Epic Pharmacy Circuit Newsletter July 2023

clinical initiatives, research and current updates in treatment

The Increasing Burden of Anticholinergic Medicines

Anticholinergics are drugs that block acetylcholine receptors in both the central and peripheral nervous systems, leading to an inhibition of the parasympathetic nervous system (also known as the rest and digest system).1 It is through this blockade that anticholinergics exert effects such as decreased respiratory secretions, gastrointestinal motility, and increased bronchodilation.1 These medications are used to treat many conditions including Parkinson’s disease, chronic obstructive pulmonary disease (COPD), urinary incontinence, allergies, asthma, the symptoms of coughs and colds, and motion sickness. However, due to their widespread activity across different body systems, anticholinergics are notorious for causing unintended adverse effects.1,2 Commonly used drugs with well-known anticholinergic effects include tricyclic antidepressants, sedating antihistamines, antipsychotics and bladder antispasmodics.1 However, there are other drug classes that possess low level anticholinergic activity such as SSRIs and opioids (See Table 1).2,4 The cumulative effect of taking multiple medicines with anticholinergic activity has been termed anticholinergic burden.5 As the burden increases, so too does the possibility of experiencing side-effects.6

Anticholinergic side effects can be more pronounced in people aged 65 years and older due to age related changes in pharmacodynamic and pharmacokinetic processes, existing frailty, and

polypharmacy.6 Literature reports that 20-50% of older patients are prescribed drugs with anticholinergic properties.8 In this population, anticholinergic burden is associated with poor health outcomes including a 60% increase in fall-related hospitalisation, 50% increased risk of dementia and a 30% increase in mortality.8 The number of patients experiencing anticholinergic burden appears to be increasing over time, thus understanding, assessing, and reducing anticholinergic burden (where possible) is an important aspect for improving patient health outcomes.6-8

Currently, there is no standardised way to assess anticholinergic burden.6,7 To date there have been several tools developed such as the Anticholinergic Drug Scale (ADS), the Anticholinergic Cognitive Burden Scale (ACB) and the Anticholinergic Risk Scale (ARS). Some tools, such as the Drug Burden Index (DBI), which is used throughout Australia, measures both anticholinergic and sedative drug use.6 Typically, the tools classify all medications a patient takes based on their anticholinergic potential, usually on a scale of 0 (low potential) to 3 (high potential) points.6,7 The major drawback to the use of these tools is the variation between the scales, as they all use different criteria to assess anticholinergic potential and may weigh the same drug differently. For example, the ACB scores paroxetine with an anticholinergic burden of 3, while the ARS scores it as 1.4,9

Although, the score may differ depending on the tool used, they may be useful to identify anticholinergic medicines and their overall burden.2,4,9

Deprescribing is a patient-centred process which aims to cease potentially inappropriate medications that may be contributing to adverse effects, have minimal treatment benefit or are no longer required as the goals of care have changed. It can be an effective way of reducing polypharmacy and subsequently a patient’s anticholinergic burden.6,10 This optimisation of medication may result in decreased falls, reduced frailty and improved quality of life.6,10 The Primary Healthcare Network in Tasmania has a number of deprescribing guides, including an anticholinergic specific guideline which can assist clinicians with the process.11 Importantly, the key to effective deprescribing is ensuring that it is a shared-decision making process, actively involving the patient at all stages. If it is necessary for an anticholinergic medicine to continue, other strategies include reducing the dose to the minimum required, trialling alternate medications or non-pharmacological therapies, or pre-emptively managing potential side effects.6,12

A thorough medication review can be helpful in recognising over-the-counter anticholinergics such as antihistamines, travel sickness medications and antidiarrhoeals (See Table 2).

Justine Forbes, Epic Pharmacy Hollywood

A medicine review completed by a pharmacist can assist in highlighting anticholinergic burden, adverse effects, and recommending potential medicines that could be deprescribed.

The main goal in assessing anticholinergic burden is to highlight the potential adverse effects this cumulative effect can have on an older patient’s cognitive and functional capacity.

Table 1: Common Prescription Medications with Anticholinergic Activity4,14

Alprazolam, Aripiprazole, Asenapine, Atenolol, Buproprion, Captopril, Codeine, Colchicine, Diazepam, Digoxin, Fentanyl, Furosemide, Fluvoxamine, Haloperidol, Hydrocortisone, Isosorbide, Metoprolol, Morphine, Prednisolone, Risperidone, Warfarin, Oxycodone, Tramadol

Amantadine, Carbamazepine

With vigilance and action of all healthcare providers and a patient-centred approach, there is a great potential for harm minimisation and improved patient outcomes.

