2022 Edition 1
clinical initiatives, research and current updates in treatment
Familial Hypercholesterolaemia: An under-diagnosed and under-treated high-risk disease Sarah Steinke, Pharmacy Practice Unit Familial hypercholesterolaemia (FH) is one of the most common inherited disorders. FH is a high-risk condition, characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels, predisposing individuals to atherosclerotic cardiovascular disease (ASCVD).1 FH is an autosomal dominant genetic disorder caused by a mutation in the gene which codes for the receptors for LDL-C.2 The heterozygote form has an estimated prevalence of 1 in 250.3 Untreated, FH-associated elevated LDL-C results in a greater than 50% risk of ASCVD in men by the age of 50 years and at least 30% of women by the age of 60 years.4 Currently, greater than 90% of Australia’s estimated 100,000 FH cases remain undetected, one in five of whom are children.5-7
Early identification and intervention of patients with FH is crucial because preventive strategies can lower the absolute lifetime cardiovascular risk and screening can detect affected relatives. However, recent evidence in Australia has found that patients are detected late in life, have a high burden of ASCVD, multiple risk factors, and do not achieve guideline-recommended LDL-C targets (box 1).8 Furthermore, genetic and cascade testing are under-utilised, posing hurdles in the prevention of FHrelated cardiovascular events.8
Diagnosis and Screening FH is usually diagnosed using clinical characteristics, such as family history, cholesterol deposits under the skin (xanthomas) and in the cornea (corneal arcus), significantly elevated LDL-C levels, and early-onset ASCVD;
however, genetic testing may provide a definite diagnosis of FH by detecting a pathological mutation.7 There are currently three accepted tools for FH diagnosis,7 with the Dutch Lipid Clinic Network Score (DLCNS) the most widely used in Australia.9 Australian and international guidelines recommend at-risk individuals be genetic tested to confirm the diagnosis.8,9 Where a pathogenic mutation is identified, systematic cascade testing of close relatives who carry a 50% risk of the disorder is a cost-effective approach to diagnose new cases of FH, particularly in younger family members.8,9 Box 1 summarises recommendations and therapeutic targets, based on moderate levels of evidence and class of recommendation, for managing FH.7
Box 1. LDL-C treatment targets for the management of FH Adults 1. LDL-C targets can be divided as follows: o LDL-C <2.5 mmol/L (absence of ASCVD or other major ASCVD risk factors) o LDL-C <1.8 mmol/L (imaging evidence of ASCVD alone or other major ASCVD risk factors) o LDL-C <1.4 mmol/L (presence of clinical ASCVD). Children ¬ ¬
For children with FH aged 8–10 years on a suitable diet, an LDL-C treatment target <4.0 mmol/L or a 30–40% reduction in LDL-C may be acceptable. In children aged >10 years who are maintained on a suitable diet, an LDL-C treatment target <3.5 mmol/L or a 50% reduction in LDL-C may be acceptable.
Current Treatment Options There is strong evidence for patients with FH to be actively treated with cholesterol-lowering medication, diet, and lifestyle modification from an early age.10 Other risk factors, such as obesity, smoking, diabetes mellitus, inactive
lifestyle, and hypertension, should also be addressed.7 HMG-CoA reductase inhibitors (or statins) remain the mainstay of treatment and represent first-line therapy for lowering LDL-C in both adult and paediatric patients with FH.11,12
Their efficacy in reducing cardiovascular morbidity and mortality is well established. However, a large proportion of patients at high risk do not reach the recommended target concentration of LDL-C.12 Continued on page 2
Second-line non-statin lipid-lowering treatments, including ezetimibe and PCSK9 inhibitors13 are less efficacious and are often used in combination with statins if the LDL-C target is not achieved with the maximum tolerated dose. Ezetimibe is the most commonly recommended second-line therapy for lowering LDL-C.12 Patients resistant to statin treatment can trial ezetimibe prior to re-introducing a low dose statin later.7,14 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme involved in the regulation of LDL receptors and LDL-C.15 By tagging LDL receptors for destruction in the liver, PCSK9 increases concentrations of LDL cholesterol.15 If PCSK9 inhibitors are added to a statin, the overall effect can produce reductions of 43–64% in LDL-C levels.15 Two monoclonal antibodies that inhibit PCSK9, evolocumab (Repatha®) and alirocumab (Praluent®) are available in Australia for FH and non–FH patients. However, long term safety data of these
agents are lacking, and they are not suitable for use in pregnancy.7 To reach very low LDL-C levels, patients may require sequential treatment with a high-potency statin, ezetimibe and a PCSK9 inhibitor.7,12 Lipid-modifying drugs such as bile acid binding resins (e.g. cholestyramine (Questran Lite®)), fibrates (gemfibrozil, fenofibrate) and nicotinic acid have been shown to improve lipid abnormalities, but there is limited evidence to support adding them to statin therapy to improve cardiovascular outcomes.7
Emerging Therapies for FH Several new pharmacological strategies have been developed to lower LDLcholesterol for patients with severe FH, many of these are still undergoing clinical trials. These therapies include oral inhibitors of PCSK9, microsomal triglyceride transfer protein (MTP) inhibitors and cholesteryl ester transfer protein (CETP) inhibitors.11
