A recent virtual education meeting provided insights from landmark lipid lowering trials on the benefits of intensive LDL-C reduction in patients with atherosclerotic cardiovascular disease (ASCVD).
The sponsored educational meeting featured discussion led by renowned Cardiologist Professor Shaun Goodman, Associate Head in the Division of Cardiology, Department of Medicine, at St. Michael’s Hospital and University of Toronto, Canada. Joining the session from Australia was Prof. Leon Simons, Conjoint Associate Professor of Medicine UNSW & Director, Lipid Research Dept, St Vincent’s Hospital Sydney.
Prof Goodman presented the latest clinical evidence with lipid lowering therapies in the reduction of ASCVD risk. He also shared insights into which patients are most likely to benefit from the addition of a PCSK9 inhibitor to statin plus ezetimibe therapy.
High-intensity statins don’t always achieve target LDL-C levels 1,2
Prof Goodman drew on lessons learned from studies, including PROVE-IT1 from 2005, which found that intensive lipid-lowering therapy significantly reduced the risk of death or major cardiovascular events in high-risk cardiovascular patients. However, he noted that even with high-intensity statin therapy, the PROVE-IT study found that almost one in ten patients with four-month LDL-C records remained above the target level of 100 mg/dL (2.6 mmol/L).1,2
The addition of ezetimibe to moderate statin therapy – insights from IMPROVE-IT3
Published in 2015, the IMPROVE-IT study3 found that the addition of ezetimibe to moderate statin therapy (simvastatin 40–80 mg) led to a further lowering of LDL-C levels and significantly lower CV events. This benefit was consistent across nearly all prespecified subgroups, including high-risk CV groups.3
Further CV risk reduction with the addition of PCSK9 inhibitors to high-intensity lipid-lowering therapy
The FOURIER trials4 and ODYSSEY OUTCOMES5 both found that the addition of a PCSK9 inhibitor to high-intensity statin therapy, with or without ezetimibe, led to further reductions in LDL-C.4,5
Prof Goodman noted that ODYSSEY OUTCOMES in post-ACS patients found that the addition of alirocumab to high-intensity or maximal tolerated dose of statins lowered the risk of recurrent ischaemic cardiovascular events.
Prof Goodman pointed out that rather than looking at the time to (TT) first adverse event, the ODYSSEY OUTCOMES study looked at time to all events experienced by patients, which he explained is important to the healthcare team, treating physician, payer, and of course the patient and their family.6 As Prof. Goodman puts it, “Real-world patients can experience non-fatal events and continue to benefit from therapy, so it’s important to account for this in any analysis.”
Absolute risk reduction benefits in high-risk patients: ODYSSEY OUTCOMES insights
Prof. Goodman presented a post-hoc analysis from ODYSSEY OUTCOMES at 2.8 years follow-up that found the absolute benefit of alirocumab on the composite primary end point was greater among patients with a baseline LDL-C ≥2.6 mmol/L (post-hoc analysis) than those with a lower baseline LDL-C level.5
Similarly, a subgroup analysis of high-risk groups – including prior CABG, diabetes, and polyvascular disease – found that the relative risk reduction afforded by the addition of alirocumab to high dose statins in each subgroup was consistent with the overall study population. However, the absolute risk reduction was greater in these high-risk groups than in the study population.6,7,8
Prof. Goodman commented that “this similar relative but greater absolute risk reduction seen across the board in high-risk patients in the ODYSSEY OUTCOMES study presents an interesting argument for its use in those patients.”
Alirocumab safety and tolerability profile in ODYSSEY OUTCOMES
The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group versus 2.1% in the placebo group; p<0.001).5 When commenting on injection-site reactions, Prof. Goodman noted “These [events] were usually very mild in nature.”
Real-world evidence quantifies the unmet need in achieving LDL-C targets
Prof Goodman described results of a Canadian study investigating lipid management in a post-acute coronary syndrome (ACS) population9 that found around 90% of patients had their lipid levels tested within 90 days of their first ACS, and around 80% did not meet guideline target levels (LDL ≤1.8 mmol/L, non-HDL ≤2.6 mmol/L).9 Of these patients, almost 40% did not undergo repeat testing, despite not being at target levels.9
Prof Goodman highlighted the challenging targets of the European Society of Cardiology/European Atherosclerosis Society Guidelines for those at very high cardiovascular risk, with an LDL-C treatment goal of ≤1.4 mmol/L. Additionally, for patients with ASCVD who experience a second vascular event within two years while taking maximally tolerated statin-based therapy, the Guidelines suggest an LDL-C treatment goal of <1.0 mmol/L may be considered.10
Insights from an Australian registry
Prof Simons briefly described the disparity between guidelines-directed statin therapy and real world use. Data from the Australian CONCORDANCE Registry in post-ACS patients11 has shown that only 55% of patients were receiving intensive lipid-lowering therapy 6 or 12 months after their hospitalisation with an ACS.8 Prof Simons noted that even when Australian patients are prescribed a statin, 43% discontinue their medication within 6 months and the median persistence time has been shown to be around 11 months.12
An online tool to help navigate PBS application for Praluent (alirocumab)
Prof Simons described the recently announced PBS listing for Praluent.13 From 1st August 2021 the following patients are now eligible for alirocumab treatment on the PBS (refer to PBS schedule for further criteria and restrictions):
- Non-familial hypercholesterolemia, with
- Symptomatic ASCVD, on diet and exercise
- Using maximum-tolerated statin + ezetimibe for >12 weeks
- LDL-C >2.6 mmol/L
- Additional CV risk factors (including severe multi-vessel CHD)
An online tool developed by Sanofi uses a simple 4-step process to assist prescribers in review of criteria ahead of the Authority application process:
- Select the PBS subsidy indication relevant to their patient.