Acclidinium, Amitriptyline, Atropine, Clozapine, Chlorpromazine, Doxepin, Glycopyrronium, Ipratropium Nortriptyline, Olanzapine, Oxybutynin, Paroxetine, Tiotropium, Umeclidinium, Tapentadol

Table 2: Over-The-Counter Medications with Anticholinergic Properties4,14

Drug Formulation Examples

Pseudoephedrine Oral decongestants

Brompheniramine, Chlorpheniramine, Dimenhydrinate, Diphenhydramine, Cold and allergy medicines

Doxylamine, Promethazine

Fexofenadine, Cetirizine, Loratadine, Desloratadine, Levocetirizine, Ipratropium

Atropine Hyoscine

Loperamide Metoclopramide

Sleep aid, sedating allergy medications

Non-sedating allergy medications

Anti-diarrhoeal medication

Travel sickness or stomach cramps

Anti-diarrhoeal medication

Migraine associated nausea medication

References are available on request.

An Update on Venous Thromboembolism Prophylaxis in Hospitalised Patients

Britney Lergessner, Epic Pharmacy Northern Beaches

Introduction

Hospital associated venous thromboembolism (HA-VTE) represents a significant danger to hospitalised patients, occurring in 9.7 per 1,000 admissions in Australia at a rate that is 100 times higher than among the Australian general population.1, 2 It is estimated to cost the Australian Health System $1.72 billion annually.3-5 Mortality from HA-VTE is estimated to be as high as 1 in 10 and account for 7% of all deaths in Australian hospitals despite being the leading cause of preventable deaths.

There has been significant progress over the past decade with reductions in rates of VTE in Australia with a new clinical care standard released in 2020.6,7

Risk Assessment and contraindications to prophylaxis

Hospital inpatients commonly have significant risk factors for VTE but also for bleeding, especially in critically ill patients.8, 9 Assessing VTE risk is challenging and has led to numerous VTE Risk Assessment Tools designed to predict VTE risk during hospitalisation.

The ‘IMPROVE’ and ‘Geneva’ risk score are the preferred tools by clinicians.9, 10 Patients with cancer, thrombophilia, pregnancy, and those who are critically unwell are at heightened risk of VTE and should be risk assessed accordingly.

Contraindications to chemical VTE prophylaxis include: patients with active bleeding, those planned for imminent surgery, those with moderate-tosevere coagulopathies and severe thrombocytopenia (< 50x109/L).11

Methods of VTE Prophylaxis

Patients who can mobilise early, i.e. within 24 hours and adhere to mechanical prophylaxis have been shown to have a lower risk of VTE. Mechanical VTE includes intermittent pneumatic compression (SCUDS – Sequential Compression Devices), venous foot pumps, and thigh or knee-length graduated compression stockings (TEDS - Thrombo-Embolus Deterrent Stockings). While they are considered relatively safe, the efficacy of mechanical compression is less than anticoagulation.6 Mechanical prophylaxis is also employed among patients in whom

anticoagulation is contraindicated. The commonly used evidence-based pharmacological treatments are low molecular weight heparin (LMWH) eg. enoxaparin and unfractionated heparin (UFH). Some data suggests LMWH is superior to UFH in regard to both reduction in VTE and bleeding rates.12, 13 Platelet count should be monitored regularly during treatment for prevention or early intervention of Heparin Induced Thrombocytopenia Syndrome (HITS) (Table 1). If left untreated, HITS can lead to thrombosis in up to 50% of patients with a mortality rate of 5-10%.14

Subcutaneous dosing for enoxaparin is 40mg daily which can be reduced to 20mg daily in renal impairment, and for UFH 5,000 units twice daily. While there is limited evidence on dosing in obesity, the American College of Chest Physicians recommend weight based dosing of 0.5mg/kg for patients with a BMI >40kg/m2 and the International Society on Thrombosis and Haemostasis suggests that rivaroxaban or apixaban can be considered in this population.16, 17