Other novel non-statin drugs on the horizon include bempedoic acid, which inhibits cholesterol biosynthesis in the same pathway as statins, and mipomersen which is an antisense oligonucleotide that inhibits synthesis of apolipoprotein B-100 (ApoB100). Apolipoprotein B (ApoB), serves as the structural backbone of three important lipoproteins, LDL, intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL), the main contributors to ASCVD.11,17 Inclisirin (Leqvio®), is a first-in-class small interfering RNA (siRNA) that inhibits the hepatic translation of PCSK9, thereby upregulating the number of LDL-receptors on the hepatocytes.16 The drug was approved for use in Australia by the Therapeutic Goods Administration (TGA) in September 2021. Inclisirin is administered as a subcutaneous injection every six months, showing considerable promise to support long-term treatment adherence.16
Figure 1. LDL receptor-mediated regulation of low-density lipoprotein cholesterol levels and recommended drugs that affect various steps of these pathways.16
Conclusion
diagnosed and under-treated.
FH is easily detected, capable of effective treatment in most cases, and there is evidence that treatment will substantially improve life expectancy. Unfortunately, lack of knowledge of FH and identification of at-risk individuals in the clinical community and general population, means that FH remains largely under-
Considerable progress has been made in developing new drugs and strategies for the management of FH which may lead to significant improvement in clinical practice for both adults and paediatric individuals. Future directions in healthcare delivery will need to focus on increasing awareness
through a multidisciplinary, patientcentred approach to improve CVD risk assessment, early identification of high-risk individuals, plus effective therapeutic and non-therapeutic management strategies as new treatments become available. References are available on request.
Growing misuse and abuse of Gabapentinoids Heather Patchell, Slade Pharmacy Box Hill Drug misuse has been a global public health concern for many years and is more often associated with medications included in the drug classes opioids, benzodiazepines, and other central nervous system (CNS) depressants, as well as alcohol and illegal substances.1 However, over the last several years there has been increasing evidence worldwide of the misuse of the drug class gabapentinoids, which includes the medications gabapentin and pregabalin. In Australia, deaths involving gabapentinoids are rising in parallel with their overall increased use, with the number of deaths increasing from 24 in 2015 to 204 in 2019.1 Ambulance callouts associated with misuse of pregabalin have increased tenfold in Victoria since 2012, making this medication one of the top ten drugs most often associated with overdose deaths in the state.2,3,4
and may also explain their reasons for misuse.2 Although not reported in premarketing clinical studies, anecdotal evidence suggests gabapentin produces similar effects as pregabalin, though less potent and with slower onset.2 The misuse and abuse of these medications has prompted some countries, such as the United Kingdom (UK) and the United States of America (USA), to reconsider the classification of pregabalin to a controlled substance. In Australia, the TGA has also recently added a Boxed Warning to the Product Information and Consumer Medicine Information for pregabalin and gabapentin.4 The enhanced warnings advise of the potential for misuse (for pregabalin), and abuse, or dependence (for pregabalin and gabapentin) as well as highlight the risk of respiratory depression and death, especially when combined with opioids and other CNS depressants.9
Gabapentinoids are approved by the Therapeutic Goods Administration (TGA) to treat certain types of seizures and neuropathic pain. When used appropriately, these medications are effective at providing relief for those experiencing nerve pain and to help control seizures. Pregabalin has the greatest evidence for reducing symptoms of diabetic neuropathy and post-herpetic neuralgia.2 Use of pregabalin for non-neuropathic pain conditions, such as lower back pain, is not supported by evidence and increases the risk of harm.2
Before prescribing or administering gabapentinoids, individual risk factors and appropriateness of therapy should be evaluated for each patient. To avoid or reduce dangerous drug interactions, a full medication list should be obtained, including any over-the-counter medications or illegal substances the patient is currently taking.2 Populations reported to be at higher risk of misuse or adverse events, such as respiratory depression, include4,10:
Despite the lack of evidence of the effectiveness of gabapentinoids to treat non-neuropathic pain, over the last several years there has been an increase in the prescribing rate for pregabalin as an alternative to opioids.2 Prescribers are also turning to gabapentinoids as another option for patients who may have a contraindication to nonsteroidal anti-inflammatory drugs (NSAIDs) or whose pain is not being relieved by paracetamol and NSAIDs.2 Although caution is advised, patients are often prescribed a combination of CNS depressants and gabapentinoids. An Australian study reported same day prescribing rates of pregabalin with opioids at 38%, benzodiazepines at 13%, and those prescribed all three medications at 4%.3,7 Studies have also shown pregabalin may be misused for its euphoric effect and self-harm.4 Greater doses may produce dissociation, relaxation, numbness, uninhibited behaviour, improved sociability and hallucinations,
- History of substance abuse disorder or drug seeking behaviours - History of psychiatric disorders - Pre-existing respiratory disorders - Being elderly - Being obese - Concomitant use of opioids, benzodiazepines, sedatives, CNS depressants, alcohol, and cannabis
The TGA advises that patients who require concomitant treatment with CNS depressants, including opioids, should be carefully observed for signs of CNS depression, such as: -
Somnolence Sedation Respiratory depression.8
Physicians should limit dosages and durations to the minimum required to achieve the desired therapeutic effect.
