11th November, A/Prof Chee L Khoo
Don’t we all hate the onerous restrictions on the PBS Authority criteria to qualify for the PCSK9 therapy. The efficacy of the agents (evolocumab, alirolocumab and inclisran) is well proven in clinical trials (1-3). Only the -mabs have been shown to have cardiovascular (CV) benefits. CV outcomes is yet to be established with inclisiran. The main reason for the onerous restrictions is primarily related to the typical patients in those clinical trials. That’s what your data shows in those target participants, that’s what we will approve the agent for. A new trial has been published showing for the first time, benefits in primary prevention patients. All very exciting.
In the FOURIER trial, evolocumab was shown to significantly reduce the composite outcomes of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularisation by 15% compared with placebo in patients who are already on statin therapy. There was also a 20% reduction in the composite of cardiovascular death, myocardial infarction, or stroke. Now, the patients in this trial were patients who at baseline, had history of myocardial infarction, nonhemorrhagic stroke, or symptomatic peripheral artery disease. This is a secondary prevention trial.
Similarly, in the ODYSSEY trial, alirocumab (which is no longer available in Australia) led to a 15% reduction in composite outcomes of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularisation in patients already on statin therapy. Once again, this was another secondary prevention trial. Patients in the ODYSSEY trial already had an acute coronary syndrome 1 to 12 months earlier.
The latest data which just came out 5 days ago was a primary prevention trial. The VESALIUS-CV was an international, double-blind, randomised, placebo-controlled trial of evolocumab in patients who are at high risk of a cardiovascular event but had not had a history of myocardial infarction or stroke (4). To be eligible, participants must have coronary artery disease, atherosclerotic cerebrovascular disease, peripheral artery disease or type 2 diabetes (T2D) of >10 years, or T2D on insulin therapy or T2D with microvascular complications. Their LDL-C had to be > 2.3 mmol/L, non-HDL cholesterol > 3.1 mmol/L or apoB of > 80mg/day and receiving maximally tolerated high intensity statins. Thus, these are patients with very high CV risks but had not had an event. This is a primary prevention trial.
The median age of participants was 66 years old. 45% had coronary artery disease, 10% had cerebrovascular disease, and 17% had peripheral artery disease. Overall, 60% patients had T2D with one third with atherosclerotic cardiovascular disease (ASCVD) and half had high risk diabetes. The median LDL-C was 3.16 mmol/L. 92% of participants were on lipid-lowering medications.
After median follow-up of 4.6 years, evolocumab led to significantly lower risks of the two primary efficacy end points compared with placebo. There was a 25% reduction in the 3-point MACE event (death from coronary heart disease, myocardial infarction, or ischaemic stroke compared with the placebo group. There was a 19% reduction in the 4-point MACE event (3-point MACE event pluas ischaemia-driven arterial revascularisation) in the evolocumab group compared with placebo. See Table 1.
Table 1
| VESALIUS-CV | Placebo | Evolocumab | Hazard ratio | p value |
| 3-point MACE* | 8% | 6.20% | 0.75 | <0.001 |
| 4-point MACE* | 16.20% | 13.40% | 0.81 | <0.001 |
| Composite AMI/CVA/ revascularisation | 15 | 12.2 | 0.79 | <0.001 |
| CV death/Revascularisation | 14.60% | 11.90% | 0.79 | <0.001 |
| Death from CV | 9.10% | 6.80% | 0.73 | <0.001 |
| MI | 4.10% | 2.70% | 0.64 | <0.001 |
| Ischaemic revascularisation | 12.50% | 10.10% | 0.79 | <0.001 |
| Coronary heart disease death | 2.10% | 1.90% | 0.89 | 0.39 |
This is a pretty significant set of data. For the first time with PCSK9 therapy, we have data showing that patients who has not had an event but at high risk of an event can benefit from further reduction of their LDL-C in addition to current lipid lowering agents.
It wasn’t a total surprise though. The line between what is primary and what is secondary prevention has been getting more and more blurry over the years. ASCVD can be conceptualised as a continuum of risk. There are patients who are at very high risk as they have had one or more major ASCVD events (e.g myocardial infarction or stroke). There are other patients who are at either intermediate risk or high risk who have evidence of ASCVD but has not had an event. These patients’ risk profile may be further modified with imaging (e.g. CTCA).
Further, we also have some patients who do not have known atherosclerosis but are deemed to be at high risk for the development and manifestations of ASCVD by virtue of high-risk conditions such as diabetes and severe dyslipidaemia burden. Lowering of the LDL cholesterol level with statins has been proven to be effective at preventing major cardiovascular events across this continuum.
Perhaps, with the release of the VESALIUS-CV trial results, there may be a relaxation of the criteria to qualify for evolocumab under the PBS Authority very soon.
References:
- Sabatine MS, Giugliano RP, Keech AC, et al. ; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722.
- Schwartz GG, Steg PG, Szarek M, Bhatt DL et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379(22):2097-2107
- Ray KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023 Feb;11(2):109-119.
- Bohula EA, Marston NA, Bhatia AK, et al; VESALIUS-CV Investigators. Evolocumab in Patients without a Previous Myocardial Infarction or Stroke. N Engl J Med. 2025 Nov 8.