Rivaroxaban 10mg daily presents an alternative oral anticoagulation option and together with fondaparinux 2.5mg daily has evidence to suggest it is non-inferior to LMWH or UFH in acute medical inpatients, though with limited comparative evidence to LMWH/UFH, it is rarely used.18, 19 Currently, only rivaroxaban, apixaban and fondaparinux is PBS approved as VTE prophylaxis for patients undergoing total hip or knee replacement. Duration of anticoagulation is typically restricted to length of hospitalisation as extended duration is associated with increased bleeding without changing rates of VTE.20, 21

There is substantial evidence to suggest that aspirin should not be used as VTE prophylaxis.22 This was best demonstrated in the ‘CRISTAL’ trial, an Australian multicentre study of patients undergoing hip or knee arthroplasty which demonstrated inferiority of aspirin compared to LMWH

(Figure 1).23 Despite this, an Australian national survey of orthopaedic surgeons suggested that over 50% use aspirin as part of the VTE prophylaxis strategy.7 There is, however, evidence that low dose aspirin daily can be used as extended thromboprophylaxis after an initial 5-10 day course of anticoagulation.24

Special Populations

Some patient populations require a more tailored approach to anticoagulation. The most common of these is patients with severe renal failure in whom UFH would be preferred over LMWH, or those with morbid obesity in which a dose increase may be required, though the evidence to support this is currently limited. In patients with extreme obesity it may be reasonable to monitor serum Anti-Xa levels which can predict dosing efficacy.25 Patients with evidence of HITS are recommended treatment with danaparoid, bivalirudin or fondaparinux.

Among patients with severe renal impairment argatroban is a suitable alternative though availability is limited.

Conclusion

Australian guidelines reinforce the importance not just of pharmacological prophylaxis but of mechanical prophylaxis, early ambulation, adequate hydration and partnering with patients/carers.6

Partnering with patients with the goal to improve compliance and achieve earlier ambulation has shown to significantly reduce post-operative VTE.27

Research has shown the successful implementation of alerts, doctorpharmacist collaborative approaches and nurse-led interventions to improve adherence.28-30 Solid evidence supports the effectiveness of a multidisciplinary approach from health professionals to reduce rates of VTE and VTE-related mortality and morbidity.

Interpretation:

≤3 points: low probability for HIT (≤5% in original study)

4-5 points: intermediate probability (~14% probability of HIT)

6-8 points: high probability (~64% probability of HIT)

Table 2: 4T Score screening algorithm for HITS15

Figure 1: Kaplan-Meier Analysis of Time to Venous Thromboembolism (Deep Venous Thrombosis or Pulmonary Embolism) Occurence from the CRISTAL trial.23

What’s New

New Drug Update - Decitabine/Cedazuridine

Elise Gill, Epic Pharmacy East Toowoomba

Brand: Inqovi 35mg/100mg tablets

Decitabine/cedazuridine is approved to treat chronic myelomonocytic leukaemia and myelodysplastic syndromes, which are disorders of stem cells. Patients who are not able to receive stem cell transplants have previously been treated with cytotoxic agents such as subcutaneous or intravenous azacitadine. This new combination of decitabine with cedazuridine allows an oral therapy option.

Decitabine has low oral bioavailability due to first-pass metabolism by the enzyme cytidine deaminase. Cedazuridine targets this enzyme to increase oral bioavailability. The fixed dose oral combination was proven to be highly similar to intravenous decitabine, with a 98% equivalence in systemic exposure when standard doses were compared.1 Furthermore, a phase III trial demonstrated the efficacy of the oral decitabine/cedazuridine combination to be consistent with intravenous decitabine clinical data, with 60% of patients responding and 21% showing a complete response after treatment.2

Decitabine/cedazuridine is taken once daily on days 1 to 5 of a 28 day cycle for a minimum of 4 cycles. The decitabine/cedazuridine combination should be taken on an empty stomach as food decreases absorption and patients should avoid combinations of gastric pH modifying medications as may affect cedazuridine bioavailability. No dose modifications are required in mild hepatic and mild to moderate renal impairment.3

Most patients will experience serious adverse effects from decitabine/cedazuridine. Common adverse effects include fatigue, nausea, dizziness, diarrhoea and constipation, however, more serious side effects, such as cytopenia, thrombocytopenia, anaemia, febrile neutropenia and pneumonia, can occur. As such, routine blood counts must be completed prior to treatment, and a dose reduction or delay may be required for some toxicities.

Whilst further investigations are required comparing decitabine/ cedazuridine directly with azacitadine, this new medication provides the first oral option for this patient group, decreasing the requirement for multiple hospital visits and injections per month.

If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: circuit.editor@epicpharmacy.com.au

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