Where gabapentinoids are contraindicated or unsuitable, other medications approved for managing chronic neuropathic pain, which has not been alleviated by non-pharmacological approaches, are available. For example, a tricyclic antidepressant (TCA) such as amitriptyline or nortriptyline, or a serotonin and norepinephrine reuptake inhibitor (SNRI) such as duloxetine or venlafaxine, may be preferred.2,3 For patients with localised nerve pain, especially older or frail patients, or patients on multiple medications, lidocaine patches are preferred to reduce risk of systemic adverse effects or drug interactions.2,3 Abrupt discontinuation of gabapentinoids is associated with withdrawal symptoms such as insomnia, headache, nausea, anxiety, sweating and diarrhoea, indicating physical dependence.2 Education on the potential for dependence or misuse of these medications should be provided for each patient, understanding these risks can lead to serious/life-threatening side effects, which are increased if gabapentinoids are used with other sedating medicines and/or alcohol. Use of real-time prescription monitoring systems, where available, may also help minimise opportunity for misuse, abuse, and diversion. Although gabapentinoids will be of benefit to some patients, others may experience harm. Healthcare providers and carers should continue to use recommended guidelines when prescribing and monitoring, to help combat this growing issue. References are available on request.
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What’s New
Dual pathway inhibition with low-dose rivaroxaban and aspirin in vascular disease Eriza Alejo, Epic Pharmacy East Toowoomba Secondary cardiovascular prevention in patients with coronary (CAD) and peripheral (PAD) artery disease, has been managed with single or dual antiplatelet therapy. However, 5% of patients with stable CAD or PAD are at risk of experiencing a recurrent ischaemic attack each year.1 Dual pathway inhibition (DPI) of atherothrombosis involves treatment with rivaroxaban 2.5mg twice daily (an oral direct factor Xa anticoagulant) to reduce thrombin generation and low-dose aspirin to inhibit platelet thromboxane synthesis. DPI demonstrated a relative risk reduction of 24% in the primary outcome (a composite of cardiovascular death, stroke, or myocardial infarction) compared with aspirin alone (100mg daily) and was superior to rivaroxaban alone (5mg twice daily).2,3
CAD or PAD patients with high-risk features such as polyvascular disease, symptomatic PAD, diabetes mellitus and kidney disease will benefit most from DPI.1,8 DPI therapy must be withheld for at least twelve hours before any invasive procedure.7 Venous thromboembolism risk will need to be assessed and low-dose rivaroxaban should not be used in place of full dose anticoagulation.9 Dual pathway inhibition using a vascular dose of rivaroxaban in combination with low-dose aspirin offers a new option for secondary prevention of atherothrombotic events in high-risk patients with CAD and PAD. References are available on request.
Dual pathway inhibition showed more major bleeding events (3.1%) than aspirin monotherapy (1.9%).1,4 Most major bleeds were gastrointestinal and rates of fatal or intracranial bleeds were not significantly increased in the combination group.2 Rivaroxaban 2.5mg (Xarelto®) has been added to the Pharmaceutical Benefits Scheme as an Authority Required (Streamlined) medication for the treatment of CAD and PAD.5 Rivaroxaban 2.5mg twice daily must be prescribed in combination with low-dose aspirin.6,7
If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: circuit.editor@epicpharmacy.com.au Every effort has been made to ensure this newsletter is free from error or omission.
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