors increase the amount of glucose in the urine, they are associated with an increased risk of genital infections (e.g. vulvovaginal candidiasis, balanitis). Other common adverse effects include polyuria, dysuria, thirst, and constipation. Hypoglycaemia can occur, particularly when used in combination with a sulfonylurea or insulin.

Serum creatinine may rise initially (potentially related to volume depletion). This is sometimes referred to as the “GFR dip”. This acute reduction in eGFR is reversible and typically followed by a partial recovery. The slower decline in eGFR compared to placebo then becomes apparent.

Ketoacidosis

Ketoacidosis has been rarely associated with the use of SGLT-2 inhibitors. A large cohort study from Canada and the United Kingdom found that SGLT-2 inhibitors significantly increased the risk of diabetic ketoacidosis (DKA) compared to dipeptidyl peptidase 4 (DPP-4) inhibitors. The hazard ratio was 1.86 for dapagliflozin and 2.52 for empagliflozin.

Diabetic ketoacidosis can occur in the setting of carbohydrate deficit. Under these conditions, serum insulin levels are low, and the body reduces the use of glucose and increases the use of fat as an energy source. Increased lipolysis, increased free fatty acid generation, and ketoacidosis can occur.

Hyperglycaemia is a classic component of DKA diagnosis. However, in patients taking SGLT-2 inhibitors, blood glucose levels can be normal or mildly elevated. This unusual presentation has been associated with delays in diagnosis.

There are many potential risk factors for the development of this adverse event. This includes acute illness or infection, surgery or trauma, dehydration, low carbohydrate intake, and alcohol abuse. Hospitalised patients are at greater risk as predisposing factors are more common in this population. To reduce the risk, SGLT-2 inhibitors should be avoided in patients on low carbohydrate diets and should be withheld during acute illness and prior to elective procedures.

The recommendation to withhold SGLT-2 inhibitors prior to elective surgery is directed towards patients with diabetes. There is currently a lack of evidence to guide recommendations for patients without diabetes who are taking an SGLT-2 inhibitor. While the risk of ketoacidosis in this group is thought to be significantly lower, the Council of Australian Therapeutic Advisory Groups currently recommends that the guidelines for patients with diabetes can also be followed for patients without diabetes. If the SGLT-2 inhibitor is withheld for surgery, it can be restarted once the patient is eating and drinking normally and kidney function has returned to baseline.

While SGLT-2 inhibitors have shown some promise as an adjunct therapy in type 1 diabetes, they are currently not recommended to be used in this population. This is due to an increased risk of DKA.

Recommendations

Heart failure

The Therapeutic Guidelines recommend dapagliflozin or empagliflozin for patients with heart failure, unless contraindicated. This should be used in addition to standard care (i.e. a renin-angiotensin system inhibitor, beta blocker and mineralocorticoid receptor antagonist for patients with heart failure with reduced ejection fraction).

Chronic kidney disease

The Chronic Kidney Disease (CKD) Management in Primary Care handbook recommends the use of an SGLT-2 inhibitor for patients with CKD and proteinuria (with or without diabetes) to reduce the risk of progressive decline in kidney function. The handbook advises against initiating an SGLT-2 inhibitor in patients with an eGFR <25mL/min/1.73m².

Potassium is an electrolyte which is essential for regulating nerve and muscle function, including cardiac muscle function. Disturbances in serum (blood) potassium affect the activity of Na/K – ATP pumps in the muscle tissue, leading to inappropriate muscle contractions.

The potassium concentration in the serum is around 3.5-5.2 mmol/L. This range describes the values between which 95% of the healthy population’s levels are expected to be. It does not necessarily mean that patients with results outside the reference range are at risk of complications. It also does not mean that all patients with levels within the reference ranges have an optimal concentration.

Hypokalaemia is a concentration of potassium in the blood below the reference range. Mild cases of hypokalaemia with serum potassium levels of 3-3.5 mmol/L can be asymptomatic, while severe cases with serum potassium of <2.5 mmol/L can lead to life threatening complications.

Healthy young patients with potassium levels slightly outside the reference ranges rarely experience problems. Older patients with acute cardiac conditions like rapid atrial fibrillation or acute myocardial infarction may require tighter potassium concentrations than the standard range to achieve optimal outcomes.

Laboratories can have different reference ranges due to different techniques used to collect and analyse specimens. This should be considered when reviewing results.

In the general population hypokalaemia is estimated to occur in 1-3% of people. People with malnutrition or on diuretics have a higher risk of developing hypokalaemia.

Symptoms of hypokalaemia include muscle weakness or cramps, lethargy, constipation, palpitations, nausea or vomiting, tingling or numbness in the limbs. In severe cases hypokalaemia can cause cardiac arrhythmias and cardiac arrest.

Common causes of hypokalaemia include

• Increased aldosterone levels caused by primary hyper aldosteronism or untreated heart failure. Aldosterone is the primary hormone regulating renal potassium excretion.
• Medicines, including loop and thiazide diuretics, nebulised or oral beta agonists and amphotericin B.

Mild cases of hypokalaemia in young patients without cardiac complications can often be managed with oral potassium supplements. Intravenous potassium supplementation could be required when the potassium concentration is <3 mmol/L with associated paralysis, hypokalaemia is associated with a cardiac rhythm disturbance, or oral supplementation is not possible. Concomitant oral and IV potassium supplementation should be considered when the patient’s potassium concentration is <3 mmol/L.

The actual increase in serum potassium from supplements is variable and depends on several factors like kidney disease or heart failure, and the presence of medicines such as diuretics, ACE Inhibitors and angiotensin receptor blockers.

Intravenous potassium supplementation should be administered at a rate of no greater than 20 mmol/hr and ideally at a rate of no greater than 10 mmol/hr when administered via a peripheral cannula. Faster rates can be administered via central lines terminating in high flow veins, such as the vena cava, in monitored settings such as an ICU.

Most people need 1mmol/kg of potassium per day to replace physiological losses. In patients who are unable to meet daily potassium requirements (e.g. patients who are nil by mouth) or when there are ongoing potassium losses (e.g. patients on large doses of loop diuretic), supplementation doses should account for this.

Aldosterone antagonists, such as spironolactone and eplerenone, are not used for management of acute hypokalaemia. They are however useful in the ongoing management of hypokalaemia secondary to hyperaldosteronism due to their aldosterone antagonist effects. They are also used in patients with recurrent hypokalaemia from loop diuretics. This includes patients with heart failure and cirrhotic liver disease.

Hypomagnesaemia can cause potassium wasting in the kidneys. Hence patients with hypokalaemia resistant to potassium supplementation should have magnesium levels assessed, and magnesium supplementation initiated where necessary.

Many foods e.g. bananas, baked potatoes, edamame, raisins and salmon are rich in potassium. Individuals with chronic hypokalaemia should have dietitian input to increase dietary potassium.