24th December 2020, Dr Chee L Khoo
It’s been a couple of years since we first previewed the PCSK9 inhibitors (PCSK9i) on the PBS for patients with dyslipidaemia despite maximal statins and ezetimibe. Since then PCSK9i have been demonstrated in many trials of its efficacy in patients with high cardiovascular risk with dyslipidaemia despite maximally tolerated statins. The qualifying criteria under the PBS has significantly loosened and suddenly we all have a number of patients who will meet those PBS criteria. Let’s have a look at which one of our patients in primary care qualify for a PCSK9i under the PBS.
What are PCSK9 inhibitors again?
Proprotein convertase subtilisin kexin 9 (PCSK9) is an enzyme in the liver that block LDL-C receptors in the liver. These receptors are meant to remove LDL-C from circulation. PCSK9 inhibitors are monoclonal antibodies which bind and inactivate PCSK9 and thereby, reduce LDL-C levels. There are currently two PCSK9i on the market, alirocumab (Praluent®) and evolocumab (Repatha®). Both are injectables and only evolocumab is approved in the PBS with very tight criteria.
Oh, I forgot to tell you that if you were to attempt to read the PBS criteria, be warned that the criteria runs into 7 and half pages long. With the lack of organisation, formatting and lots of repetitions, it is practically an unreadable document. Seriously, not something you would do during a consultation. Nonetheless, let’s have a crack at simplifying the document. Keep in mind that this class of drugs are approved for patients with dyslipidaemia (defined as high LDL-cholesterol) and very high cardiovascular risks.
There are 4 subgroups:
- Familial heterozygous hypercholesterolaemia – initial treatment
- Non-familial heterozygous hypercholesterolaemia – initial treatment
- Familial heterozygous hypercholesterolaemia – previously started but non-PBS subsidised
- Non-familial heterozygous hypercholesterolaemia – previously started but non-PBS subsidised
We will only look at the first two since the last two has pretty much the same criteria except they are already on the drug albeit not subsidised. Patients must be treated by a specialist physician (GPs can’t prescribe yet), lipid treatment must be in conjunction with dietary therapy and exercise.
First, some definitions:
The lipid criteria
- This is simple. LDL > 2.6 mmol/L despite maximally tolerated statins plus ezetimibe. Patients must have high LDL despite maximal statin (Atorvastatin 80mg or Rosuvastatin 40mg) for at least 12 weeks or have documented and proven adverse reactions to statins. Patient must have been treated with ezetimibe for at least 12 consecutive weeks in conjunction with a statin (if tolerated), dietary therapy and exercise.
The adverse reactions to statin treatment is defined as:
- Severe myalgia (muscle symptoms without creatine kinase elevation) which is proven to be temporally associated with statin treatment; or
- Myositis (clinically important creatine kinase elevation, with or without muscle symptoms) demonstrated by results twice the upper limit of normal on a single reading or a rising pattern on consecutive measurements and which is unexplained by other causes; or
- Unexplained, persistent elevations of serum transaminases (greater than 3 times the upper limit of normal) during treatment with a statin. If treatment with atorvastatin or rosuvastatin results in development of a clinically important product-related adverse event resulting in treatment withdrawal, the patient must be treated with the alternative statin (atorvastatin or rosuvastatin) unless there is a contraindication (e.g. prior rhabdomyolysis) to the alternative statin. This retrial should occur after a washout period of at least 4 weeks, or if the creatine kinase (CK) level is elevated, retrial should not occur until CK has returned to normal. In the event of a trial of the alternative statin, it is recommended that the patient is started with the minimum dose of statin in conjunction with ezetimibe. The dose of the alternative statin should be increased not more often than every 4 weeks until the recommended or maximum tolerated dose has been reached or target LDL-c has been achieved.
Symptomatic atherosclerotic cardiovascular disease is defined as:
- The presence of symptomatic coronary artery disease (prior myocardial infarction, prior revascularisation procedure, angina associated with demonstrated significant coronary artery disease (50% or greater stenosis in 1 or more coronary arteries on imaging), or positive functional testing (e.g. myocardial perfusion scanning or stress echocardiography); or
- The presence of symptomatic cerebrovascular disease (prior ischaemic stroke, prior revascularisation procedure, or transient ischaemic attack associated with 50% or greater stenosis in 1 or more cerebral arteries on imaging); or
- The presence of symptomatic peripheral arterial disease (prior acute ischaemic event due to atherosclerosis, prior revascularisation procedure, or symptoms of ischaemia with evidence of significant peripheral artery disease (50% or greater stenosis in 1 or more peripheral arteries on imaging)).
Thus, to be approved under PBS authority, these are the must have criteria:
- Familial heterozygous hypercholesterolaemia
- The condition must have been confirmed by genetic testing; OR
- The condition must have been confirmed by a Dutch Lipid Clinic Network Score of at least 6
- LDL-C >2.6 mmol/L despite maximally tolerated statin or HMG-CoA contraindicated with symptomatic ASCVD OR
- LDL-C >5.0mmol/L without symptomatic ASCVD
2. Non-familial heterozygous hypercholesterolaemia
- Since this is non-familial disease, there is no requirement for genetic testing nor Dutch Lipid Network Score.
- LDL-C >2.6 mmol/L despite maximally tolerated statin or HMG-CoA contraindicated
Symptomatic ASCVD disease PLUS the following:
- Patient must have atherosclerotic disease in two or more vascular territories (coronary, cerebrovascular or peripheral vascular territories); OR
- Patient must have severe multi-vessel coronary heart disease defined as at least 50% stenosis in at least two large vessels; OR
- Patient must have had at least two major cardiovascular events (i.e. myocardial infarction, unstable angina, stroke or unplanned revascularisation) in the previous 5 years; OR
- Patient must have diabetes mellitus with microalbuminuria; OR
- Patient must have diabetes mellitus and be aged 60 years or more; OR
- Patient must be an Aboriginal or Torres Strait Islander with diabetes mellitus; OR
- Patient must have a Thrombolysis in Myocardial Infarction (TIMI) risk score for secondary prevention of 4 or higher
Studies have confirmed the potency of PCSK9i in reducing LDL-C (1). While there is evidence that PCSK9i is effective in reducing cardiovascular events (myocardial infarction, strokes and revascularisation) but evidence for reduction of mortality is not there yet (2).
- Schmidt AF, Carter JL, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020 Oct 20;10:CD011748. doi: 10.1002/14651858.CD011748.pub3. PMID: 33078867.
- AlTurki A, Marafi M, Dawas A, Dube MP, Vieira L, Sherman MH, Gregoire J, Thanassoulis G, Tardif JC, Huynh T. Meta-analysis of Randomized Controlled Trials Assessing the Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies on Mortality and Cardiovascular Outcomes. Am J Cardiol. 2019 Dec 15;124(12):1869-1875. doi: 10.1016/j.amjcard.2019.09.011. Epub 2019 Sep 26. PMID: 31679643.