RWE - alirocumab and MACE in ASCVD patients without prior event

In a [new], methodologically advanced^1,2 real-world study of over 4,500 patients, alirocumab was associated with a >30% relative reduction in the risk of MACE (ARR 6.9%) vs. no PCSK9i| in ASCVD patients without a prior ischaemic event.¹

→ Video summary

→ Study background

→ Study details

→ Key baseline characteristics

→ Results

→ Safety

→ Additional resources

Watch Dr Bhatt's summary of the study:

Study background

• All patients with ASCVD are at very high or extreme risk of a potentially fatal CV event3
• LDL-C is the primary target for CV risk reduction and PCSK9 inhibitors such as alirocumab can reduce LDL-C levels when used alone or in combination with statins^3,4*
• Previous clinical trials in ACS patients showed alirocumab significantly reduced MACE⁴⁺
• This real-world study sought to evaluate the benefit of alirocumab in preventing MACE in ASCVD patients who had not previously experienced a CV event¹

Study Details

Key baseline characteristics

The baseline characteristics for the alirocumab group and no-PCSK9i group were well balanced¹.

Demographics¹

Adapted from Bhatt et al.

LDL-C¹

Adapted from Bhatt et al.

Comorbidities¹

Adapted from Bhatt et al.

Medications¹

Adapted from Bhatt et al.

Results

Alirocumab use was associated with a >30% relative reduction in the risk of MACE in ASCVD patients without a prior ischaemic event.¹

Overall, there was a significantly lower rate of the primary endpoint (composite of all-cause mortality, non-fatal MI and non-fatal IS) in the alirocumab group vs. the no-PCSK9i group.¹

The 5-year event rate was 14.3% (95% CI 11.8, 16.3) in the alirocumab group (n=1,556) VS. 21.2% (95% C| 18.6, 23.4) in the no-PCSK9i group (n=2,989), resulting in a 32.4% relative reduction in the risk of first MACE (ARR 6.9%) (P<0.0001).¹

Cumulative incidence of composite of myocardial infarction, 
ischaemic stroke and all-cause mortality with Parametric G-Formula¹

A lower rate of MACE in ASCVD patients without a prior event was also observed with TMLE.¹

Cumulative incidence of composite of myocardial infarction, ischaemic stroke and all-cause mortality with TMLE¹

These findings are consistent with the Cholesterol Treatment Trialists¹ Collaboration, which demonstrated a strong association between RRR in MACE per 1 mmol/L reduction in LDL-C.⁵

Relationship between relative risk reduction in MACE and LDL-C reduction¹

The falsification analysis supports the validity of the results and suggests minimal residual confounding.¹

To help prove that the lower rate of MACE with alirocumab vs. no PCSK9i was not confounded by other factors, the study assessed whether alirocumab vs. no PCSK9i was associated with any unexpected benefit in negative control outcomes, such as cancer. The incidence of cancer was similar in the alirocumab group (2.1%) and no-PCSK9i group (1.7%) (P=0.69), indicating minimal residual confounding and supporting the validity of the MACE data.' Falsification analysis¹

Falsification analysis¹

Adapted from Bhatt et al.

Safety

Alirocumab's long-term safety profile has been shown to be comparable to placebo in ODYSSEY OUTCOMES: a pivotal phase 3 trial investigating the safety and efficacy of alirocumab vs. placebo in adult ASCVD patients with prior ACS.^4,6

The most common adverse reactions at recommended doses of alirocumab are local injection site reactions (6.1%), upper respiratory tract signs and symptoms (2.0%), and pruritus (1.1%). The most common adverse reaction leading to treatment discontinuation was local injection site reactions.⁶

For more information on the safety profile of alirocumab, please refer to the Summary of Product Characteristics.

Indication, dosing and footnotes

This material is intended for healthcare professionals only.

^*PRALUENT (alirocumab) indication⁶

Primary hypercholesterolaemia and mixed dyslipidaemia 
PRALUENT^® is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, and in paediatric patients 8 years of age and older with heterozygous familial hypercholesterolaemia (HeFH) as an adjunct to diet:

• in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the 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

Established atherosclerotic cardiovascular disease

PRALUENT^® is indicated in adults with established atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels, as an adjunct to correction of other risk factors: 

• in combination with the maximum tolerated dose of a statin with or without other lipid-lowering therapies or,
• alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated

Dosing information⁶

The recommended PRALUENT doses are 75 mg once every 2 weeks, 150 mg once every 2 weeks, 300 mg once every 4 weeks (monthly), administered subcutaneously. All doses may be used for initiation of treatment.

The dose of PRALUENT can be individualised based on patient characteristics, such as baseline LDL-C level, goal of therapy, and response to treatment. Lipid levels can be assessed 4 to 8 weeks after treatment initiation or titration, and dose adjusted accordingly (up-titration or down-titration). Intense LDL-C reduction is expected with PRALUENT 150 mg once every 2 weeks and 300 mg once every 4 weeks (monthly), where 150 mg once every 2 weeks is the maximum dose.

For the treatment of HeFH in paediatric patients 8 years of age and older: 

• for patients with a body weight of less than 50 kg, the recommended dose is 150 mg once every 4 weeks and, if additional LDL-C reduction is needed, a dose of 75 mg once every 2 weeks is recommended
• for patients with a body weight of 50 kg or more, the recommended dose is 300 mg once every 4 weeks and, if additional LDL-C reduction is needed, a dose of 150 mg every 2 weeks is recommended

Lipid levels can be assessed 8 weeks after treatment initiation or titration and dose adjusted accordingly. If a dose is missed, the patients should administer the injection as soon as possible and thereafter resume treatment on the original schedule.

⁺PRALUENT significantly reduced risk of MACE (primary endpoint) in the overall trial population (N=18,924) in the ODYSSEY OUTCOMES trial (15% RRR, HR 0.85 [95% CI 0.78, 0.93], P=0.0003). ^4.6

^#No-PCSK9i represents no PCSK9i monoclonal antibodies (alirocumab or evolocumab) or PCSK9 small interfering RNA (inclisiran).1

^¥claims database, representing an insured population in the US.¹

ACEi = angiotensin convertase enzyme inhibitor; ACS = acute coronary syndrome; ARB = angiotensin II receptor blocker; ARR= absolute risk reduction; ASCVD = atherosclerotic cardiovascular disease; CABG = coronary artery bypass graft; Cl = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; HeFH = heterozygous familial hypercholesterolaemia; HIS = high-intensity statin; HR = hazard ratio; ICBVD = ischaemic cerebrovascular disease; IS = ischaemic stroke; ITT = intention-to-treat; LDL-C = low-density lipoprotein cholesterol; LIS = low-intensity statin; MACE = major adverse cardiovascular event; MI = myocardial infarction; MIS = middle-intensity statin; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin/kexin type 9; PCSK9i = proprotein convertase subtilisin/kexin type 9 inhibitor; Q2W = every 2 weeks; RNA = ribonucleic acid; RRR = relative risk reduction; RWE = real-world evidence; SD = standard deviation; TMLE = targeted maximum likelihood estimation.