- Enter the patient’s current lipid treatment.
- Add the patient’s LDL-C level (recorded within the last 8 weeks).
- Add other criteria (such CV risk factor)
Training and support for patients
Sanofi has partnered with a team of pharmacists to offer patient injection training support. In addition, physicians are able to apply for a training device to instruct patients during consultations. Prof Simons described his approach to patient instruction: “I just move to the other side of the desk, do the injection myself first with the training device, then get them [the patient] to do it themselves.”
Praluent® is indicated to reduce the risk of cardiovascular events (myocardial infarction, stroke, unstable angina requiring hospitalisation) in adults with established cardiovascular disease, in combination with optimally dosed statins and/or other lipid-lowering therapies.
This article was commissioned by Sanofi Australia Pty Ltd. The content is independent and based on studies and the author’s opinion. The views expressed do not necessarily reflect the views of Sanofi. Before prescribing, please review the Praluent® (alirocumab) full product information14 via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.
Please review full Product Information before prescribing. For full Product Information click here or contact Sanofi Medical Information on 1800 818 806.
MINIMUM PRODUCT INFORMATION: Praluent® (alirocumab (rch)) INDICATIONS Primary hypercholesterolaemia: as an adjunct to diet and exercise to reduce LDL-C in adults with primary (heterozygous familial or non-familial) hypercholesterolaemia in patients with moderate to very high cardiovascular risk: – In combination with a statin, or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with maximum tolerated dose of a statin, – alone or in combination with other lipid lowering therapies in patients who are statin intolerant or for whom a statin is contraindicated who are unable to reach LDL-C goals. Prevention of cardiovascular events: to reduce the risk of cardiovascular events (myocardial infarction, stroke, unstable angina requiring hospitalisation) in adults with established cardiovascular disease, in combination with optimally dosed statins and/or other lipid-lowering therapies (see full PI). DOSAGE AND ADMINISTRATION 75 mg subcutaneously every 2 weeks or 300 mg every 4 weeks. May increase to 150 mg every 2 weeks if inadequate LDL-C response. Measure lipid levels from 4-8 weeks of initiating/titrating Praluent, to assess response and adjust dose if needed. To administer 300 mg, give two 150 mg injections consecutively at two different injection sites. Inject into thigh or abdomen or upper arm that is not tender, bruised, red or hard (rotate site). Allow to warm at room temperature (up to 25°C) for 30-40 min before injecting; do not warm in any other way. See full PI. CONTRAINDICATIONS Hypersensitivity to the active substance or to any of the excipients. PRECAUTIONS General allergic reactions, immunogenicity, very low LDL-C levels (long-term effects unknown), pregnancy (category B1), lactation, children (< 30 mL/min/1.73 m2 ) not studied. INTERACTIONS Not anticipated. ADVERSE EFFECTS Common adverse reactions: injection site reactions, pruritus, upper respiratory tract signs and symptoms. Others, see full PI. NAME OF SPONSOR Sanofi-Aventis Australia Pty Ltd, 12-24 Talavera Road, Macquarie Park, NSW 2113. DATE OF PREPARATION 14 January 2020. Based on Full Product Information with TGA date of approval of 17 May 2016, with most recent amendment on 10 January 2020. Praluent® is a registered trademark of Sanofi-Aventis Australia Pty. Ltd trading as Sanofi, ABN 31 008 558 807 Talavera Corporate Centre, Building D, 12-24 Talavera Road, Macquarie Park, NSW 2113. www.sanofi.com.au. MAT-AU-2101642. Date of preparation: August 2021.
- Cannon CP et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495–504.
- Wiviott SD et al. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol 2005;46:1411–1416.
- Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015;372:2387–2397.
- Sabatine MS et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376:1712–1722.
- Schwartz G et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med 2018;379:2097–2107.
- Goodman SC et al. Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery. J Am Coll Cardiol 2019;74:1177–1186.
- Ray KK et al. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol 2019;7(8):618–628
- Jukema JW et al. Alirocumab in Patients With Polyvascular Disease and Recent Acute Coronary Syndrome: ODYSSEY OUTCOMES Trial. J Am Coll Cardiol 2019;74:1167–1176
- Sarak B et al. Lipid Testing, Lipid-Modifying Therapy, and PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Eligibility in 27 979 Patients With Incident Acute Coronary Syndrome. Circ Cardiovasc Qual Outcomes 2021;14:e006646.
- Mach F et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41(1):111–188.
- Brieger D et al. Intensive lipid-lowering therapy in the 12 months after an acute coronary syndrome in Australia: an observational analysis. MJA 2019;210:80–852.
- Simons LA et al. Long-term persistence with statin therapy — experience in Australia 2006-2010. Aust Fam Phys 2011;40:319–322.
- Praluent PBS listing available at pbs.gov.au
- Praluent Approved Product Information
Praluent® is a registered trademark of Sanofi-Aventis Australia Pty. Ltd trading as Sanofi, ABN 31 008 558 807 Talavera Corporate Centre, Building D, 12-24 Talavera Road, Macquarie Park, NSW 2113. www.sanofi.com.au. Date of preparation August 2021. MAT-AU-2101642